EDITORIAL ADVISORY COMMITTEE

Giovanni Berlucchi

Mary B. Bunge

Robert E. Burke

Larry F. Cahill

Stanley Finger

Bernice Grafstein

Russell A. Johnson

Ronald W. Oppenheim

Thomas A. Woolsey (Chairperson)

The History of Neuroscience in Autobiography

VOLUME 5

Edited by Larry R. Squire

Elsevier Academic Press
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Contents

Samuel H. Barondes

Joseph E. Bogen

Alan Cowey

David R. Curtis

Ennio De Renzi

John S. Edwards

Mitchell Glickstein

Carlton C. Hunt

Lynn T. Landmesser

Rodolfo R. Llinãs

Alan Peters

Martin Raft

Wilfrid Rall

Mark R. Rosenzweig

Arnold Bernard Scheibel

Gerald Westheimer

Samuel H. Barondes

BORN:

Brooklyn, New York

December 21, 1933

EDUCATION:

Columbia College, A.B. (1954)

Columbia College of Physicians and Surgeons, M.D. (1958)

Peter Bent Brigham Hospital (Medicine, 1958–1960)

National Institutes of Health (Postdoctoral Research, 1960–1963)

McLean Hospital (Psychiatry, 1963–1966)

APPOINTMENTS:

Albert Einstein College of Medicine (1966)

University of California, San Diego (1969)

University of California, San Francisco (1986)

Chair, Psychiatry, UCSF and Director, Langley Porter Psychiatric Institute (1986–1993)

Founding Director, Center for Neurobiology and Psychiatry, UCSF (1993)

Jeanne and Sanford Robertson Professor, UCSF (1996)

HONORS AND AWARDS (SELECTED)

Fogarty International Scholar, NIH (1979)

Herman Stillmark Lectin Centennial Medal, Estonia (1988)

McKnight Endowment Fund for Neuroscience, President (1989–1998)

Institute of Medicine (1990)

J. Elliott Royer Award in Psychiatry, University of California (1990)

J. Robert Oppenheimer Memorial Lecturer, Los Alamos (2000)

National Institute of Mental Health, Board of Scientific Counselors, Chair (2000–2003)

Samuel Barondes played a major role in bringing a molecular and genetic approach to neuroscience and psychiatry. In early work he helped establish the requirement for brain protein synthesis in long-term memory and demonstrated the rapid transport of proteins in brain axons. Turning his attention to cellular interactions, he discovered discoidins—slime mold relatives of the discoidin-domain proteins involved in synaptogenesis—as well as galectins, a family of glycoconjugate-binding proteins, some of which are found in neurons. A gifted writer, he has published three books about psychiatric genetics and molecular psychiatry for a general audience.

Samuel H. Barondes

Brighton Beach Childhood

Writing this memoir has caused me to reflect on my good fortune. I have been very lucky to have had the privilege of participating in such an exciting period of discovery in neuroscience and psychiatry and of enjoying warm personal relationships with so many talented members of these rich scientific communities. I am particularly grateful to the mentors who shaped me, the colleagues and trainees who sustained me, and the continuing elaboration of our work by others. My parents were born in Eastern Europe in 1902, and each left for America in their late teens, in the aftermath of the First World War. My father, Solomon, was raised in Zbaraz, which was part of the Austro-Hungarian empire and is now in Ukraine. My mother, Yetta Kaplow, came from Kraisk in what is now Belarus. These were both Fiddler-on-the-Roof-type villages in which their families, each with eight children, eked out a living and were guided by the Jewish traditions of the time. Although my parents had almost no formal schooling they were literate in Yiddish, Russian, and Hebrew. As immigrants they went to night school and became fluent in English.

Both my parents came to America following in the footsteps of an older brother. My father's voyage was arranged by his brother Nathan who had settled in Quincy, Massachusetts and had become a junk dealer. But neither Quincy nor the junk business appealed to my father who soon moved to New York City with the hope of becoming a professional singer. He settled in the lower east side of Manhattan, which then had a thriving Yiddish theater, worked as a waiter in restaurants in this theater district, then as a salesman in a clothing store. His singing ambitions were not fulfilled until many years later.

My mother's immigration was made possible by her older brother, Joe, who arrived in New York City shortly before World War I and soon found himself in the US Army. Sent to France as an infantryman he was gassed in the trenches but survived without disability. Upon his discharge he was offered some schooling and became an accountant in New York and, over the years, a wealthy man. When my mother arrived she went to work in a clothing store near the one where my father was employed.

When my parents married several years later they moved to Brighton Beach, a seaside community of six-story brick apartment buildings in Brooklyn. Helped by a gift from Joe they opened a small fabric store on a street lined with mom-and-pop businesses. Being in the store all day provided a great opportunity for reading, which my mother took full advantage of. The store and their apartment were just a few blocks from a wide beach and a splendid boardwalk, which both extended for several miles to Coney Island, Brooklyn's famous amusement park district. It was golden America, the promised land, even when the Depression came.

By the time I was born in 1933 the Depression was in full force. My parents told me that we were very poor during my early childhood, but I, of course, remember none of it. I do know that the bad economy influenced the elementary school I attended, a Jewish parochial school for boys called the Yeshiva of Brighton Beach, which provided religious studies in the morning and secular studies in the afternoon. The long school day was particularly attractive to my parents because they both worked in the store and it was a convenient way for them to have me, their only child, occupied all afternoon in those days when there were no after-school programs. My parents were also pleased that I would be getting a Biblical and Talmudic education as well as a secular one, but a school day that went until 5 PM was clearly a major attraction.

The Yeshiva of Brighton Beach was, for me, mainly a blessing. In the first grade it became clear that I was an enthusiastic student, the first in my class to read the Bible in Hebrew. By the time I was 10 I eagerly participated in discussions of ethical arguments in the Talmud, a series of volumes of commentaries by eminent rabbinical scholars, parts of which go back 2 millennia. These talents were greatly prized by my teachers who considered the study of the Bible and its Talmudic commentaries as an act of worship. I also did well in the usual elementary school curriculum, which got me a gold medal on graduation but was not valued as highly.

The downside of my schooling was that it was largely in the hands of orthodox rabbis who expected not just the study of the Bible but also the relentless practice of the way of life that it prescribed—a practice that was not always in tune with that of the greater world around me. Some of their demands were not hard to fulfill. For example they required that we always wear a traditional head covering, but they were willing to accept a baseball cap in its place. Others were more difficult to satisfy, especially those that concerned the observance of the Sabbath, because it is forbidden to do work of any kind on this day of rest, and working on the Sabbath is a concept that orthodox rabbis have interpreted very broadly. In the modern world they have extended this prohibition to such simple activities as flipping a switch to turn on the lights or the radio. Even as a child this seemed unreasonable to me. But the rabbis at my school had zero tolerance for any behavior they believed to be forbidden.

Despite my discomfort with the rules of orthodoxy I went to a high school that was organized along similar lines. I did this mainly to please my mother who had several eminent rabbinical relatives and who hoped that I too would become a rabbi. I was already strongly inclined against this but bowed to her wishes, knowing that I would eventually conduct my life as I pleased.

My father also was in favor of this choice of high school but for a different reason. As the family store began to bring in a comfortable living he had the time and the means to indulge his passion for singing by studying with excellent teachers. With this training, his haunting lyric tenor voice, and a great talent improvising on traditional synagogue themes, he became a superb Cantor. In the process he befriended other Cantors, such as Jan Pierce and Richard Tucker, who studied operatic singing and became leading tenors at the Metropolitan Opera. My father, too, sang operatic arias, mainly by Puccini, Verdi, and Mozart, but his greatest talent was in interpreting Jewish liturgical music. Despite this he refused to become a full-time Cantor because he did not want to be dependent on the whims of a congregation. So he restricted his cantoring to special holidays and to making records, while guaranteeing his independence with the earnings from the store. Nevertheless, he believed that it was appropriate for the son of a Cantor to attend a religious high school, much to my mother's delight.

The high school I attended, Talmudical Academy, introduced me to a world outside of Brighton Beach. Located in a central part of Brooklyn, it was a 20-minute subway ride away. One of its attractions was that it was just a few blocks from Ebbetts Field, home of the Brooklyn Dodgers. Another attraction was its excellent secular afternoon classes that followed a morning of Talmud. Taught by teachers who were also employed by the public high schools, the afternoon curriculum was particularly strong in science. The success of our education was assessed each year when we, like all high school students in New York, took standardized achievement tests. Students like me, who scored close to the top in these exams, were viewed with respect by our classmates. Instead of being ostracized as a hopeless nerd I was elected president of the student council.

But it was to Brighton Beach that I returned every night and with happy anticipation. There was always the beach and the boardwalk where I liked to hang out. If I needed pocket money I would collect discarded soda bottles that were easy to find on the beach and brought 2 ¢ apiece, quite a bonanza at a time when a movie ticket cost only a dime. There were also fascinating discussions going on at various spots on the boardwalk where adults would congregate to dream together about the creation of a harmonious socialist world in the aftermath of World War II And just down the boardwalk were the amusements of Coney Island with its rides, shows, and penny arcades.

My teenage years were also greatly enriched by 2 months each summer at camps in upstate New York. I started these adventures just before high school, and over the years I graduated to senior boys counselor. Going to camp was 2 months of continuous outdoor activities in the countryside. And, for the first time in my life, there were girls, dances, and coed theatrical productions that I participated in avidly, often writing original skits and the lyrics for musicals. This new world facilitated my transition from the cloistered existence of all-boy parochial schools to the liberation of college.

There was, however, a final challenge: my mother was still interested in making me a rabbi and urged me to go to Yeshiva University. But I had decided to move into the greater world. Since I was only 16, and my parents insisted that I continue to live at home during college, I narrowed the choices down to Brooklyn College, which was only about 20 minutes away by subway, and Columbia, which would extend the ride by at least an hour more in each direction. Despite this inconvenience I liked the feel of the Columbia campus, and I was thrilled by the possibility of a daily escape to Manhattan. When Columbia admitted me I was ready to go, despite my mother's disappointment. My father was proud—an immigrant from Zbaraz with a son at Columbia.

As I look back on my experiences in Jewish parochial schools I consider them a valuable preparation for my subsequent life and career. Although I was, from a young age, skeptical about the aspects of my education that were based on revealed truth, I could put that aside while incorporating its emphasis on living a virtuous life and a life of learning. My father, who had a strong philosophical bent, would also talk with me about wisdom and morality on our frequent evening walks on the boardwalk. He sometimes liked to base our conversations on phrases from the Talmud, many of which have stayed with me ever since. One of his favorites, roughly translated: “Who is a rich man? He who rejoices in his portion.”

College at Columbia

When I started Columbia College in the Fall of 1950 I had no clear plans for the future. This was just fine with the College, which did not require the selection of a major course of study. Instead it prided itself on offering a liberal education shaped by its famous core curriculum. This emphasis on great ideas of western civilization was particularly valuable for me because I was less informed about these matters than many of my classmates, and I was delighted to be offered so many samples of the wisdom of the ages. My 3 hours a day on the subway were regularly devoted to reading, and the jostling ride went unnoticed as I immersed myself in Aristotle, Sophocles, Spinoza, and Freud.

There was also a science course requirement that I began to satisfy in my sophomore year by taking the course in introductory psychology. Taught at Columbia as an experimental science, it was organized around Principles of Psychology: A Systematic Text in the Science of Behavior by Fred S. Keller and William N. Schoenfeld, the two professors in charge of the course. Having just been published in 1950 this was a very unusual introductory textbook. Instead of providing a broad survey of approaches to psychology it confined its attention to behaviorism and emphasized the ideas of the world's leading behaviorist, B.F. Skinner, whom the authors idolized.

Discovering that psychology could be based on experimentation rather than introspection was very exciting to me. I was captivated by the simple experimental apparatus that was used to study bar-pressing by rats and the manipulation of their rates of response by schedules of reinforcement with food pellets. I was particularly impressed that the pattern of responses could be recorded graphically in the course of the experiment as a cumulative response curve, providing a quantitative picture of behavior on a piece of paper, and that the results were predictable and reliable. I was also swept up by the almost religious zeal of my teachers who insisted that this was the approach that would finally lead us to an objective understanding of the forces that control all human behavior. I wanted to learn more.

At the start of my junior year I supplemented my scientific education with a course in chemistry, a subject that I already loved since high school, and also signed up for several more psychology courses. The one in abnormal psychology taught by Ralph Hefferline really grabbed me. As the year progressed I began thinking more and more about a career in academic psychology.

Then Uncle Joe, my mother's older brother, intervened. He had, by then, made a small fortune in real estate and established himself as the senior member of our extended family. He had always taken a great interest in me since I was the first of the American-born generation, and he was eager to see me prosper. One afternoon, in the first semester of my junior year, he came to our house to talk to me about my future plans. I proudly informed him that I wanted to do research in psychology and hoped some day to be a professor.

His response, which is permanently etched in my memory, was not at all what I expected. He began by telling me he approved of my ambition, even thought it was a great idea. “But first,” he said, “you have to go to medical school. That will broaden your horizon and provide you with some security if your research doesn't work out. When you've finished medical school you'll be in a great position to start doing exactly what you want to do—research in psychology. And you'll also be in a great position to do many other interesting things, should you decide to change your mind.”

The amazing thing about my conversation with Joe—this down to earth man with no formal education—is that it immediately altered the course of my life. When I greeted him that day I was pretty clear that I was on my way to a Ph.D. in psychology. In a matter of minutes I was seriously—and for the first time—entertaining the possibility of becoming a medical doctor. As the idea sunk in, I arranged to take the additional science courses that were required for medical school.

Joe's intervention soon paid me a great intellectual dividend. In the second semester of my junior year I began a course in physics, a subject I knew nothing about and that, until then, I had no intention of studying. Fortunately Columbia was among the first to offer an introductory course that did not require much background in math, a forerunner of those now referred to as “physics for poets.” For me it was transformative. Based on a new textbook—Introduction to Concepts and Theories in Physical Science by Gerald Holton—it opened my eyes to the way science uses quantitative methods of observation and experimentation to explain the world. I had already had a taste of this in looking at the graphs that rats generated in Skinner boxes. But that now seemed like child's play in comparison with the work of Galileo, Newton, Faraday, and Einstein. And even though I did not understand all the nuances I got the big picture, a picture of a world made a bit more comprehensible by the cumulative discoveries of generations of scientists.

A great benefit of my enthusiasm for so many classes was my election to Phi Beta Kappa in my junior year. This guaranteed my admission to most medical schools even though I had not taken the usual premedical program of studies. Urged by my parents to remain close to home, I decided to continue at Columbia by moving on to its medical campus further uptown.

In anticipation of this move I filled my senior year with sciences. To round out my understanding of psychology I also took a class called “The Biology of Behavior” that was not a mainstream listing of the behavioristdominated psychology department but was offered, instead, by Columbia's School of General Studies. Its instructor, Murray Jarvik, opened my eyes to the value of brain research in the study of behavior. Murray will also figure later in my story and became a lifelong friend.

Columbia Medical School

Columbia's College of Physicians and Surgeons is on 168th street in Manhattan, about 3 miles north of the main campus. When I started there in the Fall of 1954 I signed up for lodgings at Bard Hall, the student residence. Freed at last from the long daily subway rides to Brighton Beach, I had a comfortable room overlooking the Hudson River and the continuous company of stimulating classmates.

I approached all the medical school classes with high hopes. Some were taught by leading researchers such as Erwin Chargaff, whose discovery of the ratios of the four bases in DNA was crucial for the Watson-Crick model of the double helix. Elvin Kabat's lectures on immunology, which emphasized his own experimental work, were particularly inspiring. I even liked anatomy.

But the big disappointment for me was psychiatry. Having started medical school with the belief that academic psychiatrists would be engaged in experimental studies of behavior, I was surprised to learn that my teachers cared only about psychoanalysis and were not interested in research. Even though I was intensely curious about psychopathology, and was fascinated by the concurrent brilliance and craziness of a manic-depressive patient I worked with, I was uncomfortable with the prospect of devoting myself to a field that seemed to rely so heavily on strongly held opinions rather than scientific evidence.

As I progressed into the clinical years of medical school I was drawn to endocrinology, a field that had already developed quantitative laboratory tests to aid in diagnosis and treatment. Endocrinology also appealed to me because the pituitary, which controls other glands, is itself controlled by secretions from nerve cells in the hypothalamus, and these, in turn, are influenced by emotions. Viewed in this way endocrinology was not only grounded in science but also relevant to aspects of human behavior that I found interesting.

I was also pleased to discover that I liked working in the clinics. This was particularly true in endocrinology, which offered excellent treatments for some prevalent disorders such as hypothyroidism, thus guaranteeing many satisfied patients. By the end of my third year in medical school I decided to get training in endocrinology and opted for a medical internship at the Peter Bent Brigham Hospital in Boston, just down the street from Harvard Medical School. A main attraction was its chief of medicine, George Thorn, a distinguished endocrinologist.

Becoming a Physician at the Brigham

My first day at the Brigham opened another exciting chapter in my long education. Arriving on the ward in one of the starched white cotton suits the hospital provided, but with little understanding of what I was supposed to do, I was surprised to find my fellow intern, Donald Harrison, already busily at work with the patients. Donald had gone to medical school at the University of Alabama, which offered a much more practical education than I had received. He had been a whiz student and I was immediately in awe of the way he combined exuberant enthusiasm, Southern charm, high intelligence, and hands-on medical knowledge. Fortunately he was also an enormously generous person who was eager to teach me the rudiments of patient care in exchange for a few bits of the book-learning I had accumulated at Columbia. A few months with him and I had picked up the tricks of the trade.

My 2 years at the Brigham, the first as an intern and the second as a medical resident, were filled with many such comradely experiences that come when a small group of young people keep working to exhaustion for a worthy cause. The only time off from our continuous duty was every other night and weekend. But the work was exciting and this intense process of initiation had the desired effect of minting skilled physicians.

The Brigham was also an important site of medical innovation, which attracted some unusual patients. Being interested in endocrinology, I had the opportunity to work with people with adrenal diseases who were drawn there because of George Thorn. We were also encouraged to start thinking about doing research. Having decided that population control was the most important world problem, I submitted a pie-in-the-sky proposal to Dr. Somers Sturgis, a professor of gynecology, on male contraception which proposed to make antibodies to sperm cells and to use them for birth control. As I now reread the proposal I see how naive it was. But even though nothing came of it, I found that I enjoyed thinking about experiments.

The Brigham's interest in making us into medical scientists was not restricted to encouraging such armchair speculation. In order to be invited to complete the medical residency, it was necessary to leave after 2 years of clinical training, for at least 2 years in the lab. In those days, in which all medical doctors were subject to the draft, the most desirable way to do this research was as a member of the United States Public Health Service (USPHS)—one of the uniformed services—and to be assigned to a research unit at the National Institutes of Health (NIH). Located in Bethesda, MD, a suburb of Washington, the NIH was, at the time, establishing itself as the world leader in biomedical research. And every year they accepted a handful of young doctors for research training while concurrently serving as commissioned officers in the USPHS. For trainees like me at the Brigham, getting one of these plum positions was the perfect way to learn to do research while fulfilling the requirement for 2 years of uniformed service as a medical doctor.

Of the units at the NIH that offered these positions which interested me most was in the Clinical Endocrinology Branch of the National Institute of Arthritis and Metabolic Diseases. Competition for this position was intense, and applications and interviews had to be arranged more than a year advance, in the midst of my hectic internship. Of all the jobs I ever applied for this was the one that I was most eager to get, and most worried would elude me. I was very relieved to learn, in April 1959, that I would be appointed as a Senior Assistant Surgeon in the USPHS and was assigned to the Clinical Endocrinology Branch under the supervision of J. Edward Rall, beginning July 1, 1960.

Becoming a Scientist at NIH

The 3 years I spent at the NIH were, in my mind, the time of transition from being a student to being an adult. For the first time in my life I would be making a living, earning about $6,000 dollars a year, a princely sum 20 times as much as the $300 dollars per year I had earned as an intern. This meant I could have a real residence; first, a house I shared with two friends; and then, a little apartment of my own at 2700 Q Street in Georgetown, a 20-minute drive to NIH. And I had a serious girlfriend, Ellen Slater, whom I had known since medical school and would eventually marry.

Yet, in many ways I was still a student. Even though I had become a competent physician, I would need a lot of guidance to get started in research. This need was particularly pressing because Ed Rall, who hired me, had just decided to turn his attention to administration and encouraged me to figure out my own path.

Fortunately there was Ira Pastan. Ira had arrived as a trainee in the Clinical Endocrinology Branch a year before I did and had settled into the lab of Jim Fields, one of the labs that was open to me. Warm, insightful, and already a productive young scientist, Ira took me under his wing and taught me the essentials of biochemical experimentation. He was doing metabolic studies on slices of thyroid gland and, after some brief discussion, I decided that I would do similar experiments with slices of the pituitary gland, that master gland seated beneath the hypothalamus that had first attracted me in medical school. Having learned that the hypothalamus contained serotonin and norepinephrine, two neurotransmitters that might regulate pituitary functions, I decided to study their effects on the metabolism of pituitary slices using the same techniques that Ira was using in the thyroid.

The results were dramatic. Both serotonin and norepinephrine increased glucose oxidation by pituitary slices by way of the hexose monophosphate pathway, and the increases were impressive—up to fivefold. Within months of arriving at NIH I submitted a paper to Endocrinology, a top journal, which soon accepted it. But the micromolar concentrations of the neurotransmitters needed to produce these effects suggested that they might not be acting as ligands for receptors but in some other way. I soon found evidence for an alternative mechanism by blocking the action of the amines with monoamine oxidase inhibitors, drugs already in use by psychiatrists to treat depression. The effect of the drugs indicated that metabolites of norepinephrine and serotonin were the active agents, rather than the neurotransmitters themselves, raising questions about the physiological significance of this in vitro effect. My paper about this was promptly accepted by the Journal of Biological Chemistry, then the top journal in the field.

These early experiences at NIH influenced me greatly by showing me—and others—that I was a competent experimentalist. They also brought me into contact with several outstanding NIH scientists to whom I turned for help. Among them was Julie Axelrod who was then doing his Nobel Prizewinning work on norepinephrine metabolism and who gave me reagents, encouragement, and advice. Julie and I became friends and remained in touch for the rest of his life.

But my career in the laboratory was almost aborted by an unexpected event. Shortly after I arrived at NIH as a commissioned officer in the USPHS, John F. Kennedy was elected President. As is now well known, but was then top secret, Kennedy had Addison's disease—adrenal insufficiency—with very low levels of corticosteroids that required daily replacement therapy. Because symptoms of Addison's disease can be exacerbated by stress, Kennedy's doctors wanted to have someone around who could immediately deal with any signs of deterioration in his condition. From what I have been able to piece together they decided to assign this duty to a young endocrinologist in the uniformed services who had worked with patients with Addison's disease. Because of my experience at the Brigham I was a reasonable candidate and, after being sworn to secrecy, was asked if I would like to be considered. I said yes, and assuming they would never pick me, thought no more of it.

A few days later my mother called me in a panic. Government agents, she told me, were asking questions about me all over Brighton Beach, and she was worried that I was in some kind of trouble. She was greatly relieved by my explanation that they must be checking out my security clearance for an important assignment but still worried because one of the people they interviewed was an artist who had a studio in our basement.

To understand why she continued to be worried I need to tell you more about the ideologies of the people of Brighton Beach. As I described my childhood you might have the picture of a community filled with orthodox rabbis on the lookout for violators of the laws governing the Sabbath. But the fact of the matter is that the most prominent belief system in the Brighton Beach of my youth was not Judaism but Socialism, and many residents were even members of the Communist party. My mother had reason to believe that this might include the man with the studio in our basement who was interviewed by the government agents.

Whether or not her belief was correct, I was soon politely informed that my services at the White House would not be needed after all. The explanation I was given was that they had chosen someone from the Navy because this had been Kennedy's branch of the service. I never found out what really happened, and my FBI file, which I later obtained, makes no mention of this episode. Whatever the reasons, I was free to continue with my research at NIH.

Gordon Tomkins and Marshall Nirenberg: From Endocrinology to Molecular Biology

My research was about to take a major turn because of a conversation with Gordon Tomkins, a brilliant and charismatic scientist who would soon become my mentor (Fig. 1). About 7 years older than me, Gordon was a Californian who had gone to medical school at Harvard and also interned at the Brigham. Interested in hormones he had thought about doing some clinical work but decided he belonged in the lab and got a Ph.D. in biochemistry from UC Berkeley. When I met him he was settling into a position as head of a newly formed Laboratory of Molecular Biology, which was located just around the corner from the Clinical Endocrinology Branch in NIH's massive Building 10.

Fig. 1. Gordon Mayer Tomkins (1926–1975) in 1974.

My first conversation with Gordon is as memorable to me as the one I described with my uncle Joe. When he asked me what I was interested in I answered “endocrinology,” and he offered a startling response: “You know what endocrinology is? Endocrinology is just molecular biology.” To which I replied, “What exactly is molecular biology?”

To justify my ignorance you must understand that this conversation happened early in 1961, when molecular biology was not exactly a household word. But Gordon had already realized that hormones work by regulating gene expression, and he decided, on the spot, to tell me why. In the course of the next 2 hours he explained the central dogma of molecular biology: that regions of DNA act as templates for the synthesis of specific messenger RNAs that, in turn, encode the structures of specific proteins. In Gordon's view hormones work by changing the synthesis of certain messenger RNAs and the proteins they encode, thereby influencing biological functions. His explanations were so convincing and his personality so warm and inspiring that, by the end of the conversation, I asked him if I could join his lab.

He told me he had a better idea. Instead of immediately working with him—which was especially problematic because he would soon be going to Paris for a sabbatical—I should first work with a young biochemist whom he had recently hired as a member of his unit. In Gordon's view this young man, whose tiny lab was just a few doors away, was a brilliant experimentalist who could teach me a lot. Furthermore he had only one post-doc in his lab, and Gordon thought he could also use another pair of hands. This was how I came to work with Marshall Nirenberg.

Moving into Marshall's lab turned out to be a very lucky break, because the following month he and his post-doc, Heinrich Matthaei, made an extraordinary discovery. They had developed a system for studying in vitro protein synthesis by extracts of Escherichia coli, and they were adding various types of RNAs to the extracts to see if they could direct the incorporation of radioactive amino acids into proteins. Among those they tested was a synthetic RNA, polyuridylic acid (poly-U). This simple experiment had two amazing results: poly-U did, indeed, direct the synthesis of radioactive protein; and the protein product contained only a single amino acid, phenylalanine. Because there was already reason to believe that sequences of three nucleotides in RNA directed the incorporation of a particular amino acid into protein—the so-called triplet code—these results raised the possibility that the code for phenylalanine was a sequence of three uridines, a possibility that was soon confirmed.

Amazing as that result was in itself, it quickly became clear that Marshall and Heinrich had not only found the first component of the genetic code but also a way of finding the nucleotide triplets that encoded all 20 of the amino acids found in proteins. As they set out to follow this lead, I was given the assignment of finding out what happens to poly-U when it is added to the E. coli extract. Over the next year I discovered that poly-U associates with clusters of ribosomes that were just being implicated in the translation of messenger RNA into protein. This was not only interesting in itself but also was further evidence that the synthetic polynucleotide was, indeed, acting like a real messenger RNA. I also discovered that a single molecule of poly-U could direct the synthesis of multiple copies of the artificial protein called polyphenylalanine, providing direct evidence that messenger RNA could be used over and over again, and was not used up in the synthesis of a single protein molecule. These findings were considered to be of such great importance that when Marshall and I submitted them to Science they were promptly published as back-to-back papers.

Even more exciting than these successful experiments was my immersion in a lab that was engaged in one of molecular biology's greatest adventures, the race to decipher the genetic code. Marshall had become the frontrunner with the initial finding with poly-U. But as soon as that became known, others began using the same approach. Most notable among them was Severo Ochoa, who had already won a Nobel prize for work with polynucleotide phosphorylase, the enzyme used to make poly-U. Over the next few years Marshall would earn his own Nobel prize. But despite my association with this groundbreaking research and the thrill of being pictured in the newspapers as a member of NIH's “code of life team” I decided to follow a plan I had made with Gordon to join him in Paris for the last 3 months of his sabbatical. In July of 1962, with Marshall's blessing, I set sail for France.

Those 3 months were a welcome respite from years of hard work. Although Gordon had a lab at the CNRS laboratory in Gif-sur-Yvette, in the outskirts of Paris, he had wound down his experiments because of the summer vacation season, and there was a lot of free time for conversations, visits with scientists at the Institut Pasteur, and exploration of Paris. It was also a great opportunity for me to travel through the French countryside with Gordon and his wife Millicent, a gifted artist and singer, who gave solo performances at churches along the way. In the course of these excursions Gordon and I frequently talked about our future plans.

Mine were once again in flux. The exciting discoveries in Marshall's lab, the inspiring mentorship of Gordon, and my considerable personal success at the lab bench had, together, hooked me on a career in science. But instead of simply cruising in the wake of these two exceptional young men I wanted to find my own way, and this led me back to my college ambition to be an experimental psychologist and my short-lived interest in psychiatry. Having learned from Gordon that “endocrinology is molecular biology” it did not require much imagination to consider that the brain mechanisms that control behavior could also be thought of in terms of this exciting new field. And because I was also interested doing something that would be clinically relevant, it occurred to me that much of psychiatry is also molecular biology and that my new training might even qualify me for a career in psychiatric research.

I also had an idea about bridging the gap between molecular biology and behavior which came from Mike Sporn and Wes Dingman, two contemporaries of mine at NIH. Mike and Wes were interested in messenger RNA, which had then been identified in bacteria but not yet in mammals, and we collaborated on a study showing that RNA isolated from rat liver nuclei had potent messenger activity in E. coli extracts, a simple experiment then considered to be so significant that it was published in Nature. But even more important to me than this bit of work was that Mike and Wes got me interested in the idea that messenger RNA synthesis was involved in the storage of memories in the brain, which suggested a way of using molecular biology to study a mental mechanism.

Mike and Wes had already done a pioneering experiment that supported this idea by injecting 8-azaguanine, an analogue of a normal precursor of RNA, into the cerebrospinal fluid of rats just before training them in a swimming maze. They found that rats injected with this chemical did not show the same progressive improvement of performance as controls that were injected with saline. This raised the possibility that the drug-treated rats had difficulty learning because their brains were making dysfunctional 8-azaguanine-containing messenger RNA and that synthesis of functional brain messenger RNA was needed for normal learning. These findings, and the alternative interpretations they considered, were published in 1961 in the first issue of The Journal of Psychiatric Research, but got little attention because of their appearance in this obscure new publication.

When I mentioned this line of research to Gordon he suggested that I discuss it with a psychologist friend whom he had met as an undergraduate at UCLA. The friend, who was studying memory in mice, turned out to be none other than Murray Jarvik, who taught me behavioral biology at Columbia. Murray happily agreed to come to NIH for some experiments, bringing with him a simple apparatus for measuring passive-shockavoidance learning. To test the role of messenger RNA in learning we used a new drug, actinomycin-D, which inhibits RNA synthesis, and measured the effects of injecting different doses into mouse brains by studying incorporation of a radioactive precursor into RNA. We were disappointed to find that mice whose brain RNA synthesis was substantially inhibited learned the simple passive avoidance task as well as controls and had normal memory 3 hours later; and experiments with larger doses of actinomycin were abandoned because of the toxicity of the drug. Nevertheless, the approach was so exciting that it got me several invitations to present symposium papers, including one at the American Psychological Association in 1964. These presentations, which combined the tutelage of Gordon Tomkins with speculations about the molecular processes that control synaptic connections, were subsequently summarized in Nature as “Relationship of Biological Regulatory Mechanisms to Learning and Memory.”

While the experiments with Murray Jarvik were ongoing I began getting tempting job offers. But I had already decided to satisfy my ambition to become a psychiatric researcher by signing up for a residency in psychiatry at McLean Hospital, a Harvard-affiliated mental hospital in a suburb of Boston. Gordon, who was skeptical, assured me that if I hated working with psychiatric patients NIH would take me back and give me a laboratory of my own. Comforted by his continuing friendship I put my three eventful years at NIH behind me and set out for three more at McLean.

Becoming a Psychiatrist and Neuroscientist at McLean

My life was also about to change in another way. Right after the move from NIH, Ellen Slater and I got married. Fortunately I had been awarded a special fellowship, which paid a living wage rather than the meager resident stipend of the time. This allowed us to live in a small apartment in Cambridge at 60 Brattle Street and to pay tuition for Ellen at the nearby Harvard School of Education, which she soon began attending. We could also afford an occasional babysitter when our first daughter, Elizabeth, was born the following year.

Both of us really needed that help. Ellen, who had majored in poetry and French literature at Vassar, was struggling to integrate graduate studies in a more practical subject—psychological counseling—with the mothering of a demanding infant; and I was working overtime learning psychiatry, setting up a lab, and doing my share of baby care. But it was also the best of times, building a family while each of us learned a new field. McLean proved to be a wonderful place for me to learn psychiatry, providing stimulating teachers such as Alan Stone and Alfred Stanton and fascinating patients, many drawn from the vast faculty and student populations in the Boston area.

I was also pleased with the laboratory facilities. Directed by Jordi Folch-Pi, a distinguished neurochemist, they were located in a brick building on the bucolic McLean campus, a short walk from the ward where I worked. The scientists, who all had appointments at Harvard, greeted me warmly as a young colleague. I was the first psychiatry resident to work in their midst and they were happy to forge this link with the clinical world that surrounded them.

But the biggest break of all was the appearance of Harry (Hersh) Cohen, a graduate psychology student from Tufts who sought me out shortly after I arrived at McLean. Hersh had heard about my interest in memory and received permission to do the research for his Ph.D. thesis with me. This stroke of good luck made it possible for me to keep working on the molecular basis of memory storage—a field that was heating up—while holding down my job as a full time psychiatry resident. It was also wonderful to feel that I was no longer simply a trainee, because I now had my first graduate student.

Early Studies of Protein Synthesis and Memory

Hersh did not waste much time in getting started. Because we had no behavioral equipment at McLean he went to the hardware store and got the materials to build it. In a matter of weeks he made two mazes with electrified floors, which we used to train mice to escape or avoid shock, a more complex task than Murray Jarvik and I had employed. With these mazes we reexamined the effects of actinomycin D and again were stymied by its toxicity. This led us to shift our attention from RNA synthesis to protein synthesis using a new drug, puromycin, that had already been used by others for this purpose.

Puromycin, whose general effects on mammalian protein synthesis were discovered around 1959, was first used in memory experiments by Josefa and Louis Flexner and colleagues at the University of Pennsylvania. In July 1963, just as I arrived at McLean, the Flexners published a paper in Science showing that injections of puromycin into mouse brains 1 day after maze-learning impaired memory tested 3 days later. In contrast, identical injections 6 days after training had no effect on memory. In the next 2 years Bernie Agranoff and colleagues at the University of Michigan, who were studying learning in goldfish, also began reporting effects of puromycin on memory. But Agranoff's group found that injections of puromycin after learning impaired memory only if given within 30 minutes after completion of training, which was a much shorter interval than the Flexner group reported.

When Hersh and I examined the effects of puromycin injections before training—so that protein synthesis was already inhibited when the mice learned to solve a maze—our results fit better with those of the Agranoff group. In our first study we found that injections of puromycin into the mouse brain before training did not interfere with learning but that memory deteriorated in the 3-hour period after training and was virtually absent thereafter. These and other controlled experiments were interpreted to mean that memory during training and for minutes after training ("short term memory") is not dependent on brain protein synthesis, whereas memory thereafter ("long term memory") requires brain protein synthesis. In the paper we published in Science we also raised the possibility that the Flexners' finding of an amnesic effect of puromycin injections 1 day after training could mean that there is a third phase of memory storage that operates over this longer time frame.

Axoplasmic Transport of Brain Proteins

In the course of these behavioral experiments, I turned my attention to a distinctive feature of neurons that might have bearing on the role of protein synthesis in memory storage. It was known, from experiments with peripheral nerves by Paul Weiss and others, that neuronal proteins are slowly transported from a site of synthesis in nerve cell bodies down the axon to nerve terminals. If protein synthesis was, indeed, required for memory, and if this protein works by facilitating synaptic functions in nerve terminals (in addition to or instead of on the postsynaptic side), it became important to know how quickly new proteins are transported to the nerve terminals along the short axons in mouse brains. To study this I took advantage of the recent finding that homogenization of brains under appropriate conditions shears off nerve endings, which can be isolated on sucrose gradients as particles called synaptosomes. The method I invented was to inject radioactive leucine into mouse brain and to compare the rate of radioactive protein appearance in whole brain homogenates and in synaptosomes—including soluble and particulate fractions of synaptosomes that could be separated by further disruption and gradient centrifugation. Early in my psychiatric residency I worked out this method, which I described in a paper in Science in November 1964. In subsequent work I showed that radioactive protein begins to appear at nerve endings within 15 minutes after its synthesis, during the same period that short term memory is being converted into protein-synthesis–dependent long term memory.

My work with axoplasmic transport of proteins proved particularly auspicious because it brought me to the attention of Frank Schmitt. Frank, a distinguished biophysicist at MIT, had founded the Neuroscience Research Program (NRP) in 1962 to help develop the nascent field of neuroscience. This was largely accomplished by organizing small work sessions at NRP headquarters in the Brandegee Estate in Brookline. While I was still a resident at McLean, Frank asked me if I would participate in a work session on axoplasmic transport, which would be held the following year, in April 1967. The conference would be an important one because it would bring together a rich mix of people including the great Paul Weiss, the acknowledged leader in the field. But Frank was very concerned that Paul, a senior scientist with a strong personality, would be too domineering to serve as chair of this work session, and he and his colleague, Fred Samson, asked me to take on that task—jokingly explaining that my psychiatric training might be helpful in chairing a meeting that was likely to become very stormy. I was particularly pleased by this request because it helped me realize that I was becoming recognized as a player in neuroscience despite my lowly position as a psychiatry resident. Fortunately the Work Session on Axoplasmic Transport, which was published as an NRP Bulletin, proved to be a great success, and Paul Weiss and I became friends.

First Job at Einstein

In my final year of residency I was actively recruited by the faculties of several venerable East Coast schools. But I was most attracted to a New York City newcomer, Albert Einstein College of Medicine, which offered me an assistant professorship of psychiatry with a joint appointment in molecular biology. The Department of Molecular Biology, which had been founded by Bernie Horecker, a distinguished biochemist, was probably the first of its kind in a medical school, reflecting the innovativeness that was typical of the Einstein of that time. My startup package consisted of a brand new laboratory in the Department of Psychiatry built to my design by remodeling a large tile-walled space that was originally used as a lavatory—an indication of the lack of research space in psychiatry departments of that period. My only duties as a psychiatrist were to meet with and supervise residents and to spend a few hours a week seeing patients. The rest of my time could be devoted to research, which was soon supported by a research grant and a Career Development Award from the National Institute of Mental Health (NIMH).

Coming back to New York, our home town, was exhilarating for Ellen and me. It became even more so with the birth of our second daughter Jessica less than a month after we arrived. We rented an apartment with a view of the Hudson on Palisades Avenue in Riverdale and settled into our wonderful new life.

Protein Synthesis and Long Term Memory

Work in the laboratory had also gotten off to a fast start because Hersh Cohen, now a newly minted Ph.D., joined me at Einstein as a post-doc to continue our work on protein synthesis and memory. That work had been greatly advanced by the Agranoff group's experiments with acetoxycyclohemide, a protein synthesis inhibitor that worked by a different mechanism than puromycin. In 1966 they published a paper in the first volume of a new journal, Brain Research, which reported that acetoxycycloheximide injections into goldfish brain immediately after learning blocked memory measured 3 days later, confirming their results with puromycin. But the picture was clouded by the Flexners' 1966 report that, in striking contrast with their pioneering study with puromycin, acetoxycycloheximide injections into mouse brain 1 day after training did not interfere with memory—which raised the possibility that the amnesic effect of injections of puromycin so long after training was due to some other effect of the drug.

Fortunately Hersh and I quickly discovered the reasons for this discrepancy. We found that puromycin produces abnormalities in brain electrical activity, including occult seizures, suggesting that this action—which is not shared by cycloheximide or acetoxycycloheximide—contributes to puromycin's amnesic effect. This interpretation was supported by the finding that diphenylhydantoin, an anticonvulsant, attenuated the amnesic effect of puromycin but not that of the other drugs. The upshot of these studies was that puromycin, which had played such an important role in sparking this line of research, was not really useful in studying the relationship of brain protein synthesis to memory because of the drug's powerful side effect on brain function, and that its amnesic effect when injected 1 day after training appeared to be due to occult seizures (like the retrograde amnesic effect of electroconvulsive shock) rather than to inhibition of brain protein synthesis.

Having cleared up the confusion generated by puromycin's side effects, Hersh and I went on to a long series of experiments that showed that intracerebral or subcutaneous injections of cycloheximide or acetoxycyloheximide before training have no effects on initial learning but do indeed interfere with memory measured a few hours after training and thereafter, and that the critical protein synthesis is initiated within minutes after training under our experimental conditions. These results were consistently obtained in carefully controlled studies with mice that studied maze learning motivated by either shock avoidance or a water reward. When taken together they strongly supported our conclusion, and that of the Agranoff group, that learning and “short term” memory are not dependent on brain protein synthesis, whereas “long term” memory, which is being established in the few hours after training, is, indeed, dependent on brain protein synthesis. The implication of these results was that the newly synthesized proteins play a role in the alteration of the functional synaptic connections that store the memory, which became the topic of a historic work session at NRP in 1967 (Fig. 2).

Fig. 2. Participants at Consolidation of the Memory Trace Work Session, Neuroscience Research Program, Brookline, MA, November 1967. Left to right. Back row: Hersh Cohen, David Quartermain, Joe Parks, Ted Melnechuk, Richard Roberts, Bruce McEwen, Adrian Rake, Jan Bures. Middle row: Patricia Dimond, Catherine LeBlanc, George Adelman, Wardwell Holman, Everett Johnson, Tony Deutsch, Bernie Agranoff. Front row: Roy John, Steve Chorover, Samuel Barondes, George Koelle, Seymour Kety, Gardner Quarton, Neal Miller (Work Session Chair), Frank Schmitt, Murray Jarvik.

Brain Protein and Glycoprotein Metabolism

While this work on memory was going on I continued to study the rapid transport of newly synthesized brain proteins to nerve endings. Further proof came from autoradiographic studies of synaptosomes with the electron microscope, in collaboration with Bernard Droz. We found that labeled protein could be directly visualized in synaptosomes within 15 minutes after injections of radioactive amino acids, and the significance of the finding coupled with the novelty of the technique led to its publication in Science. I also became interested in the possibility that not all proteins at synapses originated in the neuronal cell bodies and that some could be made by mitochondria in nerve terminals.

Further work in this general area was done with Gary Dutton, a new post-doc and with Howard Feit, an M.D.-Ph.D. student. With them I began studying the metabolism and axoplasmic transport of microtubule protein (tubulin), a specific brain protein known to be a major component of axons. Tubulin was a particularly attractive subject because it was easy to purify from brain homogenates by precipitation with vinblastine followed by electrophoresis on polyacrylamide gels. A major result of these studies was that this structural protein, a major component of axons, turns over with a half life of several days. This finding helped change the picture of the brain, which had been viewed as structurally very stable. The true picture was that the neuron was constantly changing, a theme elaborated in Cellular Dynamics of the Neuron, the 1969 book I edited, which was based on a Paris meeting on the subject.

Included in that book was a report of our findings in a new field, the modification of brain proteins by glycosylation, which I had begun studying with my post-doc, Gary Dutton, and with Marty Zatz, an M.D.-Ph.D. student. I had become interested in glycosylation for two reasons. First it seemed to me that this posttranslational modification might be an important way to modulate the function of brain proteins and could even play a role in short term memory in ways already envisioned for posttranslational phosphorylation. Second I had already become interested in the possibility that the glycoproteins on cell surfaces and in the extracellular matrix might play a role in cell adhesion and recognition, an interest that I would pursue for many years.

Life Changes

In the midst of this scientific excitement, disaster struck. Little more than a year after we arrived in New York Ellen found a lump in her breast. Although she was only 29, and the experts we consulted assured us that it was a benign fibroadenoma, it proved to be a cancer. Nevertheless, after radical surgery and extensive radiation, we were convinced that she was cured. As we gradually went back to our normal lives we began thinking about schools for the children and buying a house, which raised questions about where to settle down.

I had, by then, come to the attention of other universities, which prompted Einstein to quickly promote me to tenure. I had also been appointed Director of Einstein's Interdepartmental Institute for Training in Research in the Behavioral and Neurological Sciences, a pioneering program organized by Saul Korey in 1957 with generous support from the NIH, and a program that fit with my personal goal of increasing the role of biological science in psychiatry. But despite my professional satisfaction at Einstein, Ellen and I were reluctant to put down roots in New York. Instead we were increasingly drawn to California, which I had visited several times because of a generous offer from Stanford.

The turning point came when Salvador Luria invited me to give a lecture at the Salk Institute for their nonresident fellows. When I accepted this invitation I was contacted by Arnold Mandell, a young biological psychiatrist who had just been appointed as the founding Chair of Psychiatry at the brand new medical school at the University of California in San Diego. Arnie said he would come to my talk and would like to show me around.

It was a thrilling visit. I was stunned by the majestic appearance and intellectual vitality of the Salk Institute, the warm reception I received from Jonas Salk and the assembled scientists, and the grand vision for UCSD that was just beginning to rise on a vast campus across the road. When Arnie explained his dreams of a research-based Department of Psychiatry, and offered me a full professorship on the spot, the opportunity to participate in this new adventure seemed irresistible. On a return visit with Ellen she was as enthusiastic as I was.

Before making our final decision we had another treat in store for us. The whole family had been invited to spend three weeks in Boulder, Colorado at the Second Intensive Study Program of the Neurosciences Research Program—another of the contributions of NRP to my personal scientific development and that of the emerging field of neuroscience. It was a great experience for me because it led to lasting friendships with other participants, such as Gunter Stent. It was also a wonderful holiday for the children, their first time in the mountains and on horseback, and helped to convince us that we were ready to move west. Four months later, in December 1969, we all got in the car to move to La Jolla.

Building Psychiatry and Neuroscience at UCSD

Our departure came at a convenient time for my coworkers. Hersh Cohen, who was being recruited for faculty positions, made a surprise move to Wall Street and now holds a major position with Citigroup. My two M.D.-Ph.D. students got their degrees and moved on to clinical training, Marty Zatz in psychiatry and Howard Feit in neurology, and both went on to academic careers. Gary Dutton, a post-doc, decided to join me at UCSD with salary support from my NIH grant. So did Larry Squire, whom I had met at Einstein where he was a post-doc in Murray Jarvik's lab, and who welcomed the opportunity to check out California.

Having Gary and Larry join me in this move allowed me to get a research program going while I attended to my other duties at UCSD. These were quite numerous because our Department of Psychiatry was then made up of just two faculty members: Arnie Mandell and me. I had tried very hard to entice Sol Snyder to sign up with us, and UCSD was willing to offer him a full professorship despite his young age, but Johns Hopkins had the good sense to make him the same offer—and to eventually make him the founding chair of their new Department of Neuroscience. Which left it up to Arnie and me to do all the teaching, clinical work, and administration, as well as to build up our labs. It was a great relief when Lew Judd arrived the following summer to share the enormous load.

As soon as I arrived at UCSD I also began working to help build an interdepartmental neuroscience program like that at Einstein. The nucleus of this program had already been established by Bob Livingston. Working with him and Jon Singer, a professor of biology, I submitted a proposal to the Alfred P. Sloan Foundation, which was, at the time, very interested in fostering neuroscience. They gave us a generous grant, which I administered, to support students, post-docs, and research. This grant provided funding for about 10 years and played an important role in the development of UCSD's neuroscience program, which is now a world leader.

Ellen also had a lot to do to get us settled. After months of searching she found us an affordable Frank Lloyd Wright-style house with an ocean view at 1642 Kearsarge Road, on the lower part of Mount Soledad. It was within walking distance of downtown La Jolla and the La Jolla Elementary School, which my daughters would attend, and a 5-minute drive to UCSD. We could not believe our good fortune.

But as soon as we moved in, disaster struck again. Ellen's cancer had spread to her liver; and this time we knew it was a death sentence. Seizing what time she had left we lived through grim treatments and exhilarating remissions for a year and a half. When it ended she was only 33, and I was alone with my two little girls, barely 5 and 7 years old.

What saved me during my darkest time was Ellen's parents. In the midst of her illness they retired and moved to La Jolla, just a few miles from our home; and when Ellen died they were there to help me with the responsibilities of a single parent. Their presence was also a godsend for Elizabeth and Jessica who knew that they could always rely on their beloved Grandma Fanny.

Molecules and Memory

While I was reeling from this tragedy, the work in the lab went on. Larry Squire began using cycloheximide to more clearly define the sequential phases of memory in mice, an interest he would maintain in his later research on human memory. Much of his work used the Deutsch Carousel, an automated machine designed by Tony Deutsch, a professor of psychology at UCSD, to study learning and memory of a discrimination task. With this apparatus Larry found evidence that a protein-synthesis dependent component of mouse memory can already be detected during the course of prolonged training, which helped refine our view of the stages of memory. He went on to show that anisomycin, a protein synthesis inhibitor that is structurally different from cycloheximide, is equally effective in blocking long term memory, which greatly increased our confidence that the amnesic effect of these drugs is really due to inhibition of protein synthesis rather than to some unknown side effect. While completing these studies Larry established his own research program at UCSD where he is now Distinguished Professor of Psychiatry, Neurosciences, and Psychology (as well as editor of this series of volumes).

As we became convinced that newly synthesized brain proteins are needed to store long term memories, and that reversible modifications of existing proteins are probably essential for short term memory, the next problem was to identify the relevant proteins. In the early 1970s this seemed to be an impossible task, because the proteins involved in a particular memory were likely to be confined to a limited number of neurons in the vast mouse brain. Encouraged by conversations with Eric Kandel, who had already discovered electrophysiological correlates of learning in single cells of Aplysia, I decided to try to follow his lead in the hope of ultimately identifying the proteins involved in plasticity at identified synapses. Working with Aplysia californica also was attractive because these animals live along the coast of La Jolla and could be readily harvested from tide pools that were within a few miles of our lab. And even though I had no experience in cellular neurophysiology, I had recruited Werner Schlapfer, a post-doc, and Paul Woodson and Jacques Tremblay, two graduate students, who were eager to give it a try.

By 1974 we began describing various forms of synaptic plasticity measured in identified cells in the abdominal ganglion of Aplysia and the influence of exogenous neurotransmitters and drugs. To examine the molecular effects of these reagents we turned to Irwin Levitan, a postdoc with a background in biochemistry. He found that serotonin and octopamine increased levels of cyclic AMP in the abdominal ganglion as well as the phosphorylation of a prominent protein peak that could be resolved by electrophoresis on a polyacrylamide gel. The combined results of the electrophysiological and molecular studies was very encouraging because they raised the possibility that this phosphoprotein might be involved in a form of memory. But the amount of tissue in the abdominal ganglion was too small for detailed studies of such proteins with the molecular tools of the mid-1970s. To me this seemed like a decisive limitation of this line of research that made it less attractive than the other project I was concurrently engaged in, which was turning up abundant pure proteins with intriguing functional properties.

Slime Molds, Discoidins, and Vertebrate Lectins

The competing project in my lab grew out of my interest in glycosylation of brain proteins and their potential role in the formation of synaptic connections. The development of synaptic connections was of particular interest to me because I believed that abnormalities in the molecules that control this process might be responsible for the variations in neuronal circuits that may lead to certain forms of mental illness; and my fascination with cell surface glycoconjugates had been kindled by Vic Ginsburg, another young member of Gordon's Laboratory of Molecular Biology, whose lab was across the hall from Marshall's. Vic was one of the early proponents of the now widely accepted idea that specific cellular associations may be controlled by the precise structures of the complex carbohydrates on and around cell surfaces. Just as Marshall was working on a nucleic acid code that determined the structure of proteins, Vic believed there is a sugar code that determines intercellular interactions. But unlike the nucleic acid code which is inscribed as a template made up of four nucleic acid building blocks, the sugar code was presumed to be based on progressive incorporation of six sugar building blocks (galactose, mannose, N-acetyl-glucosamine, N-acetyl-galactosamine, fucose, and sialic acid) into complex sugar chains under the direction of a particular combination of enzymes, the glycosyltransferases, that are expressed in particular cells. How these complex sugar structures on cell surfaces actually mediate cell-cell interactions was not something Vic worried about. But their potential role in this process was what excited him. It was Vic's idea, and its relevance to the formation of specific synaptic connections that stimulated my work with Marty Zatz and Gary Dutton, and that formed the basis of one of the papers—"Brain Glycomacromolecules and Interneuronal Recognition"—that I presented at the NRP meeting in Boulder in 1969.

The direction of my thinking about this problem took a big turn in 1972 with the arrival of Steve Rosen, a new post-doc. Steve had begun his graduate work at Cornell with an interest in memory but went on to do his thesis on cell adhesion in Dictyostelium discoideum, a cellular slime mold. This organism exists in two forms: as a unicellular ameba that lives on soil bacteria; and as a member of a colony of thousands of cells that stream together, adhere to each other, and differentiate into a multicellular organism called a fruiting body. The transformation from unicellular nonadhesive cells to aggregating adhesive cells is induced by starvation and occurs over the course of about 8 hours. As a graduate student Steve made the serendipitous discovery that, in the course of this transformation, the aggregating cells make a substance that agglutinates erythrocytes. This raised the possibility that the agglutinin is responsible for the developmentally regulated adhesion, and we agreed that when he came to my lab we would try to find out.

When Steve arrived he quickly confirmed his earlier observations. Working with David Simpson, another post doc, he set out to isolate the active component of the extract by a standard protein purification technique, gel filtration on a Sepharose column, which separates proteins on the basis of their molecular weight. To his great dismay none of the fractions that came through the column had any agglutination activity. But because of our preconceived notion that the agglutinin might bind to carbohydrates, and knowing that Sepharose is a cross-linked polymer of galactose, he washed the column with a solution of galactose. This released the pure galactose-binding-protein, which we named discoidin, a new member of a class of proteins called lectins that had previously been found in plant extracts. Studies of the effects of simple sugars as inhibitors of hemagglution by purified discoidin showed that N-acetyl-galactosamine binds discoidin better than galactose, and that other simple sugars do not bind at all.

These encouraging results, which we began publishing in 1973, suggested that cell adhesion involves interactions between carbohydratebinding-proteins and their ligands on cell surfaces or in the extracellular matrix. In the next few years Steve and Dave, working with Bill Frazier, Chen-Min Chang, and Dick Reitherman, accumulated evidence in support of this idea. In the course of this work they found that there are actually two discoidins, discoidin I and II, which are synthesized at different stages in the development of the multicellular organism, and that other species of slime molds also have their own distinct lectins.

Stimulated by this work Tom Nowak, a new graduate student, began looking for developmentally regulated lectins in embryonic chick tissues by making extracts and screening for substances that agglutinate erythrocytes. He found some agglutination activity, but none that was blocked by simple sugars. Then, in the midst of these discouraging results, a paper describing an animal lectin was published by Vivian Teichberg and colleagues in the April 1975 issue of PNAS. Using methods like those in our papers on discoidin, they had detected agglutination activity in extracts of the electric organ of an eel, purified the relevant protein on a Sepharose column by elution with lactose, a beta-galactoside, and named the pure protein electrolectin. The main difference between their method and ours is that they included dithiothreitol, a reducing agent, in all their solutions. If dithiothreitol was omitted the lectin was quickly inactivated by oxidation.

When Tom repeated his experiments using dithiothreitol or another reducing agent, beta-mercaptoethanol, he too found lactose-binding agglutinins in various tissue extracts. Concentrating on an agglutinin from embryonic chick muscle he discovered that its synthesis, like that of discoidin, was under striking developmental control, with an increase of 10- to 100-fold between 8 and 16 days of embryonic development and a decline thereafter. Tom went on to purify the lectin with the help of David Kobiler and Larry Roel and to show that it is present on the surface of differentiating muscle cells. We soon found that it is also expressed in other cell types of interest, including neurons.

These discoveries, following on the heels of our work with discoidin, led me to rethink my research priorities. Although I had worked for more than a decade on the molecular basis of memory storage, and Irwin Levitan had some promising findings that might allow for identification of molecules involved in synaptic plasticity in Aplysia, the work on lectins seemed more attractive for several reasons. First, the developmentally regulated lectins we found in slime molds and chick tissues were abundant proteins that we could easily purify in milligram quantities, in striking contrast with the minute quantities of poorly characterized proteins that Irwin had identified as radioactive peaks on polyacrylamide gels. In the 1970s, before recombinant DNA techniques made possible the synthesis of limitless quantities of any protein by translation of its cDNA, having milligrams of pure protein was a very big deal. Furthermore, the lectins had intriguing properties: they bound specific sugar-containing molecules on and around cell surfaces, which made them reasonable candidates for roles in specific cellular interactions. If we were lucky, lectins might even influence the formation of specific synaptic connections, a hypothesis I put forth once again in Neuronal Recognition, a book I edited in 1976. These considerations led me to gradually phase out my work on learning and memory as well as the Ph.D. explorations of my other students—Steve Flanagan, Elaine Traynor, Susan Newlin, and Paula Shadle—and commit myself to studies of lectins.

The Impact of Genetic Technology

The focus on lectins led to several discoveries. The first was stimulated by work in the laboratory of Rick Firtel, a colleague at UCSD. In 1981, using newly developed recombinant DNA techniques, Rick and his colleagues discovered that there were actually three genes encoding discoidin I, and published the deduced amino acid sequences of the three proteins. When we inspected these sequences we found that all forms of discoidin I contain the sequence arg-gly-asp, a sequence also found in fibronectin, a human cell adhesion molecule. Because it was already known that synthetic peptides containing this sequence block attachment of fibroblasts to extracellular matrix, Wayne Springer, a post-doc, and Doug Cooper, a graduate student, tested the effects of similar peptides on the adhesion of slime mold cells to various coated surfaces, and on their streaming into aggregates. We found that the synthetic peptides blocked attachment and streaming, as did univalent antibodies to discoidin I. From these and other experiments we concluded that, as with fibronectin, this sequence of three amino acids in discoidin I is a critical element in its biological function and that this part of the protein, rather than its carbohydrate-binding site, is the one clearly involved in cell adhesion. So the role of discoidin I in adhesion was confirmed, but the biological significance of its interaction with sugars—the reason we were interested in it in the first place—is still not completely clear.

Exciting though these findings were, the path of their discovery, and the ambiguous role of the carbohydrate site of discoidin I made me reconsider my commitment to continued work with slime molds. The main attraction of this experimentally favorable model system was as a potential source of discoveries that would guide research on humans. Indeed Wayne Springer and Andy Feinberg were busily developing methods to examine cell sorting in slime molds, which we hoped to apply to human cell recognition. But in our analysis of the action of discoidin I the guidance was clearly the other way around: our progress in understanding slime molds was based on discoveries already made with human fibronectin.

This conclusion was premature. Beginning in 1993, with extensive sequencing of human DNA, many investigators found human proteins that contain discoidin-domains, as well as evidence that these domains play important roles in cell signaling and adhesion. Among these human proteins are two that are now called discoidin-domain-receptor-1and-2 (DDRl and DDR2). These integral membrane proteins were first identified in a genetic screen for tyrosine kinases. Then, in comparing their sequences with those in the gene data base, the computer revealed the surprising finding that the tyrosine kinases each have an extracellular domain that resembles discoidin I. This resemblance raised the possibility that these proteins bind to extracellular matrix; and, because their ligands were not then known, they were named discoidin-domain proteins. The suspicion that they might bind to extracellular proteins soon led to the discovery that they bind specifically to collagen and that this interaction activates specific intracellular signaling pathways.

Of particular interest to neuroscientists, DDRl is abundant in the brain, and has been directly implicated in synapse formation. So too are other discoidin-domain-containing proteins such as neuropilins and neurexins, which participate in brain cell adhesion and synapse formation by interactions with semaphorins and with neuroligin. Recently RSl, a cell adhesion protein that interacts with neuronal cells in the retina, has been shown to be an octamer of eight subunits each largely composed of a discoidin domain; and mutations in this domain cause retinoschisis, a common X-linked form of hereditary macular degeneration that affects males early in life. So the discovery of discoidin did contribute to studies of neuronal cell adhesion and synapse formation after all.

Although I did not then know how genetic technology would make our discovery of discoidin relevant to cellular interactions in the human brain, it was already clear in the mid 1980s that vertebrate genes and tissues had become experimentally accessible in ways that I did not anticipate when plunging into slime mold research. Meanwhile we kept turning up new galactose-binding lectins in a variety of animal tissues. First Eric Beyer, an M.D.-Ph.D. student, purified one from chicken intestine that had different properties than the one we had found in chick muscle. Then Howard Ceri, Robert Cerra, Hakon Leffler, and Carl Sparrow found several galactose-binding lectins in rat and human tissues, and Marie Roberson found another lectin in Xenopus. When our immunohistochemical studies with fluorescence and electron microscopes localized these lectins on cell surfaces and in extracellular matrix, I drew attention to this new class of extracellular proteins with a review in Science. In other immunohistochemical studies with Tom Jessell, Jane Dodd, and their student, L.J. Regan, we found evidence for two different lectins in subsets of neurons of dorsal root ganglion and spinal cord, a step toward addressing their potential role in neuronal interactions that first attracted me to this field.

Further discovery of related lectins followed when Michael Gitt began supplementing our biochemical work with gene cloning in the mid-1980s. While screening human cDNA clones with an antibody raised against a purified mammalian lectin, Michael found a few that encoded a second related lectin. When he identified the human genes that encoded these two lectins in genomic DNA he named them LGALS1 and LGALS2 (which encode the lectins we now call galectin-1 and galectin-2).

As I became increasingly familiar with the new genetic technology I also began paying attention to its application to studies of heritable human diseases. Having served briefly as a consultant for the Hereditary Disease Foundation, I had been informed by Nancy Wexler of the search for the Huntington's disease gene; and, when the gene was mapped in 1983, I decided to explore the application of this technology to psychiatry. With the help of David Housman, who had played a key role in the Huntington's disease project, I organized a small conference—"Looking for Genes Related to Mental Illness"—at the Neurosciences Institute, the successor to the Neuroscience Research Program, which had been moved to Rockefeller University under the direction of Gerry Edelman. The highlight of this conference, held in October 1984, was the report by Housman and his post doc, Daniella Gerhard, of genetic studies of manic-depressive patients from Amish families identified by Janice Egeland. Using the same approach that had located the Huntington's disease gene, they had some evidence that a gene on chromosome 11 might influence the risk of developing manic-depression (bipolar disorder), a finding they would publish in Nature a few years later.

As I developed my interest in lectin genes, and in the gene variants that influence the risk of mental illness, my professional life was about to undergo another major change. In 1985 I received a letter from Zach Hall asking if I would be interested in moving to the University of California School of Medicine in San Francisco (UCSF) as Chair of the Department of Psychiatry. I was already a big fan of UCSF, which my mentor Gordon Tomkins had joined in 1968, and which I visited several times around 1974 when, shortly before his untimely death, Gordon tried to recruit me to help set up a new neuroscience program. Zach Hall was eventually hired to head that program which he developed into a world leader. Now Zach was asking if I would help build bridges between neuroscience and psychiatry.

Zach's inquiry came at a time when I was ready to consider such a move. Both my daughters were in college at UCLA, which greatly diminished my parenting responsibilities. With their departure I was eager to begin a new life, even find a wife, and it seemed to me that this might be easier if I moved to San Francisco. The city itself was yet another attraction. And UCSF was rich in colleagues and close friends, including Steve Rosen who was studying a lymphocyte lectin (L-selectin) like those we had been looking for in slime molds. Although I was not eager to take on the administration of a vast psychiatry department, the resources it could provide seemed an ample reward for these new responsibilities.

The hardest thing about leaving La Jolla was the many friends I had made. Most of them were the people I worked with every day, such as David Segal and Lew Judd. But I would also miss the members of the First Thursday Dinner Club, which I had joined at its inception in 1979 along with Gustav Arrhenius, Francis Crick, Sandy Lakoff, Richard Lerner, Walter Munk, Leslie Orgel, Roger Revelle, Ellie Schneour, and Charlie Thomas. Drawn from UCSD, the Salk Institute, and the Scripps Research Institute, we met every month in La Valencia Hotel for conversations that I always looked forward to. It was also hard to leave my home on the La Jolla hillside, where my children had grown up, and my mother-in-law Fanny. Nevertheless, I accepted Zach's challenge. In September 1986 I drove up to Los Angeles to visit my daughters and continued north to San Francisco to begin yet another new life.

Building Psychiatric Science at UCSF

The challenge proved to be even greater than I had imagined. The psychiatry department I inherited was still steeped in the psychoanalytic traditions that I had found so limiting when I was a medical student, and many of its faculty members were not happy with Dean Rudi Schmidt's decision to bring me in to steer it in a more scientific direction. Furthermore, the Langley Porter Psychiatric Institute, in which the department is headquartered, had just a few tiny labs, so space and resources would have to be diverted to build facilities for research. Such changes were bound to meet with the resistance I continuously struggled with during my 7 years as Psychiatry Chair.

Fortunately there were some young people at UCSF who helped me move the department in this new direction. The first one I hired was David Cox, a medical geneticist. Along with Victor Reus, a biological psychiatrist, we set out to build an NIMH-sponsored program to hunt for gene variants in patients with bipolar disorder, following the lead of Housman and others. To flesh out this program I hired Nelson Freimer, a recent Langley Porter graduate, and enlisted the participation of Rick Meyers, a young geneticist in the physiology department. They soon joined forces in a new Neurogenetics Laboratory we built on the site of an abandoned kitchen in Langley Porter.

Stanford, which is just a short drive from UCSF, was another source of talent. Among its psychiatry residents was Rob Malenka, a cellular neurophysiologist, and John Rubenstein, a molecular biologist with training in child psychiatry, both of whom I recruited as assistant professors. They were soon joined by three more young psychiatrist-scientists: Larry Tecott, a behavioral geneticist from our own residency program; Mark Von Zastrow, a cellular neurobiologist from Stanford; and Allison Doupe, who had done a psychiatry residency at UCLA and a post doctoral fellowship in systems neuroscience at Caltech. This group formed the core of UCSF's Center for Neurobiology and Psychiatry, which I have led since concluding my term as Chair of Psychiatry at the start of 1994.

While these recruitments were going on I continued my research on lectins with the help of Hakon Leffler, Doug Cooper, and Michael Gitt, in a new lab built on the site of a former suite for occupational therapy—a more elegant shell for remodeling than the lavatory I had converted when moving to Einstein 30 years earlier. I also continued a collaboration with Tom Jessell on lectin expression in the nervous system, along with two of his Columbia trainees, Mary Hynes and Linda Buck—before her Nobel Prize-winning discovery of olfactory receptors. But my main aim during that period was to find all the vertebrate lectins we could, instead of concentrating on their biological functions. With the help of Steve Massa, Yuko Oda, Phillipe Marschal, and Margaret Huflejt, we discovered and characterized a number of new human, rodent, and frog galactose-binding-lectins. Hakon Leffler was particularly interested in discovering the specificity of each lectin by examining its affinity for various galactose-containing saccharides, a project he now continues as Professor of Laboratory Medicine at Lund University in his native Sweden.

We did, however, devote a lot of attention to an unusual feature of these lectins. Like discoidin, none of them has a signal peptide characteristic of secreted proteins. Yet we knew that they become concentrated on the surface of cells and in the extracellular matrix. Working with a cell line of mouse myoblasts, Doug Cooper found that its lectin is initially confined to the cytoplasm and then accumulates in membrane evaginations which pinch off, releasing it outside the cell. The details of this novel secretory mechanism have still not been worked out.

As it became clear that all the lectins we found share a carbohydraterecognition domain of about 130 amino acids, and that members of this family were also being discovered in other laboratories, and given a variety of names, I contacted the main investigators to reach a consensus about nomenclature. We agreed on the name galectin, with each of the known mammalian galectins receiving a number, and new ones to be numbered in the order in which they were found. This name has caught on: PubMed citations of galectin continue to grow exponentially, and galectins were recently the subject of a special issue of Glycoconjugate Journal, which the editors kindly dedicated to me.

Other Activities

Throughout my career I have been an eager participant in communities outside of my home institution. In recent years this has included membership in the scientific boards of biotechnology companies such as Dupont-Merck Pharmaceuticals, Guilford Pharmaceuticals, and Renovis Inc. The repeated meetings of these groups have taught me a lot about the practical applications of biomedical research and have fostered friendships with other members such as Sidney Brenner, David Martin, Sol Snyder, and Corey Goodman. Sidney also invited me to serve with him on Singapore's International Advisory Committee for Biomedical Research, and it has been fascinating to see how this small nation has positioned itself as a significant player in this field.

But my most enduring and gratifying extramural association has been with the McKnight Endowment Fund for Neuroscience. An offshoot of the Minneapolis-based McKnight Foundation, its support of neuroscience began with consultations in the mid-1970s with Fred Plum and Julius Axelrod. They convened a founding committee that I was asked to join along with Edward Evarts, Seymour Kety, and James McGaugh. At our initial meeting in July 1976, chaired by Julie, we created a Scholars Awards program to help young faculty establish an independent career. This remains an influential program that supports about six new Scholars each year, many of whom have become leaders in the field. I served on the initial selection committee for these awards and have been associated with the development of new McKnight awards ever since.

In 1986 Russ Ewald, the Executive Director, persuaded the Board of Directors of the McKnight Foundation to provide long term support for this program by spinning it off as an independent nonprofit organization—the McKnight Endowment Fund for Neuroscience. Fred Plum was the founding President, and I succeeded him 3 years later, serving for almost a decade. I was succeeded by Torsten Wiesel and then Corey Goodman (Fig. 3) but continue to participate in various McKnight activities. I am very gratified by my long association with the McKnight Foundation and believe that its sustained commitment to neurosciences has had an impact that rivals that of the Neuroscience Research Program, which helped me so much in my youth.

Fig. 3. Presidents of the McKnight Endowment Fund for Neuroscience at the McKnight Conference on Neuroscience, Aspen CO, May 2000. Left to right: Torsten Wiesel, Samuel Barondes, Fred Plum, Corey Goodman. (Photo kindly provided by Peter Mombaerts.)

My involvement with the McKnight Foundation also changed my life in another way, by bringing me together with my wife, Louann Brizendine. Already on the UCSF faculty, Louann was acquainted with Larry Ellison, the billionaire founder of Oracle, and had interested him in the possibility of establishing a foundation to support biomedical research. Knowing little about such activities she was advised by Eugene Roberts, a mutual friend, to consult me because of my work with McKnight. Early in 1996 Louann came to see me about this, and we soon developed a personal relationship, marrying in 2002. The foundation she worked to establish, with the help of Joshua Lederberg became the Ellison Medical Foundation, which Josh continues to lead.

Aside from the McKnight Foundation, my most important extramural affiliation had been with the National Institutes of Health, a beloved alma mater which I have served almost continuously since I left in 1963 and which I returned to for several brief sabbaticals as a Fogarty Scholar, beginning in 1979. One of my favorite assignments was as Chair of the NIMH Genetics Workgroup whose members were Aravinda Chakravarti, Mary Claire King, Eric Lander, Bob Nussbaum, Ted Reich, Joe Takahashi, and Steve Warren. In 1997 we prepared a report that continues to shape NIMH policy on psychiatric genetics and that established the principle of sharing clinical data and DNA samples. I most recently served on NIMH's Board of Scientific Counselors, which I chaired from 2001 to 2003.

I have also developed a new career as a writer of books for a general audience. My interest in publishing goes back to Cellular Dynamics of the Neuron in 1969 and continued with my editorship of Current Topics in Neurobiology, a series that included my 1976 book Neuronal Recognition. Over the years I served as Chair of the Publications Committee of the Society for Neuroscience and was on the founding editorial boards of The Journal of Neurobiology, The Journal of Neuroscience, Glycobiology, and Molecular Psychiatry.

But I really got the writing bug when I was commissioned to write Molecules and Mental Illness, a volume on biological psychiatry in the Scientific American Library, which was published in 1993. It was followed in 1998 by Mood Genes, about the hunt for the gene variants that predispose people to mania and depression, and, 5 years later, by Better Than Prozac, about psychiatric drugs. Another one is in the works.

Looking Ahead

In reviewing my life in science it is hard to avoid the temptation to speculate about the future. I do this with trepidation because my past record of prognostication is a mixed one. On the one hand the prediction that molecular biology would transform neuroscience, which came to me via Gordon Tomkins, has been fulfilled so convincingly that students find it hard to believe that it was not always self-evident. On the other hand the impact of molecular research in psychiatry has not yet been as great as I expected.

This is not to say that psychiatry has remained the same. During my training the intellectual core of the field was mainly Freudian, psychiatric residents were taught that psychopathology was the result of the traumas of early childhood, and the standard treatment was a form of wide-ranging psychoanalytic psychotherapy designed to undo this damage. Now the field has incorporated a great deal of brain science; residents are well aware that genetic susceptibility to mental disorders has an etiological role on a par with life events, and the more focused psychotherapies that have largely replaced psychoanalysis are heavily supplemented with drugs that influence molecular targets in the brain.

But, impressive though these changes have been, progress has been slower than I anticipated. Geneticists who have been searching for relevant gene variants in patients with mental disorders have been frustrated by the complexity of the problem, because so many genes appear to be involved that it is hard to implicate any one with certainty. And despite the identification of a series of intriguing molecular targets for new psychiatric drugs, creating them has proved to be extremely difficult. As scientists at pharmaceutical companies know only too well, many promising compounds have been abandoned because of undesirable side effects, whereas others simply do not work or are no better than those already available.

Nevertheless, I remain optimistic. We keep finding more affordable ways to identify variants in individual genomes, so the massive screens this makes possible are bound to identify many of the genes that influence the risk of mental illness. We also keep learning so much about the proteins and small molecules in the brain, and about ways to manipulate them, that new treatments will certainly follow. So it seems to me that it is just a matter of time until we successfully translate this growing knowledge and technology into new ways to alleviate mental suffering.

In the end, what has been most rewarding to me about my activities in neuroscience and psychiatry is that it has allowed me to combine my interests in elegant science with my enduring fascination with the moral and psychological issues that I was introduced to in my childhood. This rich mixture was the allure that drew me to these fields. The allure remains.

Selected Bibliography

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Cooper DN, Lee S-C, Barondes SH. Discoidin-binding polysaccharide from Dictyostelium discoideum. J Biol Chem 1983;258:8745–8750.

Cooper DNW; Massa SM, Barondes SH. Endogenous muscle lectin inhibits myoblast adhesion to laminin. J Cell Biol 1991;115:1437–1448.

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Flanagan SD, Barondes SH, Taylor P. Affinity partitioning of membranes: Cholinergic receptor-containing membranes from Torpedo californica. J Biol Chem 1976;251:858–865.

Flanagan SD, Taylor P, Barondes SH. Affinity partitioning of acetylcholine receptor enriched membranes and their purification. Nature 1975;254:441–443.

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Freimer NB, Reus VI, Escamilla MA, Mclness LA, Spesny M, Leon P, Service SK, Smith LB, Silva S, Rojas E, Gallegos A, Meza L, Fournier E, Baharloo S, Blankenship K, Tyler DJ, Batki S, Vinogradov S, Weissenbach J, Barondes SH, Sandkuijl LA. Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23. Nat Genet 1996;12:436–441.

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Gitt MA, Barondes SH. Evidence that a human soluble ß-galactoside-binding lectin is encoded by a family of genes. Proc Natl Acad Sci U S A 1986;83: 7603–7607.

Gitt MA, Barondes SH. Genomic sequence and organization of two members of a human lectin gene family. Biochemistry 1991;30:82–89.

Gitt MA, Colnot C, Poirier F, Nani KJ, Barondes SH, Leffler H. Galectin-4 and galectin-6 are two closely related lectins expressed in mouse gastrointestinal tract. J Biol Chem 1998;273:2954–2960.

Gitt MA, Massa SM, Leffler H, Barondes SH. Isolation and expression of a gene encoding L-14-II, a new human soluble lactose-binding lectin. J Biol Chem 1992;267:10601–10606.

Gitt MA, Wiser MF, Leffler H, Herrmann J, Xia Y, Massa SM, Cooper DNW, Lusis AJ, Barondes SH. Galectin-5: Sequence and mapping of galectin-5, a beta-galactoside-binding lectin found in rat erythrocytes. J Biol Chem 1995; 270:5032–5038.

Gitt MA, Xia Y, Atchison RE, Lusis AJ, Barondes SH, Leffler H. Sequence, structure, and chromosomal mapping of the mouse Lgals6 gene, encoding galectin-6. J Biol Chem 1998;273:2961–2970.

Gremo F, Kobiler D, Barondes SH. Distribution of an endogenous lectin in the developing chick optic tectum. J Cell Biol 1978;79:491–499.

Herrmann J, Turck CW, Atchison R, Huflejt M, Poulter L, Gitt MA, Burlingame AL, Barondes SH, Leffler H. Primary structure of the soluble lactose binding lectin L-29 from rat and dog and interaction of its non-collagenous Pro, Gly, Try-rich sequence with bacterial and tissue collagenase. J Biol Chem 1993;268: 26704–26711.

Hinek A, Wrenn DS, Mecham RP, Barondes SH. The elastin receptor: A galactosidebinding protein. Science 1988;239:1539–1541.

Huflejt ME, Jordan ET, Gitt MA, Barondes SH, Leffler H. Strikingly different localization of galectin-3 and galectin-4 in human colon adenocarcinoma T84 cells. J Biol Chem 1997;272:14294–14303.

Huflejt ME, Turck CW, Lindstedt R, Barondes SH, Leffler H. L-29, a soluble lactose binding lectin, is phosphorylated on serine-6 and serine-12 in vivo and by casein kinase I. J Biol Chem 1993;268:26712–26718.

Hynes MA, Buck LB, Gitt M, Barondes S, Dodd J, Jessell TM. Carbohydrate recognition in neuronal development: Structure and expression of surface oligosaccharides and ß-galactoside-binding lectins. In Carbohydrate recognition in cellular function, CIBA Foundation Symposium 145. Chichester, UK: John Wiley & Sons, 1989;189–218.

Hynes MA, Gitt MA, Barondes SH, Jessell TM, Buck LB. Selective Expression of an endogenous lactose-binding lectin gene in subsets of central and peripheral neurons. J Neurosci 1990;10:1004–1013.

Kobiler D, Barondes SH Lectin Activity from embryonic chick brain, heart and liver: Changes with development. Dev Biol 1977;60:326–330.

Kobiler D, Beyer EC, Barondes SH. Developmentally regulated lectins from chick muscle, brain, and liver have similar chemical and immunological properties. Dev Biol 1978;64:265–272.

Leffler H, Barondes SH. Specificity of binding of three soluble rat lung lectins to substituted and unsubstituted mammalian ß-galactosides. J Biol Chem 1986;261:10119–10126.

Leffler H, Masiarz FR, Barondes SH. Soluble lactose-binding vertebrate lectins: A growing family. Biochemistry 1989;28:9222–9229.

Levitan IB, Barondes SH. Octopamine- and serotonin-stimulated phosphorylation of specific protein in the abdominal ganglion of Aplysia california. Proc Natl Acad Sci U S A 1974;71:1145–1148.

Levitan IB, Madsen CJ, Barondes SH. Cyclic AMP and amine effects on phosphorylation of specific protein in abdominal ganglion of Aplysia california: Localization and kinetic analysis. J Neurobiol 1974;5:511–525.

Lindstedt R, Apodaca G, Barondes SH, Mostov KE, Leffler H. Apical secretion of a cytosolic protein by Madin-Darby canine kidney cells. J Biol Chem 1993;268:11750–11757.

Lipsick JS, Beyer EC, Barondes SH, Kaplan NO. Lectins from chicken tissues are mitogenic for Thy-1 negative murine spleen cells. Biochem Biophys Res Comm 1980;97:56–61.

Lobsanov YD, Gitt MA, Leffler H, Barondes SH, Rini JM. Crystallization and preliminary x-ray diffraction analysis of the human dimeric S-Lac lectin (L-14-II). J Mol Biol 1993;233:553–555.

Lobsanov YD, Gitt MA, Leffler H, Barondes SH, Rini JM. X-ray crystal structure of the human dimeric S-Lac lectin, L-14-II, in complex with lactose at 2.9 Åresolution. J Biol Chem 1993;268:27034–27038.

Loomis WF, Wheeler SA, Springer WR, Barondes SH. Adhesion mutants of Dictyostelium discoideum lacking the saccharide determinant recognized by two adhesion-blocking monoclonal antibodies. Dev Biol 1985;109:111–117.

Mahanthappa NK, Cooper DNW, Barondes SH, Schwarting GA. Rat olfactory neurons can utilize the endogenous lectin, L-14, in a novel adhesion mechanism. Development 1994;120:1373–1384.

Marschal P, Cannon V, Barondes SH, Cooper DNWXenopus laevis L-14 lectin is expressed in a typical pattern in the adult, but is absent from embryonic tissues. Glycobiology 1994;4:297–305.

Marschal P, Herrmann J, Leffler H, Barondes SH, Cooper DNW. Sequence and specificity of a soluble lactose-binding lectin from Xenopus laevis skin. J Biol Chem 1992;267:12942–12949.

Massa SM, Cooper DNW, Leffler H, Barondes SH. L-29, an endogenous lectin, binds to glycoconjugate ligands with positive cooperativity. Biochemistry 1993;32: 260–267.

McDonough JP, Springer WR, Barondes SH. Species-specific cell cohesion in cellular slime molds: Demonstration by several quantitative assays and with multiple species. Exp Cell Res 1980;125:1–14.

Mclnnes AL, Escamilla MA, Service SK, Reus VI, Leon P, Silva S, Rojas E, Spesny M, Baharloo S, Blankenship K, Peterson A, Tyler D, Shimayohsi N, Tobey C, Batki S, Vinogradov S, Meza L, Gallegos A, Fournier E, Smith LB, Barondes SH, Sandkuijl LA, Freimer NB. A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci U S A 1996;93:13060–13065.

Mehrabian M, Gitt MA, Sparkes RS, Leffler H, Barondes SH, Lusis AJ. Two members of the S-Lac lectin gene family, LGALS1 and LGALS2, reside in close proximity on human chromosome 22q12-q13. Genomics 1993;15: 418–420.

Mir-Lechaire F, Barondes SH. Two distinct developmentally regulated lectins in chick embryo muscle. Nature 1978;272:256–258.

Newlin SA, Schlapfer WT, Barondes SH. Heterosynaptic stimulation modulates the duration of post-tetanic potentiation at an Aplysia synapse without affecting other aspects of synaptic transmission. Brain Res 1980;181:107–125.

Newlin SA, Schlapfer WT, Barondes SH. Separate serotonin and dopamine receptors modulate the duration of post-tetanic potentiation at an Aplysia synapse without affecting other aspects of synaptic transmission. Brain Res 1980;181: 89–106.

Nirenberg MW; Matthaei JH, Jones OW, Martin RG, Barondes SH. Approximation of genetic code via cell-free protein synthesis directed by template RNA. Fed Proc 1963;22:55–61.

Nowak TP, Haywood PL, Barondes SH. Developmentally regulated lectin in embryonic chick muscle and a myogenic cell line. Biochem Biophys Res Comm 1976;68:650–657.

Nowak TP, Kobiler D, Roel L, Barondes SH. Developmentally regulated lectin from embryonic chick pectoral muscle: Purification by affinity chromatography. J Biol Chem 1977;252:6026–6030.

Oda Y, Herrmann J, Gitt MA, Turck CW, Burlingame AL, Barondes SH, Leffler H. Soluble lactose-binding lectin from rat intestine with two different carbohydrate-binding domains in the same peptide chain. J Biol Chem 1993;268:5929–5939.

Oda Y, Leffler H, Sakakura Y, Kasai K-I, Barondes SH. Human breast carcinoma cDNA sequence encoding a galactoside-binding lectin homologous to mouse Mac-2 antigen. Gene 1991;99:279–283.

Outenreath RL, Roberson MM, Barondes SH. Endogenous lectin secretion into the extracellular matrix of early embryos of Xenopus laevis. Dev Biol 1988;125: 187–194.

Regan LJ, Dodd J, Barondes SH, Jessell TM. Selective expression of endogenous lactose-binding lectins and lactoseries glycoconjugates in subsets of rat sensory neurons. Proc Natl Acad Sci U S A 1986;83:2248–2252.

Reitherman RW, Rosen SD, Barondes SH. Lectin purification using formalinized erythrocytes as a general affinity adsorbant. Nature 1974;248:599–600.

Reitherman RW, Rosen SD, Frazier WA, Barondes SH. Cell surface species-specific high affinity receptors for discoidin: Developmental regulation in Dictyostelium discoideum. Proc Natl Acad Sci U S A 1975;72:3541–3545.

Roberson MM, Barondes SH. Lectin from embryos and oocytes of Xenopus laevis: Purification and properties. J Biol Chem 1982;257:7520–7524.

Roberson MM, Barondes SH. Xenopus laevis lectin is localized at several sites in Xenopus oocytes, eggs and embryos. J Cell Biol 1983;97:1875–1881.

Roberson MM, Wolffe AP, Tata JR, Barondes SH. Galactoside-binding serum lectin of Xenopus laevis: Estrogen-dependent hepatocyte synthesis and relationship to oocyte lectin. J Biol Chem 1985;260:11027–11032.

Rosen SD, Chang CM, Barondes SH. Intercellular adhesion in the cellular slime mold P. pallidum inhibited by interaction of asialofetuin or specific univalent antibody with endogenous cell surface lectin. Dev Biol 1977;61:202–213.

Rosen SD, Haywood PL, Barondes SH. Inhibition of intercellular adhesion in a cellular slime mold by univalent antibody against a cell surface lectin. Nature 1976;263:425–427.

Rosen SD, Kafka JA, Simpson DL, Barondes SH. Developmentally-regulated, carbohydrate-binding protein in Dictyostelium discoideum. Proc Natl Acad Sci U S A 1973;70:2554–2557.

Rosen SD, Simpson DL, Rose JE, Barondes SH. Carbohydrate-binding protein from Polysphondylium pallidum implicated in intercellular adhesion. Nature 1974;252:128, 149–151.

Schlapfer WR, Tremblay JP, Woodson PBJ, Barondes SH. Frequency facilitation and post-tetanic potentiation of a unitary synaptic potential in Aplysia california are limited by different processes. Brain Res 976;109:1–20.

Schlapfer WT, Woodson PBJ, Smith GA, Tremblay JP, Barondes SH. Marked prolongation of post-tetanic potentiation at a transition temperature, and its adaptation. Nature 1975;258:623–625.

Schlapfer WT, Woodson PBJ, Tremblay JP, Barondes SH. Depression and frequency facilitation at a synapse in Aplysia california: Evidence for regulation by availability of transmitter. Brain Res 1974;76:267–280.

Seetharaman J, Kanigsberg A, Slaaby R, Leffler H, Barondes SH, Rini JM. X-Ray crystal structure of the human galectin-3 carbohydrate recognition domain at 2.1-A resolution. J Biol Chem 1998;273:13047–13052.

Segal DS, Squire LR, Barondes SH. Cycloheximide: Its effects on activity are dissociable from its effects on memory. Science 1971;172:82–84.

Shadle PJ, Barondes SH. Adhesion of human platelets to immobilized type I trimeric collagen. J Cell Biol 1982;95:361–365.

Shadle PJ, Barondes SH. Platelet-collagen adhesion: Evidence for participation of antigenically distinct entities. J Cell Biol 1984;99:2048–2055.

Shadle PJ, Ginsberg MH, Plow EF, Barondes SH. Platelet-collagen adhesion: Inhibition by a monoclonal antibody that binds glycoprotein IIb. J Cell Biol 1984;99:2056–2060.

Simpson DL, Rosen SD, Barondes SH. Discoidin, a developmentally regulated carbohydrate-binding protein from Dictyostelium discoideum: Purification and characterization. Biochemistry 1974;13:3487–3493.

Sparrow CP, Leffler H, Barondes SH. Multiple soluble ß-galactoside-binding lectins from human lung. J Biol Chem 1987;262:7383–7390.

Springer WR, Barondes SH. Direct measurement of species-specific cohesion in cellular slime molds. J Cell Biol 1978;78:937–942.

Springer WR, Barondes SH. Cell adhesion molecules: Detection with univalent second antibody. J Cell Biol 1980;87:703–707.

Springer WR, Barondes SH. Evidence for another cell adhesion molecule in Dictyostelium discoideum. Proc Natl Acad Sci U S A 1982;79:6561–6565.

Springer WR, Barondes SH. Externalization of the endogenous intracellular lectin of a cellular slime mold. Exp Cell Res 1982;138:213–240.

Springer WR, Barondes SH. Monoclonal antibodies block cell-cell adhesion in Dictyostelium discoideum. J Biol Chem 1983;258:4698–4701.

Springer WR, Barondes SH. Protein-linked oligosaccharide implicated in cell-cell adhesion in two Dictyostelium species. Dev Biol 1985;109:102–110.

Springer WR, Cooper DNW, Barondes SH. Discoidin I is implicated in cellsubstratum attachment and ordered cell migration of Dictyostelium discoideum and resembles fibronectin. Cell 1984;39:557–564.

Springer WR, Haywood PL, Barondes SH. Endogenous cell surface lectin in Dictyostelium: Quantitation, elution by sugar, and elicitation by divalent immunoglobulin. J Cell Biol 1980;87:682–690.

Squire LR, Barondes SH. Actinomycin-D: Effect on memory at different times after training. Nature 1970;225:649–650.

Squire LR, Barondes SH. Inhibitors of cerebral protein or RNA synthesis and memory. In Gaito J, ed. Macromolecules and behavior, 2nd ed. Appleton-Century-Crofts, 1972;61–82.

Squire LR, Barondes SH. Variable decay of memory and its recovery in cycloheximide treated mice. Proc Natl Acad Sci 1972;69:1416–1421.

Squire LR, Barondes SH. Memory impairment during prolonged training in mice given inhibitors of cerebral protein synthesis. Brain Res 1973;56:215–225.

Squire LR, Barondes SH. Anisomycin, like other inhibitors of cerebral protein synthesis, impairs long-term memory of a discrimination task. Brain Res 1974;66:301–308.

Squire LR, Barondes SH. Amnesic effect of cycloheximide not due to depletion of a constitutive brain protein with short half-life. Brain Res 1976;103:184–189.

Squire LR, Kuczenski R, Barondes SH. Tyrosine hydroxylase inhibition by cycloheximide and anisomycin is not responsible for their amnesic effects. Brain Res 1974;82:241–248.

Squire LR, Smith GA, Barondes SH. Cycloheximide can affect memory within minutes after the onset of training. Nature 1973;242:201–202.

Tecott LH, Barondes SH. Genes and aggressiveness. Curr Biol 1996;6:238–240.

Traynor AE, Schlapfer WT, Barondes SH. Stimulation is necessary for development of tolerance to a neuronal effect of ethanol. J Neurobiol 1980;11:633–638.

Traynor ME, Woodson PBJ, Schlapfer WT, Barondes SH. Sustained tolerance to a specific effect of ethanol on post-tetanic potentiation in Aplysia california. Science 1976;193:510–511.

Tremblay JP, Schlapfer WR, Woodson PBJ, Barondes SH. Morphine and related compounds: Evidence that they decrease available neurotransmitter in Aplysia californica. Brain Res 1974;8:107–118.

Tremblay JP, Woodson PBJ, Schlapfer WT, Barondes SH. Dopamine, serotonin and related compounds: Presynaptic effects on synaptic depression, frequency facilitation and post-tetanic potentiation at a synapse in Aplysia california. Brain Res 1976;109:61–81.

Woodson PBJ, Schlapfer WT, Barondes SH. Amplitude and rate of decay of post-tetanic potentiation are controlled by different mechanisms. Brain Res 1978;157:33–46.

Woodson PBJ, Schlapfer WR, Tremblay JP, Barondes SH. Cholinergic agents affect two receptors that modulate transmitter release at a central synapse in Aplysia california. Brain Res 1975;88:455–474.

Woodson PBJ, Schlapfer WR, Tremblay JP, Barondes SH. Resting and stimulated values of model parameters governing transmitter release at a synapse in Aplysia california. Brain Res 1976;109:21–40.

Woodson PBJ, Schlapfer WT, Tremblay JP, Barondes SH. Synaptic depression at a synapse in Aplysia california: Analysis in terms of a material flow model of neurotransmitter. Brain Res 1976;109:41–59.

Woodson PBJ, Traynor ME, Schlapfer WT, Barondes SH. Increased membrane fluidity implicated in acceleration of decay of post-tetanic potentiation by alcohols. Nature 1976;260:797–799.

Woodson PBJ, Tremblay JP, Schlapfer WT, Barondes SH. Heterosynaptic inhibition modifies the presynaptic plasticities of the transmission process at a synapse in Aplysia california. Brain Res 1976;109:83–95.

Zatz M, Barondes SH. Fucose incorporation into glycoproteins of mouse brain. J Neurochem 1970;17:157–163.

Zatz M, Barondes SH. Particulate and solubilized fucosyl transferases from mouse brain. J Neurochem 1971;18:1625–1637.

Zatz M, Barondes SH. Rapid transport of fucosyl glycoproteins to nerve endings in mouse brain. J Neurochem 1971;18:1125–1133.

Additional Publications

Agranoff BW, Davis RE, Brink JJ. Memory fixation in the goldfish. Proc Natl Acad Sci U S A 1965;54:788–793.

Dingman W, Sporn MB. The incorporation of 8-azaguanine into rat brain RNA and its effect on maze-learning by the rat: An inquiry into the biochemical basis of memory. J Psychiatr Res 1961;1:1–11.

Flexner JB, Flexner LB, Stellar E. Memory in mice as affected by intracerebral puromycin. Science 1963;141:57–59.

Leffler H, ed. Special issue on galectins. Glycoconjugate J 2004;19:433–629.

Teichberg VI, Silman I, Beitsch DD, Resheff G. A beta-D-galactoside binding protein from electric organ tissue of Electrophorus electricus. Proc Natl Acad Sci U S A 1975;72:1383–1387.

Vogel W. Discoidin domain receptors: Structural relations and functional implications. FASEB J 1999;13(Suppl):S77–82.

Joseph E. Bogen

BORN:

Cincinnati, Ohio

July 13, 1926

EDUCATION:

Whittier College, A.B. (1949)

University of Southern California, M.D. (1956)

APPOINTMENTS:

Assistant in Surgery, Cornell Medical School (1957)

Research Fellow in Neurophysiology, California Institute of Technology (1958)

Research Associate in Neurophysiology, Loma Linda University (1959)

Assistant in Neurology, Loma Linda University (1963)

Clinical Professor of Neurosurgery, California College of Medicine (1964)

Consultant in Neurosurgery, California Institute of Technology (1968–1990)

Clinical Professor, University of Southern California (1973–2005)

Adjunct Professor, UCLA (1984–2005)

Visiting Professor, California Institute Technology (1995–1999)

HONORS AND AWARDS (SELECTED)

Fellow, American College of Surgeons (1968)

President, Southern California Neurosurgical Society (1976)

President, Los Angeles Society of Neurological Sciences (1985)

Award of Merit, California Association of Neurological Surgeons (1988)

Best of Show, Descanso Bonsai Society (1996)

Joseph Bogen was a neurosurgeon who pioneered “split-brain” surgery for epilepsy and studied (with Roger Sperry and Michael Gazzaniga) the first “split-brain” patients of the modern era. He was also an effective popularizer of concepts of hemisphere specialization and wrote widely about consciousness as a neurobiological phenomenon.

Editor's Note: Joseph Bogen was working on this chapter up to the time of his death on April 22, 2005. It was completed by the editor to achieve an appropriate length and consistent style; and by his daughter, Meriel Bogen Stern, who has also added a few paragraphs (printed in italics) to provide factual background at various points in the narrative.

Joseph E. Bogen

How I Got This Way

It is a special honor to be asked to contribute to this history of neuroscience in autobiography, particularly because it is the only honor I have received for scientific work. This is because unlike almost all of the other contributors, I am not a professional scientist: Save for three summers as a graduate student and 2 years as a post doc, I have never been paid to do science. Being in this illustrious company is largely attributable to my long association with Nobel laureate Roger Sperry. So these selected stories from my life hope to explain how I came to that association. The stories are true, so far as memory serves, although there are bits of digression where some moral might be served.

Earliest Years

According to my mother (Esther Bogen Tietz), she and I graduated from medical school together; she was then 8 months pregnant. Four weeks later on July 13, 1926 I was born on the steps of Christ Hospital in Cincinnati, Ohio. She was apparently working too hard as a medical intern to give my birth much attention. Thirty years later when I was an intern we worked well over 100 hours every week; in her time it was probably even more demanding. As far as I know, when she went to medical school my mother was the only woman. She said later that she had been tricked into going to medical school by my Uncle Emil who graduated from the same medical school 3 years earlier. She had been studying to be an artist, but he told her she would be a much better sculptor if she took the medical school courses in anatomy and physiology. Then, when she had excelled, he said she might as well finish up and get the degree.

My father, J.B. Tietz, also graduated in 1926, from law school. I remember nothing of him until I was five. A few days after I was born, my mother returned to work and I was put in the care of my grandmother. My only recollection of those days was a colorful birthday party for me, possibly when I was 4 years old. I recall, from visiting a few years later, that there was a rather long stairway down from the second floor. Some 60 years later, I spent some time with my Uncle Dave who was quite active in his early 90s, playing golf three times per week, attending chess club each Friday night, and singing in a barbershop quartet. When talking a bit about those days he confessed that one day when he was left in charge of me when I was 3 years old, his attention was diverted and I rode my little tricycle off into space. He saw me tumbling head over heels all the way down the stairway and was certain I had sustained great injury until I quickly stood up. He told me this story on three different occasions in 4 years. There was no question of senility by any other criterion; it seems he had never totally absolved himself of this rare dereliction of duty. For the most part I was the object of unfailing affection for my four first years.

When I was 5 years old, my family, including my 1-year-old brother, Bob, moved into a newly constructed house. There was a deep wood on the other side of the country road. In the woods was a sparkling brook with clay banks, tadpoles, and crayfish. My father took us to neighboring farms where there were many animals. He once took me to Lunken airport for a flight in a “pusher,” a plane with the motor mounted backward. On that trip we stopped for lunch. I do not recall what I ate but he ordered “ham and Swiss on rye,” which has seemed to me ever since to have a certain manly air about it. One day my father arrived home in a panel truck full of Oh Henry candy bars; it was tangible evidence that he could win a case and take somebody's assets.

I helped my father plant trees, which probably contributed to my becoming what is nowadays called a “tree hugger.” And I helped him with the dozens of rabbit hutches. The rabbits were subjects in my mother's Ph.D. research on the newly discovered Friedman test for pregnancy. I was fascinated to see some woman's urine injected into the ear vein of a rabbit, after a blood sample had been removed. And a few days later when the rabbit was anesthetized, I was just tall enough to see it supine on the kitchen table, its belly shaved and painted purple (with potassium permanganate); then it was opened up long enough to draw another blood sample and to observe the ovaries before the wound was closed and the rabbit awakened. (There would be ovulation if the urine had contained the gonadotropins of pregnancy.)

Once, when I was 6½, my father killed a chicken by holding it on a stump with one hand while lopping off its head with a hatchet. He was fairly fearsome looking with spattered blood and that hatchet in his right hand. The most memorable aspect, however, was seeing the headless chicken, running around the yard and occasionally flapping its wings while my 2-year-old brother was saying, “chicken dead, chicken dead.” My mother explained how the chicken's spinal cord controlled its movements independently of its brain. I doubt that my little brother got much out of this lecture; but it stayed with me permanently.

The Separation

The influence of a physician/scientist family on my later career choice did not become very evident until I was almost 24 years old. This seems, in retrospect, the result of being angry with my family for most of the years subsequent to separation at age 7. For most of 17 years afterwards I was aimless, lazy, and difficult. For reasons I only understood later, I was put in a boarding school at age 7. It was run by Edna Mae Waterman Castle of whom I will only say that she has ever since been in my memory the living embodiment of The Wicked Witch of the East. At boarding school for grades two and four (ages 7 and 9) I was constantly in trouble, especially so when my parents forgot to visit on promised weekends. I remember waiting in vain one Saturday, staring for hours out the window at a drenching, endless rain; nobody came. Other years I boarded with various people (paid by my parents) and attended public schools where I was persistently a problem.

My mother did come on some weekends to take me places, like the zoo. On one occasion when I was in the fourth grade she sent a friend who picked me up and took me to an auditorium. I recall being high up in the back and seeing a parade of people wearing gowns. I eventually learned that it was the ceremony in which my mother received her Ph.D. in biochemistry. Sometimes she took me to the hospital where she worked. On a couple of occasions, when I was about 9 years old, she allowed me to play with a brain model, about 3 feet high, which she had constructed from glass tubing filled with various gases. (Getting a chemistry degree in those days included expertise in glass blowing.) At the base of this big glass brain there was a panel of toggle switches. Tripping one caused a red tubing to turn on, a streak of red all the way from the outer wiggly surface down through the brainstem and crossing over to descend in the short piece of spinal cord. Other toggle switches lit up other pathways: green, white, and a bluish color. Looking back now almost 70 years, the details are doubtful; mainly I was left with the idea that brains have lots of pathways, and brains are very colorful! Sometimes my mother was accompanied by my father who was almost always difficult. He was spending each summer in the BOMC, a U.S. Army program, living in tents, marching around, and firing various guns. So far as I recall, his favored expression acquired there was what he called “The Voice of Command,” which he enjoyed using frequently. As the years went by these characteristics worsened. In retrospect this was related to his inability to have much of an income as a lawyer.

One Saturday that my mother came for me was sufficiently influential that it deserves a story and title of its own.

Sam's Streamlined Lime Green LaSalle

When I was promoted, in 1977, to Clinical Professor of Neurological Surgery, one of my colleagues asked,

“About time you got a new car, isn't it?”

“Next year, maybe, when this one is 10 years old.”

“What kind?”

“Another Oldsmobile, probably.”

“Why not a really good car? Surely you can afford it.”

“I guess I'm just an old fogey at heart,” I replied, knowing he would never understand the real reason. The real reason had to do with what happened when I was 10 years old, in 1936.

My mother came to pick me up from the place where I boarded. She said, “Don't dawdle—we're going to see Sam G's fancy new car. I hear it was very expensive.”

“Sam, the dermatologist? Skin doctors don't do surgery—they only charge for office calls. So how can Sam afford a big, expensive car?”

“The old saying about dermatologists is that their patients never die and they never get well. If the doctor is affable as well as able and available, they keep on coming back. So Sam's practice is enormous; and he can see many dozens of patients a day because the essential exam he has to do takes just a few minutes.”

Even then I realized that last point was the clue. My mother was a psychiatrist, which meant, in those days, that her patients rarely died and hardly ever got well; but she was certainly not rich. The difference was that in her specialty, a conscientious exam could not be done in just a few minutes. My pathologist uncle was not rich, either.

“I thought we were going to the museum with Uncle Emil.” “Emil's going to meet us at Sam's house because he can walk there from the hospital where he has been visiting some old friends.”

My Uncle Emil had become a national authority on tuberculosis. Before that he had invented the first machine that would smoke a cigarette to determine separately the chemicals in the mainstream and the side stream, instead of just burning a coffin-nail in a dish. Even earlier, in 1926, he had invented the first quantitative test for urine and breath alcohol levels. His claim that one could measure drunkenness this way was laughed at in the beginning. In 1924 everybody thought it was ridiculous except for his professor Shiro Tashiro. Now of course, alcohol level is usually tested in exhaled air instead of by a blood test. Later on, he became a Clinical Professor of Infectious Diseases at UCLA. For about 20 years he ran the lab at Olive View Tuberculosis Sanitarium. His wife, Jane Skillen, became a thoracic surgeon after graduating from the University of Michigan Medical School. He married this Irish woman (in 1933) to get, he said, “hybrid vigor, that's what we need.”

Anyway, so Emil, although at this time only 40 years old, was an Eminence in the circle of my mother's physician colleagues. The mantle rested easily on Emil's shoulders. He was habitually solemn and matter of fact with his fellows. This derived in part from his having been the ruler at home among 12 siblings (including 6 adoptees, orphans of a Russian pogrom). His mother was a mellow, tolerant type who spent most of her time in her garden. Her husband was one of the first professional social workers, wrangling money from the rich and doling it out to the poor. His activities kept him traveling most of the time. The resulting “Children's Republic,” as it was called, was not very democratic, according to my mother's recollection.

Emil was already there at Sam's house when we arrived. And there it stood gloriously! The lime-green, streamlined beauty, a hood ornament embodying panache, chrome everywhere, pants over the rear chromespoked wheels, and broadly striped white wall tires.

“It's quite lovely, Sam,” my mother kindly observed.

I was speechless. It was every 10-year-old boy's dream-mobile. Had the story ended there, the image of that car would have slipped into my psyche to remain there for decades as a long-term goal.

Sam turned to my uncle and asked, “Emil, you haven't said anything. What do you think?”

Uncle Emil paused in his deliberate way, then spoke: “It is impressive, Sam. But it's not for a doctor. A doctor should drive an Oldsmobile or maybe a Buick. But not a La Salle, Sam, not a La Salle.” He turned away toward my mother's Ford and said, “We should go to the museum now, so we'll have time to see all the new exhibits.”

On the Farm

The two times during childhood that I was an eager student were when I lived on my aunt's dairy farm in New York and attended a one-room school house with 12 to 15 students of different ages. My cousin Ruth and I were the only students in the fifth/sixth grade (we did 2 years in one) and then later in the eighth grade. I studied mostly what I wanted those years. And I spent a lot of time with a big globe of the world; bigger and better than any in the city schools I attended. Best of all was a large model of the solar system with all the planets on rods of appropriate lengths so that each could rotate around the sun. It was then that I decided I would be an astronomer. I spent many hours at night gazing at the sky, learning to locate many constellations and individual stars. Ever since those times in the one-room schoolhouse I have believed that having 30 students reading in the same chapter of the same book at the same time is stupid, if not institutionalized mental illness.

Memories of the farm are both mostly vague, and vaguely pleasant by now, until I make definite effort and then the rosy film fades and there returns the recollection that farming was hard work; this was most true of the fall: oat mowing, raking, bundling, wagon loading, and especially the threshing. Later in the year, for many weeks, I was up before dawn in the winter, stumbling around one or another dark pasture rounding up the cows for the morning milking. The rubber boots were easy to hose off, a complication that was repulsive at first but soon became routine, save for the rare occasion when the cow patty was wet and a mistaken step at an angle caused a slip and fall into the source of the slide. And there was slopping the hogs and feeding the chickens, all before breakfast. Nobody ever told me I was going to college; but along with having professional parents, being on the farm helped convince me.

The Looney Bin

I rejoined my parents, brother, and 5-year-old sister as I began high school in Cincinnati at the age of 13. This was because my mother's increased recompense included a large apartment on the middle of the second floor of the newest addition to the hospital. This location had an additional advantage as the women's receiving ward was on one side and the men's on the other, also on the second floor. Hence those wards were close by my mother's home and office, a help as she was still the receiving physician who screened the incoming patients for any complicating medical problems as well as providing a tentative diagnosis.

This was the Longview State Hospital for the Insane, a 5000-bed facility where, in the back wards, people were actually chained to their beds. In those days there were no psychotropic drugs. My mother, who, as I have said, had her Ph.D. in biochemistry by this time, tried whatever seemed to work, including Metrazol convulsions. A man named Meduna claimed that nobody who had epilepsy was ever schizophrenic, so the way to stop schizophrenia was to give convulsions. It was really a cockamamie idea. But he claimed success so other people were trying it because in those days there was nothing else, except hot towels and cold showers and chaining people to their beds. So she used Metrazol and then she used insulin and then when Cerletti and Bini came out with electroshock she was the first person to use it west of New York. (Kalinowsky was the first person to use it in this country.) Electroshock therapy was effective with depressed patients (and still is) but it did not do much for the schizophrenics. There was day and night a lot of screaming and not just from the back wards! There was a parking space in front of the building used mainly by visitors but also where my father's car was parked. Late one Sunday afternoon I was washing his car (I was then 14). Patients who showed improvement often had trial weekends at home before being discharged. A car arrived, returning a patient, a commonplace event in those days, except when I looked up from washing the car I saw that the patient was undressing. She was soon totally naked at which point she threw her arms upward toward the men's receiving ward and screamed, “Come and get it boys, one at a time!” Some of the patients were sufficiently sound that they worked around the grounds as gardeners. One recollection I had was my mother saying, “These folks are less disturbed (one of her favorite words) but it would be better if you don't turn your back on any of them.”

There was other bad news: First, the hospital was far from high school and the friends I made there. Second, my father's desire to keep in practice led him to buy a bullet trap, which he placed at one end of my room so that from the far end of the living room the target in the trap would be almost 50 feet away. His shooting while I was in bed did not bother me when I was reading, but I was afraid to go to sleep because of the possibility that I might get out of bed, forget for a moment, and walk into the line of fire. (This may have contributed to a lifelong problem with insomnia!) My father bought me a Mossberg .22 bolt-action rifle so I could join him. One evening while firing from a sitting position, I pulled the trigger. There was a click from the hammer falling, but the bullet did not ignite. Thinking that it had been a misfire, I ejected the cartridge. It was hang fire that exploded in midair, making a clanging noise as it dented the piano. My mother's patience was exhausted and we were forced to take the bullet trap down into the basement of the hospital and do our shooting there. Another problem with living with my family was that my father's quick anger was augmented by seeing me every day. Once when I reached for the bread instead of asking he stabbed the back of my hand with a fork and spoke some words I have forgotten. On another occasion he was furious, over what I never knew, and said, “You are going to get a good hit for that—there will be no warning and you won't see it coming.”

In high school in Cincinnati, Ohio, I was an indifferent student, except for algebra, and I was a disciplinary problem. During my sophomore year, at age 14, I ran away from home on my bicycle with the ridiculous goal of pedaling to California to live with my grandmother. By nightfall I had reached a fire station some 40 miles into the Kentucky hills where the fireman kindly called my worried parents. They came at night to retrieve me; for a few days thereafter my behavior and my father's were improved.

In 1940 Joe, a loner for most of his childhood, caught the attention of schoolmates and family for winning the Cincinnati Quiz Kid contest, which qualified him and his family for a trip to Chicago where he participated in the Quiz Kid Radio Show. He remembered this episode chiefly for the disillusionment he felt when it was revealed to him that the show was “fixed.” (Questions were chosen to fit the special interests of each child, which he considered dishonest.) He appeared on the show only a few times but is included, (under the name Joey Tietz) in the book, “What Ever Happened to the Quiz Kids?” by Ruth Duskin Feldman.

In the middle of my junior year (it was 1941) my parents decided to move to Arcadia, California. My grandmother had died and my Uncle Emil, inheritor of her property, offered it to my mother. The appeal of this offer to my parents was threefold: First my father was still a poorly paid clerk in a large law firm after 15 years with no apparent prospect of advancement. Second, my mother was, I believe, burned out as the receiving physician in the Looney Bin. A third reason for our family to move was that we had never had a proper home since 1933 when, in the midst of the Great Depression, we were dispossessed. It was only years later that I understood how the rural paradise I loved at age 6 disappeared. My parents could not make the payments. My mother abandoned her struggling practice and found a job as receiving physician in a state hospital that provided a few dollars and an apartment too cramped for us all, so my brother and I were sent into what we later called “The Exile.”

I refused to move to California because I was then about to obtain a letter as a member of the swimming team and this was the most important thing in my life. I remember my father raising his fist and saying, when I had been particularly obstreperous, “You will be punished for this—you will not see it coming. You have been warned.” The Japanese bombed Pearl Harbor on December 7, 1941 and it at once became impossible to buy tires, clearly needed for the long trip to California. I remember exactly where I was on that Sunday morning—at Ronald T. MacDonald's bar mitzvah. Ronald was the younger brother of my best friend, Kenneth MacDonald. Their father had married a Jewish girl agreeing that the children would have a Jewish education. The adults deserted the party to gather around a small radio to listen to President Roosevelt's Day of Infamy address. It seemed threatening to them but my own thought at the time was that maybe it would stop the move to California so I could get my letter in swimming.

My father scoured the country for old tires for the Ford and for the small house trailer that we had used for several shorter family trips. We left Cincinnati in February 1942 with 22 tires strapped to the roofs of the trailer and the car and before we got to California we used them all.

It was on this trip that I first thought (or from the first time since age six) that my father might be both heroic and quite human. The car slid into a soft shoulder some place in Arizona. There was no help to be had. My principle memory from that episode was my father, stripped to the waist with sweat pouring off of his chest as he put a board under a jack, raised the car and then with my help, pushed the car off the jack toward the pavement. This maneuver was repeated a total of six times before the car was back onto the pavement.

We eventually arrived in California and my main recollection was of endless orange groves with a powerful scent that followed for nearly a hundred miles. I had been out once before through the orange groves. We were headed East after visiting my grandmother. I know what year it was (1938) because we were parked by the side of the road in Arizona, listening to boxing on the car radio. In a previous fight Schmeling had won a decision and Hitler had proclaimed this an example not only of the inferiority of the Negro but of the superiority of the Teutonic-Aryan master race. Just before the fight started, I went back to the trailer to get a drink. By the time I got back to the car the fight was over. Joe Louis had knocked out Max Schmeling in 2 minutes of the first round—so much for the master race. I regretted for years missing this glorious moment just because I was thirsty.

So we got to California and drove for miles past the orange groves. Somewhat alarming were posters nailed to telephone poles at frequent intervals saying that anyone of Japanese ancestry must be absent from the state by the end of the month. I was soon entered into a new high school where I quickly made a reputation for myself as the best student in algebra and the worst student in almost everything else. My misbehavior was partly related to the fact that this high school did not have a swim team. During my final semester, my trigonometry teacher took me aside and explained that he admired my comprehension of the algebraic aspects but that was not enough. He said he would get me into Cal Tech if I did all of the trig assignments; otherwise, he would flunk me and I would not graduate from high school. I slaved away, day and night, often having to redo many problems because there was so much opportunity for arithmetic errors; almost all the problems required using the thick tables of logarithms.

All Those Little Colored Balls

I first saw Linus Pauling when I was 16 years old. I was a freshman at Cal Tech, I guess I was 17 by that time. We had lectures a couple times a week and he gave one of the earlier lectures. I only remember two things of that lecture, one was that he introduced us to the whole question of powers of 10. It was a new idea for me and I think almost all of those kids. That everything could be expressed in powers of 10—especially if you wanted to talk about the size of the universe or the number of atoms in a bucket of gas. And negative powers helped with molecular distances. He had numerous models of molecules on a long lecture table: He used them all to illustrate the point that if you know the angles between the chemical bonds, then you knew the structure of the molecules, and that should tell you why when you pour something yellow into something blue it turned some unexpected color instead of green, and so on. This ultimately became a religious belief for me. The function depends on its structure, and that is what you are supposed to look for. Pauling just drove that lesson over and over his whole life, so it really was not his first lecture. As Pauling gave the lecture, a flask bubbled away over a Bunsen burner. Sometime during the lecture, he dumped a bunch of stuff into the flask and the liquid turned brown. There were other things going on, but he never said anything about them or did anything with them. So I went up after the class and asked, “What is this stuff over here in the flask?” He said, “That's my tea for lunch.” So he was making his tea while he was doing his lecture. I expect that he looked forward to giving this answer every year he lectured the freshman class.

I had the privilege of some social times with Dr. Pauling and further academic exposure before he went off to Stanford and became known for advocating vitamin C as a preventative for the common cold. However, one of my favorite stories about Pauling was when Glenda and I were invited to dinner by Norm Horowitz and his wife Pearl. This was before Norm became Chair of the Division of Biology at Cal Tech. At that time Norm's big job was developing methods for deciding if there was life on Mars. The Viking Lander was going to Mars where it was going to scoop up some of the surface and dump it into some chemical testing mix. The question was, what chemical reactions would be evidence of life on Mars? (Or at least evidence of water, a basic necessity of life as we understand it.) Also the dinner party was interesting because Carl Sagan was there. Anyway, Horowitz told a story about how he had an argument with a post doc about whether a particular chemical reaction could just take place in fine sand under the influence of strong sunlight.

He told the post doc, “You're going to Stanford this weekend. Why don't you look up Pauling and ask him his opinion? He may have some odd ideas but he is still the world's greatest chemist; see what he says.” According to Norm, when the post doc came back on Monday, Norm asked, “What did Pauling say?”

And the post doc answered, “Well, I never got to see him. He had such a bad cold all weekend he wasn't seeing any visitors.”

Joe did not maintain a C average and then attended radar school as a recruit in the U.S. Navy. He was discharged in 1946. Between 1946 and 1951, when he was accepted to medical school, he had a series of jobs ranging from camp counselor to meat cutter. At a camp for epileptic children, Joe first thought about becoming a medical doctor. Still unsure, he went to his mother and Uncle Emil's Alma Mater, University of Cincinnati and took several courses in the sciences. During his time in Ohio, Joe became more of a devotee of traditional New Orleans style jazz and a member of the NAACP. He and several friends participated in lunch-counter-style protests. Joe would go into a club and sit down to be joined by a black friend who would be refused service. Joe would make a big scene before having eventually to leave the establishment. This activity and his other unorthodox behaviors (during the winter instead of the usual scarf, he wore an orange bath towel around his neck) labeled him as “trouble.” He applied to a few medical schools but was rejected. Back in California he took more pre med school courses at UCLA and considered a career as a jazz critic. It was also during this time that he changed his surname from Tietz to Bogen, his mother's family name.

Medical School

None of the medical schools wanted me. It was about that time I met Ralph Gerard, a long time friend of my mother (I think because of the early ECT connection), at which time I asked him, “How much math should one have for a career in neuroscience?” He replied, “You can't have too much.” So I stayed in Cincinnati and repeated the calculus, understanding it philosophically as well as mechanically for the first time. I returned to UCLA for a year, while reapplying for med school. There I took mostly math courses, all from Ray Redheffer who thought I should continue on in math. The first time I visited Ray in his office, I saw that he had a chinning bar in his doorway so I chinned myself while waiting for a prior student to leave.

“One hand, one hand,” he said, looking up.

“Aw, you're kidding.”

“No,” he replied, and got up from his desk and chinned himself with each hand several times. It was the first time since being in Cal Tech that I was reminded that athletic prowess and superior mentation could impressively coexist. In addition to the math courses, I took physical chemistry. It was difficult because I was only just learning about partial differential equations. But I struggled and understood at least half of what was going on. An incidental point made by the professor was “I know I think with my big toe, because when my big toe hurts, I don't think as well.” He left me with the crucial insight that everything is connected to everything else, but some connections are more meaningful than others.

After applying to more than a dozen medical schools, Joe was accepted at USC and Tulane in New Orleans. He had been to New Orleans to look at the school and sought out some of the old-timers of jazz. On the advice of Martin Grotjahn and his mother, he chose USC despite its poor standing at the time, because, as they said to him, “With your attitude, you won't last a year in the South before being jailed, or worse!”

Going to Magoun

In the winter of my first year in med school I was talking with my mother about being a psychiatrist. She said, “Well, if you're going to be a psychiatrist you need to know some neurophysiology.”

“We get that in the second year in medical school.”

“I don't mean textbook stuff. I mean the real stuff, on the leading edge.”

“Well, where would I find that?”

“There's a man named Magoun in Long Beach. I met him at a meeting. That's where you should go.”

I asked, “How do you suppose I can do that?”

“You write him a letter saying, ‘I am a freshman medical student at USC. I would like to work in your laboratory this coming summer and I don't care what I get paid. I am willing to do anything you ask including sweep the floor. Sincerely yours.’ That should work.”

I wrote a letter just like that, word for word. Two weeks later I got a letter back and it said, “You are now a graduate research anatomist at UCLA.” The letter said I could start when the school year ended and that I would be paid $300 per month. Wow!

They had a lot of money in those days. The government was just pouring money into neuroscience generally. So I found a room in Long Beach and went straight to the labs; they were mostly Quonset huts left over from WWII. There were people from all over the world. They were mostly mature scientists from Italy, France, and England. The first summer I did a variety of jobs including making microelectrodes for Italo Calma. This involved buying steel sewing needles and observing the tips under a microscope as the tips were dipped in acid. When the correct shape appeared, a nice cone with a 1 or 2 mu diameter, the needle was dipped in varnish that would nicely coat the needle with an insulating layer but was too viscous to cover the tip. Just a little would be exposed, if everything went OK. The main thing I did in the evenings was try to learn in detail the anatomy of the thalamus. I had more than one atlas and had inordinate amount of trouble figuring out that the centre mediane (unaccented in the texts) was the same as the centrum medianum, which was the same as nucleus centralis and same as the centromedian nucleus but definitely not the nucleus mediocentralis. The extent of my immersion in anatomy, to an extent I had never before experienced, was partially explained by the fact that in the same rooming house was Miss Finland, a natural platinum blond in town for the Miss World Contest. She kept smiling at me until I took her out for a hamburger and she taught me to count to five in Finnish but that was our only date.

That was the summer that Herb Jasper came out. As I understood it, his group had a different result from Magoun's; so they agreed to repeat the experiment together. This really impressed me as the right way to do science. Of course it requires two people who can afford the travel, who can get along, and who both are sufficiently established so that neither would suffer professionally whatever the result. A big feature for me was the appearance of the Penfield and Jasper book: Epilepsy and the Functional Anatomy of the Human Brain. Jasper generously inscribed the book and said if I were to drive from Long Beach to a place far out in the San Fernando Valley that I might be able to get Penfield to sign the book. He did. Apart from its value as a memento, the book so entranced me and has pulled me back for multiple readings so that it is fair to say that it influenced my professional thinking more than any other single book.

It was toward the end of the summer that the Man spoke the Word. A group of us went to Bob's BigBoy for a burger. The group included Magoun sitting directly across the table from me, and Dr. Jack French as well as about six others from the lab. Toward the end of lunch Magoun leaned forward and asked, “Joe, what are you going to do when you grow up?”

“I would like to do experiments like the recent one (in J Neurophysiol) by Schreiner and Kling with amygdalectomy making cats regressed in their behavior.” I thought that they were both psychiatrists (Kling was). However, Magoun then said, “Yes, neurosurgeons do seem to understand the brain better—maybe it's because they look at it so much of the time.” In retrospect, he may have been using the occasion to rib Dr. French, but it made a lasting impression on me. From that time on neurosurgery seemed the way to go.

The second summer I made an effort to understand the neurophysiology, as I was reasonably familiar with the anatomy. In fact this often required asking questions to be sure the terms in various languages were the same or not. I had some helpful discussions with Bobby Naquet and the Arduinis. I again made microelectrodes, mainly for Xenia Machne. By this time electrodes were made by heating the center of a length of capillary tubing to the right shade of red and pulling to get two tapered micropipettes, which were then filled, as I recall, with 3 molar KCI At the end of the summer the Man spoke again, “You should spend your third summer in a different lab; how about going to Van Harreveld at Cal Tech?”

Going to Van H

Anthonie Van Harreveld was a peerless experimental tactician. Magoun had tackled a variety of problems using a specific technique, electrical stimulation and stereotaxy with refined versions of the Horsley-Clarke apparatus. By contrast, Van H pursued a specific problem, the chemistry of cerebral cortex, using a wide variety of methods, electrical as well as chemical. These various methods gave a figure for extracellular space in the neighborhood of 15–20%. However, the development of electron microscopy in the 1950s, when applied to brain tissue by the electron microscopists, had convinced them (and most brain physiologists) that the cells were packed with one another with little space left outside the cells. From his study of what happens to the brain in asphyxia, Van H came to believe that in the normal brain there is substantial space filled with water that runs from outside the cells to their insides, swelling them and making them butt against one another.

To show that his interpretation was correct, it was necessary to design experiments that would detect the extracellular water. This was far from easy, because the standard fixation techniques simply caused the water and electrolytes to disappear into the cells. With great ingenuity and persistence, Van H learned electron microscopy and after many trials arrived at the freeze substitution method that demonstrated the existence and stability of the extracellular water. It depended on freezing the tissue with liquid nitrogen so fast that the electrolyte shifts did not occur and then keeping the tissue frozen while silver ions migrated into the tissue over many days. He had restored the extracellular space to the brain after it had been missing for nearly 10 years.

Working with Van H was not easy for me; he regularly began an experiment every morning at 8 AM. More often than not, the experiment would be concluded in time for lunch, although some took all day, then lunch. Afternoon was devoted to writing up the work, and at 4 PM we stopped for tea, resuming work until going home promptly at 6 PM. As a result, his output was prodigious. With me, the main project was experiments with the spreading depression of Leão, one of which worked so beautifully that I did cartwheels and handsprings the full length of the hallway. Sadly, that experiment never worked again; it was my first exposure to the “first time effect” in scientific work, although not the last. This did not discourage me however; I found the work so fascinating that I spent much of the fall at Cal Tech missing med school classes and depending on classmates to keep me informed.

One project on the spreading depression worked quite well so I wrote it up. When Van H returned the paper, my entire opening paragraph had been deleted. I exclaimed, “If you leave that out only 5 or 6 people in the world will understand what the paper is about!” He replied, “There are only 5 or 6 people in the world who care.” That was my first scientific paper (Van Harreveld and Bogen, 1956). Van H must have thought I did all right because he suggested that after my internship it might be profitable for me to return to him for a year as a postdoctoral fellow; it seemed my next 2 years after finishing medical school were set.

History of Medicine: The Wrong Thinker Part 1

Medical school was a woeful experience, an endless litany of fact whose origins were rarely explained and whose usefulness was infrequently justified. My distaste for rote learning and my questioning attitude were not shared by most of the class of 96 students. This was particularly evident on one occasion when a biochemistry lecturer claimed to be deriving the Nernst equation. The class was faithfully copying what he wrote on the board. Having only a year before taken the Pchem course for chemistry majors at UCLA, I though he was bluffing.

“Where did you get that value for k?” I asked.

The class shouted me down: “Let him finish! Just copy it.”

The medical curriculum progressively became more bothersome for me, because so much was expounded without explaining its origins. Part way through the second year, four of us who lunched together agreed we needed more study of medical history, there being no course available. We met once a month to discuss readings—a sort of journal club. My Uncle Emil gave us some advice with respect to readings and arranged for some guest speakers. At his suggestion, and to emphasize the antiquity of our art, we called ourselves the Avicenna Society. Attendance grew to as many as a dozen students at some meetings. By the end of the third year, the senior faculty (such as Helen Martin, Pete Reynolds) had become aware of the Avicenna Society and decided it was something to be proud of. They invited the Society's president to give a 5-minute talk at the graduation ceremony for the class of 1955, the class a year ahead of ours. Because I was then President, I gave a talk. It emphasized that one thing that we had learned in our study of the history of medicine was that half of what was taught soon became obsolete. We were therefore particularly interested to know which half of what we were currently learning was a waste. I was not invited back.

By the third year most of the class was somewhat accustomed to me and were themselves asking an occasional question, although there was a small clique who wanted to get through each class with no interruptions. Some of us tried not to give their views much credence, partly because their leader was Pappy Spano, a recently discharged Army pilot. When we were supposed to bring a semen specimen to class for microscopic exam, Pappy set up a 30-cc graduate full of cloudy fluid and announced, “Here is enough for all, including you gals.” (There were five women in the class.) During this year I was only rarely being shouted down by Pappy's clique, and I continued to ask questions. One occasion was the most memorable. Paul Starr, the chair of the department of medicine, was delivering one of his endocrinology lectures. That day his talk was about the adrenal gland. In the course of the talk he mentioned that ectopic adrenal cortical tissue does not respond to adrenocorticotropic hormone (ACTH). This struck me as odd so I raised my hand. He ignored me for a while because he knew me. But I kept waving my hand and he said, “What is it?” I said, “I don't understand why ectopic adrenocortical tissue doesn't respond to ACTH. What's the evidence for that? And after you give us the evidence it's true, what is the explanation?” And there was a kind of dead silence in the class as this man pulled himself to his full height and looked down and said, “Young man, there are so many things in medicine for which we do not yet have good explanations that you better begin right now to stop thinking and start memorizing.”

The Original Betrayal

During my second year in medical school my mother suggested that I should “talk things over” once a week with a Dr. Balachandran. He was a small, dark man, a Freudian psychoanalyst recommended by Martin Grotjahn. He had the same penetrating gaze but with brown eyes rather than blue like Grotjahn's. I was expected to lie on a couch with him in a chair behind me. From time to time I would turn and look at him. He was almost always sitting quietly with his hands prayerfully in front of him, the five fingers of his left hand lightly touching the fingers of his right hand while a sixth finger of the left hand, apparently boneless, drooped sadly without a mate.

I was finally moved to ask, “Do your patients ever say that the sixth finger of your left hand looks like a penis?”

“Yes, quite often.” And then, after a pause, “What else comes to mind?”

After approximately 6 weeks of me complaining to him, mostly about my father, he finally spoke up for the first time and said, “Interesting that in all this time you have never mentioned your mother. What can you recall about her in your early days?” So I talked about her coming to get me and going to the zoo, and to hear Gilbert and Sullivan's Pirates of Penzance, and to the museum, and so forth.

“Did she ever take you home?” I remembered with a shudder a visit to the small apartment she had when I was about seven, and having a tantrum, kicking the black sofa on which I was lying, when she insisted that it was time for me to go back to the boarding school.

“How did you feel when you first went to the school?”

When it was time to enter second grade, my mother took me to a school I had never seen before. The backyard was a wonderful playground with slides and swings and, most memorable, a jungle gym with kids swinging around. I thought it was going to be grand. I was too busy playing to notice when my mother left. Then came the end of the afternoon and almost all of the children left. One of the teachers showed me a room where I was supposed to sleep, and took me in to dinner. “Where is my Mom?”

“She will come to see you on Saturday.” She came on Saturday, took me home and the next day took me back to the school, after I had finally exhausted my tantrum on the black sofa. There were other visits to that small apartment in the hospital. It was on a third floor hallway ending in a balcony that ran around a large atrium. I recall that I considered jumping over the railing and falling three stories to make a big splash.

“So not only did your mother not protect you against some of your father's aggression, she actually abandoned you, or so you thought.”

These sessions with the analyst were most enlightening, especially as I realized they had been arranged by my mother. They ended rather abruptly when the analyst moved on to another town.

The Fascination of Surgery

It was during my third year in medical school that I saw an operation using an artificial aortic valve. At the time there were still in the L.A. County Hospital a couple of operating rooms with little balconies for observers. You would put on a mask and cap and sit in a little balcony overlooking the operation. It was literally an operating theater.

“Hey, Bogen, they're going to do a Hufnagel on your patient.”

I was a medical student on the cardiology service and had worked up a man who had aortic insufficiency from syphilis; his aortic valve would open when the heart contracted but it would not close properly so most of the blood would whoosh right back into the heart.

This patient was about to die of congestive heart failure. He had a heart, on chest x-ray, almost as big as a volleyball. The cardiologists expected a guy like that to die in a matter of days so they were willing to let the thoracic surgeons try one of these newfangled valves. The Hufnagel valve was a little cage with a ping-pong ball in it. The surgeons would open the aorta to put it in. They did not take out the old aortic valve, they would just open up the aorta above the aortic valve, put in this cage that had the ping-pong ball, sew it into place and close the chest. They had to work very fast because in those days nobody had yet learned how to stop the heart for more than a few minutes, without brain damage. After the valve was in, every time the heart would beat, if you listened with a stethoscope, instead of hearing “lub dup,” it would go “lub click, click.” In fact, if the patient would open his mouth you could hear the ping-pong ball going “click, click” without a stethoscope. We students watched this operation and I remember when they opened the aorta, the blood went 3 feet in the air. It was absolutely astonishing. The operation was quite successful. I met the man on the steps of the hospital a couple of weeks later. He was walking up he steps. After greetings, I asked, “Can you still hear it?” He opened his mouth, “click click.”

“Does the sound bother you?”

“Only when it stops,” he replied.

It was during medical school at the Los Angeles County Hospital that Joe met and married a nursing school graduate, Glenda Miksch. After a while she became the nurse for Esther Bogen Tietz, who had built a psychiatric practice in Hollywood.

The Wrong Thinker: Part 2

My first solo publication was a paper called Student Concepts of Functional Disease. Many of the clinical faculty kept talking about “functional disease” and it was never clear to me what they meant. I felt that they were actually preaching what in those days I considered dualistic garbage; but there was no easy way to call them on it. I was pretty unhappy with many of my teachers in medical school, because I thought they were mostly an intellectually limited bunch. By the beginning of the fourth year I was so unhappy with all this talk of “functional” that, when some obstetrics (OB) doc was talking about functional bleeding, I asked “Wouldn't it be better to call it dysfunctional bleeding?”

“Yes, some people do,” he agreed. But Pappy's clique was growing restless again, and urged the lecturer to keep on. After hearing about functional hallucinations and functional pain, there came the last straw. A guest lecturer on gastrointestinal (GI) problems included in his differential diagnosis for blood in the stool, something he called “functional bleeding.” This apparently meant that it was slight and intermittent and the usual tests were unrevealing so it could be disregarded. I jumped up and said “Now what the heck? If there's blood, there's a broken vessel and there must be a structural defect in the gut, not simply dysfunction.” One student shouted, “Oh, get off it Bogen!” The professor ignored me and went on to ulcers, malignancies, and so forth.

I was so outraged that I made a large sign and posted it in the hallway. It said: A FREE BEER TO ANY MEDICAL STUDENT WHO WILL GIVE ME A WRITTEN DEFINITION OF FUNCTIONAL, AS IN FUNCTIONAL DISEASE.

I got about 3 dozen replies. Subsequently I asked them to explain their answers (passing notes back and forth during class). Where one had written, “Any illness without structural change,” I asked, “How about on the chemical level like early avitaminosis?” He wrote back, “Bogen, you are a wrong thinker and a trouble maker.” Many of them wrote, “Anything that's mental and not physical,” an almost standard answer. One wrote “It's something that can only be corrected with psychotherapy.” So I asked him, “Can people with head injury ever benefit from psychotherapy?”

“Of course,” he replied. (I knew his father was a psychiatrist.)

Several said, “Well, the problem really is here and there and you are not sure what it is.” Which, of course, is what they were learning from their teachers. I asked, “Does this depend on the amount of your medical knowledge?” The very best reply was “I may not be able to define that word, but when I use it, I know exactly what I mean.”

The second best reply was, “Bogen, I wrote you an answer, now where's my beer?” So after class we went down to the nearby Mission Street Bar and I bought everybody a beer including people who hadn't written anything. By this time it occurred to me to write up what I had. With my paper in hand I approached the two professors who were full time in the school and had (and continued to have for many years) a reputation for teaching. They were sitting in chairs not quite side by side but at a 45-degree angle so my approach was from one side. After I stood there for a bit they stopped talking, and Dr. Helen Martin said, “Yes?”

“I wrote a paper and would appreciate advice.”

“Oh good, we like having students write papers. What is it about?”

“It is about the student concept of functional disease.”

Without a further word she turned away, back toward Dr. Reynolds, and they resumed their previous conversation without comment, as if I were not present.

It then occurred to me to ask for help from Dr. Peter V. Lee who had become Assistant Dean. He read it immediately and said, “This does seem to have been written in the heat of the moment. Tell you what. You put this away for a couple of weeks and then pull it out. If you think it can be moderated, including removal of the four letter expletives, I'll help you get it published.”

I did as he said, and he was as good as his word, sending it to the Journal of Medical Education with a letter of recommendation (Bogen, 1956).

"It Ain't Over 'Til It's Over": Graduation

Spending so much time at Cal Tech contributed to the scary problem that suddenly arose the last week of school. Our med school class was to graduate on Saturday AM. When I arrived home from the lab Wednesday afternoon there was a letter from the Dean's office. It said only, “You are required to be in the Dean's office at 7 PM tonight.”

“What is this? Some prank?” I thought. However, the letterhead looked all right, and the letter was signed by Assistant Dean Peter V. Lee.

When I appeared, there were five stern faced men; the Assistant Dean Peter V. Lee, the Professor of Surgery, the Professor of Pediatrics, the Professor of Pharmacology from whom I had received an A, and a fifth man whom I did not recognize and who was not introduced.

“Have a seat Joe.” Dr. Lee was apparently the chair of this group. “You are here because some serious doubt has arisen with respect to the desirability of you graduating.”

“Uh oh,” I thought. My best friend in the faculty, Tom Brem, my advisor, had been made Acting Dean. And Dean Brem was out of town!

“Why is that?” I asked.

Dr. Lee replied, “Both Dr. Carmona and Dr. Rabdon have raised some objection to your graduation and when they did, it seems that you have made a number of enemies over the past few years and they have all jumped on the bandwagon.”

“Could these be Drs. Starr, Reynolds, and Martin?”

“Among others. There was considerable opinion that you have not been a sufficiently serious student.”

It was true that I had expressed disbelief from time to time in some

of those professors' favorite theories. And I had been rather flippant when the pediatrics professor once gave me an oral exam. He wanted to know the relative types and dilutions of milk substitutes for various ages and afflictions of infancy.

“Well, generally for a well baby in the absence of mother's milk, halfand-half water and condensed milk. For other situations I would refer to a pediatrician.” This was not what he wanted to hear.

The professor of surgery said that my lack of seriousness was evidenced by my cursory treatment of his 3-hour final exam. “A single Blue Book, when most of the class used an entire blue book for each question.” There had been four questions, the first being, “distinguish between acute appendicitis and acute pelvic inflammatory disease.” On the first page of the Blue Book, I headed two columns: one was “appy” and the other was “PID.” Down the left margin of the page I wrote age, sex, location, duration, presentation, and other distinguishing features. I filled in the resulting table and went on to the following questions treating each of them in a similar fashion. I handed in my Blue Book in less than an hour and left. I learned later that another student had used the entire 3 hours to fill up six Blue Books and that he had received an A+ on the final exam. As the story of the surgery professor's poor opinion of me unfolded, I thought I saw a slight flicker of a smile on the pharmacologist's face. It was true that I had missed a number of classes, and there was not much I could say about that. However, I suggested that since I had already been accepted at Cornell starting in July, that I might do some pediatric makeup on my return in 1 year. The pediatric professor refused to consider this solution. It turns out that it would not have helped because he was fired within the subsequent year for harassment of the hospital staff. There was also the question of my having contributed to “class disturbances” on a number of occasions.

After about an hour of discussion, Dr. Lee said that we were through and asked if I had anything further to add. I said, “Yes. I just want to say that if I erred, it was not for lack of seriousness, but more likely that I might have been too serious.” On Friday afternoon I received a phone message that I would graduate on Saturday with the rest of the class.

Sam Moore

In spite of absences, “disturbances” and misunderstandings, I graduated from med school and appeared at The New York Hospital Cornell Medical Center on June 30, 1956. Over the next few days Glenda and I moved into the assigned apartment across York Avenue from the hospital and I was put through an orientation. We new interns were outfitted in white pants and short white coats and inspected in military fashion. The inspection was done by Professor Moore who strode in after we were lined up. This was when I realized that his white coat was not only longer than ours, almost to his ankles, but also double-breasted with two rows of buttons down the front. It seemed to me reminiscent of pictures that I had seen of General Erwin Rommel, The Desert Fox. He looked us over and then left us to the Chief Resident, whose speech I have mostly forgotten except for his admonition, “You take care of the charts and we will take care of the patients,” making it crystal clear that we were not yet considered doctors. We saw a lot of surgery, mainly while holding retractors, but never did any. Indeed, over the succeeding months it became clear that if I were to do any surgery, I would have to stay for at least another year—assuming I was retained. In that pyramidal system only 8 assistant residents were retained of the 16 surgical interns. The importance of my staying for a second year had to be explained in a lengthy letter to Professor Van Harreveld. To my great relief, he said that he understood and said I could start my postdoctoral year in neurophysiology a year later than originally planned. The internship was quite demanding, as we worked well over 100 hours per week. One episode lightened the grind. I had just emerged from a room into the hallway as Professor Moore was marching down the hall with the usual collection of house staff, nurses, and medical students following behind. Seeing me, he abruptly stopped, did a brisk left face and said.

“Bogen!”

Startled, I came to attention, “Sir?”

“I read your paper in the Journal of Medical Education and I have just one thing to say.”

“Yes, Sir?”

“I may not be able to define the word, but when I use it, I know exactly what I mean.”

After which he did a right face and resumed his march down the hall followed by a somewhat bewildered retinue.

The Open Heart

In the spring of my year as a surgical intern at the New York Hospital, there was a minor epidemic of cardiac arrests in the operating suite. The chief of anesthesia insisted that his trainees use ether anesthesia. Nobody uses ether nowadays, but in 1957 they were still using it along with Pentothal inductions. There was a little room next to the operating room where they put the patients to sleep. Inductions with intravenous sodium Pentothal are very nice. If you push the stuff in fast people go out in an instant. But if it is pushed in slowly they go to sleep slowly, a period of time during which they feel pretty good. I was once standing by while the anesthesiologist was dribbling the stuff in and the patient said, “You know, if I could, I would shtay like thish all the time!” During the operation the intern would just be holding retractors. When the surgery concluded, the intern remained to take care of the patient, along with the anesthesiologist. And you would go with the patient to the recovery room where you would write postop orders.

One problem was that there was often a time at the end of the operation when the attending surgeon was gone, the resident surgeon was gone, and the only doctors left were you and the anesthesiologist. During surgery there would be a scrub nurse and the circulating nurse. But by the time the operation was over, one of them was gone and one was folding stuff up. So there would be at most one nurse available. And then the heart would stop.

This happened a few times and people were getting upset about it. Eventually it turned out to result from cardiac potassium shifts caused, in certain patients, by ending the ether anesthesia too quickly. But at first this was not clear. The thing learned first was that if you could keep the heart going, the problem would subside in 10 minutes or so and then everything would be all right. So the problem was to keep the heart and respiration going during that 10-minute interval.

The hospital Executive Committee issued a proclamation that if the anesthesiologist could not feel the pulse in the neck (in the carotid artery), whichever other doctor was there in the operating room (OR) was supposed to open the chest and start squeezing the heart. It was called cardiac “massage” but you would be squeezing it. If there was anybody else in the OR, like a nurse, the job of that third person was to feel for a femoral pulse just below the groin to see if you were squeezing the heart hard enough. Meanwhile the anesthesiologist would maintain respiration by inflating the lungs. So suddenly all of us naive interns were expected to open somebody's chest and squeeze the heart!

In that hospital an intern did not often handle a knife the entire year; all you did in the OR was hold retractors. They might occasionally let you use a pair of scissors to cut the sutures after they tied the knots. It was not like the County Hospital in Los Angeles, where I was a medical student. At the County, the intern is operating the first month he shows up, whether he knows anything or not. There, the saying was: watch one, do one, teach one. Here you were just supposed to watch for a year. In fact, it was almost 10 months, in April, before I did any surgery. I was helping one of the attendings who had private patients in this hospital. The patient needed an appendectomy. The surgeon drew a 2-inch line on the belly with a felt tip pen. Then he stopped and said, “Dr. Bogen, you ever do an appendectomy?”

“No, I haven't held a knife since I've been here.”

“Well, you take this knife and you first cut the skin where I've drawn this line on the belly; you cut right there.” And he took me step by step through the appendectomy.

You had to be on the private service for this to happen, because when you were on the clinic service, the residents wanted to do all the operating; probably the resident who was there that day thought that he should have got it instead of me. I had a bit more experience when I was helping a thoracic surgeon. All of a sudden he said, “Have you done any operating, just to start?”

“A guy helped me through an appendectomy last week.” “Well, why don't you make the incision? Right from here to here, see?”

So I took the scalpel, and I started in a bit gingerly, because he had indicated an incision about 8 inches long. He grunted, “Cut it, doc, don't scratch it!”

By the end of June, I actually ended up doing most of a gallbladder removal. But it was in April when they had first wanted us to open people's chests. I thought, Jeez! I'm going to be there all by myself in the OR, and how do I know whether to believe the anesthesiologist? Suppose the anesthesiologist says, “I can't feel any pulse in the neck.” And then I cut open the chest. Suppose there was a pulse but the anesthesiologist just could not feel it? What a hell of a fix to be in.

One time in the follow-up clinic I removed somebody's sutures a day too soon. Henry Mannix came in screaming, “What the hell are you doing, for Christ's sake?” (He was an assistant resident in the fifth year of a seven-year program. I don't know how he got that far because he had a terrible temper and blew up at the least thing.) Thinking about cardiac massage in the OR, I figured I would feel much worse and get hell from more important people than Henry if I opened somebody's chest when I should not. At the end of the year (first of July) I became a junior resident, the second step in the long ladder. After 2 months on Orthopedics I rotated to the general surgery service and covered the emergency room (ER) every other night. It was not an ER as we think of one today. There was just one nurse who was there all the time. Her job was to take care of minor wounds or call a doctor if needed. If the patient had a limb injury she would call the junior resident on Orthopedics who was Walter Shim, from Hawaii; he had been an intern with me. Walt had followed me on to the Orthopedic Service and he was just down the hall that night. The medical junior resident was upstairs in bed on the 22nd floor. The nurse's instructions included that if a patient came in who had a pain in the chest, call the medical junior resident. If the patient came in with pain in the belly, call the surgical junior resident (me).

So when a man came in shortly after 1 AM with a pain in the belly, she called me. By this time I could tell the difference between a rigid belly and a not rigid belly; a rigid belly meant paging the chief resident; if it was not rigid then I could take longer to try to figure out what was causing the pain. I stepped out in the hall a half hour later when the nurse suddenly appeared.

“The guy just died! He died, just like that!” “What's that?”

“Come with me!” she said and we ran up the hall to an exam room.

In it was a man, lying on the floor, naked. “What happened?”

“He came in with severe left chest pain so I called the medical resident. She said she would come down. I brought the man into this exam room and told him to get undressed. I came back to take his temperature, and there he was, naked, on the floor, and he wasn't breathing!”

Just then the man made a gasp, a bit like a hiccup. I said, “Well, he's not totally dead. Let's get him up on the bed!” This was possibly a mistake in retrospect, but anyway we lifted him onto the bed and he gasped again. He had no pulse. He was as pale as the sheet under him. No pulse, no breathing except for those two gasps. So he wasn't totally dead yet.

Fortunately, during the summer, I had spent a little time in the library. You never have time as an intern to do anything except run around; you are lucky to ever get to sleep. But as a junior resident I had a little time and went to the library where I started reading up about cardiac arrest. I was still worried that I might be in the operating room when there was a cardiac arrest and, being a junior resident, it would be up to me and not the intern. I came across an article about cardiac arrest. It seemed ours was not the only hospital that had the problem. This was long before anybody ever thought of pushing on the chest. A group at Johns Hopkins Hospital finally figured out that if you pushed on the chest (hard enough to crack the ribs) you could get a femoral pulse from an otherwise lifeless heart. But that came about 2 years later. In 1957, the only method was to open the chest and start squeezing the heart. This approach was well known because sometimes the heart would stop in the middle of an operation with the chest already open. They would squeeze it to get a pulse, and then to get it going again they had electrical defibrillators. If the heart went into fibrillation so it was no longer contracting, they would defibrillate, “Bang!” The shock was enough to make the body bounce right off the table. So that part of it was well known. But the problem for me was: if you have never opened a chest in your whole life, how to do it? There was that one time when the surgeon said to me, “Don't scratch it, doc!” But after I cut the skin, he took over, so I had never actually opened the chest. While I was reading in the library, in one article about cardiac arrest in the OR, there came the answer!

“If you're not sure, cut through the skin and the muscle, between the ribs about the sixth intercostal space. If it doesn't bleed, keep going into the chest. If it bleeds, sew it up.”

Now that is practical advice! You are not totally committed right from the start, on the advice of some trainee anesthesiologist you do not know. I have been dubious about people's opinion about anything, anyway. But here was a way to decide. So, at 2:00 in the morning, there was this naked guy going “gasp” just twice. There was a tracheostomy kit in the next room. It had a scalpel, scissors, sutures, gauze, and hemostats. We had been told the kit was there so if somebody's airway was obstructed and you could not get an endotracheal tube in, you could do a tracheostomy right there in the little operating room next to the dressing rooms. It occurred to me that it has everything I need for this. I told her, “Maybe you'd better get that trach tray and bring it in here.” She brought the tray in and opened it up. I took the knife and I cut through the guy's skin; it did not bleed. So I opened up the chest.

If you want to get in there, you've got to pull the ribs apart. So I asked her, “Pull up” while I pulled down with my left hand. I shoved my other hand in there and the ribs clamped down on my wrist and I could feel his heart and it was absolutely flabby. Lifeless. So I gave it a squeeze, and I asked the nurse, “Can you feel a pulse anyplace?” She tried the wrist first.

“No.”

“Do you know how to feel a femoral pulse? Have you ever done it?”

“Yeah.” Fortunately, she knew.

“Yeah, I can feel a pulse.”

I was squeezing about once per second. Let me tell you, if you have not been doing this all your life, your hand gets very tired very soon and the ribs are clamped on your wrist, and your hand is going numb and just about that time the medical resident arrived. She came down 22 floors, sauntered in and said, “What's going on?”

“Breathe for the guy!” So she got a bag and mask and she started breathing for the guy and I was pumping, squeezing the heart. She was having a little trouble holding up the chin but she managed to inflate the lungs and the guy's color started to pink up a little bit but I was about to the point where I could not do any more.

Just then Walter Shim appeared. I said, “Walter, get a glove!” I didn't have a glove on, being in such a hurry, so I was barehanded in the guy's chest. “Get a glove and relieve me 'cause I can't keep this up!”

“I was just looking for a Band-Aid.”

“Well, I don't know what you were looking for but get yourself a glove!” He realized what was happening, so he found some sterile gloves.

“You ready, Walter?”

“Yeah.” So I pulled my hand out and he put his hand in and he started squeezing. I decided the thing for me to do was to start an intravenous (IV). Meanwhile the medical resident was still bagging the patient, and Walter Shim was squeezing nicely, which we could tell not only from the pulse but because the man was bleeding from the chest. Suddenly, there at the door was Henry Mannix. Henry stood there a moment and then he screamed, “Bogen, what have you done?” I thought, “Can't he see? What is he asking this question for?” Well just about the time that he was ranting on for another few seconds or so, the chief resident, Winslow showed up. He did not shout. He just came in, took a quick look, then said, “Where's an endotracheal tube?” The nurse pointed. He picked it up, pushed the medical resident aside and intubated the guy in about 10 seconds. Then to Shim, “Keep squeezing.” He turned to Mannix, “Get the pads” to defibrillate the heart. Walt needed to be relieved because by this time his hand was totally numb. This time, I had gloves on. I put my gloved hand back in, squeezing while the chief resident and the assistant chief hooked up this machine, and they put the paddles on the guy's chest. Winslow said, “Pull out your hand.”

I pulled my hand out, Mannix pushed the button, “Bang!” and the

guy's entire body jumped up from the bed. But the heart remained lifeless. I reinserted my hand and kept squeezing. He was breathing on his own now, and being intubated, he had a nice clear airway so they do not need to bag him any more.

“Let's give it another try,” Winslow said. “Bang!” Finally, the third time they shock him, the heart started up.

The chief resident says, “Alright, his heart's beating. That's good. Now we're going to close up the chest. Henry and I'll do that. And Bogen, you go and write this up in the chart.”

Walt Shim found his Band-Aid and went back down the hall, and the medical resident went back to bed.

The chief and Mannix moved the guy into the teeny operating room next to the exam room. They filled up his chest with penicillin and streptomycin, dribbled in some Pentothal to keep him from moving, and sewed up his chest while the man was starting to wake up. Charlie Bidlo was his name. He survived with, so far as we could tell, no brain damage. He had a stormy course at first but was looking fairly good toward the end of his 30-day hospital stay.

Pretty soon the whole hospital knew about this. In that hospital they had a busy public relations department. The New York Hospital folks liked to think that theirs was the best hospital. They would never admit that the Massachusetts General might be better. And one thing that helped make them good was money. Of course, the better the hospital, the more the rich people want to go, and once the rich people go, you hit them up for money. Some really wealthy people in New York were patients. (When I was an intern, one morning my partner and I started IVs on Senator Jack Kennedy, Ella Fitzgerald, and the Foreign Minister of Saudi Arabia along with a dozen other patients before morning rounds.) So they had the Paines and the Whitneys and other rich donors. Every year they put out a brochure about the hospital. The brochure told what wonderful things the hospital had done that year. That year, the brochure was going to be about Charlie Bidlo, because opening somebody's chest in the ER had never been done before in the entire country.

Professional journalists that worked for the publication came around interviewing everybody. I remember one asked, “Tell me just what happened.” I started my story and I got to the point where I said to the nurse, “Maybe you better get that trach tray and ...”

She interrupted, “Doctors don't talk that way. They say, 'Get the emergency tray, stat.' Isn't that what you said?”

“No, that's not what I said. I said 'maybe you ought to get that trach tray.' “

“Well, that's not the way it's going to be in the story.” That was my first direct contact with the journalistic mind, with media truth.

Meanwhile, there was an epidemic of house staff opening chests. Every time somebody would die, whoever was nearby would open the chest. The hospital Executive Committee had a meeting and issued policy. The next day the chief resident, Winslow, who had closed up Charlie Bidlo's chest, said, “When we get together for rounds in the morning, we will itemize.”

We would typically make rounds about 7 AM, after the interns had started all the IVs. So if you were a junior resident, you did not have to get there at 5:30 AM, you only had to get there about a quarter to 7:00. The chief got everybody together.

“Now, we're going to make rounds. Gonna be a little bit different. Of course I want to hear what you know about the patients, and we're going to discuss what to do. And one other thing. For each patient, I'm going to tell you whether you open his chest if the person arrests or not. We're not going to have any terminal cancer patients with their chests opened up because they have finally been relieved by the Lord of their burden.”

He went through all three dozen patients. As we walked the rooms, we would come along to somebody and the intern would give a report. The chief would ask a few questions and give a few orders. Then we would step out in the hall and he would say, “Opening this one is OK.” Or, “Not this one.” We went through the whole ward like that. This guy was quite clear as to who was going to be salvaged, if possible, and who was not. They were looking for excuses to let house staff go anyway, as it was a pyramidal system. There had been 16 of us surgical interns and only half went on to become junior residents. The other 8 went somewhere; they mostly disappeared. One guy I do know about went into psychiatry. Halfway through the surgical internship he said, “I'm going into psychiatry.” I said, “Why?” He says, “Because I am sick and tired of being sick and tired.” That was shortly after an intern named Maury Hanson threw up blood and fainted while in the operating room. Elton Cahow, who had been my intern partner, went on to be an intern in medicine. He had decided he wanted another whole year as an intern! Talk about masochism! But he wanted to be really good in medicine, because he had great academic ambitions. In fact, many years later I remember reading in an American College of Surgeons Bulletin a notice that Dr. Elton Cahow had just been promoted to Professor and Chairman of the Department of Surgery at Yale.

After a month in the hospital, Charlie Bidlo went home. A bit later he came to visit my wife and me for lunch, which was nice. I next went to the urology service, learning how to catheterize bladders. A few days after I arrived, the urology resident turned to me, “Well, Bogen, it looks like your reputation is made in this hospital.”

I said, “Yeah, until the next time I screw up.” What I could have told him, but did not, was a conversation in an elevator just before I came on the urology service. I was still on the general surgery service and was in an elevator with Joe Harbison, who had been an intern with me and, like me, was now a junior resident. The elevator stopped at the fifth floor to let some people on. They came on in order of seniority: first was Frank Glenn, the Lewis Atterbury Stimson Professor of Surgery and Chairman of the Department of Surgery and Surgeon-in-Chief of The New York Hospital Cornell Medical Center. After him came an assistant professor, then behind him the chief resident and a junior resident and then an intern, three medical students, and a couple of nurses, filling up the elevator. The elevator went up four flights to where they were going to get off. As the door opened, Professor Frank Glenn, turned to my friend, put his arm across his shoulders and said to him, 'Joe, you know, opening that man's heart down in the ER was a wonderful thing. We're proud of you.” And then he went out the door, followed by his retinue. Joe Harbison waited for the door to close before laughing, shook his head, and said “The Man sure knows his troops, doesn't he?” It was as delicious as whipped cream on a hot fudge sundae.

I sent a copy of the New York Hospital Annual Report to my mother back in Los Angeles. I thought she would call me on the telephone and compliment me on my heroic deed. She did not call. About a week later I got a little package from home. In the package was one of those miniature gold painted cups you can get at trinket shops. It has a little plate on the base you can have engraved. The entire thing was about 8 inches high, a little golden cup on a stand and a plate at the bottom. It was engraved, “World's Greatest Doctor.”

A Little Something to Treasure

While on the urology service I was paged: “an old man named Lowey on the 18th floor has a bladder stone and needs a Foley.” I picked up a catheter tray and went up the elevator. After knocking, I entered to see an elderly man doubled over in pain and moaning. When the bladder spasms receded a bit I asked, “Are you Mr. Lowey?” In the middle of his misery he straightened up and answered, “I am zuh(sic) Herr Professor Doktor Otto Loewi!,” following which his spasms worsened and he was again rendered speechless and groaning. I thought, “My goodness, I thought he was dead! Here I am with a legendary man, right here, and I can help.”

“Well, Professor, I am going to fix you up.”

After 1000 cc had been drained, I clamped the tube to avoid a sudden drop in blood pressure and waited about 15 minutes (it turned out he had over 2000 cc in his bladder). While we worked he was rather talkative, feeling great, relieved, and grateful. On this and a subsequent session he was full of advice, having learned of my scientific ambitions. He particularly enjoyed telling the story of how his Nobel winning experiment came to him in a dream. “It's in my book, young man.” As I was pretty much stuck at the hospital, my wife obtained a copy of From the Workshop of Discoveries. Meanwhile I held Professor Loewi's hand, literally and metaphorically, as he went to the OR where he had a spinal anesthetic. His urologist inserted a big endoscope large enough to insert the tools with which he broke up the stone and laboriously removed it piece by piece, taking about an hour. After accompanying Professor Loewi through his procedure I spent more time in his postop care during which he lectured me further. He signed my copy of his little 62-page book, above his signature in a shaky hand he wrote,

“Facts without Theory is chaos,

Theory without facts is phantasy.”

Paul Starr and Bronson Ray

When I was rotating as an assistant resident, there was a famous neurosurgeon named Bronson Ray. So Sam Moore, who was the professor in charge of all the residents' things, said, “Well you need to spend a few months with Bronson Ray. If you want to go on to neurosurgery, before you leave the New York Hospital you should spend some time with Dr. Ray.” So I did. Ray was doing about two hypophysectomies a week. Taking out the pituitary was the best treatment at that time for metastatic breast cancer and prostate cancer. And the Memorial Hospital for Cancer was right across the street so they had these cases by the dozens. They would ship them across the street and Ray would take out the pituitary. He did so many that the neurosurgery residents were bored with it so the general surgery residents like me rotating through did all the assisting for the pituitary.

It was worth watching because he had it down to a system. Because all the operations were almost always alike, it was the same operation over and over again, like watching a guy conduct a symphony and every bar was familiar. The whole thing moved smoothly. A great contrast was when I helped him with some other cases like putting a tantalum plate in somebody's head. He said, “Which way is up? How do you do this?” It was pretty funny. Anyway, I said, “Dr. Ray I suppose I should read a little bit about the pituitary while I'm helping with all these surgeries.” He said, “Well, you go to the medical library and read anything written by ... “(Whatever the man's name was, I forget, an endocrinologist at Yale.) This was a man who had invented a clever system that my mother employed at one time. You would put a piece of endocrine tissue in the anterior chamber of the eye of a rabbit and you could watch it. You could actually observe what happened when certain things happened. For example, you put a little adrenal cortex in there and you give ACTH and so on and so forth.

So I read the paper. He said, “We had this disagreement with a group in Los Angeles about the actions of hormones and they said that the reason we didn't get the same results that they got, when we used our special technique, was because ectopic adreno-cortical tissue would not respond to ACTH.” And it dawned on me that Paul Starr, who had taught us all in medical school that ectopic adrenal tissue does not respond to ACTH, had taught us as a fact something that he had dreamed up to explain why he did not have the same results as Yale. I know this recollection is correct because we had a yearbook when we graduated from medical school, and some guy did a bunch of cartoons for the yearbook and one of them was a cartoon of Paul Starr saying “Stop thinking and start memorizing.” He remembered it the same way I did. So you could imagine how mad I was when I got to New York and I was in the library reading about how there are doctors in Los Angeles who have hypothesized that ectopic adrenocortical tissue does not respond to ACTH.

Part of the background to this was when I was a sophomore in medical school I had been particularly impressed with the physiology professor, a man named Doug Drury. He was a very solemn guy. Everybody was supposed to have a little elective in the second half of the sophomore year so I went to Dr. Drury because I liked him better than the other people. He said, “All right, I'll give you a little project. We do a lot of work with insulin and carbohydrate metabolism, and we have rabbits with pancreatectomy and what we could use would be some rabbits with hypophysectomy. Take out the pituitary. So why don't you figure out how to do that. You go to Al White and he'll show you where the rabbits are and will help you get some instruments to work with. And I tell you what. If you take out the pituitary of a rabbit and keep it alive for three days, I'll give you an 'A.' Goodbye.” So I went to Al White and asked, “Will you show me?” And he said, “Yeah I can show you where the rabbits are but I don't know how to do the surgery.” They gave me a little broom closet to work in, a little teeny room but it was enough of a room with a table and I anesthetized the rabbits.

It is really easy to kill rabbits. Anesthetizing cats is simple stuff relatively. But with rabbits it is different. Especially with the ether. If you give them a little too much ether, they are gone. So that was the first hurdle. But how to do the surgery was the hurdle before that. I had to figure out what I was going to do before I even got the first rabbit. So I looked in the library and I found a book called Experimental Surgery by a man named Markowitz. I looked in the book and sure enough there is a description of how to do a hypophysectomy on a dog. I thought, well it cannot be that different. So it was very helpful. You do it through the roof of the mouth and you have to drill away all the palate. It turns out, when you get through the base of the skull up through the palate (you have to make a hole in the base of the skull to get to the pituitary), that in a rabbit there is an enormous plexus of veins immediately under the bone. The first thing you get is this big upwelling of blood. You cannot see anything but blood. And I did not have suction and I had to mop it up with cotton. So I had a few rabbits that bled to death.

Finally after a few weeks, ignoring a few other classes and spending my time in the broom closet, I figured out how to get control of the bleeding and get through the bone. Then I scooped out the pituitary. No problem there. Then I close up the rabbit. But when I came around the next day, the rabbit was dead. This goes on week after week. One dead rabbit after the other. I got the surgery figured out. They were not bleeding to death anymore but they were all dying the next day. I figured there was something missing. Well what was missing, of course, was the ACTH, and I did not have any cortisone. Then I happened to stumble on an article about hypophysectomies. The way you do it with a rat is that you turn it upside down and run it in a jig under a drill press and it goes zip, so they were doing them by the hundreds. What they found out when doing hypophysectomies on rats is that they eat salt veraciously. I thought OK. So what I did was get a big syringe full of saline, and I stuck it in the belly, and the rabbits lived. I went around to Drury and said, “I got one!” He came around and looked and said, “It's alive all right. When did you do this surgery?” I said, “Four days ago.” He said, “Really... where did you get the cortisone?” I said, “I didn't get any cortisone.” He said, “You can't get ACTH. It's not available.” I said, “No, I just gave it a lot of salt.” He said, “Well, you got an A.” So when I got to New York with Dr. Ray doing all these hypophysectomies, I took a particular interest as I had done a lot of hypophysectomies myself.

Bidlo Lesson

The 2 years at Cornell were enriching in many ways, but probably the most important was the experience with Charlie Bidlo. If, after pondering a problem for a time, eventually coming on an illuminating conclusion, one has the fortitude to act on that conclusion, in the face of prevailing orthodoxy and if one then has the good fortune to obtain a happy result, this strengthens one's confidence when faced in the future with other weighty issues.

Adventures with Professor William Sweet of Harvard

Halfway through my second year at Cornell, and hoping to enter a neurosurgery residency after spending my post doc year with Van H at Cal Tech, I began to apply. I asked Professor Sam Moore for recommendations. He was very encouraging, saying that my application to the Mass General in Boston was the only one necessary. “You are a cinch to get in there,” he said. When I was invited to Boston for an interview, Dr. Moore arranged the time for me to meet with Dr. Sweet. Soon after returning to New York, Dr. Sweet sent me a letter asking me to return because Dr. White, his superior, had been out of town. I went to Boston again. Then I waited for some reply (follow-up letter, pro or con), but none came. As summer approached I wrote Dr. Sweet asking if he wanted me in Boston again, especially as I was leaving for California in July. He did not respond. A year later, while I was at Cal Tech I was still without a residency appointment. I again wrote to Dr. Sweet. He did not reply.

Dr. Finley Russell, a former student of Van Harreveld was working in the lab and suggested a meeting with Professor Vogel of Loma Linda University Medical School. I had never heard of Philip Vogel, but I knew that the main person at the Loma Linda program was Cyril B. Courville, author of some 500 papers and about 20 books. He was a world-famous man, and I remember him as an excellent lecturer. Finley Russell, Professor Vogel, and I met in the cafeteria. I was struck at that meeting that Professor Vogel was finishing off a mustard-laden hot dog in his left hand while spooning chocolate ice cream with his right hand. I assumed that he was testing me in some way, but having gotten to know him I (now) believe he (just) wanted to eat before the hot dog got cold, and the ice cream melted. The unorthodoxy of it was apparently, for Phil, unimportant. I bargained for only 4 more years, as I already had 2 years general surgery and a year in neurophysiology. He said, “Second year residents now spend a year with Courville in Neurosurgery. If you started in the second year, Courville would then have two residents. Then there would be no one for him the next year, so you have to do 5 years, but you can do anything you want the last year so long as you take call and attend rounds and conferences.” At this point Finley said, “You can be a research fellow in my lab, do what you want and I would pay you $500 per month.” Wow! That was more than any first-year resident got in those days, plus freedom to do more neurophysiology of my own. It was settled.

About 6 months later while sitting in Russell's lab with Professor Berry Campbell, I got a letter from Dr. Sweet. He had an opening and was offering it to me. Here I had just committed to 5 years with Vogel and now he writes! Probably one of his people got severely ill or got drafted—something changed his mind. I wrote a vitriolic letter dripping with anger and resentfulness. Fortunately, I remembered the lesson from medical school and put this letter away for several days. After all, Dr. Sweet could wait a little for an answer. I tore up the first letter and wrote to him that I had very much wanted to join him and Dr. White, but I was by now committed and asked for his understanding.

A year later I submitted a paper with Berry Campbell to the Surgical Forum, a prestigious and rather exclusive venue. It was accepted, so I went to the American College of Surgeons meeting in San Francisco. When it was my turn to present, I approached the podium adjacent to which was a table seating the members of the program committee. The chairman, Professor William Sweet, gave me a friendly smile and a complimentary introduction. Two years later, when I presented our first split-brain patient to the Surgical Forum, Dr. Sweet was in the audience. He rose to say that Dr. Van Wagenen had once opened up the head of a patient and was at that moment called to an emergency so the resident closed the head. Sweet said, “So this patient had a mock operation without callosotomy and was seizure free thereafter. Your patient may be the same, the callosotomy being irrelevant.” I knew he was wrong. I was familiar with the papers of Akelaitis and knew about Van Wagenen's patients. The patient had been only seizure free for a few weeks and was later reoperated by Van Wagenen. I managed to control my outrage and quickly left the podium trying not to alienate someone who might be on the Board 2 years hence. After I got home I sent Dr. Sweet a photocopy of the relevant papers. He did not reply.

In January of 1958 while Joe and Glenda were still in New York City their first child, Glen David was born. By the time they were back in Los Angeles, their second child Meriel was on the way, and Glen David had begun to show symptoms of what was later diagnosed as Tay Sachs disease. Soon thereafter, Joe's mother went into end-stage kidney failure, and it was left to him to continue psychotherapy for a few of her patients while finding referrals for each. Esther Bogen died in early 1960, just as Joe was beginning his residency at The White Memorial Hospital and continuing his interest in research. Glen David died at the City of Hope Hospital in 1961, just after the birth of a third child, Mira, who like her sister, was healthy.

A Little Work with Finley Russell

Fin specialized in the physiology of venoms, especially snake bites. The hallway the full length of his lab was lined with glass enclosures, each holding a different species of rattlesnake or, in a few cases, scorpions. So, after I had the dorsal root, ventral root reflex preparation working well, Fin wanted to see the effects of the various venoms, so I ended up working with him after all.

There was another way that we worked together. The laboratory was on the ground of the L.A. County General Hospital, and Fin frequently consulted for patients with snake bites, and he sometimes asked me to assist in the treatment. The cases that were particularly demanding were when the patient was allergic to the horse serum. For a few species of snake there were antivenoms produced in rabbits, but for most species of snake there was only horse serum. Because the antivenom was essential, the treatment commonly resulted in the side effects of the antivenom, including any allergic responses. When a snake hobbyist in San Diego was bitten by a South Pacific Sea Snake, he was flown to the County Hospital. The treatment featured the delivery of small doses of antivenom in an intravenous line in one arm, while introducing small amounts of adrenaline sufficient to maintain his blood pressure in the other arm. This went on for several days during which there was continuous newspaper coverage: “PACIFIC SEA SNAKE!” The hospital public relations department notified us that we were each to be awarded a County Certificate of Merit. The ceremony consisted of having us line up on either side of County Supervisor Debs while photographs were taken of him handing us the certificates.

Berry Campbell

It turned out when I got to Fin Russell's lab that I would be working mainly with Berry Campbell. Berry, who had been Professor of Anatomy at Minnesota, was made part of the Neurosurgery Department because Dr. Vogel had a big grant to study multiple sclerosis (MS). It turned out that Berry had pioneered experimental allergic encephalomyelitis as a candidate model for studying MS in guinea pigs, rabbits, and so forth. Berry helped me in many ways, above all in dissuading me slowly of the Sherringtonian views in which I had been indoctrinated. He introduced me to the work of Hendricks and George Eliot Coghill, whose views seemed dramatically opposite to Sherrington's. Berry had done a post doc with Gasser at the Rockefeller Institute. He went there to learn what he believed to be the coming thing, electrical recording from the nervous system. He had not yet learned that what was generally accepted could easily become dogma. Berry had been trained as a mammalogist but was aware that in neurophysiology it was widely thought that neurons were uniformly unimodal. So he was delighted to observe that the responses he was recorded from superior colliculus were influenced by various ambient sounds not just visual stimuli. Enthused, he took his findings of polymodal activity to Gasser, who insisted that they must be erroneous and would certainly bring disrepute to the Institute if they were ever to be published.

Most importantly, Berry encouraged me to do hemispherectomies in cats. This followed from what I might call his Basic Idea. The Basic Idea was that when the animal has only one brain, anything one does in the way of ablation, stimulation, or recording will provide useful information, because the outcomes will not be compensated or modulated by the other brain.

A Little About the Cats

During this time Joe began to operate on “The Cats.” He would bring the newly operated cats home, and Glenda acted as their “recovery nurse.” On one occasion when a family member asked Joe “How's the work going?” his only reply was, “Well, the damned cat died again.” Over 30 years later, when his daughter Mira was in veterinary school, he admitted, “Well, in those days, I sure killed my share of cats!"

They look like ordinary cats unless you know what to look for. If they get frightened, for example, they circle and they always circle toward the side of the empty half of the head. I remember we had one at home for years. In fact, this cat we had at home raised a litter of kittens. It just seemed like the most normal cat in the world, except for one time when I had the lawn mower out. I started up the lawn mower and the cat started going around like a top. The other way to tell if there is something different about them, and the only reliable way, is to look for hemianopia, the field defect. Because if you do a hemispherectomy in an adult or in a youthful cat, not an infant cat, it will have the field defect for the rest of its life.

I trained a cat to come to a whistle. We had a fairly big front yard at our house in the suburbs; there was a fence between the neighbor and us and it was only a couple of inches wide, just boards. Whenever I would come into the yard I would blow a whistle and the cat would come to me along the narrow fence. When it would come I would give it some kind of treat. People would say, “Why do you want your cat to think it's a dog?” I would say, “What do you mean?” And they would say, “Well, you whistle for a dog and for a cat you say, here kitty, kitty.” I would say, “If I said kitty, kitty, people would feel it was instinctive. This way it's obvious that the cat has learned.” Then they would say, “Well you trained a cat, big deal.” And I would say, “But you don't understand, this cat has only half a cerebrum, half the brain is out.”

I remember one fellow said, “Yeah, it did look kind of funny to me.” I said, “Well in that case, which half is out?” Unless you look for the hemianopia, the cats really look normal for the most part. The monkeys are the same. There were some hemispherectomized monkeys in Pittsburgh. Well, more precisely they were hemicerebrectomized. The way I did the cats was I took a spatula and put it right down the middle. When the guys in Pittsburgh did the monkeys, they did the same thing. They did one thalamus along with the rest of it. They are the ones who called it hemicerebrectomy. They had those monkeys for at least 10 years and they published papers. You would think that because they published so many papers over the years that people would know about this, yet no one seems to care. Patton did most of the writing along with Cooper and Kostkoff, who was the neurosurgeon. In Patton's final review he said that it was still a challenge to find something that a normal monkey can do that the hemi'd monkeys cannot do just as well. They are slower, but they learn everything. People just do not seem to want to know that.

After a couple of years with Berry, we applied for a National Institutes of Health (NIH) grant. We proposed a farm full of hemispherectomized cats followed by a program based on Berry's Basic Idea. We had a site visit that ended up in a rather unpleasant discussion in which the visitors wanted us to adopt some quantitative measurement—"based on movies of the cat reactions?!” That seemed as good to them as it seemed make-workish ridiculous to me. When I laughed it became clear that I was contemptuous of their proposal.

“We could spend the first three years just working on the measurement method before doing any testing of ideas.” That seemed the ultimate impolitic and I swore that I would never apply for a grant again. Subsequent to 1963, whatever I spent for travel to meetings, slides, poster, reprints, and so forth all came out of my earning as a neurosurgeon.

Two Professors

Vogel, as far as I know, never raised his voice, ever. And he was never unreasonable, as far as I know. He was unlike Kenneth Abbott. He got Abbott to come to White Memorial Hospital. Abbott would have been in line to be professor at Ohio State but he did not know the guy ahead of him was going to die. And Phil appealed to his Seventh-Day Adventist loyalty. So he got him out here and he was a typical product of the screaming school of neurosurgeons. I was helping him do a cervical laminectomy on an old lady in a somewhat sitting position. He stopped for a moment while he was waiting for something. And he asked the anesthesiologist, “How's she doing?” The guy answered, “She's doing all right.” He said, “What I mean is, what's the blood pressure?” The guy said, “It's about 80 over 40.” And he said, “It's what! How long?” The guys said, “I don't know, five or ten minutes or so. It's coming up a little bit.” Abbott screamed, “How could you do this to me!” He really took it personally. It is true. When you have got an old lady you do not want the blood pressure to get down there. Fortunately when they are anesthetized, the brain is somewhat protected but still in all he was a screamer.

Everybody was scared of him. I was of scared of him in the beginning. But by the time I got to be chief resident, I was no longer afraid of him. I came into the office one time and there was a screen and the secretary was in front of the screen. And I did not know that Abbott was right behind the screen and heard my conversation with the secretary. What I said to her was, “Here is this list of all the procedures that I have participated in for the last six months. Dr. Abbott wanted us to keep a list so I kept a list of all the stuff that I've done and here it is.” And he stepped out from behind the screen and said, “And make sure everybody else does that too!” And I thought to myself that he was totally unreasonable. It was not my job to make sure everybody does what they were supposed to. He was not going to tell me what my obligations were. That was really an epiphany. In a moment of enlightenment, I realized that I could not depend on this guy to decide what I was obligated to do. I needed to decide for myself because he did not know what he was doing. He was insatiable.

When I was attending, there was a new resident named Harris. Harris was still afraid of him even though he was the chief resident and had been there for 5 years. Abbott got Parkinsonism at an early age, in his 50s. It was very embarrassing, because he would shake. And he could not stand being a shaky surgeon. He was very upset. I remember when we would pass by somebody who was comatose, an obviously kind of hopeless brain case, but still on life support, he would say, “Boy, I hope they don't do that with me because that's a waste.” Anyway, with that background, he had a heart attack and was in the intensive care unit at the Glendale Adventist Hospital. I know that for a fact, but the rest is second hand from a nurse who told me. She said he was in there on a monitor going “beep, beep” with the heart. Then it stopped. She went over and sure enough it was not the beeper that was wrong, his heart had stopped. She ran out in the hall to see if there were any doctors and there was Harris the chief resident. She said, “Quick, he just had an arrest, come in!” So Harris went in there and by this time they were not opening hearts the way I did many years before. By this time everybody was doing the external thing, leaning on the sternum and breaking ribs and stuff. So Harris starts pumping on Abbott and he woke up. He woke up! And he looked up at Harris and he said, “You! STOP THAT!” So Harris stopped. And that was the last story about Abbott.

Now Vogel, he never yelled at anybody. The only time in all the years I knew him, which was many years, he only spoke harshly to me once. What happened was that I was in the operating room by myself with an assistant. We were starting to close and a nurse comes in and asks, “Is this patient supposed to go to intensive care after recovery room?” I said, “If you will look on the printed orders, you will see that anybody who has had a craniotomy is supposed to go to intensive care from the recovery room and if there is no intensive care there should be a private duty nurse.” We did not have a special neurointensive care at that time. So she went out. The next day I was helping Vogel in the same room doing a case, a craniotomy again. The same nurse came in and asked the same question. “Is this patient supposed to go to intensive care?” I looked up and said, “It's just like yesterday. Look on the printed orders!” So she went out. And he turned to me and said, “Don't ever do that again. I won't tolerate it. It's not necessary to yell at people.” So I never yelled at anybody again at the White Memorial Hospital.

Getting to Know Roger

The first time I saw Roger Sperry was when he gave a lecture at Cal Tech, which I attended as the guest of my mother, who had been working with Professor Van Harreveld on adrenaline-like substances in the blood and their variation in patients being treated with electrosleep therapy. Sperry appeared largely at the insistence of the geneticist Norm Horowitz who had been impressed, at a meeting, by Sperry's insistence that behavior was rooted in genetically determined neuronal circuits. Very few psychologists were saying such things in 1952. At this talk to a select group of faculty (Fig. 1), Sperry lucidly described and dramatically illustrated the discriminative ability of cats with various alterations of visual cortex. I was bowled over by his talk. I believe this dramatic talk led directly to his being made the first Hixon Professor of Psychobiology, a post he held for the next 3 decades.

Fig. 1. From Left to Right, Philip Vogel, Roger Sperry, Joseph Bogen.

I next saw Roger in the summer of 1955 when I was a research assistant

to Van H, whose lab and office were just down the hall from Roger's. Ronnie Meyers was finishing up his joint M.D./Ph.D. program that he had started with Roger when both were in Chicago operating and testing split-brain cats. I spent considerable time with Ronnie discussing our mutual desire to emulate Penfield by doing research with humans, including our wondering what one would see with split-brain humans.

I was intrigued by the experiments on cortical spreading depression that I was doing with Van H, so much so that I often returned to the lab after summer ended, even though the school year had started and I was supposed to be in med school. But there was nothing else at Cal Tech or in med school that compared with Ronnie Meyers split-brain cats. The split-brain cats made an impression on everybody who saw them and many who only read about them. Those cats made a particularly profound impression on me because I had been struggling over two strongly held beliefs: (1) each of us has another mind, that is, goal-directed mentation of which we are unaware and (2) all mentation needs to be explained physiologically. And here was a replicable demonstration of two minds, functioning in some ways independently, and in the same head; a duality of mind with an anatomical basis. It was for me personally the most influential scientific experiment that I have ever seen or heard of, before or since. It set the course of my life. It rarely left my thoughts. Subsequent experience with hemispherectomy patients has convinced me that each of them, having only one brain, has an unconscious in the Freudian sense—so this compounds the problem! In any case, if psychoanalytic theory, or any psychodynamic theory, is to take account of the split-brain, it has a long way to go (Bogen, 2000a).

After escaping from medical school and after 2 years in general surgery, I returned to Van Harreveld, this time as a post doc in neurophysiology. During that time Roger and I became better acquainted. Most of the time when I would pass by Roger's office, the door would be open. Sometimes he would be reading or doodling on a pad. Sometimes he would be sitting back with his feet on the desk, apparently staring off into space. Then, one day, he was gone—into the lab. Not long after, we had a third floor seminar. At one of our regular third floor seminars Attardi presented her work with Sperry on optic nerve regeneration. The slides were sections of goldfish brain, stained a bluish-black except for the regenerating fibers that were bright pink! The pink regenerating fibers were snaking their way through the neuromatous jumble of the optic chiasm. Around the front of the optic lobe they went, passing over the proximal tectum and then diving abruptly into their intended targets. It was spectacular! Unfortunately, when this work was published, the pictures were reproduced in black and white. That was 5 years after appearance of the Abstract in Anatomical Record in 1958. Such a long delay was not unusual for Roger. He often kept papers on his desk for a long time, for several reasons. One was that he liked to have some idea of how the follow-up experiments were developing before finalizing the discussion of the earlier paper.

Roger did not always delay. One day when I was visiting the lab I asked him about the Gordon paper on lateralized olfaction in split-brain patients. He said, “We have to send this olfactory paper in immediately.” “Why?” I asked. “Because I have just refereed for Neuropsychologia a paper with a similar experiment in rats. People know that with human subjects, we can do in a few weeks what would take many months in rats. If we delay, people might think that I got the idea when refereeing the rat paper.” Roger seemed to think of everything. I idolized him and hung on his every word, of which there were not very many. I thought him the experimental physiologist of our time.

In 1960 I was working at the County Hospital. I took him an essay

on epilepsy entitled, “A Rationale For Splitting the Human Brain.” His laconic comments included, “Maybe you should change the title.” Also, “Look up those papers by Akelaitis.” When I did, it appeared that the callosal surgery by Van Wagenen 20 years before had actually turned out better than was then (about 1960) the prevailing medical opinion (Bogen, 1997a). This led eventually to a nearly 30-year joint effort. I like to think of it as a collaboration, although in fact our teacher-student relationship persisted throughout. While I was at the County Hospital, one of my projects involved some behavioral experiments with rats, with results I could not understand. It seemed to me that if anybody could help it would be Roger. I took my data up to the Institute. After some technical comments he mumbled, “If you keep working with that you might come up with something dramatic.” Roger Sperry's facility for “coming up with something dramatic,” time after time, in a variety of contexts, was not simply because he kept in mind the value of a decisive, counterintuitive result. Nor was it only because he was an expert experimentalist. Nor only because he was at the same time a creative and highly disciplined presenter. Essential was his being among the deepest, the most profound, neurothinkers of our time.

On one occasion, after members of an NIH site visit team had left, I asked Roger what he had said to influence their decision. “Three of the five were psychologists,” he replied. “I said that this was the only psychology program at Cal Tech and if it were not supported there wouldn't be any.” This was not simply a ploy. Roger sometimes dryly alluded to being surrounded by molecularists plugging away without any interest in what he called “the big problems.” He meant by this both problems of society and problems identified by psychologists, requiring physiological answers. Roger's emphasis on psyche and consciousness was long present in his thoughts. This emphasis became progressively more evident in his writing. He felt his first paper to assert forcefully what he called the “Central Issue” was the “Platt piece,” that is, his chapter in New Views of the Nature of Man in 1965. In this chapter he asserted that the Central Issue is the nature of consciousness and that a correct model of brain function could not be constructed “without including consciousness in the causal sequence.”

Even by 1970, Roger had become widely recognized for the previously mentioned views and was attracting much philosophic attention, both pro and con. It was then, in 1970, that Oliver Zangwill, Professor of Psychology at Cambridge, the premier psychologist in England and possibly in the English-speaking world, came to Cal Tech for the entire month of August, at Sperry's invitation. Oliver was bent on seeing the split-brain patients for himself, and Roger wanted Oliver's reaction to his efforts to bring science into the humanities, and vice versa. After several weeks of socializing with Oliver, I was emboldened to ask him, “What are you telling Roger?” “I'm a bit concerned,” he confided, “that if he goes on in this vein it is likely to diminish the impact of his many marvelous achievements.” “How did he react to that?” I asked. “Very little,” was the stiff-lipped reply.

Oliver Zangwill's prediction was fulfilled by the time Sperry was honored with a party at Cal Tech in 1982 for having brought to the Biology Department its fourth Nobel Award. Those who had not known him early on assumed that “he's gone religious like so many old folks.” By 1990, even those Cal Tech professors who had been his friends for nearly 40 years had given up trying to defend or even to understand “the philosophy of his later years” as one of them put it. Contributing to the unhappiness at Cal Tech was Roger's habitual obliquity. Hardly helpful were his cryptic comments to senior professors, twice in my presence on the inability of quantum mechanics to save a world terribly threatened by overpopulation. “You'll never solve the really big problems of this world with quantum mechanics.” When he said this in his quiet but deprecating manner to Norm Horowitz (we were the two dinner guests of Roger and Norma), Norm became incensed.

“What does that mean?” Norm sputtered.

More About the Cats (and Monkeys too)

During the last 50 years, a large number and variety of experiments have made it clear that the corpus callosum can transfer high-level information from one hemisphere to the other. Moreover, we now know that the hemispheres are not so much “major” and “minor” as they are complementary and that each hemisphere is capable of thinking on its own, in its own way. Much of this information has come from cutting the corpus callosum, that is, the split-brain operation.

Split-brain experiments started with the problem of interocular transfer. That is, if one learns with one eye how to solve a problem, then with that eye covered and using the other eye, one readily solves the problem without further learning. This is called “interocular transfer of learning.” Of course, the learning is not in the eye and then transferred to the other eye, but that is the way it is usually described. The fact that transfer occurs may seem obvious, but it is in the questioning of the obvious that discoveries are often produced. In this case the question was: How can the learning with one eye appear with use of the other? Put in experimentally testable terms, where are the two eyes connected?

Experiments showed that the transfer actually occurs between the hemispheres by way of the corpus callosum. Sperry's scheme (with the cats, and later monkeys) was to split the optic chiasm so that the right eye goes only to the right cerebral hemisphere and the left eye to the left hemisphere, in addition to cutting the corpus callosum between the two hemispheres. This is a “split-brain cat.” The cat can be trained with the right eye to choose a cross rather than a square, while the left eye is covered. (This was originally done by Ronnie Meyers using an asymmetrical blindfold. Subsequently it was done by inserting a corneal lens similar to what would be used by humans except it was opaque.) The cat, with one eye occluded, chooses one of two doors at the end of a runway. Two cards labeled with either the cross or square are attached to the doors randomly. Only the door with the cross leads to a food reward. After the cat has learned the problem (regularly picks whichever door has the cross), one can test the left eye with the right eye covered; the split-brain cat has to learn all over again, that is, it starts at 50% (chance). For each cat the learning curve for the second eye (and second hemisphere) is very similar to the learning curve for the right eye.

Because a split-brain cat has to learn all over from the beginning with the second eye, the cat can be trained to pick the square instead of the cross when using the second eye. It then depends on which eye is open which choice the cat makes. Thus, each hemisphere has developed a different memory about what is correct. In other words, each hemisphere has its own semantic system (i.e., a system that gives meaning to symbols). That the two hemispheres could be so disparate, giving different, even opposite meanings to symbols (cross and square) may be surprising because the two thalami in a cat are quite tightly coupled anatomically. Because the anatomical coupling of thalami in a monkey is a bit less, one might expect a similar duality of mentation in split-brain monkeys. Monkeys also make better subjects because the monkey visual system is more similar to humans than cats, monkeys learn much faster, and monkeys also have a considerable capacity for fine finger manipulation. It turns out that split-brain monkeys show even more than cats a duality of mentation.

It is important to understand that the duality of minds seen after hemisphere disconnection is not an inference solely from a few clinical cases and a handful of surgical patients. Split-brain experiments have been carried out with many different species by hundreds of investigators around the world. They are virtually unanimous in concluding that each of the disconnected hemispheres can act independently of the other (Bogen, 1977).

About Bill Jenkins and His Operation

I first met Bill Jenkins in the summer of 1960 when he was brought to the ER in status epilepticus; I was the neurology resident then on call. The heterogeneity as well as the intractability and severity of his multicentric seizure disorder became clearer to me over the next months. Both in the clinic and in the hospital I witnessed psychomotor spells, sudden tonic falls, and unilateral jerking, as well as generalized convulsions. In late 1960, I wrote to Maitland Baldwin, then Chief of Neurosurgery at the NIH in Bethesda, Maryland. A few months later, Bill was admitted to the NIH epilepsy service where he spent 6 weeks. He was sent home in the spring of 1961, having been informed that there was no treatment, standard or innovative, available for his problem.

Bill and his wife Fern were then told of Van Wagenen's results, mainly

with partial sections of the cerebral commissures. I suggested that a complete section might help. Their enthusiasm encouraged me to approach Phil, because of his experience with removal of callosal arteriovenous malformations. He suggested that we practice a half-dozen times in the morgue. By the end of the summer (during which I was again on the neurosurgery service), the procedure seemed reasonably in hand. My plea to Sperry was that this was going to be a unique opportunity to test a human with the knowledge from his cat and monkey experiments and that his direction of the research was essential. He pointed out that a student about to graduate from Dartmouth had spent the previous summer in the lab and would be eager to test a human. Mike Gazzaniga started his graduate study in September and was, as Sperry said, eager to test a human subject. He and I soon became friends, and planned together experiments to be done before and after the surgery. There was some delay before the operation, during which Bill underwent testing in Sperry's laboratory. During this delay we also had an opportunity to keep a reasonably complete record of Bill's many seizures.

It was during this period of preoperative testing that Bill said, “You know, even if it doesn't help my seizures, if you learn something it will be more worthwhile than anything I've been able to do for years.” He was operated on in February, 1962. It seems to me in retrospect that, if there had been a research committee at our hospital whose multimember approval was required, the procedure would never have been done. At that time, a chief of service could make such a decision alone, which I expect was similar to the situation at the University of Rochester in the late 1930s.

From the start, our procedure included not only complete callosotomy (requiring two skull openings) but also section of the anterior commissure, accessed in most cases by entering the third ventricle through its roof. We chose to perform as complete a section as possible for two reasons:

(1) monkeys undergoing this procedure were without neurological disability and participated well in demanding psychological testing, and (2) if a complete neocommissural section failed in this ideal case (an intelligent, personable individual with supportive family whose multicentric seizure disorder could hardly have been much worse), then we would be through. Fortunately, it succeeded.

The completeness of our procedures as subsequently confirmed by magnetic resonance imaging was attained without the use of the operating microscope (which I first used in 1970), the good light that the scope provides, the bipolar cautery, osmotic diuretics, modern neuroanesthesia, and a variety of instruments only subsequently available. This is a tribute to Vogel's operative skills, including his sense of tolerable retraction and his remarkable vision at the usual operating distances (he never did take up the microscope). And how impressive it is that Van Wagenen worked under even less auspicious conditions!

Our next major step was to do a callosotomy (and anterior commissurotomy) that spared the splenium, whose section we believed by then to be the main source of disconnection symptoms. Throughout the 1960s, Vogel and I had been approaching lesions in or near the third ventricle via lengthy incisions in the middle of the corpus callosum; these patients did not show the disconnection effects of the complete section. I became increasingly confident of this conclusion, having by then considerable practice in detecting the disconnection effects by bedside examination.

These clinical findings had been stimulated by and gave increasing support to the view that the negative results of Akelaitis were not solely attributable to his lack of appropriate testing techniques. His negative results seemed also ascribable in part to the incompleteness of many of Van Wagenen's callosotomies, often described as “nearly complete” or as involving all but the most posterior end of the corpus callosum. By 1968, these considerations led to the expectation that section sparing the splenium could avoid most of the disconnection syndrome while at the same time ameliorating seizures having a rostral origin. Specifically relevant were complex partial seizures involving both anteromedial temporal regions, without generalization to the entire cerebrum when the patient was adequately medicated.

In 1968 and 1969, we operated on two patients whose seizures caused life-threatening psychomotor behavior and whose bitemporal foci appeared to be independent. Their seizure disorders were markedly improved (one subsequently obtained a steady job for the first time), and they had no discernible disconnection symptoms. In the words of Wada, this report “… revitalized our interest in re-examining brain bisection as a possible new treatment modality ... “

By now, sparing both splenium and anterior commissure has become commonplace, particularly because a section restricted to the anterior two thirds to three fourths of the corpus callosum can alleviate drop attacks, and drop attacks are in the opinion of many the prime indication for callosotomy. That drop attacks could be eliminated by callosotomy never occurred to us, even by 1974 when we summarized our criteria for operation. This was in spite of the fact that the commissurotomy eliminated Bill Jenkins' drop attacks as well as his generalized convulsions (except for two occasions in 10 years). We were still influenced to some extent by the concept of “centrencephalic seizures,” our theoretical views preventing us from recognizing a fact in front of our eyes.

The idea that extremely rapid generalization of seizures required a centrencephalon weighed even more heavily with others than with us and was probably responsible in part for the disbelief with which our reports were received. In addition, our work was done at a medical school (Loma Linda University), better known in those days for training medical missionaries than for scientific advances.

Not only was the procedure at odds with a well-known theory, it was worse! Had not this approach already been tried and failed? When I wrote to Frank Smith, then Chief of Neurosurgery at the University of Rochester, asking for as much information as he could provide, his reply was quite short, including that, “Dr. Van Wagenen always was sorry about what he did to those patients.” For over a decade there were persons in Boston who referred to us as “the West Coast butchers.” Without the excellent work of Wilson and Reeves, it is quite likely that our efforts (as well as of others, like Wada) would not have been widely accepted.

History teaches us much. Among other things, we see that a conception can repeatedly arise and be fashionable only to lose acceptance again in the face of reactive criticism, although in some cases sufficient support eventually accumulates so that the idea will survive somewhat longer with each reincarnation. Even so, we know that no matter how useful a therapeutic technique is, the odds are high that it will eventually be outmoded. Meanwhile, however, callosotomy has illustrated to a notable degree the interplay among social, scientific, and clinical concerns.

Block Design

Having standardized psychological testing on Bill Jenkins (as well as for subsequent split-brain patients) seemed obviously desirable to me. This required finding some psychologists accustomed to giving standardized tests, and some way to pay them. Vogel shrugged off the idea. I supposed it was a result of his having learned surgery at a time when, if a brainoperated patient left the hospital speaking sensibly and walking without assistance, the operation was a success. Even Sperry shrugged: what theoretical preconception would be falsified? His interest in “useful information” can be illuminated by the time I returned from a meeting, finding him eager to hear what had transpired. I had been going on for about 5 minutes, when he asked, “Was there anything that would change how we look at things?” By this time I had read almost all of his writing. “Well, I think not.” He shrugged and was no longer interested in the report.

After Bill had recovered from his surgical ordeal (and was feeling better), he was eager to participate in some laboratory experiments. After some months a helpful social worker got in touch with a psychologist who occasionally tested clinic patients. She arranged some funding and he agreed to meet. He seemed to me not only quite elderly but actually quite infirm. I explained the patient and how interesting it was. I asked him, “Do you give the standard tests?” “Oh yes, the Wechsler.” I didn't know much about the test, and neither did Mike, and he reluctantly agreed after some argumentation.

“Old Daddy Edwards” as I learned he was sometimes called around the hospital, acceded to our request. He sat across from a card table (part of his equipment) from Bill. Mike and I sat on the other two sides watching. The testing went along for an hour or so, somewhat tediously from our point of view, until Dr. Edwards pulled out the Block Design subtest. Bill pushed the blocks around somewhat ineffectually. Meanwhile Edwards was timing in his usual fashion and ended up with a zero score. I suggested that he use one hand at a time. Dr. Edwards objected because it was customary for subjects to use both hands. However, he was persuaded to try this momentarily, so we asked Bill to use only his right hand only while sitting on his left hand. Then we asked him to do it with his left hand. He had considerable success. Mike and I looked at each other as if we had caught a glimpse of the Holy Grail. “Now try it with just your left hand,” I asked. He was quite successful! “Now try the next pattern.” With his left hand he did the next one quite quickly.

“No!” Edwards said, “He is supposed use both hands.” It was getting a little tense, because he insisted on doing it the standard way and we were anxious to further pursue our Grail. Dr. Edwards quietly prevailed and he finished the tests. We thanked him, and he replied, “Yes, it was interesting. We should test 20 or 30 more of these epileptic patients with various lesions.” So this fumbling with the two hands seemed to be an example of what Akelaitis called “diagnostic dyspraxia” and which we had subsequently termed “intermanual conflict.”

We realized Edwards was in the dark as to what had happened and what sort of patient Bill was, or why we were so wreathed in smiles. My next move was to borrow a set of these Wechsler blocks (one needed a license to buy them), and then I eventually obtained a set of the Kohs colored blocks. We retested Bill, and sure enough he had the same discrepancy between the left hand doing well, and the right hand doing poorly, and this persisted for at least 2 years. When we showed the data to Sperry he commented in his usual soft, skeptical way, “Well, I guess you boys have got that fellow pretty well trained by now.” It was true that not all patients showed this discrepancy. The second patient did not show this discrepancy, being actually rather.poor at the test with either hand. However, occasional patients did show the discrepancy (Bogen, 1987).

The variation in this result contrasts greatly with those features found with great regularity among the patients, for instance the inability to name or describe an object in the left hand (with vision obscured), in spite of the fact that the object can be readily retrieved by feel from a collection. That is, there was excellent tactile, same-hand retrieval. This inability we called anomia, although it is greater than that because the deficit also involves a failure of description. Some of the brighter patients eventually learned to use minimal cues, such as temperature or a pain-producing feature of an object, in order to guess at its name.

Intermanual Conflict

Intermanual conflict has been noted in split-brain patients by a number of people, and when one of the patients first told me about it I just could not tell anybody else because I did not think they would believe it. He and his wife came to the office and I said, “How are things?” He said, “All right except I'm having a little bit of trouble with my left hand.” I said, “How's that?” He said, “Well, I picked up the paper to read it and my left hand took the paper away and set it down. So I picked it up again and my left hand came up and set it down again. So I picked it up and this time the left hand came up and picked up the paper and threw it on the floor.” I never reported that because it was just too exotic. But better than that he came to see me in the office another time. He was operated in February and this was sometime in the summer. The patient told me he was pretty good because he had gone to the ball game and this was something he had not done in years because of the convulsions he was having so often. He enjoyed the ball game and went shopping with his wife. Nothing seemed unusual, and it was good that he was able to do those things. But then he said, “Well, what was unusual was she bought some licorice, which I don't like, and we had this shopping bag between us on the way home and my left hand reached in the bag and pulled out the licorice, which I don't like.” I said, “Well, what happened?” He said, “The left hand brought it up to my mouth so I ate it but I didn't like it.” You cannot put that in a professional journal but it was a true story.

There are a lot of these stories about intermanual conflict. The one I did put in a paper was about when the occupational therapist came to me and said, “You should have seen Rocky yesterday. He was buttoning up his shirt with one hand and the other hand was coming right up undoing the buttons right behind it.” Akelaitis noted it in his split-brain patients in 1939. He saw some of that and called it diagnostic dyspraxia. Intermanual conflict you can understand. But what if you put a person's left hand behind his back and then he cannot tell with his right hand whether he is feeling his own left hand or whether he is feeling your left hand? He cannot tell the difference. That is where the whole idea of “alien hand” came in.

We also wanted to see if patients had a lack of transfer like the monkeys. So Mike Gazzaniga fixed up two handles under the table where the patient could not see them. There was a smooth one and a rough one. The idea was that the patient would be rewarded if he pulled on one and would hear some kind of noise if he pulled the other one. Then as soon as he learned with one hand, we would test him with the other hand and see if he learned from the beginning—the same way a split-brain cat would have to learn from the beginning if you switched hemispheres. The question was how to reward him. So I asked him, “What would you really like to be rewarded with?” He said, “A chocolate malt.” I said, “OK, come to the lab hungry. Don't eat breakfast. We'll have a chocolate malt there and we'll give you a sip of chocolate malt every time you get the right answer.” So we had the chocolate malt there. He pulls the wrong handle and gets the noise then he pulls the other handle and gets a sip of chocolate malt. He just keeps pulling the proper handle and getting the malt. One trial was all it took. It would take a monkey days to figure out what was going on. With a human being one trial was enough. It was obvious if we wanted to do some kind of testing that we could not do it with the monkeys now. We had to do something else. Then a lot of things came after that. In the beginning Sperry was not that interested. He just thought he would let me and Gazzaniga do it. But it became apparent to Sperry after the second patient that anything you could do with a monkey you could do a lot faster with human beings. He got a lot more interested.

Mike Gazzaniga was a good friend of mine when we started out. But eventually I developed a bunch of negative feelings about him because I think he just kind of muddied everything up for everybody. He keeps changing what he says. I wrote him one time and said, “I am going to criticize some of your views at the Neuroscience meeting, you may want to show up.” He wrote back that he had another meeting elsewhere. However, he said, his views were evolving. I would say they revolve from year to year. People have asked me, “Do you agree with Gazzaniga?” When they ask me now my answer is, “Which?”

At the same time that the Split Brain Project was beginning, Joe also began his medical practice. He was not sure how to proceed until he met Walter Holleran, the Medical Director at one of the first HMOs (a term not used until much later), The Ross-Loos Medical Group.

Going to Work

Walter Holleran was a lovely man, more than personable, with the engaging good humor often attributed to the Irish. He had another quality, often also attributed. He drank heavily, which eventually resulted in disaster. Walter valued the intellect and readily appreciated my desire to devote time to research. He understood my desire to avoid certain kinds of neurosurgery, including infants. “Charlie Carton has been doing that for us.” Another was stereotaxy for Parkinsonism. “You are right that doing one or two cases a year of a specialized nature is inconsistent with good practice, especially, if as you say, Ed Todd is readily available.” In fact, we referred only three or four such cases in the 18 years that I was at Ross-Loos, largely due to the introduction of dopamine agonists only a few years after I started in practice in January 1964. A third area that I had hoped to avoid was operating on carotid artery obstructions. It had never seemed like neurosurgery to me. And I was not very comfortable clamping off the blood supply to somebody's brain. I was quite aware of the territorial dispute between neurosurgeons and vascular surgeons, both claiming to do carotid surgery. What I was not aware of was what Walter said next, “Sure and you are correct. Did you know that I am a vascular surgeon?” So our discussion went swimmingly with me getting about one third of the usual surgery and Ross-Loos getting what amounted to two thirds of my time. Everybody was happy with this arrangement, with the possible exception of my wife.

Gerstmann Syndrome? Taking the Board Exams

The time came for me to take the board exams in Chicago. When I took it you only had to pass it once. If you do not pass the board exam, it does not keep you from practicing because you can get a state license but it is almost essential if you are going to be a specialist of any kind. You have to practice for 2 years before you can take the boards. That's the way it was then. So after you practice neurosurgery, in my case for 2 years, then you hand in all your cases. Every case has to be summarized, a story describing the case and what was the matter and what you did and how it turned out. All that has to be handed in, 2 years worth when you take the exam, and they look at that. They had just introduced the written exam at that time. I think it was one of the first years, so they did not give it much weight. Now the written exam has much more weight than it had in 1966 when I took the board exam.

I figured I knew what one examiner meant when he asked about the language areas of the brain, so I said, “Well, there's a focus area.” He said, “Well, where is it?” I said, “It's right there, the posterior third of the anterior frontal gyrus.” He said, “All right, what else?” I said, “Well, there's Wernicke's area.” I later wrote a paper called “Wernicke's Region—Where Is It?” and I got 22 different answers from the literature (Bogen and Bogen, 1976). But I was not going to argue. I said, “Well, it's about here you see.” I waved my finger around. The posterior third of the superior temporal gyrus wrapped around in there, you see. Although of course, a lot of people think the supramarginal gyrus is more important, on and on. Anyway, he said, “Well, what else?” I said, “You know Penfield claims that there's a supplementary speech area.” He said, “What do you mean claims?” I could hardly keep from laughing. He said, “You don't think it's true?” I said, “Well, it's probably as true as most things.” I didn't know how I was going to be graded in that exam. The way they had it set up was in each section was that there was a neurosurgeon and a specialist in that field. So for the neuroanatomy they had a neurosurgeon asking questions together with an anatomist.

Then for neurology there was a neurologist that I had never heard of. He was some local neurologist they brought in. But I had heard of the neurosurgeon in the exam and I heard he was really a bear. So I came in and they were very polite at first, “Sit down doctor, we're very glad to see you.” And then there was a little silence and he looked at me and said, “What would be the first sign of a left parietal tumor?” I didn't give him the smart-ass answer which would have been “You mean in the right handed?” because I knew that was what he meant. I said, “Well, the first sign might be a seizure, a generalized seizure.” The reason I said that was because I had a patient just like that who had a left parietal tumor and the way the case presented was with a convulsion. And I knew they had my cases so I thought he was talking about that. He said, “I don't mean that. I mean a neurologic problem. What would be the first sign?” I said, “Well, the first sign of a left parietal tumor might very well be some mild, vaguely describable difficulty in thinking. The person would have a hard time characterizing.” He gave me a really hard stare and said, “You're from Los Angeles?” I said, “Yes sir.” He said, “Did you ever hear of Jan Neilsen?” I said, “Yes sir, he was my first professor of neurology.” He said, “Well, didn't he teach you about Gerstmann syndrome?” I said, “Yes sir, he did.” He said, “What is it?” I said, “Well, it's agraphia, acalculia, finger agnosia, and right-left disorientation.” He said, “Well, why didn't you say so in the first place?” And at that point, the neurologist who had been sitting there smiling through this whole thing spoke up and said, “Maybe the doctor doesn't believe in it.” I said, “That's right.” The guy just about blew a gasket. It really was funny.

Now the reason for not believing it is that they do not necessarily have to go together. There are plenty of people who have agraphia and alexia as a sign of an angular gyrus lesion. And that is the main thing they have got. As you know they can also have alexia without agraphia, but it is much more common to have agraphia and alexia together. Dejerine pointed that out in 1890. But what Neilsen always emphasized was that if the lesion is at all deep in the angular gyrus, you are going to get a lower quadrantanopia, maybe even a hemianopia because it gets down into the optic radiations. The optic radiation goes right underneath there. The angular gyrus is around the end of the superior temporal fissure. Draw a superior temporal fissure and the gyrus around that is the angular gyrus. If you draw the Rolandic fissure back the gyrus around that is the supramarginal gyrus. So if the lesion is in the angular gyrus, it is back a little further. In fact that would be the location if you had a bilateral, balance syndrome. A little further forward in the “supramarginal gyrus, if it is unilateral, you would get hemineglect. If you get it bilaterally in the supramarginal, you do not get hemineglect. So hemianopia is frequently an accompaniment to agraphia or alexia or acalculia.

Arthur Benton is one of the great figures in neuropsychology. He showed that you can get any combination you want of agraphia, acalculia, and alexia. And it is an individually variable thing, and it just depends on the extent of the lesion. Now it is true that if you see somebody who has agraphia and acalculia and finger agnosia and right-left disorientation, that tells you exactly where the lesion is. That is true. It is in the left angular gyrus. There is probably hardly any such thing as an exception. But that combination does not very often occur. It is a rare thing. It is much more common for people to get alexia along with the agraphia. And it is fairly common for people to have acalculia without finger agnosia. Gerstmann had a whole theory that he did not think that these things went together just by the coincidence of where they are represented in the brain. He thought that, in fact, they told you something about how people learned to calculate. They start with their fingers, so having finger agnosia explained why they have got acalculia. Well, that is not the case, because people have acalculia without finger agnosia all the time. So the whole Gerstmann theorizing is what I did not believe. And the idea that those four things are fairly commonly together is not so accurate. It is much more common to see agraphia together with alexia, and if the lesion is a little deeper, hemianopia.

Joe left Chicago not knowing whether or not he had passed he boards. However, he looked forward to meeting Aaron Smith in Omaha, a trip he had planned to take on the way home. He began a long friendship and correspondence with Smith, which he intended to describe further here, but this was never completed.

It was about a month after the Board exam and trip to Omaha that I received a letter from Professor Guy Odom at Duke University and Secretary of the Board. It read, “We are happy to inform you that you have passed the Board Exam. We wish to emphasize that you did poorly on the radiology subset of the exams and should study those areas.”

Summer of 1969

I got a telephone call from Roger Sperry and he said, “How would you like to go to New York and give a talk?” I said, “Sure, what's that all about?” He said, “Well, maybe you've heard there's an International Neurological Congress. They have them every four years. It's a big deal. So they've got it at the biggest hotel they could find, the New York Hilton. There's a man named Derek Denny-Brown, a professor at Harvard, and neurologistin-chief at the Boston City Hospital and various other things, a political power in neurology.” Derek Denny-Brown was very strongly opposed to the idea of complementary hemispheric specialization. And whenever someone would come up with some evidence from lesions that a right hemisphere was special in some way, he would come up with some kind of argument to show that it had been misinterpreted. But in spite of his strong feelings on the subject, he was apparently a man of open mind because in this International Congress he decided to put on a plenary symposium for everybody on cerebral dominance. It turns out that he invited Oliver Zangwill, Henri Hecaen, Wilder Penfield, Brenda Milner, and Roger Sperry. He asked Roger Sperry to bring Gazzaniga along but by this time he and Gazzaniga were not on speaking terms so he said, “How about if I take you along?” I said, “Sounds good to me.” I was kind of amused by this whole thing anyway. I did not realize what a sterling, major-league cast was involved until I got there but I was pretty impressed with the whole thing. So I worked very hard on a 20-minute talk. I rehearsed it repeatedly. When I found out who was on the program I was not sure who was going to precede me. But since I knew all these people and I knew what they all had to say, I made up about a half-dozen ad libs that I would throw in just in case they were appropriate, depending where I came into the program. In fact, I actually used two or three of them. It appeared as if I was very clever, but the fact is I had worked very hard dreaming these up the night before. I rehearsed and spent most of the night before working on this talk.

There was a lot going on at this meeting, and there were various specialized meetings running in parallel all over the hotel. I was going to some of them, and I was walking down the hall to the elevator and there stood two icons of neurology, Edwin Weinstein and a man named Eberhart Bay from Germany. These two guys were particularly prominent, even more prominent than Derek Denny-Brown, in urging a sort of holistic view and an anti-localizationist view which for a lot of people also meant an antihemispheric specialization view, which is a mistake but that was the way they felt. I saw these two guys whom I had heard about a lot, and I recognized who they were but they did not know me. I stood there for a while as they were talking and then they stopped and they turned to see what I was doing. And they said, “Yes?” I said, “Well, I wanted to ask you a question being that you are world-famous experts.” One said, “Well, what's the question?” I said, “My question is that since most people agree that the left hemisphere in most humans, right handers at least, is dominant for language is there any a priori reason why the right hemisphere might not be dominant for something else?” Professor Bay being a little older and from across the ocean and taller besides, answered first. He said, “No, there is no a priori reason but nobody has produced any really persuasive evidence in my opinion that such a thing exists.” Dr. Weinstein spoke up and said, “Your a priori reason ... you don't understand how the brain works. The brain works as a whole. You don't have these compartments and so on.” I said, “Well, language is in the left hemisphere, maybe the right hemisphere is good for something else like nature, or music or I don't know... “ At that point he said this wonderful line (which I should have had a recorder but I did not), “In my experience the people who best appreciate nature are the people who can talk about it the best.” And at that point it was clear to me that a conversation could not proceed any further in a constructive fashion.

The next day came the symposium and it was pretty impressive because Zangwill rolled out all this lateralized lesion data and then came Brenda Milner and Roger Sperry. Penfield was getting a little old and kind of wandered around a little. Then Henri Hecaen was supposed to give a 20-minute talk, but it was in French and it lasted at least 45 minutes and it just went on forever. But these 4000 neurologists in this huge ballroom stayed and paid attention. It was a good thing my talk was so well rehearsed because I had never addressed that large an audience before. My feet were a little colder even than they are now with my peripheral neuropathy. But I had rehearsed it so often that the whole thing rolled off fairly well. And Sperry was quite flattering afterwards. I said, “Penfield gave a pretty good talk.” He said, “Well, he's not alert, it was all old stuff and he wasn't really tuned in to the rest of the speakers like you were.” I thought that was flattering.

The main point was that after that symposium, I do not think there were any serious objections among neurologists to the idea of hemispheric specialization. It was as if it had just turned over that one afternoon. I never met Professor Bay again but I met Ed Weinstein a few times and subsequently he was very friendly and he was no longer offering objections to the idea of hemispheric specialization. Of course that kind of data from lateralized lesions, that is loss of function when a lesion is in one hemisphere or the other, and the split-brain data have now been kind of overshadowed or superseded by imaging. Because instead of inferring function from loss or instead of having this highly specialized situation with the split brain, you can take normal people with positron emission tomography (PET) scanning or functional magnetic resonance imaging (fMRI) and you can see the hemispheric specialization. It is pretty dramatic in pictures. That, of course, has made the whole story almost unarguable. Anyway, that was interesting, a paradigmatic shift overnight.

Hemispheric Specialization

A small example of the application of the complementary hemispheric specialization idea involved a friend of mine, Gabriele Rico. Ms. Rico obtained a Ph.D. at Stanford University in 1979 with her thesis describing her highly successful method for teaching composition to backward English students. The method emphasized the linking on paper of clouds of visual images. She included as a rationale for her method the emerging theories of right brain/left brain function: She had asked that I be a member of her doctoral committee to serve as a resource with respect to this rationale. “Clustering,” as the process she developed is called, is today in university composition texts as well as elementary and high school texts and has been turned into a software program for use in schools.

Subsequently Gabriele wrote a small book entitled Balancing the Hemispheres. There was an impressive demand for this booklet, but the publisher was reluctant to print more copies because of an article by Professor Curtis Hardyck debunking the right brain/left brain story. At Gabriele's request I wrote a letter in rebuttal of Professor Hardyck's critique. Gabriele subsequently wrote that because of my letter, the book was reprinted. Indeed it continues to be in print over 2 decades later. Her trade book, Writing the Natural Way, based on split-brain research, is still in print 23 years after publication. There has been widespread acceptance of the basic ideas not only by the general public but also by the scientific community as evidenced by the advertisement in Science, placed by the American Association for the Advancement of Science, to request submissions for their contest entitled Science and Engineering Visualization Challenge, with the slogan, “It takes both sides of the brain.” (See Science October 2004, p. 610 and October 15, 2004, p. 508.)

During the past 20 to 30 years (a full generation), the scientific community has come to accept as a well-established fact what was called complementary hemispheric specialization. Scientists discussing the evidence, as well as its implications, have generally spoken in probabilistic terms of continuities, of relative rather than absolute differences. But the media have emphasized polarities, have ignored reservations, and have simplified their accounts for a general public whose capacity for understanding science is apparently believed by most media folk to be even less than their own. As a result the general public acquires a view that is not only simplified and sensational but, especially in television, distorted and degraded, in a word, vulgarized.

In Between

All the time that I was at Ross-Loos, Walter Holleran was supportive of our special work arrangement. It was only when he became quite ill and eventually died that this changed. What happened to Walter could be considered comic if it had not been so tragic. Walter loved rumaki (appetizers held together by toothpicks) as much as he loved alcohol. Indulging in both one night at a party he was apparently too hasty. The next day he was ill and was eventually diagnosed with peritonitis, and at operation it was found that a toothpick had perforated his bowel. He was hospitalized for months and never fully recovered. The arrangement I had made with Walter disappeared entirely when Ross-Loos was swallowed up by Cigna. This was perhaps best illustrated by the occasion when a Cigna executive happened to look through the open door of my office. Seeing me sitting at my desk, pencil in one hand as I gazed off into space, he asked “What are you doing?”

“I am working on a paper.”

“A paper? What kind of paper?”

“A scientific paper—you know, for a journal.”

“Well! We don't work on scientific papers around here.

We do patient care. Does Dr. B— know about this?”

“Why don't you go tell him,” I snarled.

My situation at Ross-Loos had been steadily deteriorating, especially when it developed that if l ordered a scan of somebody's head, it had to be approved by somebody on the “8th floor.” This seemed to me outrageous, and it became obvious that I had to leave Ross-Loos. Then what happened was that they were getting ready to shut down Professor Vogel's residency program at the White Memorial Hospital. I said, “Look, you're the professor, but why don't you give up being the director of the residency program and give it to 'what's his name' who is a good surgeon and let him be the director.” I do not think he said anything. He just shook his head. Now the guy I suggested he should make the director was an African American guy, and a smart guy who would have jumped at the chance. He would have been one of the very few program directors who was black. But Vogel would not do that. But he was from the old school, and he felt he knew what he was doing and that he was doing things right, which in my opinion he was not. Of course there is the possibility that they would have shut down the residency no matter what because the school, Loma Linda Medical School, had moved out to Loma Linda. That had been the teaching hospital and they were in the process of getting rid of the training programs that were not part of universities. Anyway I was a little upset that he would not change anything in order to continue the program.

It was about this time that Ted Kurze asked me how many patients I was carrying usually. I said, “Anywhere from six to ten. I hardly every get more than twelve. I usually have around six to eight in the hospital at a time.” He said, “Why don't you bring them up to Huntington.” So Kurze wanted me to come to the Huntington Hospital and I jumped at the chance because I could see that the residency was dying down there at White. Vogel was not going to change anything. And this was 10 minutes from my home. I thought this was terrific. It is still a little country clubbish but it was even more so in those days. That was over 25 years ago. Well, what I found out eventually working at the Huntington is that it is not anything like the White Memorial Hospital where everybody tries to be civil as possible and never yell. Here if you want to get something done you have got to scream. They just will not do it right unless you yell at them. Because they really do not think you are sincere unless you yell. It was a great disappointment to me. Actually I only had to do that a couple times. It was very hard for me to change the whole style of dealing with people. There were people who just would not do what you expected them to do unless you raised your voice and then they knew you meant what you said.

Joe left Ross-Loos in 1981, returning after 18 years to a small office at the White Memorial Hospital, where he saw patients and assisted other neurosurgeons at area hospitals including the Huntington Hospital in Pasadena. He joined the New Hope Pain Clinic and worked there until 1986 when he discontinued doing much surgery to concentrate on his writing and speaking engagements. His income during this time, for the most part, came from expert testimony and review of malpractice cases.

One project he worked on in particular was the republication of the book A New View of Insanity: the Duality of the Mind, by A.L. Wigan, 1844. Joe considered Wigan his personal hero, calling himself the founder of “Neo-Wiganism,” (Bogen, 1971), and having his own personalized auto license plate that read “4Wigan.” Having met publisher Joe Simon, he introduced him to Wigan's work and together they researched and designed, and Bogen financed the reissue of the “nearly extinct” work of Arthur Ladbroke Wigan.

Memory

Jun Wada had a wild idea, which he first introduced in Japan. When he got to Montreal, Ted Rasmussen agreed that it was something that they ought to do. The problem was knowing which hemisphere a person is talking with. If one does a temporal lobectomy, we take off less if it is the left temporal lobe than if it were the right temporal lobe. That is a longstanding idea. We measure back from the tip of the temporal lobe, say, 5 cm on the left and 7 cm on the right, because on the right you can afford to take off more and have a lesser chance of impairing the person's language. Sometimes the right hemisphere function can be just as important as the left hemisphere function but it is not nearly so obvious. For most people to earn a living they have to be able to have pretty good language. However, it turns out that it can also be hard to get along with a damaged right hemisphere.

Okay, so, we would like to know what the language hemisphere is, and that is how Rasmussen decided that the Wada procedure, as it has been called ever since, was something worth trying. What you do is shoot sodium Amytal up one carotid artery. It goes into the left hemisphere on that side, blanks out the hemisphere, and paralyzes the contralateral arm and leg for 4 to 5 minutes. During that time if you talk to the person and carry on a nice conversation while that hemisphere is narcotized, and the person keeps carrying on a reasonable conversation, then you know it is not the language hemisphere. Then you do it with the other side and usually find that they do not talk anymore, so that is the language hemisphere.

Then came another reason to do Amytal studies, which is to test memory. It is well known that if you lose both temporal lobes you are in a fix because you will be left with severe amnesia. You can even develop Klüver-Bucy syndrome, which is pretty horrible. Nowadays it mostly happens to people from getting herpes encephalitis. People with bilateral temporal lobe damage do not have any learning ability left; it is called anterograde memory loss. They still have some old memories and they may have immediate memory but they do not have the kind of memory you need to learn anything new. If one (lobe) is so badly damaged that the person cannot remember anything with that one, then he or she certainly needs the other one, and you do not want to take that one off, although that has happened. Sometimes only one temporal lobe was taken off and the person still ended up with a bilateral defect because the unoperated (lobe) was scarred up. So you do the sodium Amytal test not only to find out which hemisphere the person is talking with. You also find out if a patient can learn things when one hemisphere is not working. You can do that with the hemisphere that has the language and also with the other one. You show material to the patient and then you ask the patient to pick it out later on. If he or she can remember what was shown, then you figure the person has got the ability to store the facts away. That means the hippocampus on the unnarcotized side is still in good enough shape, and you can afford to take the other one off it you have to. Then you would test the other side just to make sure of what is going on.

One thing we did was we wanted to find out which hemisphere they would sing with, which nobody else ever did. So we would inject one hemisphere (usually the right), and they would keep talking. For example we would say, “Say (a sentence) with the word hospital” and the guy would say, “I'd like to get out of this hospital.” The way we did this then was a bit gross. The patient got these big needles stuck in his neck. It is done in the groin now, but then there was a big needle stuck in the carotid artery, which was bobbing up and down with the pulse rate in the guy's neck. Then we said, “Sing with me” and we would sing happy birthday. The guy would join in singing “happy birthday to you, happy birthday dear doctor, happy birthday” (monotone). No melody! And when we would inject the other side, he could not talk. You would say, “Hold up your hand,” and he did not understand what you were talking about. You would look at him and sing “happy birthday to you” and the guy would join in singing, da, da, da, da and carry a tune with the nonspeaking hemisphere! Sometimes they would sing the words because the words kind of come automatically. It is like an aphasic who can sometimes sing or utter overlearned phrases like “Hail Mary full of grace the Lord is with thee.” If you have some kind of overrehearsed stuff it will come out just like song lyrics but it is not really language. You are not creating a new sentence with, for example, “happy birthday” in it. Creating some kind of novel sentence or understanding a complex sentence, that is language.

Some people thought our Amytal paper was quite important. I remember Frank Benson went around saying how great it was. These days everybody is familiar with the right brain/left brain idea showing that a person can sing when they cannot talk and when they can talk they cannot carry a melody so well. So that is not such big news anymore, as when we published this paper, about 1965 or 1966.

Heilman and Valenstein wanted to put out a book on behavioral neurology called Clinical Neuropsychology, and they asked me to write a chapter about the corpus callosum. That was in 1979. It had some mistakes in it, but it took me years to figure out what was wrong: meanwhile other people read it and quoted it so that the error has been passed on for generations of students, and I was the guy who started the whole stupidity. Anyway, it is the term “alien hand,” which I introduced and which is wrong.

Eventually they wanted to put out a second edition, which did appear in 1985. I said, “Okay, I'll update my chapter" and I spent a lot of time and worked hard on it. Then I got the galley proofs back in 1984, and Valenstein had taken out big portions of what I wrote. I had written a big thing about faces, and he took that out. Well, that could be justified because the same subject, facial recognition, was discussed by someone else in another chapter. But still, I thought he should have talked to me about it, not just taken it out without saying anything. He took out some other things for reasons I could not understand. Perhaps he thought he knew more about some things than I do. So finally I decided, all right, I will sign the agreement, I will send the galley proof back, and then I took the material on faces and put it in a book edited by Benson and Zaidel.

The second edition in 1985 was a big success. Then came 1991 and Valenstein calls me up again. He says, “We're going to do a third edition. Would you update your chapter?” I said, “Yes, Ed, I will update the chapter with the understanding that if you don't like something about it we're going to talk about it. You know, you're not going to take stuff out without talking about it.” He said, “No problem.” One reason that I was willing to go to all the work and effort to bring the thing up to date was because I wanted to chide Mike Gazzaniga for giving these different opinions. Every year he would come out and say something a little different from last year. I said to myself, “How about some ongoing truth? How about a little stability.” But his style was that every time you write a paper you give “our new interpretation based on our recent new evidence.” He would not explain why differing views were wrong, nor would he mention that he had said something differently the year before. In fact, in 1985 he came out with two opinions that were mutually inconsistent in two different journals in the same year. I decided to put all of this in my chapter. I thought this chapter was going to be my swan song because by this time I had already had kidney cancer in 1987 and found out that I had diabetes, and also my blood pressure was a little elevated. So I figured this was my last chance to put it all in. I also wanted to blast Marcel Kinsbourne, who is a long-time friend of mine, because he wrote a chapter in which on one page he said that we cannot depend on introspection to tell us what the situation is, although it may give us some clues, and then five pages later he says the objective evidence would suggest that you can have two minds inside of one head with the two hemispheres but our unquestioning understanding of the unity of self would be against that. I said, “Wait a minute, a few pages ago he was against introspection. Now this introspective feeling that we're one unified person means all the other evidence should be put aside?” So I wrote about this. I was unhappy back then because my position for more than 30 years has been that the objective evidence is that everybody has got two minds in the usual sense of mind, not one. No matter how unified you think you are, and how unitary everybody says they are, they are not. Because that is an “introspection” and it is no more reliable than a hundred other introspections, which have already been disproved.

So I got a big long letter from Ed Valenstein—three pages. The first two pages had a lot of pretty good suggestions, I thought. The third page of his letter attempted to get me to take out all of the stuff about Gazzaniga and Kinsbourne, which was my main motivation for writing in the first place. He says, “We should not deal with personalities” so I wrote back thanking him for all of his good suggestions in the first two pages and then I said this is not a matter of personalities. I am not the least bit critical of their personalities. In fact, as far as I am concerned they both have delightful personalities. I have enjoyed their company on many occasions. Charming guys, both of them. What I am complaining about is what they have written not their personalities. He did not answer the letter. Then I got the galley proof. He took it out! Another thing he took out was a long paragraph with the definitions of the words that were going to be used through the rest of the chapter. He took out the definitions! What's the sense in that? Because he thought that anyone who would read the book should know what those words mean?

Norman Geschwind was Kenny Heilman's teacher. So Kenny Heilman believes in Geschwind and he passes that on to people including Valenstein. But a lot of stuff that Norman said he never believed himself. I know that because I knew Norman. Furthermore, a lot of what he said turns out to be wrong. This is because Norm would turn out a couple of bright new ideas every day for lunch. If you keep coming up with a bright new idea everyday, they are not all going to be right. However, he would teach it to people, sometimes even after it was shown to be wrong. Like his claim that what makes humans different from chimpanzees is the angular gyrus, and it is the angular gyrus that gives humans cross-modal associations. If a human learns to tell things apart, say, squares and triangles by sight, then he can tell them by feel in the dark. Ettlinger claimed monkeys cannot do that. Well, it is not true. At the very time he was saying that, Davenport showed that monkeys could do it. Then, later on, Weiskrantz and Cowey showed that monkeys could do it. So the whole beautiful theory came tumbling down.

So it was while I was having this big surprise looking at the galleys that I began to have nose bleeds. I thought my blood pressure might be elevated and asked my wife to measure it right then and it was 220/110. It was at that moment that I decided that I was not going to have anything more to do with Ed Valenstein. I called up Jeff House at Oxford University Press of New York. Because it was the Thanksgiving Holiday, I left a voicemail saying that if they replaced what had been cut out by Valenstein and if I could have a page proof to reassure myself that the restoration had actually taken place, then I would send the revised galley proof to him. Otherwise, they should just forget my chapter, leave it out. The next Monday I received phone calls from New York and Florida (from Kenny Heilman) telling me that the chapter was essential for the book and I could have it the way I wanted. This is a nice happy ending except for the fact that I started having those nose bleeds and it chased my blood pressure higher than it had ever been before and that is a good reason never to write a chapter for somebody else's book!

Zaidel

Joe became good friends with Eran Zaidel when he and his wife Dahlia Zaidel were at Cal Tech working in Sperry's lab. They continued their association over the years. This story is about one of their later collaborations.

What happened was his grant application was turned down. This was about 1986 or 1985, maybe. So he said to me, “Well, I would like to make you a co-principal investigator, a Co-PI.” He thought that would increase the chances of him getting the grant from NIH. I said, “Well, applications aren't my style of writing, but I tell you what, I've got to make some contribution for you to stick my name on it. So my contribution, besides just lending you my name, will be for me to rewrite the first page (which was the abstract). Then I don't care if you have 30, 40, 50 pages of garrulousness, so long as the first page is not embarrassingly wordy.” This was the way I talked to him. I got away with it because he has got a tough hide. You know what a sabra is—it is a kind of cactus that grows in Israel. For years the people who were born in Israel called themselves Sabras. They named themselves after the cactus because it has such a leathery exterior, but it is nice and soft and tasty inside.

So I rewrote the first page and he put it in and they did not give the money right off. They wanted to have a site visit, so they sent a committee. One person came from New York City, a pompous ophthalmologist; then the neurology chairman from Tucson, Al Rubens, who I knew reasonably well; then some lady I had known about but I never saw before, a linguist from some place like Johns Hopkins; and then one more person I cannot remember. So I guess there were four of them and the fifth wheel was an administrative bureaucrat from NIH who did not know anything about the subject but he knew all about the money, or rules, or whatever. Now I did not think it had anything to do with me but I got a phone call from Zaidel that said, “You have to come out here. The site team is coming tomorrow and you've got to make a presentation.” I said, “That was not part of the deal.” He said, “Well, you've got to. You're co-investigator and they want to see you and hear what you have to say.”

So, I went out there and heard a pitch that he made for how a certain line of investigation was going to produce interesting results and how another line they were following might be enormously illuminating if it turns out but it is not so clear. You do not know how things are going to turn out. Anyway, then it came to my turn. And I had thought about it a little bit so I stood and went to the head of the table and said, “Now these projects are promising, it seems to me, although of course there's a possible chance of some failure. But what I am proposing as my part of this is something that cannot possibly be a failure. That is that we have all these split-brain patients and they've had all these psychological investigations, literally hundreds of papers. And the anatomy is not really well known. The only reason we know that they are split is that all these psychologists have had to take my word for it. We've tried to get CAT scans but you can't see anything. What we have to do is MRIs and I'll tell you people very frankly that I am not the kind of guy who applies for grants very often. As a matter of fact, everything I've done I've done on my own money. I pay for my own trips to meetings, I buy my own slides, but getting MRIs is really more than I can manage. It's just too expensive for me to pay for. So we have to get some money to get MRIs to document the anatomy on these patients. One way or another we're going to get the anatomy, but it would be a lot nicer if we could do it legally and NIH got some of the credit, so it's done right.” And Zaidel was absolutely … he thought sure I had killed the whole project talking to these people that way. He got his grant and it has been renewed about five times since. I think it was 1985. So we got the money, and I took them out there to my favorite radiologist, and he did MRIs and we sent the bill to Zaidel on his grant and he paid. He did not pay the full price. They gave him a price break. Anyway, the radiologist got paid a fair amount, and he got his name on the paper. I called up Bob Joynt, who was the editor of the Archives of Neurology at that time. I said, “Bob, all these people have been pushing me really hard to get this anatomy thing on the split-brain patients so they can refer to it and say they're dealing with split-brain patients. If I send you a paper and keep it really short …” He said, “Yes, sure we can publish that. Just a few pages.” So I said, “All right.” So I sent him a three-page paper and it came out in 6 weeks.

I told my friend the plastic surgeon, “That's the fastest turnaround I ever saw.” And he said, “Well, it must not be a very good journal.” But I did not mind. People have been referring to it ever since. I got reprints, so I sent a reprint to each one of those people who was on the site team with a little note saying thank you and we did what we said. And I never heard back from any of them. Zaidel said I ought to benefit a little bit from this grant once in a while so he helped me get a computer. But the latest thing is that he hired this guy, Dave Kaiser, who was a student of mine 10 years ago, this computer person, because he needs that sort of expert help. And when I mentioned I was having trouble with my web page, he said, “Dave will do it.” So tomorrow I am going to go there with a whole brief case full of stuff and Dave Kaiser, I think, is going to upload it into my web page. So it is going to be a lot bigger after David Kaiser gets done with it.

Consciousness

In the spring of 1994, there was a conference on consciousness at Claremont. More than half the speakers there were philosophers, and I became progressively fed up throughout the day with their arguing amongst themselves about their favorite intangibles. After dinner came the featured speaker of the evening, Ned Block. When he finished, there was, as usual, time for questions. I was sitting in the front row, so after raising my hand, I jumped up on the stage saying, “Do you mind?” I grabbed the podium. “If you really want to make some progress in this subject,” I said, “let's start talking about how brains work. If you don't, you're just going to be flailing around here with a lot more unknowns than you have equations, and you're going to get nowhere …”

Half the people in the audience booed, and the other half clapped and said “Yeah, yeah!” It was really amazing. A little later they had a wine and cheese reception. Bernie Baars, the editor of Consciousness and Cognition, came up to me. “Would you write that up? We would like to publish that in our journal.” The background for this was that beginning about 1990, I spent a lot of time trying to figure out just what do I believe about consciousness. So when Bernie asked me for a paper, I was ready. So I turned what I had already been writing for myself into a two-part paper for Bernie. We had a lot of long distance phone conversations. The article appeared in 1995. About 2 years later, Bernie called me on the phone. I had read his latest book by then and knew that he had used a lot of the stuff that I told him without saying where he got it. There was also the fact that his book gave Gazzaniga credit for thinking up the split-brain. He was complimenting me and thanking me, and he said, “You know, I was just reading your article a few days ago, the two-part paper in our journal, about consciousness…” I said, “Yeah.” He said, “You know there's some pretty good stuff in there.” This was 2 years after it appeared.

In the same conversation he went on to tell me his new theory. I said, “Bernie, don't tell me consciousness comes from prefrontal cortex. You may need prefrontal cortex to think ahead, or to be socially responsible, but you don't need it to be conscious.”

He says, “Well, why don't you send us a paper that says that. We'll publish it in our journal.”

I said, “Have you got the journal handy? Look in part two of that paper you published. Can you find it?”

“Of course, I have it right here.”

“Well, open it up and look at page 147. Page 147 begins, “Human C does not require prefrontal cortex. I've written it for you already, Bernie.” He said, “Well, maybe for people to notice it, it would have to be in a separate paper.”

Gerald Edelman got a Nobel Prize for his work in immunology and now directs the Neuroscience Institute near San Diego. Edelman wrote several books about consciousness, one called, The Remembered Present in which he says, “You have to have language to be humanly conscious.” Primitive consciousness other animals might have, but to be humanly conscious, he says you have got to have language. I wrote something about his views, and one of his minions said, “You just don't understand Gerald. When he says you have to have language to be conscious he means to have a fully developed consciousness.” I wrote back, “Look, I knew Richard Feynman at Cal Tech. And after having met Feynman, it's my conviction that neither you nor I, nor anyone else we know, is going to have 'fully developed consciousness.' “

The problem is, of course, that one confuses the property of consciousness with its contents. If you are a dolphin, you are not going to have the same contents of consciousness as humans do. They are conscious of auditory information that humans are not conscious of. Once philosopher Dave Chalmers was invited to the Helmholtz Club. He came and like most philosophers he referred to Nagel's article, “What is it like to be a bat?” and to Nagel's characterization of consciousness as “being what it is like to be something.” At the end of his talk I said, “Look, I read this article by Nagel and he said at least three things. The first thing he says is that consciousness is the reason we'll never solve the mind/brain problem. However, if you look at the second paragraph, he says, 'Consciousness is a property we share with many other species, although it's difficult to say exactly what it is.' Now that's the consciousness we are trying to understand. A third thing he says, and this is what everybody's referring to, is that the reason we'll never be able to figure out consciousness is because we'll never know what it is like to be a bat. Of course you'll never know. That doesn't mean we won't understand consciousness. I don't have the slightest idea what it's like to be my wife.”

Well, the place cracked up. You cannot know fully what it is like to be somebody else, it is very hard. Bats may have a better chance of knowing what it is like to be a dolphin than we do because they are using echoes all of the time, like dolphins. People continue to confuse the contents of consciousness with the property of consciousness, which we share with a lot of other species. Francis (Crick) had the right idea, which is, if you want to understand consciousness, you first have to recognize not only that it is produced by the brain, but that this means you have got to learn neuroanatomy. You are not going to be able to think constructively about how brains work if you do not know the structure of it. How things work depends on how they are put together.

Going to Helmholtz

In 1995 Professor V. Ramachandran (Rama) invited me to give a talk at the Helmholtz Club. This was a group of neuroscientists having day-long meetings once a month at UC Irvine. It was organized in 1992 by Rama, Francis Crick, and Gordon Shaw, who were soon joined by fellows from UCLA (including Joaquin Fuster and the Schlags), USC (including Michael Arbib and Irv Biederman), and Cal Tech (including John Allman), as well as participants from UC San Diego and Salk. From 1986 onwards, Terry Sejnowski acted as chair, secretary, and treasurer although the group had no formal structure.

In my talk on hemispherectomy, I included Aaron Smith's movie of Earl Cozad stressing the presence of consciousness in a global aphasic and, more important, consciousness in someone with only one hemisphere. After the talk Pat Churchland asked me, “How come Gazzaniga never refers to hemispherectomy?”

“I don't know. Why don't you ask him?” I suggested. So far as I know, she never pursued the subject. In this connection she has lots of company. Hemispherectomy is not mentioned in any of the 35 books on consciousness that I have read. Only a few of them bother with the split-brain and, with a few exceptions (Christof Koch), the ones who do discuss the split-brain are often confused on the facts and as a consequence incoherent in their conclusions. It seems what was all the rage in 1981 when Roger Sperry shared in the Nobel Prize has become by 2000 quite passé.

The principal value of speaking at the Helmholtz Club was being added by Terry Sejnowski to his list of invitees. In the years I attended, 1995–2003, the group varied in size depending on the invited speaker and other considerations, from as few as a dozen to three times that many. Throughout the years the most faithful attendee, in addition to Terry, was Francis Crick whose presence was essential. It was for me a sad development that my deafness and dialysis eventually ended my participation in 2003.

Anencephalic Psychology

Here are a couple examples of what I call “closed-box psychology.” It resembles an engineer comparing output to input without knowing anything about the contents of the box. (I am aware that the usual term is “black box.") The outstanding example of closed-box psychology is probably psychoanalysis because of its theoretical complexity and extensively developed lexicon (rivaling astrology). I have been a fan, of sorts, of psychoanalysis ever since my mother took it up in 1948 when she found a teaching analyst, Martin Grotjahn. He soon nominated her for the Los Angeles Psychoanalytic Institute; but they were reluctant to let her in. By this time she was a clinical professor of psychiatry at USC, and worse there was that Ph.D. in biochemistry. They were afraid she would cause trouble. It turned out later that they were right.

In those days there was still a bitter antagonism between the so-called biological psychiatrists and the psychoanalysts. There is still some of that; but it was really intense then. She already had a national reputation as an “organic” psychiatrist. So for somebody like her, one of the first people to use insulin coma and then electroshock, to apply for training in the Psychoanalytic Institute was rare, perhaps unique.

When my mother died in 1960, I went through her old papers and there was a copy of a letter she had sent to Ralph Greenson. Ralph Greenson was the therapist for many movie stars, including Marilyn Monroe at the time of her death. And he was President of the Institute. The letter explained why she wanted to join the Los Angeles Psychoanalytic Institute. She was volunteering at the Camarillo State Hospital and there were some young psychiatrists there who had just gotten out of the Army, having previously had psychoanalytic training. She wrote that in spite of the fact that she had so much more experience with schizophrenic patients than they had, she had the impression that they were sometimes able to communicate with the patients when she could not. They seemed to have some understanding she did not have, and she wanted it. The Institute eventually let her in.

In the 1940s, I had a girlfriend who was in psychotherapy with an analyst. She was full of gossip about the psychoanalytic community and told me that some of the analysts called my mother Madame DeFarge. This was the character in the Tale of Two Cities who would sit knitting at the guillotine. My mother would sit in the class when guys were lecturing about Freud et al. and she would knit continuously. From time to time she would ask a question that had the effect of dropping the guillotine knife on somebody. So they referred to her as Madame DeFarge—rather typical of psychoanalysts to find a literary metaphor.

Eventually it came to a head. The medical people, including teaching analysts Grotjahn and Judd Marmor and some others with medical training, got fed up with the lay analysts who were so antagonistic to physiological or chemical considerations. So they left and formed a new group called the Los Angeles Society for Psychoanalytic Medicine, and they took about half the people out of the Institute. I understand there have been further schisms. It seemed to me partly because psychoanalysis served, for a lot of people, the same function as religion serves true believers. And if you are a true believer, then you will differ not only with nonbelievers but with other true believers from time to time.

On the other hand, there are the critics of psychoanalysis. Christof Koch asked me to read the chapters in his book on consciousness. In an early version he was pretty vitriolic about the nonscientific nature of most of the psychoanalytic stuff. It was not his usual measured attempt at scientific objectivity. I said, “I'm not sure why you're writing in this style unless it's your view that if you put the hammer to psychoanalysis you'll win a lot of friends. The fact that you alienate the psychoanalytic community is not important because they are not as influential as they once were; the number of people who don't like them is much greater. So I can see that if you're doing this on purpose it would make sense. Otherwise, it's just gratuitous, and not in the style of the rest of what you're writing.”

I do not know for sure why they are so vitriolic. But I think I know why. It is not simply because they are dogmatic, which many are. And it is not simply because so much of psychoanalytic theory is baloney. And it is not just because there are so many cozeners among them. The most important reason (I believe) is that some of what they say is so true it hurts. This is the part that John Kihlstrom was getting at when he wrote of “the cognitive unconscious,” although he assiduously avoided any mention of Freud. And it asserts what Wegner's The Illusion of Will was about, that we rationalize so much of our behavior, often not knowing its true origins. What the castigators of psychoanalysis rarely say, but what seems to me glaringly obvious, is that psychoanalysis exemplifies the pitfalls of attempting to understand mentation without reference to brain. Such an approach may have been reasonable when adopted by Freud, but it is not reasonable now.

In June 1978 The Massachusetts Institute of Technology sponsored a 3-day conference, chaired by Noam Chomsky, on the subject of brain and language: The meeting took place at a large estate in the woods about an hour's drive from Boston. I was picked up by a limousine at Logan airport. Several minutes later, the limo picked up the famous psychologist/ philosopher Jerry Fodor. During the hour long ride, about 45 minutes consisted of Fodor's explaining that a scientific psychology has no need of brain any more than understanding software requires a knowledge of computer hardware. For me this seemed similar to claiming that a scientific understanding of cars need not involve any mechanical knowledge, just because people can drive cars without knowing anything much about carburetors, universal joints, or even fan belts. That was 25 years ago and there are still plenty of people preaching this sort of anencephalic philosophy/ psychology.

Someone might say, “But that was over two decades ago.” Sadly, many philosophers have not changed. In the spring of 1997, Owen Flanagan came to Cal Tech at the invitation of Christof Koch. At dinner he mentioned that on leaving Duke, he informed his philosophy colleagues that he might see some neurolab or neurocase material. They recoiled in horror. He may have embellished the tale a bit but the message was clear. Philosophers (those anyway) do not dirty their hands with data. Is it really the sad truth that natural philosophy (what we now call science) has so far separated off from its origins that it has left behind only papyrologists—people who take paper in, put paper out, and while reading and writing assiduously, earnestly avoid the tangible? Do they consider direct contact with data to be of negative value? Are they, like some redneck in the novel Tobacco Road, actually proud of their ignorance?

Flanagan can be rewarding because he explains how other philosophers are wrong, and he does it in a readable style. Unfortunately, even Flanagan reveals a surprising neuroignorance. It seems that philosophers are still devoting time to whether or not consciousness is epiphenomenal. This is the idea that consciousness is like heart sounds. The sounds can tell us some of what is going on in our hearts (just as consciousness can tell us some of what is going on in our brains), but the sounds do not have any effect on the function of the heart.

To explain epiphenomenality, Flanagan contrasts two pictures: in the first, a hot stimulus to the hand causes a feeling of pain, which leads to withdrawal of the limb; he calls this “the standard view.” In the second, the stimulus causes the pain and the withdrawal in parallel; he calls this (correctly) the epiphenomenalist view. The fact is the second has been “the standard view” for over a century. The withdrawal is a spinal reflex and the pain is epiphenomenal for the behavior, although likely not for the memory of the occasion.

The reader will have by now recognized some of my convictions about consciousness: (1) There is such a thing. We routinely ascribe consciousness to some entities and not others and with fairly widespread agreement. Moreover, we label levels of consciousness (as with the Glasgow Coma Score) for both diagnostic and therapeutic purposes, again with fairly good agreement. (2) Consciousness depends on brains and is to be understood (so far as we can) in naturalistic terms. (3) Whatever the mechanism producing consciousness, it exists in duplicate. In each hemisphere exists the machinery for consciousness. Of course, we all know that almost all cerebral anatomy exists in pairs; it is obvious in any frontal or horizontal section of the cerebrum. However, few authors connect this fact explicitly with the problem of consciousness. Is the duality of anatomy like the runners of a sleigh, such that if one is damaged or removed the sleigh cannot go? Is the duality more like two harnessed horses, such that if one is removed, the remaining member of the pair can still pull the sleigh, not as fast or as far, but enough? The answer unquestionably is the latter. Otherwise hemispherectomy would not have become a routine procedure in 18 of 25 epilepsy centers.

Not only is the cerebral anatomy double, and not only is it unarguable that one hemisphere is enough for consciousness; beyond that, two hemispheres following callosotomy have been shown to be conscious simultaneously and independently. As Nagel said of the split-brain, “What the right hemisphere can do on its own is too elaborate, too intentionally directed, and too psychologically intelligible to be regarded merely as a collection of unconscious automatic responses.” And, “If the patients did not deny awareness of what is being done [by their right hemispheres], no doubts about their consciousness would arise at all.”

Much of the meandering inconclusiveness of discussions on consciousness results from there being so many different usages of the word. However, almost all usages have in common the idea of subjectivity. Hence, I believe: (4) Explaining subjectivity should have priority. Finding a physiologic basis for subjectivity is hard enough without trying to explain all the other different stuff that people mean or might mean when they say “consciousness.” (5) Mammalian brains have considerable power for generalized computation but special functions (e.g., subjectivity) commonly require specialized structures. Such an hypothesized structure has been facetiously termed a “subjectivity pump” by Marcel Kinsbourne. Well, that is exactly what some of us are looking for. And the mechanism for subjectivity is double, as shown by the duality of the anatomy, the success of hemispherectomy and the split brain results (in cats and monkeys as well as humans).

A bit more gentle opinion about philosophy was expressed by Crick and Koch. “...while philosophers have, in the past, raised interesting questions and pointed to possible conceptual confusions, they have a very poor record, historically, of arriving at valid scientific answers.” One frustrated scientist's opinion was less generous. In his chapter in what still remains one of the best books ever about consciousness, A.E. Fessard wrote, “...we doubt that epistemological discussions and metaphysical hypotheses, which in this field cannot be easily avoided, can ever be of real utility. By their subtleties and intricacies of points of view, by the fallacy of certain analogies, the mixture of facts with respectable but unverifiable beliefs, they have obscured, more often than clarified, the naive notion every normal man has of his own consciousness.” Perhaps the last word in this review should be left to a professional philosopher: Because I believe consciousness requires brain, it seems to me that before people go on about consciousness, they should know something about brain. I asked my cousin Jim Bogen, a Philosophy Professor, “If someone wants to philosophize about quantum mechanics, shouldn't he know how to do QM first?” “The good ones do,” Jim replied. “Well then, if someone wants to philosophize about consciousness...” He interrupted, “They should be conscious.”

During the previous 2 years, Christof Koch had sent me two or three chapters of his own book, The Quest for Consciousness, as acknowledged on the back cover of that beautiful book, which appeared January 2004. With this book in my hands I thought, “This promises to be the most deeply informed and most scientifically thoughtful book written on the subject.” In the course of my review of these chapters, I noticed he needed some help with various clinical aspects I knew he would not be familiar with. Once a month he came to my home for dinner, and I would indicate what might be improved in the manuscript. In the course of writing my own book, Christof said he would be happy to return the favor and review my chapters in the same way. I gave him Chapter 1, The Prologue, the Notes for Chapter 1, and the First Interlude (as well as Appendix A containing some philosophic considerations).

A month later we met again for dinner at my home. Turning to the subject of my book, he said, “Well, I showed it to Francis, and he had the same impression.”

“Well, what's that?”

“We think you're trying to write two books in one, and we think it's probably a mistake.” He went on, “You've got a scientific book here, and you have a lot of autobiography, and combining the two is unlikely to find a welcome with almost any publisher.”

Well, it was partly the continued urging of Gabriele that led me to continue along this path as she had an entirely different view of the matter, and I figured since I was writing the book at her urging, I thought I should listen to her than to this particular opinion of two people whom I admired very highly, or I should say whom I considered the very best that science could offer.

Again Christof came to dinner, now in February 2004, having read Chapter 2 and having given it considerable attention, his impressions scribbled in the margins. The criticisms that Christof had to offer were multiple, the most important being: “This stuff is really harder to read than it should be,” followed by “It seems kind of archaic, the way you present material.” I asked him, “What's difficult about it?” “Well, for example, here is this expression 'cerebellar cortex,'” and I had to ask myself, “What is he talking about?”

“People don't talk that way. I mean you could talk about the 'cortex,' or you could talk about the 'cerebellum,' but this is a really funny expression, this 'cerebellar cortex.'” I mean here is a man who is as prominent as one can get with an endowed Chair at Cal Tech, a man responsible for my being a professor each year for the last several years, and he is no doubt as good a scientist as anyone can be. His chosen field is computational neuroscience and the man does not know what the word 'cerebellar cortex' means!

The next day, instead of thinking “This is ridiculous,” I said to myself, “Well, the fact that throughout his entire career (he was 47 years old) the only contact he has had with the word 'cortex' was when it has referred to the 'cerebral cortex.' By contrast, by the age of 30, I was comfortable with the terms 'adrenal cortex,' 'cerebral cortex,' 'cerebellar cortex,' even 'pulmonary cortex.' I had to keep in mind that all of us have clay feet, and it may well be that my biggest clay foot is getting outraged at people's ignorance.

Epilogue

On April 10th Joe and Glenda celebrated their 50th wedding anniversary, and on April 13 he was admitted to the hospital. He died on April 22, 2005. The following was the last thing Joe wrote. It was found on his computer desktop dated March 8, 2005.

After a rather aimless youth, my fascination with brain function and the inspiration of outstanding investigators instilled in me a capacity for hard work and reawakened a childlike joy of discovery, of arriving at fresh understandings. These were accompanied by a desire for celebrity. With increasing maturity this desire to be acclaimed became distilled as it were, into a desire for approbation by the few I most admired rather than the crowd. And there came that special reward of scientific endeavor, the friendship of inquiring minds plus the reward of meeting folks of like interest throughout the world. With the progressive restriction of activity attributable to age and severity of disease, all that has faded relative to the companionship of family, including two loving and accomplished daughters who so wisely chose admirable husbands. The importance of family is a truth seemingly known all along to Glenda, my wife of 50 years. Ours has been a tumultuous marriage, often suffering from my devotion to work and verging on divorce on two occasions followed by wonderful reconciliations. Nearing the end, it is her love that turns out to be most important.

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Alan Cowey

BORN:

Sunderland, County Durham, UK

April 28, 1935

EDUCATION:

University of Cambridge, B.A. (1957)

University of Cambridge, M.A., Ph.D. (1961)

APPOINTMENTS:

Sunderland, County Durham, UK April 28, 1935

University of Cambridge, B.A. (1957)

University of Cambridge, M.A., Ph.D. (1961)

Postdoctoral Fellow, Center for Brain Research, University of Rochester, New York (1961, Sponsor Robert W. Doty)

University of Cambridge, Demonstrator (1962)

University of Harvard, Visiting Fulbright Fellow (1966)

University of Oxford, Senior Research Officer (1967)

Royal Society Henry Head Research Fellow (1968)

Reader in Physiological Psychology (1973)

Professor of Physiological Psychology (1980)

MRC Research Professor (1997)

HONORS AND AWARDS (SELECTED)

British Psychological Society, Spearman Medallist (1967)

European Brain and Behaviour Society, President (1986–1988)

UK Experimental Psychology Society, President (1990–1992)

Fellow of the Royal Society (1988)

Member Academia Europaea (1989)

Royal College of Ophthalmologists Medallist (1992)

Fellow Academy of Medical Sciences (1998)

Hon D.Sc., University of Durham (2000)

Royal Society Ferrier Medallist (2004)

Alan Cowey began his research by making perimetric measurements of visual field defects in monkeys with cortical or retinal lesions and showed that only the latter produced absolute blindness in the field defect. Later, he discovered and plotted cortical visual area V2 in monkeys. Subsequently he carried out behavioral experiments of visual acuity in monkeys and explained the effects on acuity of cortical lesions by studying the magnification factor of the retina in the thalamus and area V1 by anatomical and electrophysiological methods. He also studied the selective effects of a variety of brain lesions in monkeys and patients on form, motion, and color and interpreted their disorders by testing normal subjects with a combination of psychophysical, neuroimaging, and magnetic brain stimulation methods. He also combined studies on patients and monkeys to elucidate the neural basis of blindsight.

Alan Cowey

There are several reasons for writing an autobiography, whether it is a lengthy book or, like this one, a cameo. Common among them is “to set the record straight,” which can be a disguise for settling old scores. Another can be to impress contemporaries with a catalogue of enviable and perhaps overlooked glittering achievements that, once acknowledged, will ensure the status of avatar. A third would be to take a last opportunity to ensure that one is remembered for as long as possible by providing a literary form of Last Will and Testament, for, as the much lamented playwright Arthur Miller said just months before his death, “I'll probably be forgotten completely. Most of the work in the world is forgotten completely—99.99 per cent of all art work is forgotten” (UK Sunday Times, October 2, 2004). I hope to avoid all three of these, which collectively amount to autohagiography. But I recognize that in attempting to present personal information and insights into “the causes of interesting things,” which is the fourth reason and the one I hope to follow, there is a real danger of seeming to dally with the first three. And of course there is always the hazard in the elderly of confusing memory with imagination.

Ancestry

If developmental psychology, which I have never professionally studied but about which many of my friends and colleagues entertain and educate me, means anything at all it is that parents are important. They disagree about the relative importance and interaction of parental genes and the childhood environment (which can even include the absence of parents) but I have never heard anyone say that parents do not matter and I now recognize the role my own parents, however unthinkingly, played in shaping my career. Tearful winners at the annual Hollywood showbiz extravaganza called “The Oscars” often thank their parents (along with their dog or their manager or their hairdresser) for their success but do so without explanation. It is explanation that interests me.

I was born into a working class community in Sunderland, a town in the North East of England, in 1935. My mother was a practicing Roman Catholic but rather selective about the bits she practiced. My father was a nonpracticing Protestant but he never allowed his lack of practice to stop him protesting about my mother's religious life. She was born locally of parents who had emigrated from county Roscommon in Eire to seek employment in England in the late 19th century, like many of their contemporaries. Were it not for the European Union I suppose the present UK government might now call them illegal immigrants. My maternal grandmother, the only grandparent I met, became a laundry-maid in an agricultural college near Sunderland where she met and married my maternal grandfather, who had found work in the mining industry. He was a “shot firer,” which means that he drilled holes in the coal face and filled them with explosive which broke down the coal face so that the hewers could then remove the coal into the pony-pulled carts that conveyed it to the lifts which took it to the surface. The mine was close to the seacoast and much of the firing and hewing was done under the sea; working conditions must have been deplorable. They had five children but my grandfather died in his early 40s of Bright's disease (chronic glomerulonephritis) when my mother was still a girl. In an era when social security was almost nonexistent my grandmother managed by taking in washing at home, which was in a miner's terraced house in the east end of the town and very much on the “wrong side of the tracks.” As most young people at that time left school at the age of 13, my aunts and uncles already had jobs in the local factories and there was no destitution. But my mother was the youngest child and after leaving school she was not allowed to work in the local wire-mill with two of her sisters, which she wished to do. Instead she helped my grandmother with the washing and ironing and with anything that involved reading letters because my grandmother was illiterate; the only record of her hand that I possess is the birth certificate of one of my mother's sisters, marked by a cross where my grandmother had to “sign” it when registering the birth. I only discovered this as a young man when my mother mentioned it and explained that such things were not discussed because people were becoming ashamed of it. So I asked her about my father's parents and was told that neither of them could read nor write, which made her parents rather more distinguished!

Circumstances changed during the second half of the First World War, when so many men had been killed that women finally got to do what were previously and exclusively men's jobs. So she happily went to work in the local mill, which made ropes for the large local fishing industry. She met my father in 1919 after he came back from the war and they married in 1922. They could not afford wedding photographs so there is no pictorial record of the kind we now all take for granted. In fact I never saw a photograph of any of my grandparents.

Like my mother, my father was born in 1899 and went to the local elementary school. Being good at reading, writing, and sums he passed, at age 12, the exam that existed then and was normally taken at age 13 and which allowed the pupil to leave and seek a job. What a contrast with the present world where the smarter that people are the longer they stay in formal education! On the strength of his reading and writing he went to work in the town hall but was made to leave by his father, who insisted that as soon as he was old enough—14—he should have a proper profession like his own, i.e., learn a skilled trade in the shipyards. I have a group photograph of the shipwrights of Short's Shipyard; my father is the little boy sitting cross-legged on the ground at the front and holding a chalkboard saying “Short's shipwrights, 1914.” He must have been 15 or nearly so at the time. Later that year and without telling his parents he enlisted in the army after presumably lying about his age. When he did tell them it seemed too late for parental interference. He joined the Hussars, did basic training, and was soon in France where his job was to transport horses to and from the front line. Although not widely known at the time the British army had lost so many men in the carnage of Flanders that tens of thousands of underage soldiers had been recruited and by the end of the war the total number of boy soldiers (including those who had died) approached 250,000. They are memorably described in First World War, by Martin Gilbert, 1995, and in the National Archives Learning Curve at www.spartacus.schoolnet.co.uk/FWWboy.htm. It happened again in Germany toward the end of World War II, when Hitler created the Jungvolk to help to defend the fatherland.

When news of the appalling casualty lists, including boy soldiers, began to filter through, my grandmother went to the local army office and demanded that her boy be discharged. 1 have his Certificate of Transfer, dated 30 October 1916. Rather than discharge him on the legal grounds of being too young to be in the army or too young to serve abroad (where the legal lower age limit was 19), the army transferred him—and thousands like him—to reserve regiments that were meant to be used solely in support work. As a result he ferried horses across the channel until he was deemed “acceptable” to join the front line again when he became 18. When I asked him 50 years ago what he learned to do in the army he said “smoke, drink, and sleep anywhere.” He did the first two with enthusiasm and died at the age of 63 of chronic bronchitis and emphysema, caused partly by the lingering poison gas that he often encountered in the trenches. He was so unwell from his late 40s onward that he needed help to do the simplest manual jobs like sawing wood, sanding, climbing on to the roof, drilling, etc. I was that “help” and I became his apprentice at weekends and during the school holidays when he taught me his full range of manual skills. Often I would have preferred to be doing something else, like playing football, but without the instruction I would not have been able to tackle several scientific things years later. Without either of us knowing it at the time he shaped much of my outlook on how to deal with practical technical problems in life.

My parents married in 1922 and moved into rented rooms, close enough to the shipyard for my father to cycle to work and finish his training as a shipwright. My mother wanted to continue to work but unemployment was high after the war ended and she had no special training of any kind. She also gave birth to my brother in 1923 and at that time being a working class mother meant staying at home. Then the famous economic depression arrived in the mid-20s and my father was out of work. In fact much of the local population—which depended on shipyards, coal mines, and steelworks—was unemployed. My father decided that it was time to change his occupation and bought an old hand-drawn two-wheeled cart on which he transported his two shipwright's toolboxes (I still have one of them and its tools) and a set of long ladders round the streets in more affluent parts of town. He knocked on doors and managed to make a living repairing roofs (mostly retiling), replacing gutters and spouts, and doing joinery. He also learned how to hang wallpaper, do simple plumbing, and rewire the then primitive electrical systems. It was while doing repairs for a local doctor that the doctor offered him a job collecting the “doctor's money.” This was a small sum, paid weekly to the doctor, either in part repayment for medical work already carried out or as an insurance for medical work that might be necessary. My father accepted and became a sort of debt collector or insurance agent. The practice grew and soon involved him in collecting for one of the then-named Friendly Societies that specialized in insurance against the cost of funerals, etc. My mother helped him by taking over some of the collecting and one of my earliest memories is of accompanying my mother in a pushchair on her rounds. In 1933 my brother was due to take the 11-plus exam but developed acute appendicitis and had his appendix removed instead of taking the exam. As a result he lost the opportunity to go to the only grammar school in the entire town. It seems that no one minded the missed opportunity and he remained in the elementary school until, aged 15, he left and went to work in a local shipyard. He started as an apprentice shipwright but really wanted to be a sailor. The Second World War provided the opportunity.

Life as a Young Boy

The War to end all Wars was followed in 1939 by World War II I am aware of the existence of false memories and how difficult it can be to establish the veracity of childhood memories. Nonetheless, I trust my memories of the outbreak of war in 1939 when I was 4 and my mother cried, and neighbors and relatives suddenly became more friendly and outgoing and listened to the wireless in groups. My father was too unfit to be conscripted but had to return to the shipyard to replace younger men who were leaving in droves for the army. He lasted only a few months before being declared unfit to carry out hard manual work and returned to door-to-door collecting. In 1940 my brother, now aged 18, tried to join the Royal Navy but to his and my parents' shock he failed the medical exam. He had a serious heart murmur and was told that he would have to lead a quiet life. What a hope! My father would have none of it and took him to see the aforementioned doctor who was still my father's employer. The doctor thought that the murmur might not be life threatening and, armed with a statutory signed form signifying that my brother was fit to be a sailor, he successfully joined the merchant Navy as a trainee ship's engineer. He joined the convoys that sailed across the Atlantic or from Scotland to Murmansk. I hardly saw him again for 5 years because shore leave was short and he had a girlfriend and soon a wife. His departure briefly changed my life because my brother and I, despite the age difference, had shared a double bed for the last 2 years (there was no third bedroom and no room for two single beds) and I regarded him as my “guardian,” although he probably disliked having to share with a child. Years later I visited him on board ship in London docks in 1956 and we had our only conversation of note as two adults. He was puzzled and critical that I had chosen to become a student, which meant living on a small grant and doing “book-work,” which he loathed. I failed totally to convince him that it was a good life, both enjoyable and worthwhile, and that the things he relished, like visiting exotic places, would happen to me in good time. After an uninterrupted career as a ship's engineer he died on board ship in Hamburg harbor in 1962, aged 39. The heart murmur had finally shouted. My brother taught me that one must not live in cotton wool in order to minimize risk. Hang the risk, he did what he wanted for 21 successful years.

School Days

My first school was a Kindergarden (sic), a nice misspelling of the German that I only appreciated many years later. The real reason I was there was to enable my mother to do more door-to-door collecting work and thus increase her income, presumably because it cost less to send me to preschool than the extra income she earned. The school was in an old terraced house only a short walk from where I lived and there were two classrooms, with about 10 children in each. The two sisters who owned and ran it believed in order, discipline, and learning but they were kind and I was happy there. When I left, aged 5, and entered the local elementary school I discovered that the education I had already received (starting to read and write, learn poetry by listening to it, do simple sums, recite the multiplication tables) gave me a head start. Much better than being trundled round town in a pushchair. The following 6 years were entirely run-of-the-mill, except that most of the school windows were shattered during one of the frequent night bombing-raids in 1942–1943; the explosion killed members of several families in the street next to the school but, echoing the emotional incomprehension of the very young, was briefly welcomed by the pupils because we all had an unexpected week-long holiday. But the less attractive outcome was that Morrison air-raid shelters were installed in local homes and I spent the next 2 years sleeping on a mattress in a metal box frame with steel mesh sides to stop flying glass. My father was an air-raid warden, whose job was to go outside whenever the town siren sounded and check that people did not linger on the streets and, if it was dark, to make sure that their light-proof blinds were drawn. It is pointless to deny that for me it was an exhilarating experience. There was the constant hint of danger, the possibility of staying up after normal bedtime, the excitement of having to carry a gas mask and my father's spare shrapnel helmet, and, probably most important, the opportunity to listen to excited grownups shouting, arguing, and cursing. It nicely complemented my Kindergarden education. When I now watch TV shots of children taking part in dangerous demonstrations of all kinds throughout the world I am not surprised by their fearless enthusiasm.

When I was 11 years old I took the 11+ exam, the exam my brother had failed to take because of his appendicitis. The selected few (about 1 in 20) went on to the only nondenominational grammar school in town. I passed and moved on to Bede, named after the Venerable Bede who first translated the Bible into English. With the benefit of hindsight it was the first great change in my life. Although my parents were pleased, they were not overtly overjoyed and this was in keeping with their undemonstrative manner, which also meant that they had never put any pressure on me to work for the exam or suggested that not to pass would count as a failure. Bede school plunged me for the very first time into challenging academic studies, while encouraging sport. Being good at the latter protected me from the widespread physical and verbal bullying directed at academic pupils ("bookworms") so that my peers tolerated my success in exams. My greatest physical discovery was that I could control a ball, run fast, and jump high. As a result I became a games player: basketball, soccer, rugby, cricket, and athletics. It was athletics that briefly enlarged my life by allowing me to compete in local and then national events and to meet people so curiously different from me. At the age of 17 I believed that I could become a major athlete. It was not the only mistake I made as a young adult.

While flirting with the idea of a sporting life I encountered teachers whose dedication to academic things I initially had no time for. To a callow youth who loved football they were sad figures of fun. But some of them impressed me by their ability to mount an argument and even to listen patiently to what boys like me had to say. One in particular became an outstanding influence on my career. He taught biology but was also an accredited athletics coach, which made him more acceptable to young boys. But his passion was literature and the theatre and he directed the school plays. When I was about 15 he asked me what books I had read. With respect to novels the answer was “none” because I grew up in a household with only three books, one of them my mother's Bible and the other two about the Royal Family and the First World War in pictures (I still have all three). So he gave me books that he said I should read. The first was George Eliot's Adam Bede (published 1859), a masterpiece of 19th century English literature, which I enjoyed without quite knowing why: something to do with the arresting and coruscating prose, and its ability to express through the lives of ordinary rural people the fate, sadness, and the strength of the human spirit. I am still mildly abashed that I read it without realizing that George Eliot was a woman and that she was one of the first English feminist novelists, something espied by Charles Dickens nearly 100 years before I discovered it. The second was Emily Bronte's Wuthering Heights, which he asked me to write something about. I wish I had kept a copy of what I wrote! My report was brief and he had the grace to say “that I had obviously read the book.” I was clearly not destined for a career in English Literature. Fifty-five years later, I find that his comment often applies to writers of papers, books, and grant applications.

It was this schoolteacher's outlook on life that affected me for the rest of my own life. He thought that it was a mistake to concentrate on only one thing; that hobbies are as important as one's paid job; that literature informs us about human behavior; that failing to achieve is less important than having tried; and that no matter how many people believe something, it might be wrong. With respect to the latter it was he who weaned me off religious belief (something for which he might now be disciplined) and taught me that always thinking for oneself can be a lonely and even socially intimidating act. I have not a shred of doubt that this largely unremembered and often criticized schoolteacher was responsible for my conversion from a working class boy with a conventional predilection for football and comic books, which I still read at age 15, to someone ready for something different.

About 1 year before I was due to leave school I decided that I might go to University and study science. The obvious places were Durham or Newcastle because both were distinguished and almost on the doorstep, enabling me to live cheaply at home. But a different teacher, educated at Oxford, suggested that I should try for Cambridge because he thought it was the “best” UK university for science and that it might be a good idea to live away from home in order to gain experience. I duly applied, visited Cambridge for 5 days in early December to take the entrance examination [now abolished] and be interviewed, and was awarded a place on condition that I passed my A-level subjects later that summer, which I duly did. My Cambridge marks were modest and I think I was accepted because I was good at games and even then Cambridge was looking for promising if educationally undistinguished candidates from a working-class background. Unfortunately Cambridge, like Oxford, required all entrants at that time to have passed the “O” level exam in Latin, which I had never studied. To the rescue came a previous lecturer in classics at Cambridge who, having retired, did part-time teaching at my school. He assured me that I could learn the rudiments of Latin grammar in 6 months, in his and my spare time, and that I could memorize the set-book, Virgil's Aeneid Bk III, so that I could translate any section of it from Latin into English in an exam. He was right and the experience taught me two things. First, a normal and determined youthful mind can learn almost anything if it wants and needs to and, second, that anything acquired in this way is rapidly lost if not subsequently used. Just a few weeks after passing the Latin exam I forgot almost everything about Virgil and Aeneas. Cambridge University abolished its archaic requirement not long after.

What had my parents provided that I can now see to be so important? As long as I complied with a few basic rules concerning honesty, hard work, thrift, and respect for others, they let me be my own man from a very early age, rarely objecting to what I wanted to do. I had immense freedom, although I did not realize just how much at the time. When I was 16 they let me cycle to London and back with a group of three friends to see the Festival of Britain. They taught me, entirely by example, that nothing should be considered impossible until you have tried to accomplish it. Their own aims were modest but not because they were timid. Finally, they demonstrated that no one should feel inferior simply by being poor or ill-educated; at least in western society we can all overcome that.

University

I arrived in Cambridge in 1954 to study natural sciences at Emmanuel College. The culture shock was huge, as it must have been for many of us who had rarely spent more than a few nights away from home. The ancient and inadequately heated buildings, upper-class accents, seemingly effortless superiority of undergraduates from private schools [in England confusingly called public schools], and rituals like dining every evening while wearing a collar and tie and academic gown were alienating. But they were small beer when compared with what my parents had to deal with at the same age. It took only one term, lasting 8 weeks, to discover that Cambridge was an opportunity of a lifetime and I realized that the first stage of my life was over. Apart from visits to my parents and my girlfriend Pat, who became my wife, I never again lived in my home town. Cambridge was my new home.

Studying science at Cambridge was a revelation. For the first 2 years I had lectures, supervisions, and practical classes from 9 AM to 1 PM every day from Monday to Saturday and practical classes from 2 PM to 5 PM, three days each week. My subjects were zoology, botany, biochemistry, and organic chemistry. It sometimes seemed like a treadmill but for each subject I had a supervisor, with whom I and another student met each week to discuss the essay each of us had written. I got more from this weekly meeting than from all the lectures and practicals. It encouraged me to think critically, for as a schoolboy I had concentrated on regurgitating scientific facts or Virgil's Aeneid. Being asked for my opinion about a scientific problem was novel and, at first, intimidating. For one of my first botanical essays my supervisor (E.J.H. Corner, FRS) asked me to read “The Thalassiophyta and the sub-aerial transmigration” by F.H. Church and to write what I thought about it. I was mystified but grasped that its thesis was that the evolution of aquatic plants had reached an advanced stage before plants ever became terrestrial. It was probably the first time that anyone had suggested to me that received scientific wisdom might be wrong, something I now realize is common in neuroscience, for example that the adult human brain has no neuronal plasticity. My supervisor in zoology was A.J. Ramsay, also FRS, whose lectures and research involved chiefly invertebrates. He asked me to write an essay on why so-called higher organisms were evolutionarily more advanced than lower organisms. I made a complete hash of it because I thought the answer was self evident. “What is the evidence,” he said, “that Amoeba ceased to evolve millions of years ago and is not still evolving?” But he said it kindly. I suppose this time at Cambridge is when I finally stopped taking things for granted. Another advantage of Cambridge is that it offered an optional 6-week fourth term in the summer. I opted to take this at the end of my first and my second years, first doing field work in biology and then histology. The latter was entirely practical and I learned to fix tissue, embed it in paraffin wax or nitrocellulose, section it on a rocking microtome, and stain it with a variety of vital dyes and with other methods including Golgi's, before examining, describing and drawing it with the aid of rather primitive microscopes without the aid of a drawing tube. I would like to be able to say that my specimens and drawings equalled in quality those of Cajal (of whom I had never heard at the time), but their inferiority was less important than the fact that I learned what was possible with my own hands. Ten years later it stood me in good stead.

The Cambridge Tripos system, where one studies several subjects for 2 years and then selects one for the final year is still one of the finest I know. How can we possibly know at age 18 what we really want to study? In my case I first wanted to be a Botanist, then thought it was Zoology, and finally decided it was what is now called Behavioral Neuroscience. I therefore changed from Zoology to Experimental Psychology for the last part of my Tripos and alongside it studied History and Philosophy of Science. My college at first resisted my last-minute move but it was probably a token opposition in order to make sure that I was changing for good reason. My tutor explained that I would need the permission of the Head of the Psychology Department. Being young and in a hurry I went to the Psychology Laboratory and asked if I could see the Professor about my proposed switch of subject. His secretary looked stern and dismissively explained that he was a very busy man and that he might be able to see me next week if I first wrote a letter of explanation. At that moment he came in from the adjoining room to see his secretary and, rather stiffly, asked what I wanted. I am still astonished and gratified that he invited me into his office, talked to me for half an hour, and agreed that I could join the course. His name was Oliver Zangwill, son of the socialist writer and painter Israel Zangwill, and although his interests were very wide indeed his personal research concerned the effects of brain damage on memory and spatial perception and how the normal brain controlled perception, memory, and action. I had met my first clinical and behavioral neuropsychologist. What a stroke of luck for me!

There were about 20 of us studying experimental psychology and we were taught by a staff of not more than 8 or 9, which provided a generous staff/student ratio but could hardly cover the entire subject satisfactorily. Wisely they did not try. Social, abnormal, educational, and individual psychology were hardly mentioned; instead the course taught in depth on learning theory, physiological psychology (Weiskrantz), perception (Gregory), attention (Broadbent), memory (Zangwill), human skills (Welford), information processing, and animal behavior (lectures in the Zoology Department by Thorpe and Hinde). There must have been more but this is all I recall. It was a golden time for me. I now had only one essay to write each week instead of three and my supervisor was Richard Gregory, who influenced me more than he can possibly know and subsequently became and remains a friend. The weekly tutorial was an opportunity to discuss a single topic that had been studied for a whole week. The topic could be narrow (What is the least amount of light we can see?) or broad (Is the brain just a complex machine?) and the almost complete absence of any detailed syllabus meant that the choice of topic was enormous. Choice? Yes, Richard would ask me and my supervision partner (Anne Treisman for one term) what we would like to think and write about. He would sometimes query our choice and make suggestions if we seemed at a loss but on the whole we picked the topic. It was a liberating if risky business but I learned much about myself and the nature of scholarship (reading original papers, thinking rather than accepting, having an open mind, not being overawed by reputation, only declaring an opinion if prepared to defend it, never dismissing an idea without examining the evidence, being prepared to differ even at the risk of offending a friend). One assignment suggested by Richard was to read Donald Hebb's Organization of Behavior, 1949. This stretched to three supervisions over 3 weeks (roughly 15% of the duration of the course just for one book) but I realize that it was an investment. When I subsequently became a supervisor of students at Cambridge and then at Oxford I modeled my approach on Richard's. In 1980 I was still asking tutorial pupils at Oxford what they would like to write about for the next tutorial. Regrettably, it would now be considered unacceptable. The teaching of science has become more regimented, lecture- and exambased, constantly appraised, and accompanied by elaborate Power-Point presentations that must be accessible to the students whose knowledge and understanding are increasingly evaluated by essays and dissertations that include (and very occasionally consist entirely of) written work that has been pilfered or bought from the web. Plagiarism is on the increase although forbidden. It is we and our Universities, not our students, that are to blame for we have not been sufficiently alert to the rising tide of rewarded mediocrity, spoon feeding, stifling bureaucracy, mission statements, government insistence that all students must succeed, and the promotion of factual knowledge rather than understanding. “More formal training” is the cry; but it is not the recipe for independent thinking.

I must now turn briefly to another aspect of my life as a student because I was within a whisker of following a career that did not involve scientific research or university teaching. My genes made me good at school games and success at athletics might have tipped the balance when I applied to Cambridge. For 3 years at Cambridge I trained whenever I could at least 5 days each week by running, lifting weights in the gym, or pole-vaulting into a sand-pit that in the winter was occasionally frozen until anyone wanting to use it had dug over the sand. I am not sure how much good it did for my physical health (the necessary absence of alcohol was presumably good) but it was definitely an entrée to a life with a collection of heterogeneous sociable students from backgrounds different from mine. What we shared was a belief in testing oneself to the limits of physical endurance, helping each other, teaching our skills to others (for example by tours to schools in the summer break), and learning how to accept and deal with defeat. Athletics brought my first trip abroad, taught me my physical limitations, and made me many friends. Indeed it was so important at that time that I decided to become a school teacher and to combine teaching of games and science, like my mentor. I duly applied to Loughborough, the leading English establishment for physical education, and after an interview that included a hilarious set of physical tests that included back flips in their gymnasium, was accepted to study for a teaching diploma in education and physical education, neatly embracing both of my aspirations.

Luck and serendipity intervened again. My research project in my final undergraduate year involved attempting to measure eye position in observers whose head movements were restricted but not abolished. Measuring eye movements now is fairly straightforward if one has the equipment and software, but 50 years ago it was rarely attempted and most investigators just assumed that subjects in perceptual experiments were following instructions to fixate. By reading U.S. Air Force technical reports describing the filmed eye movements of pilots while they were taking-off and landing I learned that the pilots were often not looking where they were supposed to look. It was Richard Gregory who suggested to Larry Weiskrantz (my research project supervisor) and then to me that one might determine where the eyes were looking by taking advantage of the fact that specular reflections from a source effectively at infinity, like the sun or moon, do not change their relative position with respect to the border of the iris when the eyes continue to fixate but the head moves. But they do change their relative position to ocular landmarks when fixation changes. My job was to see how this held up with light sources much closer (1 meter). After calibrating the system by photographing the eyes while the subject gazed in turn at each dot in an array of 150 dots at 5-degree separations I found that head movements of up to 1 cm in any direction could be tolerated while still allowing any fixation to be correctly identified from the position of four specular reflections on each eye. With a maximum head movement off about 5 mm, easily obtained with head baffles, the accuracy was about 2 degrees. The entire experience of carrying out this research for a few months was the most intellectually rewarding and practically satisfying experience of my life as a student (Cowey and Wesikrantz, 1962) and many undergraduate students of my own in the past 45 years have said much the same thing: The research project can be the most important part of their scientific education. Larry suggested that the real challenge would be to do it with monkeys, where eye movements and visual fixation had never been assessed even though they were important in evaluating the results of experiments on their vision, and that I might like to stay on at Cambridge and make it part of a Ph.D. Oliver Zangwill nominated me for a Medical Research Council studentship and I withdrew from my postgraduate studentship in physical education at Loughborough. I have carried out research ever since.

A Graduate Student at Cambridge

I began my Ph.D. in 1958. My supervisor was Larry Weiskrantz and I shared a large office with Charlie Gross and several others. My project was to use the technique of monitoring eye fixation with monkeys while the monkeys were carrying out a visual detection task. The scientific rationale was to discover whether monkeys in which small parts of the primary visual cortex were surgically removed had a small island of induced total blindness (a scotoma) in the retinotopically corresponding part of the visual field, like neurological patients described by Holmes (1918) and many others. But the bigger intention behind the investigation was to test the theory of encephalization of vision, i.e., the idea that in evolution the visual striate cortex becomes progressively more important for vision until in humans it is entirely responsible for visual perception. So, would the monkeys have absolute or relative defects? I had never tested a monkey before and I had no apparatus. While waiting for the monkeys to arrive I built a perimeter, consisting of a plexiglas hemisphere with small bulbs embedded in it and four more powerful light sources top and bottom and at each side. The hemisphere was made by heating a Perspex sheet and bending it over a mold of plaster of Paris in the departmental workshop, an activity that would now be prohibited by diktat of the Health and Safety-at-Work police. The only photographic illustration, taken from my thesis, appeared in Cowey and Weiskrantz (1970). Facing the perimeter was a metal panel, contoured by panel-beating (which I learned to do at evening metalwork classes) to fit the face of an average macaque monkey and containing a contoured spy-hole that a monkey could peep through with its preferred eye. Adjustable metal plates meant that the monkey had to press its head into the face mask in order to look through the peep-hole. In the center of the perimeter was a plane mirror that provided a reflection of the monkey's own eye. To my relief, I found that monkeys like to look through a peephole and that the mirror attracted the monkey's attention, meaning that if I moved the mirror to different positions I could photograph its viewing eye over the entire perimeter. This allowed me to present brief flashes over the entire visual field and to photograph the eye with a cine-camera beneath the lower edge of the perimeter on each presentation. It all sounds easy but it took about a year to train the monkeys and to measure their detection thresholds and then to repeat the measurements after the striate cortex corresponding to the macula had been removed. The outcome was that each of the three monkeys had a macular field defect but that it was relative, not absolute. Only when the macular of the retina was subsequently destroyed by xenon-arc photocoagulation were they absolutely blind in the field defect. It now sounds old hat, but this was the first demonstration of perimetrically plotted residual visual sensitivity with a field defect caused by a cortical lesion in monkeys and it seemed to confirm that monkeys differed from patients and that the explanation was encephalization of function.

I have glossed over the problém of how to make retinal lesions that correspond in size to the retinotopic cortical lesions but it was one of the most fascinating parts of my research. Larry Weiskrantz and I contacted a leading ophthalmic surgeon at Moorfield's Eye Hospital in London and described what we wanted to do. He was enthusiastic and one Sunday—when there were no patients in the clinic—we drove to London with a van containing five monkeys, parked in the hospital car park, anesthetized them in the back of the van, and then took them, in turn, upstairs to the library. The library? Animals were not allowed into the operating theater so the xenon arc photocoagulator was brought into the library and the monkeys were in turn propped up with books and drapes on a library table for the procedure. It would all now be impossible. The retinal lesions produced absolute fields defects (Cowey, 1967; Weiskrantz and Cowey, 1967; Blakemore et al., 1968) and it was at last incontrovertibly clear that extensive residual visual processing still took place within field defects caused by visual cortical lesions in monkeys. But the apparent difference between the cortical organization of vision in monkeys and humans was even then not certain, and in our article in 1963 Cowey and Weiskrantz speculated that perhaps the difference was caused by asking patients whether they had seen anything whereas the monkeys were rewarded for responding appropriately, which is not the same thing. It is the difference, now widely acknowledged, between reports on phenomenal vision and forced-choice guessing, i.e., blindsight.

Three other aspects of being a research student in Cambridge in the 1950s deserve a comment. When I took up my studentship, Oliver Zangwill invited me to chat about it in his office, which was like being invited into the inner sanctum. Never an easy man, he seemed to wrestle with what should have been a perfectly straightforward occasion, not helped by his notorious inability to maintain eye contact for more than a fraction of a second except with his dogs. So painful was it for him to look straight at anyone that he would swing his head and eyes sideways or in an arc up and down. Even when confrontation was unavoidable he always managed to look into the far distance. His antipathy to eye contact was a particular problem when lecturing because he had to avoid a room full of eyes. I therefore found it difficult to pay enough attention to what he was saying, which was roughly how to be a successful research student and whether to register for a Ph.D. The latter confused me because I thought that it was at least partly the point of being a research student. No! He described the history of the Ph.D. and why it had only recently become a kind of union card (his term) that one might need in order to carry out research or take a post in North America. He himself did not have a doctorate; Richard Gregory, Donald Broadbent, C. Grindley, and Alan Watson, all well-known in the department, also did not have doctorates. “It used to be the case,” he said “that one tried research and if it worked there was no need for the doctorate, and if it failed one gave up research and did something else, so there was no need for the doctorate.” But he sighed and said that times were changing and I might find it desirable to have a doctorate for an academic post outside Britain.

The second memorable aspect of my 3 years as a research student was my interaction with Charlie Gross. Toward the end of his period as a graduate student working on the functions of the frontal lobes in monkeys he decided that in order to understand how our ideas about the frontal lobes and brain function in general had developed he needed to read original papers that were often cited but probably without being read. He moved back to the early part of the century (Fulton, Holmes etc.), then the 19th century (Ferrier, Goltz, Munk, Flourens), then 1000 years to the Arabian scientists (e.g., Alhazen), and finally to the Greeks (Hippocrates, Aristotle). I initially thought it was a waste of time but his enthusiasm was infectious and I now realize that he was the very first person to convince me that the present is inexplicable without an understanding of the past. His example was one reason why, aged 60, I opted to provide the opening course of lectures in the new Oxford M.Sc. in Neuroscience on the topic of the history of research on the brain.

The third aspect concerns intellectual freedom and independence. Charlie Gross and I were both supervised by Larry Weiskrantz who, as I discovered when talking to other graduate students with different supervisors, was the antithesis of autocratic. He suggested rather than ordered, explained rather than pronounced, and had an open-door policy with respect to his students. He was the best possible kind of supervisor for a young neuroscientist. While Charlie and I were respectively studying the frontal and occipital lobes of monkeys, the first articles on the anatomical basis of memory in Planaria (flatworms) appeared. They were so strikingly novel and seemed to be addressing the cellular and molecular basis of learning and memory that Charlie and I suggested to Larry that we should study the phenomenon. Larry provided the funds to allow us to make a water T-maze and assemble the apparatus to study conditioning to a light associated with a weak electrical shock, which made the planarian contract. We then cut the planarians in half and both halves regenerated, but there was no evidence that any of the regenerates remembered the task. What a pity that there was at that time no Journal of Unreproducible Results because I discovered years later that many other investigators had been similarly unsuccessful. But it was not time wasted, for I learned the hard way why published experiments should constantly be queried, in my case especially with respect to blindsight.

During the second of my 3 years as a research student Larry Weiskrantz took sabbatical leave to work with Hans-Lukas Teuber in New York. He left Charlie and me “in charge” of the lab and, as this was before e-mail or cheap telephone calls, it meant that rapid communication was out of the question. Oliver Zangwill was, as required by University regulations, appointed as my stand-in supervisor, but he explained that he had every confidence that I would be able to cope without his help but that I should consult him if there any serious problems. I took this to mean that I was really on my own and so it proved. I had a wonderful time doing what I wished and discovering that it often did not work. It was the best possible education.

During the final year Larry had returned and I was completing my perimetric study of field defects caused by removal of parts of striate cortex, V1. Why the defects were not absolute needed an explanation and the likely ones were that the retina also projects to extrastriate cortex or that some other noncortical pathway is responsible, like the superior colliculus. But the extrastriate cortex in primates seemed to be unresponsive to visual stimulation, at least under anesthesia (Talbot and Marshall, 1941; confirmed by Daniel and Whitteridge, 1961). I was therefore specially excited by the results being reported by Bob Doty (1958), which indicated widespread extrastriate visual activity in cats, even under anesthesia. Larry suggested that I might like to become a postdoctoral fellow with Doty, whom I had never met, and he wrote to Doty and to the Rockefeller Foundation. Within a couple of months I had arranged to start work with Doty in Ann Arbor in September 1961, supported by the Rockefeller Foundation. I had to have my doctorate first, of course, and I started to write it on April 1, giving myself 3 months to complete it. I tested monkeys in the mornings, analyzed results and worked on figures and text corrections in the afternoons, and wrote fresh text at home in the evenings. My wife, Pat, typed what I had written or had corrected the previous day. Various people, notably Larry, read chapters and made comments and the revision of the first draft became the final version. I often wonder whether the development of word processing about 20 years later often holds up the production of a thesis by encouraging repeated but unnecessary revisions.

The regulations for appointing examiners at Cambridge at that time stipulated that the candidate should not know the identity of the two examiners until the thesis had been submitted, an arrangement preventing a thesis from being designed to please a particular examiner. But hints abounded and in my case Larry suggested during my writing that I should read the recent review by David Whitteridge of Giles Brindley's new book on the Physiology of the Retina and Visual Pathways. A nod is as good as a wink and I paid particular attention to what Whitteridge wrote for it was clear that he would be one of my examiners. I was wrong; Brindley, not Whitteridge, was the physiological examiner! But all went well.

Postdoctoral Science

I mentioned previously that I was set to travel to Ann Arbor to work with Bob Doty. Not long before being due to leave England he wrote to say that he was moving to Rochester, New York, to start a new group in the recently created Center for Brain Research, directed by E. Roy John, and that he would understand if I decided not to take up the Rockefeller Fellowship. Because it was Doty that I wanted to work with and I knew nothing about either Ann Arbor or Rochester, there was no problem in simply changing geographical direction. Pat and I sailed to New York early in September. Yes, sailed! In 1961 transatlantic air travel was expensive whereas autumnal ocean crossings on a relatively small passenger liner were cheap. So we had 7 days at sea. It should have been five and a half but one of the seasonal hurricanes swept up the northern seaboard and made life on board uncomfortable. That was when I found that, like my brother, I am not seasick. Decks were almost bare and dining rooms equally empty, and—to my dismay—the swimming pool had to be closed. So I wrote a scientific paper (Cowey, 1962) and pondered why about 1 in 20 people do not suffer from seasickness. I even thought that I might study it and that the explanation might be financially rewarding. Pie in the sky. It is still unclear why people are or are not seasick and I have also met several scientists whose amazing discoveries brought them little financial reward (Howard Florey and his team who found how to grow and extract penicillin, and Cesar Milstein, who developed monoclonal antibodies).

Understanding seasickness eluded me. But one lesson I learned from the voyage is that the best environment for writing a scientific paper is alone and far from colleagues and the telephone (I would now add fax and e-mail). Being instantly accessible at all times is creatively disruptive, like being a servant a century ago. You might smile, but modern life in a university means that we are increasingly required to be “on call” to administrators, managers, research evaluators, teaching assessors, editors, health and safety committees, the press, and even to government. It is all deeply regrettable but fortunately it is too late for anyone to fire me for saying so. About 15 years ago I was admonished by my University for calling, along with Ray Guillery, a meeting of neuroscientists to discuss how best to introduce a new course leading to an M.Sc. in Neuroscience. Apparently it was not my business to arrange such a meeting even though the conventional procedure had been slow and obstructive. The happy outcome is that Oxford, finally faced with incontrovertible evidence of the need and therefore the opportunity to teach neuroscience, finally introduced the hugely successful Neuroscience M.Sc. in 1991.

My time in Rochester was what a postdoctoral position should be: an opportunity to learn something new and useful, both practically and conceptually. Bob Doty showed me how to record from the dorsolateral visual cortex using surface silver ball electrodes or from deep cortex using penetrating bipolar electrodes. The equipment was state-of-the-art for that period, meaning that everything took place in a lead-shielded room and using banks of cumbersome amplifiers, preamps, and oscilloscopes. Projecting brief stimuli was a bit of a problem but I used an electroencephalographic (EEG) pen, with a cardboard flap glued to the end, to form an electromagnetic shutter in the light path from a projector. After passing through an iris diaphragm to provide brief small spots of light, the beam was reflected from a small adjustable mirror and could thereby be directed at any part of the wall in front of the animal. Although homemade, the device worked without trouble throughout my stay. The wall could be covered with large pieces of white paper so that “receptive fields” could be drawn on it during the experiment.

Doty had been using the midpontine pretrigeminal preparation, which provided an EEG characteristic of alertness, and I used the technique for several of the preparations. By sectioning the pons in the coronal plane just in front of the trigeminal nerves, having approached it from above and behind across the top of the cerebellum and under brief barbiturate anesthesia, the forebrain could then be kept in an alert aroused condition without any painful input via the trigeminal nerves. Other sensory nerves were infiltrated with local anesthetic and the eyes were immobilized by attaching the conjunctiva to a metal ring. This preparatory surgery took several hours and I then stimulated and recorded for about 12 hours. Once Bob was satisfied that I could do all this on my own, I spent the next 10 months plotting the topographic representation of the retina on occipital cortex and trying to discover how it arose. The first device for averaging signals was still some years away so the records were based on single trials, each evoked potential displayed on an oscilloscope with a long persistence phosphor so that it could be inspected, measured and if necessary photographed. Now that about 30 different visual areas have been described in monkeys (Felleman and Van Essen, 1991; Van Essen et al., 2001) it is probably difficult to imagine how excited I was when I discovered in the squirrel monkey that surrounding striate cortex was another band of cortex (V2), which was roughly a retinotopic mirror image ofV1. By electrically stimulating striate cortex the connection between retinotopically corresponding points in V1 and V2 was revealed and this connection could be abolished by delicately severing the white matter along the border between them (Cowey, 1963). Just before leaving Rochester I was able to record from several macaques and found that here too the extrastriate cortex was visually excitable and retinotopically mapped. Why V2 had not been reported before in monkeys is still a puzzle but a likely explanation is the level and type of anesthesia. Discoveries often hinge on apparently small changes in procedures, like the pH of a neurohistological reaction.

Almost every neuroscientist I know has a story about just missing an important discovery and I am no exception. While recording from V2 in squirrel monkeys I sometimes moved the surface electrode further forward as a control for volume conduction. If I moved it over the caudal superior temporal sulcus I recorded a prominent evoked potential, which was even more conspicuous when I used a penetrating electrode in the dorsal bank of the sulcus. I noted this in several preparations but did not have time to explore its nature for the end of my post doc loomed. The mysterious activity was of course arising in area MT, so termed by Allman and Kaas (1971a,b) in their pioneering and influential studies on the extrastriate visual areas of the owl monkey, studies which arguably more than any others led to the explosion of interest in cortical visual areas. Had I stayed for a much longer period in Rochester, as temptingly suggested by Bob Doty and which I seriously considered, it was this source of mysterious evoked potentials that I would have worked on. My observations were far too inadequate to publish but in a—for me—particularly nostalgic moment during my Festscrift in 2002 my colleague and collaborator Paul Azzopardi showed slides of action potentials taken from my lab records of 1962. Cortical area MT—often called area V5 in Europe because when it was first described in macaque monkeys by Zeki (1971, 1974) it was not immediately recognized as being homologous to area MT—has since become one of the most intensively investigated cortical visual areas because of its central role in the perception of visual motion. If only—as everyone who kicks himself for missing an opportunity says—I had followed it up. The fact is that hardly anything that remains unpublished will be influential; when Charles Darwin was painstakingly working on his theory of evolution through natural selection there were others following the same scent, notably William Wallace. But Darwin published first and, rightly, got the credit. I do not lose sleep over area MT.

Back in Cambridge, 1962–1966

While in Rochester I was invited to apply for a Demonstratorship (roughly an Assistant Professorship in the USA) in Experimental Psychology in Cambridge. I applied and was appointed without being interviewed. It was too expensive for Cambridge to pay my travel costs, they already knew me, and the post was probably not widely advertised. I did have a curriculum vitae (CV), which I had to send by regular mail, for fax and e-mail did not exist, but I had published or had in press only three papers. Having served on countless appointing committees since then, especially in the past 30 years, I know how fortunate I was, for no one with my slim list of publications would ever be appointed now. I returned to Cambridge late in 1967 and immediately started a course of lectures and practical classes. But as Larry Weiskrantz was still there I was fortunate to be able to collaborate with him even though I did not have my own research grant. Without his support, life would have been much more difficult.

My job was to lecture and give practical instruction to undergraduates reading experimental psychology. As it was my first “proper job” it took most of my time. I also gave one-to-one supervisions (tutorials) for 6 hours each week, especially on topics in physiological psychology, animal behavior, and learning theory but also across most of the syllabus. It was a period when all University tutors were expected to be able to discuss any topic in their subject. That time is long gone and with detriment to our students. First, experts are often the worst instructors in their own specialty; we stupefy students with our expert knowledge. Second, in having to teach outside my own narrow research interests I learned a great deal about things whose relevance to my own interests I might otherwise never have encountered. Third, I met students whose mental agility was greater than mine and with whom a tutorial was as much of a challenge for me as for them. Michael Morgan, now Professor of Visual Psychophysics at City University in London, is a good example.

In the time remaining, and chiefly in the vacations, I returned to the problem of the nature of the surviving visual sensitivity following damage to the primary visual cortex. When I went to Rochester I had left behind in Cambridge a macaque monkey with a cortically induced macular field defect, whose extent and threshold sensitivity I had plotted in Cambridge. When I returned a year later I found that the defect had remained unchanged but that with renewed repeated testing its size gradually diminished and the residual sensitivity within it improved (Cowey, 1967). At that time the accepted wisdom was that the brain showed no genuine repair of damage and that impairments of perception or movement or language were permanent once the more-widespread immediate effects had diminished. The evidence that repeated practice improved visual sensitivity within cortical field defects, especially at the edges, prompted my own subsequent investigations on rats (with Hugh Perry) into the nature of visual development and the importance of the age at which brain damage occurs in influencing the extent of any recovery. However, the paper in 1967 was cautious in its interpretation of the nature of the recovery with practice, acknowledging that spontaneous but late recovery can occur in some patients and that “the shrinkage of the defect with time may reflect the animal's increasing ability [with practice] to detect such a [weak] stimulus near the edge of the defect.” I am intrigued to see that nearly 40 years later the effects of training on visual recovery within areas of cortical blindness or within regions of motion blindness are still being vigorously pursued along similar lines (e.g., Williams et al., 2004; Huxlin and Pasternak, 2004) and that the existence and interpretation of any recovery remains as controversial as ever (Reinhard et al., 2005; Horton, 2005; Sabel, 1999).

While in Cambridge I also supervised my first research student, Richard Latto. Richard chose to work on the frontal eye-fields (FEF) in primates, using the monkey perimeter that I had built and following up much earlier and pioneering work by Margaret Kennard (1938, 1939), who demonstrated that unilateral lesions centered on Brodmann's area 8 (FEF) in monkeys produced a prominent contralateral neglect, which gradually resolved. Together Richard and I discovered three new things. First, in a perimeter the defect appeared to be no different from a field defect produced by unilateral damage to V1. Why, given that there was no damage to what was then regarded as the cortical visual system? Second, sensitivity within the field defect increased with practice but the defect could still be demonstrated over a year later. Third, a bilateral lesion produced a bilateral defect, showing that the initial unilateral defect was not simply unilateral neglect caused by the now dominant and inhibitory role of the FEF in the undamaged hemisphere. Although many distinguished experiments involving single unit recordings from neurons in FEF of behaving monkeys were carried out in the 1960s and 1970s there was a clear slackening of interest thereafter for about 20 years, arguably because the FEF seemed to be no more than motor cortex for the eyes and the earlier behavioral results remained inexplicable and were increasingly ignored and even forgotten. Several developments restored interest in the FEF in the 1990s: Functional brain imaging indicated their top-down role in visual search; renewed single cell recordings indicated that the FEF respond to visual stimuli far sooner than previously thought, as soon as cells in V2 (Bullier, 2001a,b; Nowak and Bullier, 1997; Schmolesky and Wang, 1998); transcranial magnetic stimulation (TMS) applied to FEF changes the regional cerebral blood flow not only in the eye-fields themselves but also in the posterior parietal cortex (Paus et al., 1997); the timing of the effect of TMS over FEF indicates that it exerts its effects on visual search by this downward projection to parietal cortex (O'Shea et al., 2004). From being motor cortex for the eyes the FEF have been promoted to having a major top-down role in visual attention and visual search. Hardly surprising that their removal makes primates visually inattentive. At last we can understand Margaret Kennard's early findings.

Despite teaching duties, this period was scientifically productive for me. In addition to the research mentioned above I met two outstanding undergraduates who carried out their final year research projects with me. I hesitate to say that I supervised their work because even at that stage they were even then outstandingly independent. Their names were Colin Blakemore and Edmund Rolls. Colin chose to study the basis of the recovery from the misreaching that follows retinal damage to the macula or damage to its representation in V1 in both human patients and monkeys. Is it mediated by surviving macular projections to other parts of the brain (aberrant projections to remaining V1, visual cortex outside V1, or the midbrain visual centers) or is it independent of them? He addressed this by studying monkeys with retinal lesions, where all projections from the macula have been destroyed. The recovery from the initial “past-pointing” was indistinguishable from that of cortically induced past pointing, neatly disproving a hypothesis (Blakemore et al., 1968). The result certainly affected my thinking about the nature of visuomotor recovery from brain damage and I hope that it provided a modest nudge to his subsequent distinguished career in neural plasticity.

Edmund Rolls opted to study the relationship between the variation with retinal eccentricity of the density of ganglion cells and retinal cone receptors in macaque monkeys and squirrel monkeys and their relationship to cortical magnification factor and to visual acuity of the two species with respect to eccentricity, which I had been studying behaviorally. Edmund's investigation was entirely neurohistological and he and I independently made the cell counts. Fortunately we obtained the same result (Rolls and Cowey, 1970), namely that magnification factor correlates closely with cone and ganglion cell density in both species and that it provides a satisfactory explanation for the variation in visual acuity with retinal eccentricity. This result has stood the test of time with one major and important exception, namely that the fovea of the retina, is overrepresented in V1, i.e., its magnification factor cannot be predicted from the density of ganglion cells concerned with the fovea (Perry and Cowey, 1985, 1988). The latter became a contentious issue in the 1980s and 1990s because it contradicted the simple and attractive principle that the amount of primary sensory cortex devoted to the peripheral sensory surface faithfully mimics the receptor density at the latter and that this is true for all modalities. Instead, the foveal projection is preferentially elaborated in V1, which necessitates more neurons and therefore more space. But this preferential cortical elaboration closely corresponds with psychophysical results that showed a variety of previously anomalous visual thresholds at the fovea itself (Jüttner and Rentschler, 1966, 2000; Strasburger and Rentschler, 1996; Strasburger, Rentschler, and Harvey, 1994). This special status of the representation of the fovea in human V1 has never been directly demonstrated but a good bet is that it might be resolved by functional neuroimaging (e.g., Engel et al., 1994) as long as we can trust the available measurements of ganglion cell density and its variation with retinal eccentricity so that they can be related to the topography of the functional activations in V1 produced by localized retinal stimulation. I am constantly reminded how long it can take to establish something beyond reasonable doubt.

Not long after taking up my Demonstratorship in Cambridge, Oliver Zangwill invited me to dinner in King's College, where his professorial fellowship was based. I imagined that the occasion, in one of the finest Gothic dining halls in Cambridge and close to what hordes of tourists regard as the finest perpendicular Gothic chapel in Europe, was simply a friendly and totally informal occasion. Instead I discovered that Zangwill intended to gently “instruct” me about things that every young university teacher should know, especially getting the right balance between teaching, research, and administration. He explained that doing a stint of administration was not just useful to the community but could be a comfort at times when research was not going well. In later years I often wondered whether he was reflecting on his own research career! Perhaps I took him too seriously because in the space of 4 years I had become a Fellow and Tutor at my old college (Emmanuel), was secretary of the college residential building committee at a time when the college was designing and constructing a new set of buildings, was academic librarian in the Psychology Department, and was secretary of the faculty board, a job that was little more than being a scientific amanuensis. I had too often said “Yes” when I should have said “No.” But I was entitled to sabbatical leave and arranged to work with Charlie Gross at Harvard for most of 1967. Freed from these duties I did little but research for the entire time. Hans Kuypers and his colleagues had recently published the first systematic anatomical study of the forward cortical projections of V1; Mishkin and his colleagues had shown that temporal neocortex was necessary for normal visual object processing in macaques, and Brenda Milner and others had drawn attention to the importance of the temporal lobes for object perception in man. Charlie and I accordingly compared the effects of what we called foveal prestriate lesions (roughly areas V4 and TEO) and more rostral inferior temporal lesions (area TE) on the aquisition and retention of visual pattern and color discriminations in macaques. We found a double dissociation in the effects: Prestriate lesions impaired perception whereas TE lesions impaired visual memory (Cowey and Gross, 1970). Our collaboration had been so close that we decided on the order of authors by tossing a coin. At the time, I doubt whether either of us realized that the analysis of the role of different occipitotemporal visual areas would occupy visual neuroscientists for at least a further 30 years.

With the benefit of hindsight I can now appreciate that we were working in the heyday of analyzing brain function by making lesions and studying their effects, using the reasoning, if not the precise techniques, of giants like Ferrier, Lashley, Pribram, Chow, and Mishkin from 80 to 20 years earlier. This single-method approach has almost died with the end of the last century. By making reversible lesions with local anesthetics, recording from and stimulating single cells in awake behaving monkeys, applying specific neurotransmitter agonists or antagonists to clusters of neurons, obtaining high resolution structural magnetic resonance (MR) scans of experimental lesions, and studying the effects of lesions by modern neurohistological methods, the number of monkeys used has decreased as the amount we learn from each one has increased. However, it is commonly asserted that we no longer need such studies at all because computers can simulate behavior and show us how it is mediated; I have not yet encountered a single example of computer simulation of memory, perception, emotion, or consciousness that tells me how the brain brings about these things.

Oxford

Not long before I was due back in England I received the good news that Cambridge had promoted me to Lecturer, which meant that I had a tenured University post and a College Fellowship to the retiring age of 67. But almost at the same time I learned from Larry Weiskrantz that he had accepted the Chair of Psychology in Oxford and that he would like me to join his department there and help in setting up a new laboratory for studying primate behavior. He made clear it that he could not offer me a permanent University appointment but that he would attempt to create such a position once I was there. It was a straight choice between a secure post in Cambridge, with an attached College Fellowship, and a new start in Oxford at a lower salary, without tenure or a College fellowship but with the prospect of better facilities. At the same time I received a telephone call from the Senior Tutor at Lincoln College Oxford, followed by several letters, who explained that he had heard via Larry that I might be taking up a post in Oxford and that the College would be pleased if I could give tutorials in Psychology to their Psychology/Philosophy undergraduates if I decided to move. That a small medieval Oxford college (founded 1427 and mostly built in that century) would take such trouble to find a part-time tutor in a minor subject surprised and intrigued me. I have never regretted taking the riskier option. I resigned while still at Harvard, we sold our house in England without ever setting foot in it again, and had our possessions moved to Oxford. I wrote to say goodbye to lots of friends in Cambridge who, on the whole, were puzzled and lukewarm. To paraphrase one of them “Why resign from a 'real job' in the best university in the world for science in order to take a soft-money position in an undistinguished psychology department in a medieval university that barely tolerates real science?” With that kind of stinging comment on my mind I arrived in Oxford with my family 1 week before starting a new career there. How wrong they were!

Oxford Collegiate Life

I was in Oxford to carry out behavioral neuroscience on monkeys. But I also had a duty to teach undergraduates for Lincoln College. The first time I dined there the Senior Tutor, who had in a sense recruited me while I was at Harvard, asked me to sit next to him in dinner. He was the historian J.B Owen and we did not talk about science. I asked him how old the dining hall was and he said, in a matter-of-fact, rich, New Zealand voice, “Oh, finished about 1440, the oldest unspoiled dining hall in Oxford.” He was not exaggerating and I have since dined there more than a thousand times. So what? Who cares? Why does it matter? It matters because a self-governing community of like-minded academics whose statutory duties are not only to engage in teaching and research but also to govern the institution—its finances, buildings, teaching, selection of students, staff, and mode of operation—is the best model I have yet met for dealing effectively with education, research, and academic community life. I also appreciated working with academics from almost every other subject than my own and from the scientists I learned a great deal about other subjects than mine: anatomy, pharmacology, physiology, cell biology, biochemistry; but it was establishing friendships—not just the much vaunted “contacts"—with scientists in these fields that proved so helpful to my neuroscience. I was elected to a senior research fellowship in 1968 and am now an Emeritus Fellow. When elected I discovered that I was a “penicillin fellow,” funded by the bequest from William Morris (subsequently Lord Nuffield and founder of Nuffield college) to provide College Fellowships for the three members of the team that, under the direction of Howard Florey, had first shown the dramatic therapeutic effectiveness of penicillin (Chain et al., 1940) and discovered how to culture the mold and produce its antibacterial product in sufficiently large quantities to treat infections. I got to know Norman Heatley well (he died aged 93 in 2004) and am constantly amazed that those who oppose research on animals on the grounds that the results are not applicable to man continue to deny that antibiotics (which have saved hundreds of millions of lives) did not arise as a result of Heatley's experiments on mice. He gave to three groups of mice, all inoculated with Streptococcus pyogenes, Staphylococcus aureus, or Clostridium septique, either penicillin or a placebo. Whereas all 73 mice given a placebo died, 66 out of 73 treated mice survived. It was a momentously important medical experiment, one of the greatest of the 20th century, yet its significance is still dismissed on the grounds that “animals are just different from man.” Talking to Heatley (who was not first author of the paper because The Lancet listed them alphabetically) for just 5 minutes would disabuse anyone of that astounding prejudice. But why was I a “penicillin fellow"? The simple answer is that by 1968 the great period of the biochemical development of antibiotics had ended and the college no longer needed three Research Fellows dedicated to just that. I was therefore appointed to teach psychology on the grounds that it was biomedical, the College had no Fellow in that increasingly popular subject, and, at that time, psychology could only be studied with either physiology or philosophy, in both of which the college was strong. It was another stroke of luck for me that I was on hand at the right time.

The Department of Experimental Psychology in 1967 occupied a Victorian villa, next door and in the shadow of the magnificent but bogus classical façade of Rhodes House, home of the Rhodes Trust and Rhodes scholars. Further down the road a large hole in the ground marked the footprint of the new Psychology/Zoology building. Another fortuitous event had precipitated this initially uneasy partnership. The new Linacre Professor of Zoology, John Pringle, had wanted a slim 25-story, 260 feet high, Zoology skyscraper, built on the edge of the University Parks where it would dominate the science area and the Oxford skyline. The architect's portrayal of his grand design, described as like something from San Gimignano, can be found in the exquisite and revealing book called Unbuilt Oxford, by Howard Colvin (1983). The democratic Congregation of the University rose up and resoundingly voted against the scheme. Instead, the present 5-story Ziggurat structure was built and although Pringle got the total square footage he desired the University awarded one third of it to Psychology, which also needed to expand. So the psychologists got what they wanted on the coat tails of Zoology and the firm promise of these new premises was an important factor in attracting Larry Weiskrantz, me, and many other psychologists to Oxford. However, I had to spend the first 2 years in the Victorian villa, where we established laboratories and a colony of monkeys in the back garden. It would now be impossible: security was slight; the now strict mandatory temperature and humidity controls for the animals did not exist—just as they do not exist in the wild!—and unlike now the animals could even look out of windows. There was no surgical suite but David Whitteridge generously allowed us to use the facilities in the Physiology Department, some of which were probably created and used by Sherrington. The problem was that the two departments were on opposite sides of a major public road through the science area. This was solved by anesthetizing the monkey in Psychology, wrapping it in a blanket in a cardboard box, and carrying it to the Physiology Department. Thirty years later a similar but slightly longer journey was needed to take monkeys to the MRC imaging center in order to obtain structural images of their cortical lesions. This required written permission from the UK Home Office, a formal addition to my animal research license, and transporting the anesthetized animals in a locked metal box while in an authorized University vehicle without windows. It's called progress.

A year after arriving in Oxford I became the Henry Head Research Fellow of the Royal Society, solving any problems of a salary for 5 years. It was not a post I had applied for because at that time there was no application procedure. Instead one had to be proposed by a fellow, with the support of the head of the host department. The culprits turned out to be David Whitteridge and Larry Weiskrantz. Fergus Campbell, at that time one of the world's best known visual psychophysicists and author of the article in Scientific American on “Taking the Psycho Out of Psychophysics"—pointed out that it was the best scientific job in Britain because the holder was known as the head fellow of the Royal Society and had no other duties. If only! Although I continued to teach for 6 hours each week, I spent the 5 years working with Larry Weiskrantz to develop a neurohistology lab, proper surgical facilities, automatic behavioral testing methods, and a program of research on various aspects of visual perception and memory.

With respect to neurohistology I was helped enormously by meeting Tom Powell in Oxford and Brian Boycott in London, although this was tricky because neither liked the other. Tom Powell was notoriously prickly but before coming to Oxford I had several times met Walle Nauta at MIT, who said that I should approach Powell if I was serious about introducing experimental neuroanatomy in the Psychology Department. I doubt whether Powell would have agreed to see me had I not had this slight connection with Nauta. As a result I went to Powell's lectures, got to know his young colleagues and learned how to perform autoradiography, the Golgi technique, and the Fink-Heimer methods for staining degenerating nerve preterminals. I realized that Powell had decided I was a serious scientist when he invited me to be the internal examiner for several of his doctoral students and he asked whether I might have a job for his youngest histologist, Caroline Healy-Yorke, after his current grant ended. I did have a post and she worked with me in psychology for the next 20 years, producing histology—and scientific gossip—of the highest quality. I owed a lot to Tom Powell.

It seemed strange to some colleagues in Oxford that the Psychology Department had a group of experimental neuroanatomists and—at its peak—three full-time histologists. I remember having the same feeling when Hans-Lukas Teuber became head of the Psychology Department at MIT in the 1960s and promptly appointed one of the world's leading neuroanatomists, Walle Nauta from Switzerland, to lead a rapid expansion of what was then called physiological psychology and that included Emilio Bizzi, Peter Schiller, Ann Graybiel, and Gerry Schneider. It exemplified the young subject of neuroscience, where understanding how the nervous system controlled behavior benefited from methods and ideas that were hitherto traditionally and strictly segregated. I have continued to use anatomical methods to solve, or illuminate, behavioral problems and at present count have published 57 articles whose primary techniques were anatomical. Naturally I did not do this on my own and although there are too many to list I should highlight Hugh Perry, Ben Reese, Glen Jeffery, Rafael Linden, and Peter Somogyi. Peter deserves special mention for several reasons. I met him about 1980 while he was in Oxford, developing his technique of revealing how several neurons in a chain of neurons could be followed, now called microcircuitry. In order to get as close as possible to the human brain, he wanted to study thalamocortical and intracortical connections in monkeys that had sustained small geniculate lesions or intracortical injections of tracers. I was able to provide and operate on monkeys that were going to be perfused for other purposes and, as a result, we carried out our investigations without involving additional animals.

Peter Somogyi's work attracted international recognition and the then recently appointed Professor of Pharmacology, David Smith, with whom Peter had first come to work in Oxford, proposed to the Medical Research Council that it should set up a new MRC Unit to investigate anatomical neuropharmacology. The time was ripe, Peter was clearly outstanding, and both I and Charles Phillips (then the Head of the Anatomy Department) were members of the MRC Neurosciences Board. Council debated the proposal and asked Phillips and I to seek international opinion about its merits. We divided the work and I contacted Walle Nauta, Janos Szentagothai, and Max Cowan. Everyone contacted was enthusiastic and the MRC ANU was officially opened in 1985. I attended its 20-year celebrations in March 2005, where its leading role in European Neuroscience was evident and had already been recognized by the election of Somogyi to the Royal Society in 2001. He is another scientist with whom I have been lucky and privileged to work.

Jim Gowans, head of the MRC cellular immunology unit in Oxford until he became head of the MRC in 1977, once said to me that it was a good idea for every scientist to change direction every 10 years or so. “It makes one young again, with no laurels to rest on.” I think he meant a sea change rather than a slight veer and he had done just that by taking on the job of running the MRC and doing it again when he became Secretary General of the Human Frontier Science Program in 1989. It was during the latter period that he was visiting the Psychology Department in connection with HFSP support for a workshop on blindsight. His words touched a chord because I liked doing new things, even at the risk of being criticized—as I have been—as a scientific butterfly. In 1985 I began two new lines of research that seemed risky at the time but have proved to be hugely gratifying, at least for me. The first was work on cortical color blindness with my friend and colleague Charles Heywood. We were both interested in prosopagnosia (agnosia for faces) when Freda Newcombe offered us the opportunity to examine the color blindness of one of her prosopagnosic patients. Twenty years on, patient MS is still densely prosopagnosic but he also remains completely color blind in the sense that he cannot reliably name a colored surface or pick out the odd color in three surface colors. It took us another 10 years to establish that his brain is nevertheless still processing information about hue and wavelength and that he is an outstanding example of how differences in hue can be used to generate the perception of contour (and therefore shape) and motion of contours even though the hue itself is invisible (for review see Heywood and Cowey, 2004). Expressed more generally, MS shows that the brain can use sensory information to generate a percept even when there is no phenomenal experience of the attribute usually attributed to that sensory information (in this case color); MS is a particularly striking example because he can paradoxically perceive chromatic contours in the absence of color perception. Several such examples have since come to light but it is still a challenge to show exactly how the brain achieves this.

An unforeseen outcome of the work on cortical color blindness is that it became embroiled in an ongoing international disagreement about the properties and functional role in perception of V4 in monkeys and man. There is no disagreement about the position of extrastriate area V4 in macaques but little consensus about whether the properties of its cells indicate that it should be regarded as an area concerned primarily with wavelength, color constancy, form perception, visual selective attention, visual search, or all of these. It would not be an exaggeration to describe some of the views expressed about V4 as arousing passionate indignation. But they seem mild when compared to declarations about the anatomical position of human V4 and whether it corresponds to the region of maximum change in regional blood flow when subjects are performing perceptual tasks involving color as opposed to a variety of form discriminations and whether the lesion that leads to cortical color blindness corresponds to human V4 or to nearby more rostral areas. When something so apparently straightforward arouses such passions it usually indicates that different methods, criteria, terminology, prejudices, or all of these are responsible. Anyone interested would get a good impression of the quarrelsome altercation by consulting Heywood and Cowey (2003); Bichot, Rossi, and Desimone (2005); Tootell et al., (2004); and Zeki (2003). I suspect that the dispute will outlast me.

The second example concerns blindsight. Although I had worked for many years on residual visual sensitivity after damage to V1 in monkeys I was not initially involved in the subsequent work on blindsight in patients with similar brain damage. Such patients showed highly significant forced-choice discrimination of visual stimuli presented in their field defects despite denying that they had seen anything (Pöppel et al., 1973; Weiskrantz et al., 1974). At the time it was still believed—not unreasonably—that damage to V1 had different effects in monkeys and humans and that so-called evolutionary encephalization of function was the explanation. The new work with patients showed that patients and monkeys were not that different after all and that studying the biological basis of the residual discrimination in monkeys and any changes in it with time or practice might be helpful in evaluating and treating patients. Blindsight also demonstrated that the perceptual effect off sensory cortical damage depend on how one assesses it: asking subjects to say yes or no about visual stimuli indicates blindness whereas forced-choice guessing uncovers good, sometimes almost perfect, discrimination. My interest in impaired color vision introduced me to the work on residual color processing in blindsight by Petra Stoerig (1987) and, after discussing it at a conference, we decided to collaborate and to study residual visual processing in patients and monkeys contemporaneously and, where possible, to combine it with neuroanatomical investigations. This was my second major change in research in the 1980s and it exceeded all initial expectations. After publishing 26 jointly authored papers I think we understand much more about not only color processing in blindsight in both patients and monkeys but also motion, contour, and the nature of awareness (for reviews see Stoerig and Cowey, 1997; Cowey, 2004). Twenty years ago I would never have guessed that a chance meeting with a young German behavioral neurobiologist would lead to such a productive scientific collaboration.

This was also a period during which cognitive neuropsychologists increasingly studied the effects on perception, usually measured by reaction times, of unseen stimuli. With respect to blindsight the usefulness of the approach was first demonstrated by Marzi et al. (1996). An unseen target in the blind part of the visual field affected reaction time to seen targets in the normal field. Sure enough, when Petra Stoerig and I tried this with monkeys (and other patients) it worked; stimuli delivered in a hemianopic region a few 100 ms before a target in the normal hemifield significantly and prominently delayed reaction times to the latter (Cowey, Stoerig, and LeMare, 1998).

But one piece in the jigsaw was missing. Before we could be certain that the work on monkeys provided a means of studying blindsight we had to show that the monkeys were like patients in not having any visual percept of visual stimuli that they could discriminate by forced-choice responding. In other words we needed a yes/no task. Petra and I resolved this by training monkeys to touch real visual stimuli but to respond in a different way on trials when no visual stimulus was delivered. The result could hardly have been clearer. The same stimuli that could easily be detected and localized by forced choice guessing were categorized as blank trials, ie., “no,” when the yes/no task was used (Cowey and Stoerig, 1995, 1997). By a simple adjustment of the way in which monkeys were tested, a longstanding paradox disappeared and as a bonus the work already carried out on the anatomical consequences of removing V1 in monkeys was instantly relevant to work on humans. For example the retrograde transneuronal retinal degeneration known for many years in monkeys (van Buren, 1963; Cowey, 1974) and confined to the color-opponent retinal ganglion cells (Cowey et al., 1989) showed why some stimuli were much more easily discriminated in blindsight and which anatomical pathways were probably responsible (Cowey, 2004).

One of the major planks of critics of work on animals, at least in the UK, is that it is scientifically irrelevant to human disorders. This accusation has often been leveled at me, by telephone calls in the middle of the night, pamphlets distributed in the center of Oxford, noisy demonstrations outside my department, and the systematic vandalizing of my car outside my home. It would be a comfort to know that at least some of my research is effective in refuting the accusation but I doubt it, for a particularly depressing aspect of the antivivisection debate is that there is no proper debate. It mostly amounts, by both sides, to a well-worn and almost ritualistic exchange of insults, clichés, and prejudices. In 40 years I have on only a few occasions witnessed or read an account of a genuine, open-minded, intellectually honest debate about the ethics of research on animals. I have read accounts of events leading up to and during the infamous but unsuccessful, criminal prosecution of David Ferrier in London in 1881, brought under the Cruelty to Animals Act, and it has an astonishing contemporary ring, as if no progress had occurred in more than a century. It has become a political, emotional, violent, and social problem rather than an intellectual and ethical one and I am less confident about the outcome than almost anything else in neuroscience.

Why Anatomy Matters

I wish I could remember which one of two eminent visual neurophysiologists in a lecture I attended in Oxford many years ago declared that “Physiology without anatomy is impossible,” meaning that we could never properly understand physiological results on the receptive field properties of cortical visual cells until we understood the anatomical microcircuity underlying them. It did not take long for my surprise to become agreement for I realized that I would never understand the residual vision, now known as blindsight, without some idea of where and how the brain processed the underlying sensory information. I will give just a single example but more can be found in Cowey (2004). There are 10 known pathways from the eye into the brain (see Stoerig and Cowey, 1998), the two most numerous being to the superior colliculus (about 1.5 x 10⁴ fibers in the macaque monkey) and the dorsal lateral geniculate nucleus (dLGN) of the thalamus (at least 10⁶ in macaques). When V1 is removed there is almost complete retrograde degeneration of projection neurons in all six principal layers of the dLGN (Michailovich et al., 1975) and it is usually assumed that the other pathways are unchanged and that they must be mediating the visual processing that underlies blindsight. The truth is rather different, for the interlaminar layers of the dLGN do not degenerate, or at least not conspicuously. These cells are part of the koniocellular, or K, projection (for review see Hendry and Reid, 2000), thought to arise from bistratified retinal ganglion cells and to signal information about wavelength (Dacey, 1994, 2000). The fact that they survive destruction of striate cortex almost certainly reflects the fact they also project to extrastriate areas such as V2, V4, and inferior temporal cortex and, as recently shown by Sincich et al. (2005), to the motion area MT. Their numbers have never been accurately assessed but they seem to be as common as magnocellular (M) cells, i.e., as many as 104on each side of the brain. This is as many as all ganglion cells in an animal like the rat, which seems to see quite well! The next step is surely to use diffusion tensor imaging (DTI) to trace surviving pathways in the human brain now that it has been shown that DTI can reveal the entire pattern of thalamocortical projections noninvasively (Behrens et al., 2003). Francis Crick often argued passionately for more, not fewer, anatomical studies on macaque monkeys as a means of understanding how billions of neurons give rise to perception, memory, awareness, etc. (Crick and Jones, 1993). He is right, but perhaps DTI will provide some answers with respect to long pathways in discrete bundles.

Transcranial Magnetic Stimulation: Panacea or Delusion

My last major technical change of direction occurred in 1995, when I read an article about reversibly disrupting cortical neurons—and visual perception—by applying a brief magnetic field above the occipital skull and inducing a similarly brief electrical field in the tissue beneath (Amassian et al., 1989). It seemed that the technique, known (strictly speaking wrongly) as TMS, must surely be useful in investigating a wide range of perceptual and cognitive functions. I purchased my first, single pulse, TMS machine speculatively and the first qualitative results were disappointing. Using myself as a subject the best I could do was produce a faint smudge of light (phosphene) in the center of my visual field by stimulation delivered above the occiput. It was while wondering what to do next that my colleague Vincent Walsh asked if he could use the equipment and try something more cognitive. Our first paper (Ashbridge, Walsh, and Cowey, 1997) demonstrated that a single pulse of TMS applied above the right parietal cortex about 100 ms after presenting a visual search array impaired performance on serial (conjunction) search but not on parallel (pop-out) search. The effect disappeared once the task had been mastered but reappeared as soon as new stimuli were used (Walsh, Ashbridge, and Cowey, 1998). We were also joined by Eric Corthout, who extended Amassian's findings by showing that there were at least four time periods between –100 and +200 ms of the presentation of a 4 ms foveal letter target at which a single TMS pulse impaired identification of the letter, indicating that TMS could be used to disentangle the contributions to perception of cortico-fugal, feed-forward and reentrant events (Corthout et al., 1999a,b; 2000a,b; 2001; 2002; 2003). From these small beginnings about 20 people were using TMS in the Oxford Psychology Department by 2005 and similar developments occurred worldwide.

TMS has been used to study many aspects of sensation, perception, learning, awareness, priming, voluntary movement, top-down planning, mood, and recovery from brain damage (Cowey, 2005). Yet it remains a controversial tool. Quite apart from the important issues of safety, it has been suggested that the exact site of action of TMS, whether it affects excitatory or inhibitory neurons or both, and how long the effects of one pulse last are all unknown or uncontrolled. These are all valid points but some have already been successfully addressed (Cowey, 2005). It is important to remember that TMS is just a tool and that it can be used well or badly, as my father taught me. It is also proving to be especially useful when used in conjunction with other techniques, notably EEG, and structural and functional MRI. It is neither panacea nor delusion but behavioral neuroscience would be poorer without it.

Helping to Administer Neuroscience

A common complaint is that there is too little time for research because “there is too much admin.” But there is good and bad administration of science. The bad includes rampant petty bureaucracy, needless and tedious inquiries whose results disappear into untraceable filing cabinets, micro-management by administrators, unnecessary mission statements, unrealistic and overspecified goals, and strategic planning by nonscientists or failed scientists. The good includes the difficult business of creating and preserving the best possible scientific environment. When I was young I imagined that if something was scientifically desirable it would just happen. I had to learn that things only happen if people work hard to bring them about and that doing so actually helps one's own science.

My first involvement in promoting neuroscience occurred just after coming to Oxford. Following a meeting in 1967 called by the Organisation for Economic and Cooperative Development (OECD) to consider which areas of interdisciplinary research to encourage, a small group of neuroscientists led by Larry Weiskrantz and including Konrad Akert, Hans Kuypers, and (I think) Otto Creuzfeld lamented the fact that European brain scientists from different disciplines and countries rarely met professionally, let alone collaborated. They agreed that a new international society was needed, not just more funds for existing national organizations. I subsequently joined the group and, as the youngest member, incautiously agreed to be its secretary. Following many letters to major neuroscientists in western Europe, we formed a steering committee consisting of Akert, Cowey, M. Frankenhaeuser, Kuypers, Paillard, Ploog, Scherrer, van Hof, and Weiskrantz. We prepared and circulated an announcement of our intention to start a new international and interdisciplinary Society subsequently called the European Brain and Behaviour Society, or EBBS. The steering committee arranged a meeting of about 30 brain scientists in Rotterdam in April 1969 to plan the organization of the society (aims, rules, membership, etc.) and EBBS was formally started on April 15. Larry Weiskrantz and Elizabeth Warrington were appointed President and Secretary, respectively. The first annual meeting, hosted by Jacques Paillard, took place in Marseilles 6 months later. I have glossed over how much work was involved but the outcome was gratifying, with one dramatic and painful exception. Jan Bures had been an enthusiastic and polite but outspoken member of those assembled in Amsterdam in 1969. He continued to support EBBS but his views about international science were not welcomed by the governing regime in Czechoslovakia following the Russian invasion of 1968 and he was progressively stripped of his scientific stature within his own country together with some of his facilities. Naturally he simply became even more famous in the West but for 18 years he was unable to travel to any western country to lecture or even just to attend meetings. These events are movingly described in his autobiographical chapter in volume 4 of this series (Bures, 2004).

EBBS held its 37th annual meeting in 2005 in Dublin and a glance at the program shows that its core is still behavioral neuroscience. At the first annual meeting the committee met representatives of IBRO, who were concerned that EBBS might be trying to take over some of IBRO's responsibilities. It was an uneasy meeting but much helped by the fact that one of the IBRO representatives was Han-Lukas Teuber, who knew many of the EBBS committee and who proved to be a skilled negotiator and adroit mediator. One reason for mentioning these events is their extraordinary resemblance to those occurring in the United States at about the same time (Doty, 1987). As Doty points out, in 1965 a group of brain scientists “came to recognize the diffuseness of neuroscience, a part of many disciplines but lacking a focus of its own.” A new society was needed, “But what kind of society should it be?” After several meetings of the group, the Society for Neuroscience was formed in July 1969, just 3 months after EBBS. As in Europe “There was significant sentiment against forming a new society ... from the more established scientists already satisfied with their professional ties.” Given that the reasons for establishing EBBS and SfN were so similar, why has the latter been so much more successful in terms of membership and prestige? With the usual benefit of hindsight and a little insight it is not difficult to see why. First, the SfN decided to have its own journal—the Journal of Neuroscience—whereas EBBS voted not to have a journal despite overtures from both Brain Research and Behavioural Brain Research. I think the decision was a mistake for neuroscience in Europe although it was finally rectified by the creation of the European Neuroscience Association a few years later and, shortly thereafter, the European Journal of Neuroscience. Second, the SfN boldly decided to cover the gamut of subjects under the umbrella of neuroscience, both in its annual meeting and its journal, whereas EBBS initially emphasized the behavioral component. I recall Hans Kuypers protesting at the policy of EBBS in refusing to allow anatomical contributions to the annual meeting unless they made reference to their relevance to some behavioral problem. For anatomy also read pure physiology, pharmacology, biochemistry, and neurochemistry. Fortunately the mistake was finally recognized by the formation of the Federation of European Neuroscience Societies (FENS), which is about as close as one could get to the SfN while still preserving the independence of the component organizations. I learned a lot about people and their scientific politics by my association with both EBBS and EJN. From 1986 to 1988 I was President of EBBS and at that time the trickiest part of the job was still its relationship with ENA!

In 1976 I began to serve on MRC Committees and had I realized from the outset how many years I would serve I might have declined the initial invitation. I was a member of the Neurosciences Grants Committee for 5 years and chairman for 2 years. It was followed by 4 years on the Neuroscience Board, which looked after the more long-term program grants, MRC Units, and scientific policy in the neurosciences. I was chairman of the board for 2 years. Finally, for 4 years I served on council, which dealt with MRC policy (which included long-term planning) for much more than just neuroscience. The grants committee provided an unparalleled opportunity to discover who was doing what in UK Neuroscience, the Board made it possible to meet many of them on subcommittee visits to MRC establishments, and the council taught me why and how to prioritize. As there were never enough funds to cover all grant applications, or all proposals for radically new lines of work, awarding funds necessarily reflected both scientific excellence and medical importance, which often seemed not to be highly correlated. This is all familiar to those who have followed this path but I still meet colleagues who do not understand why science funding works the way it does.

With respect to my own neuroscience in Oxford I was especially helped by having served on MRC official bodies. In the late 1980s Larry Weiskrantz and I asked to see the, then, head of the MRC, Dai Rees, about how best to promote interdisciplinary behavioral neuroscience in Oxford. We were not proposing that people should be made to collaborate, which does not work but is increasingly required by the misguided policy of some funding organizations that earmark funds for projects that involve scientists from different disciplines in different countries. We simply wanted to make it much easier for those who wanted to collaborate to do so. The MRC was already considering its own scheme to create and fund a small number of Interdisciplinary Research Centres (IRCs) and Dai Rees suggested that Oxford should put in an application. A small committee of the usual suspects (Blakemore, Cowey, Guillery, Rolls, Stein) agreed to coordinate the attempt to get over 100 neuroscientists to agree on a final proposal that was based on suggestions from the entire community and was agreeable to the University, which was initially suspicious about a new supradepartmental group in a conservative and rigidly compartmentalized university whose science was organized along departmental lines. It took over a year—an eyeblink in a university that is 700 years old—but the IRC in brain and behavior officially began in 1990. I was the first director, with Colin Blakemore and Edmund Rolls as codirectors. By longstanding agreement this changed with the renewal in 1996 when Colin became the director until 2002. Many of us, including some on the founding committee, were anxious about whether this center without walls would work but it was a gratifying success. Its funds allowed us to appoint scientists whose interests and skills (optical imaging, computational neuroscience, confocal microscopy, neuroimaging, software development) crossed the old departmental boundaries and to purchase capital equipment that was not readily affordable by any one department. Many neuroscientists from outside Oxford became members of the IRC by virtue of collaborating with it and within a few years we had about 300 members and a portfolio of projects that would have been unthinkable without the IRC. In the early 1990s Colin Blakemore spearheaded a similar application to the McDonnell-Pew Foundation for funds to create a Centre for Cognitive Neuroscience in Oxford. The membership was little different from that of the IRC but its intellectual focus was less cellular/molecular and more systems/philosophical. Colin was its director but several of us served on the boards of both centers. The McD-Pew Board introduced network grants to cover the costs of travel and accommodation for international collaborations and there were about 10 of these at any one time. They proved to be a remarkably cheap and efficient way of pump-priming international collaborations in neuroscience. For example they funded my own collaborations with Petra Stoerig in Germany and Lucia Vaina in Boston. Together, the two centers also organized and largely funded the annual Oxford Autumn School in Neuroscience, under the direction of Edmund Rolls. There have now been 12 such schools, each one covering four topics and with more than half of the lecturers from outside Oxford. About 300 graduate students and post docs attend, many from abroad, and for some of them it is their first taste of neuroscience. I believe that the IRC and the McD-Pew Centre flourished because they were created and managed entirely by the scientists whose needs and aspirations they served.

What's In a Name?

There is still no undergraduate degree in neuroscience or a Department of Neuroscience at the University of Oxford, despite the fact that the number of neuroscientists is as high or higher than at any other UK university. Colleagues and students often comment on this anomaly. Does it matter? I think it does. Prospective undergraduates have heard of neuroscience but cannot find it listed as a degree subject. The closest they can get to something resembling a degree in neuroscience is to take the joint honors School of Physiology, Psychology, and Philosophy (PPP) and opt to take only the first two of the Ps. But this still omits whole swathes of neuroscience. Other UK universities swiftly recognized the problem and that the solution does not necessarily require new buildings—the dread of university treasurers and accountants. It does require more than a self-service smorgasbord of parts of existing subjects but in truth the extra work is fine-tuning rather going back to the drawing board. Perhaps Oxford takes literally the idea that “if one can't be first it is better to be last.”

Things are much better with respect to formal postgraduate teaching of neuroscience. In 1988 several Oxford neuroscientists, led by Ray Guillery (then Professor of Anatomy), proposed that the University should introduce a taught M.Sc. in Neuroscience. The chief justification was that postgraduate research in neuroscience required both knowledge and practical skills that many prospective research students lacked. I have already mentioned that the University of Oxford was displeased when, exasperated by the tardiness of the University and on behalf of my colleagues, I arranged a meeting of neuroscientists to discuss the issue and also invited members of the central administration. I now realize that the administrators were probably infuriated by such unilateral action. Happily, the pressure to introduce the Neuroscience M.Sc. was irresistible, although the University rightly insisted that any postgraduate course must never consist of a collection of undergraduate lectures; it must be genuinely postgraduate. The outcome, after much planning, was a 12-month course in neuroscience that consists entirely of new lectures, practical classes, and research projects. In advertising the course, it was stressed that we welcomed applicants whose first degree was not in neuroscience. As a result we received applications from students with a background in subjects as diverse as engineering, math, zoology, computation, and social psychology. As there were, and still are, more than 100 applicants each year for about 20 places, the chosen few are a pleasure to teach and most have gone on to successful careers in neuroscience. If I had to help again in designing such a course I would make very few changes. With respect to myself, the requirement that the new course must not consist of a rehash of existing lectures meant, as one of the organizers, that I had to lecture on new topics. I decided that after 35 years of lecturing on perception I would instead teach the history of neuroscience, starting with the Greeks whose ideas had inspired my friend Charlie Gross 40 years earlier (Cowey, 2001). With respect to teaching, it was my last major innovation and I discovered that the vast majority of young neuroscientists have not the faintest idea of the history of their subject and, therefore, the reasons why they are studying particular phenomena. Perhaps it is just my age; as Hans Lukas Teuber once said at a conference, when asked by Karl Pribram why he always talked about the past, “How else can I be original?”

Functional Neuroimaging

At a Winter School in Switzerland in 1990 I met Per Roland, who described the exciting discovery, shown by positron emission tomography (PET), that specific brain regions increase or decrease their blood flow according to what the person being scanned is doing. Per was studying the brain regions concerned with language, movements, and thought. I suggested that we collaborate on a study of the cortical regions activated (or inhibited) when subjects were discriminating shape or brightness or color or motion or depth-from-retinal disparity. The outcome was a collaboration, involving several colleagues in Stockholm and Oxford, in which we attempted to reveal the occipital and temporal cortical areas activated during a task in which the subject had to indicate which of three stimuli was different from the other two but where the odd-one-out was defined only by shape or brightness or color or texture or motion (Gulyas et al., 1994a,b; 1998). I still believe that the paradigm is one of the best for revealing functional activations associated with specific sensory attributes. However, PET could not provide the spatial resolution needed to distinguish between adjacent or overlapping functional visual areas and it was not possible to study the same subject repeatedly because of the restrictions on the amount of radioactivity that could be delivered each year. After I was first scanned by PET I was disconsolate to discover that it could not be repeated for a year. Something else was needed, namely functional magnetic resonance imaging (FMRI).

FMRI is now such an established technique that it is extraordinary to recall that as recently as 1994 the regional changes in cerebral blood flow that it seemed to reveal were sometimes dismissed as artefacts caused by head movements. As a member of an MRC visiting committee to the MRC functional imaging unit at the Hammersmith Hospital in London I listened to a distinguished physicist declare that FMRI was a waste of time and money. He was right to say what he believed but the world now knows that he was wrong. Fortunately the chairman of the visiting committee was George Radda, then Director of the MRC Magnetic Resonance Spectroscopy Unit in Oxford, who was convinced that the signals were not artefacts. A couple of years later he and I and John Newsome-Davies (Professor of Clinical Neurology in Oxford and my successor as chairman of the MRC Neuroscience Board, which meant that I knew him well) got together to discuss how best to introduce FMRI to Oxford. We usually met in the MRS Unit at 7:30 AM or early evening so that we could get on with other things as usual during the rest of the day. It took about 2 years to plan the new unit and to raise the funds from a variety of sources. At a crucial stage the University agreed to lend us the final million pounds (now repaid) and Paul Matthews, then at McGill, agreed to be the first Director. Nine years on and under his direction, Oxford's center for functional brain imaging is a leading international center of research in cognitive neuroscience (especially pain, recovery from stroke, visual attention, intersensory perception, topdown processing), image analysis, using diffusion tensor imaging to study anatomical pathways, and the physics of magnetic imaging. However, from an autobiographical point of view I want to stress that none of this would have happened without a concerted effort from a group of friends who shared experience and contacts in the national administration of biomedical neuroscience. All those hours in London bore fruit yet again.

On a slightly different point, no one appointed to a scientific position in FMRIB was more than 40 years old and, given the choice, I would always go for the younger candidates. To do so is becoming more difficult in UK universities as they vie with each other to excel in the farce called “research assessment exercise” by trying to attract aging stars whose publication record and grant income inflate the score and therefore boost the funds awarded to the university from central government. A young Charles Darwin would have difficulty in getting a job nowadays because his publication record would be too poor!

Coda

Our lives often appear to follow a straight course, like time's arrow. Any perturbations get smoothed out and many of them are mental and never observed by anyone else. But when I reflect on my own life I can see how nonlinear it can be. I have changed my aspirations, beliefs, preferences, methods, and skills many times in response to changing circumstances, and never more so than in science. I started as a botanist, changed to zoology, then to psychology (with a preference for animal learning theory) and finally to systems neuroscience, although the term did not exist then. Within the latter I was initially interested in the phenomenon of perceptual consciousness and awareness in monkeys (Cowey and Weiskrantz, 1963), put that to one side for more than 20 years, then returned to it after 20 years. If accused of dabbling or spreading myself too thin I might have to plead guilty. But science needs dabblers and especially in a subject as broad as neuroscience. To return for a moment to interdisciplinary research, it is often assumed that it will successfully take place as long as funds are provided for it and given to a group of investigators who say, because they want the funds, that they will collaborate even though they are widely dispersed. But at some point interdisciplinary thinking has to go on inside one head. Dabblers help here.

Another factor that is often not apparent in a scientific career is the element of luck. I did not plan my career in any detail at any point, following instead a very broad interest in the brain and how it controls behavior and taking opportunities as they arose. It was not a random walk but there was no road map either. I was fortunate to meet several outstanding students, post docs, and colleagues with whom I collaborated or from whom I learned things. If I had never met Richard Gregory, Larry Weiskrantz, Walle Nauta, Charlie Gross, Hugh Perry, Peter Somogyi, Petra Steorig, Charlie Heywood, or Vincent Walsh (to name only a few), my career would probably have been very different. Free will certainly exists but acting on it is constrained by luck.

Finally, I have always been struck by the extent to which science is, almost everyday, a social activity. I expect the solitary scientist still exists but I have never encountered one. For me one of the greatest pleasures in a life of science is interacting with students, technicians, and colleagues. They have shaped my career but there are too many of them to mention here. The most influential of all is my wife Pat, but as she is not a scientist her huge influence on my life will have to wait for a different kind of autobiography.

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David R. Curtis

BORN:

Melbourne, Australia

June 3, 1927

EDUCATION:

University of Melbourne Medical School, M.B., B.S. (1950)

Australian National University, Canberra, Ph.D. (1957)

APPOINTMENTS:

John Curtin School of Medical Research, Australian National University (1954–2005)

Department of Physiology (1954–1973)

Department of Pharmacology Professor and Head (1973–1988)

Division of Physiological Sciences, Later Neuroscience (1988–1989)

Director and Howard Florey Professor of Medical Research (1989–1992)

University Fellow (1993–1995)

Visiting Fellow (1995–2005)

HONORS AND AWARDS (SELECTED)

Fellow, Australian Academy of Science (1965)

Council (1974–1977)

Burnet Lecturer (1983)

President (1986–1990)

Fellow, Royal Society of London (1974)

Fellow, Royal Australasian College of Physicians (1987)

Companion, Order of Australia (1992)

Centenary Medal (2003) Honorary Member

Australian Physiological Society Australian Neuroscience Society Australian Association of Neurologists Neurosurgical Society of Australasia

Honorary Fellow

British Pharmacological Society

David Curtis pioneered the use of microelectrophoretic techniques to examine the effects of potential synaptic transmitters on single identified neurons in the mammalian central nervous system (CNS) in vivo. He similarly examined the effects of compounds that blocked or enhanced synaptic transmission at the synapses of particular excitatory or inhibitory pathways. He thus contributed to the identification of a number of central transmitters, particularly glycine, gamma-aminobutyric acid (GABA), and aspartic and glutamic acids.

David R. Curtis

Family and Schooling

I was born at the beginning of the economic depression of the late 1920s–1930s. At this period our family circumstances were not particularly affluent because the salaries of public servants had been reduced by the government of the day. I was very fortunate, however, in having parents very aware of the value of education, although neither had attended a secondary school. My father, Edmund David Curtis (1900–1973), was the son of a building contractor. He had left school at the age of 16 to join the Postmaster General's Department (PMG), a Federal Department then responsible throughout Australia for all postal, telegraph, and telephone services, and later national AM and FM radio and television transmission.

By dint of night classes, correspondence courses, and in-service training, in what was a developing technological organization, my father progressed through the PMG to achieve engineering qualifications in 1924. At the time of his retirement in 1963, as Head of the PMG Engineering Division in Victoria and a Member of the Institution of Engineers Australia, he had participated in the replacement of Morse code instrumentation by teleprinters, in the transition from manual to automatic telephone exchanges, in the introduction of national radio and later television, and long-distance transmission by coaxial cable and by microwave radio. He had a particular interest in these developments as Head of the Research and Development Laboratories in Melbourne.

Hence I was strongly influenced by a home environment of scientific inquiry, particularly in matters electrical and mechanical. Education in mathematics and later physics and chemistry was stressed, and a well-equipped workshop was available at home. I have strong early memories of a childhood being involved in the construction of electrical, and later electronic, apparatus including radio receivers and audio amplifiers, and of mechanical equipment, as well as in the design and manufacture of items of wooden furniture. A major undertaking in 1943–1944 was my construction of a single channel ink-recording electrocardiograph, using thermionic tubes and other components then becoming available at Disposal Stores. All members of the family tested proved to be alive, and this project was important as an introduction to a maintained interest in electronics, which was of inestimable value to my subsequent eventual career in neurophysiology.

Shortly after my birth my family had settled in the Melbourne suburb of Ormond, and from 1932 until 1938 I attended the local State Primary School. This was followed by 2 years at the Tooronga Road Central School in Malvern where I first came in contact with science. My academic achievements led to the award of a Junior Government Scholarship, which enabled me to attend the Melbourne Boys High School for 4 years.

This was a selective high school, and I was fortunate in having outstanding teachers in pure and applied mathematics, physics, and chemistry, and access to very good laboratories. In the December 1944 state-wide matriculation examination, a requirement for university entry, I gained Honors in both mathematical subjects and the State Exhibition in physics and was granted a Senior Government and a Gowrie Scholarship tenable at Melbourne University. These results qualified me for entry into either the Medical or Engineering courses. Biology had not been available as a subject at the Boys High School, but my parents had encouraged me to read a number of general biology text books. As a consequence, I chose Medicine rather than Electrical Engineering, a decision I have never regretted.

Melbourne University Medical School 1945–1950

This was then the only medical school in Melbourne. The physics and chemistry syllabuses in the first year of the course were less demanding than those for the matriculation examination. Thus, I was able to concentrate on zoology and botany, and the less academic aspects of university life. Professors influencing my interest in the nervous system in the preclinical years included Roy D. Wright (Physiology), whose somewhat obscure lectures necessitated long periods with textbooks, and Sydney Sunderland (Anatomy) who was an outstanding neuroanatomist. Pharmacology, a minor component of the physiology course, was more relevant to materia medica than to scientific pharmacology, and the CNS scarcely featured in Biochemistry.

My preclinical examination results included the Exhibition in physics and Honors in pathology, and my three clinical years were spent at the Royal Melbourne Hospital adjacent to the University, with shorter periods at the Royal Women's and the Children's Hospitals. At that time there were no university clinical departments in the teaching hospitals. Although some medical and surgical lectures were given at the University, the bedside teaching of medical students depended on honorary physicians, surgeons, and specialists appointed by the hospitals to care for patients.

Final examination results, which included Honors in Medicine and in Obstetrics and Gynecology, and the award of the degrees of Bachelor of Medicine (MB) and Bachelor of Surgery (BS), led to my appointment as a Junior Resident Medical Officer (RMO) at the Royal Melbourne Hospital from January 1951.

Hospital Appointments 1951–1953

Life as a RMO in the then major City Hospital in the 1950s was never meant to be easy. Hours of duty were long, nights “off” were rare, and weekends off even rarer. Both my first year as a Junior RMO (1951) and a second as a Senior RMO were periods of intensive activity and learning in medical, surgical, emergency, and specialty wards. The only vacation I remember was an unpaid week in August 1951 when I married Lauri (nee Sewell), my most wonderful, understanding, and supportive wife.

Neurology and neurosurgery had been regarded as too specialized for medical students, but I was particularly fortunate in both my RMO years to enjoy terms in the Neurology/Neurosurgery Ward with two distinguished clinicians. The neurologist was Dr E. Graeme Robertson, a Melbourne graduate, who while training at the National Hospital for Nervous Diseases, Queen Square, London, had collaborated in research in the early 1930s with Derek Denny-Brown, a former colleague of John Eccles in Oxford and later Professor of Neurology at Harvard. The neurosurgeon Mr. Reginald S. Hooper, was also a Melbourne graduate and had trained in Oxford with Sir Hugh Cairns. His assistant, Mr. John B. Curtis (not related to my family) had also trained in Oxford. All were supportive and patient with a RMO whose interests were becoming centered on basic research rather than on further clinical involvement.

Third-year resident appointments at The Royal Melbourne Hospital were limited to potential physicians or surgeons training toward recognition as specialists. Hence I applied for the position of Neurological Registrar at the Alfred Hospital, which also was affiliated with Melbourne University. Here in 1953 I came under the influence of Dr. Leonard B. Cox and his assistant Dr. John A. Game who had trained at Queen Square, London.

Until their deaths I remained personally in touch with all five clinicians, particularly through meetings of the Australian Association of Neurologists and the Neurosurgical Society of Australasia. I later became an Honorary Member of both bodies.

This continuing excellent clinical experience, however, confirmed my resolve to undertake laboratory-based research relevant to neurological disorders rather than to be involved in clinical neurology or neurosurgery. Early in 1953 I read Sherrington's 1906 monograph Integrative Action of the Nervous System followed by his 1932 monograph Reflex Activity of the Spinal Cord, of which one of the coauthors was John Eccles. I failed to gain a grant from the National Health and Medical Research Council (NHMRC) to commence research in Professor Wright's Department of Physiology in 1954, and he suggested that I write to Eccles. Wright had played a major role in the foundation in Canberra of the Australian National University (ANU) in 1946, and in the subsequent appointment in 1951 of Eccles to the Foundation Chair of Physiology in the University's John Curtin School of Medical Research (JCSMR).

Canberra

In 1901 the Commonwealth of Australia was created by the federation of the then six separate states, and, after much argument and negotiation, a site for the Australian Capital Territory was chosen in 1909, 240 km southwest of Sydney. Planning for the capital city began in 1911, and the name Canberra was selected in 1913. The Federal Parliament, which in the meantime met in Melbourne, moved to Canberra in 1927. At the time of the creation of the ANU in 1946 Canberra's population was 14,100, in 1953 it was 28,645, and by 2004 this had increased to 324,000.

John Curtin School of Medical Research

The ANU had been established in 1946 by the Federal Government as an all-research university (Foster and Varghese, 1996), and the JCSMR was one of four original Research Schools. John Curtin had been Prime Minister from 1941, when planning for the ANU had begun, until his death in 1945. Sir Howard Florey, an Australian who was then Professor of Pathology at Oxford, had a major influence on the origin and development of the JCSMR (see Fenner and Curtis, 2001). In 1953 the early JCSMR departments were housed in “temporary” buildings, which are still in use by the ANU, and the “permanent” building, now (2005) in the course of demolition and replacement, was occupied early in 1957.

Eccles had moved from Dunedin in September 1952 and commenced research in Canberra in March 1953 (see Curtis and Andersen, 2001). I wrote to him in August 1953 and received a very encouraging letter and a number of recent reprints. We arranged to meet in Melbourne in November when he was to lecture about his recent intracellular studies of the ionic basis of synaptic transmission in the mammalian spinal cord. At this time I had begun reading his 1953 monograph The Neuro-Physiological Basis of Mind, which had introduced me to an entirely new literature dealing with membranes, ionic conductances underlying resting, and action and synaptic potentials, all subsequent to my lectures in physiology some 6 years earlier.

I was fascinated by the lecture, which included much unpublished material, and after a short discussion of my background and interest in the pharmacology of central synaptic transmission I was virtually assured of a 3-year Research Scholarship to commence in his laboratory in February 1954. My appointment was confirmed soon after this by the ANU, which also provided a house for me and my family about 2 km from the University.

My wife and I, and our 16 month old son, Christopher Mark, arrived in Canberra on February 16. Our daughter Belinda Jane was born later that year in October. We had some difficulty in accepting that this rather small town was destined to be the nation's capital. February 16, 1954 is a very significant date in the history of science in Australia, because on that day Queen Elizabeth II in person founded the Australian Academy of Science by presenting its Charter to a number of Petitioners, which included 10 Fellows of the Royal Society of London then resident in Australia. This was the second time that a reigning monarch had presented a Charter to such a body since 1662, when King Charles II had presented his Charter to the Royal Society of London. Eccles (FRS 1941) was one of the petitioners, served on the Academy's inaugural Council and was its second President (1957–1961). I was later elected to the Academy in 1965 and was its eleventh President (1986–1990).

JCSMR Department of Physiology

In 1951 Eccles' outstanding achievement in Dunedin had been the intracellular recording of resting, synaptic and action potentials from spinal motoneurons in vivo, in collaboration with Jack Coombs and Laurence Brock. These results led him to discard his electrical hypotheses of central excitatory and inhibitory synaptic transmission, and to accept that these processes were chemical in nature. Another significant finding in Dunedin was that the convulsant alkaloid strychnine blocked the short latency and duration “direct” inhibition of spinal motoneurons. His aim in Canberra was to extend his research to provide further understanding of synaptic transmission in the mammalian CNS.

The Department's temporary (1953–1957) laboratories in a long prefabricated “hut” included three electrically shielded rooms, an electronics/mechanical workshop, a photographic darkroom, and an excellent range of specialized equipment. Apart from oscilloscopes, few items of appropriate apparatus were then available commercially. In Dunedin Jack Coombs, a brilliant physicist, had designed an innovative, versatile, reliable, and readily operated electronic stimulating and recording unit (the ESRU), and a number of these had been manufactured in New Zealand for the new Department in Canberra.

Coombs accompanied Eccles to Canberra and had also designed stable and low noise amplifiers, “cathode-follower” input stages necessary for recording through high-resistance electrolyte-filled microelectrodes and many other items of equipment. All of these initially depended on thermionic “valves,” and radio-B “dry” and “lead-acid” batteries. Oscilloscope traces were photographed on still or moving 35-mm film using Grass kymograph cameras, and averaging was performed by superimposition of many photographed traces. Many hours were spent in measuring filmed responses and in calculating results using logarithmic tables or slide rules, and later a hand-cranked calculator.

Eccles had appointed an excellent and very helpful technical staff, including Arthur Chapman, who had previously been his laboratory assistant in Oxford, Sydney, and Dunedin, and Gerry Winsbury, an innovative and skilled engineer. Much of the mechanical equipment, including sturdy animal frames, micromanipulators, and microelectrode “pulling” machines, was designed in the Department, and was made in the Department or by members of the JCSMR main workshop.

The major contributions of Eccles to CNS neurophysiology in Oxford, Sydney, and Dunedin had depended on the use of cats. Accordingly, arrangements were made in Canberra to provide an adequate supply of these animals for the continuation of his and his colleagues' research.

Introduction to Research

My introduction to neurophysiological research in 1954 was to observe the Coombs, Eccles, and Paul Fatt team completing their major study, which had begun a year earlier, of the biophysical properties of the membrane of spinal motoneurons and the nature of the ionic events underlying excitatory and inhibitory post synaptic potentials (EPSPs and IPSPs). I thus acquired knowledge of the animal preparation, including the dissection of hind limb peripheral nerves, lumbar laminectomies, the procedures necessary to maintain anesthetized cats for 24 hours or longer, and the preparation and filling of single- and double-barrel microelectrodes, then pulled by Fatt by hand over a small flame.

Eccles, Fatt, and K. Koketsu were also completing a study of the cholinergic excitation by impulses in motor axon collaterals of ventral horn interneurons that monosynaptically inhibited motoneurons, a recurrent inhibition blocked by strychnine. They named these interneurons “Renshaw” cells in honor of Birdsey Renshaw (1911–1948) who had earlier at the Rockefeller Institute in New York recorded their action potentials extracellularly. In addition Eccles, Fatt and Sven Landgren were engaged in a study of “direct” short latency and duration inhibition in the lumbar cord, which proved to be disynaptic. “Direct” IPSPs were shown to be blocked by intravenous (IV) strychnine whereas monosynaptic EPSPs were not affected.

There was indeed a wealth of research activity, ready access to experienced investigators, particularly Eccles, for advice and many techniques with which to become familiar. Furthermore, the developing JCSMR library was located in the same building, with continuous access to an accumulating range of current and back-numbers of all major neurophysiological journals. Friday afternoon seminars dealt with new results, drafts of papers in preparation, and critical analyses of other investigators' publications. Hours of experimentation were long, often exceeding 24 hours, generally twice weekly. I had no other means of transport than a bicycle, but I rapidly became accustomed to very early morning arrival at the Department and a return home in the early hours of the next day, despite frequent and severe winter frosts in Canberra.

My first direct hands-on involvement in research was with Coombs and Landgren in mid-1954 in the extracellular recording and plotting of field potentials in lumbar spinal segments generated at areas of synaptic excitation by impulses in different groups of muscle and cutaneous afferent fibers. These fiber groups were characterized by their electrical thresholds and conduction velocities. A requirement for straight single-barrel microelectrodes led to the manufacture of a primitive spring loaded puller and the use of an electrically heated coil to melt the glass. This ultimately led to my involvement in the development of a considerably more sophisticated gravity and solenoid driven puller capable of dealing with multibarrel micropipettes (see Curtis, 1964).

Tetanus Toxin and Strychnine

In 1905 Sherrington had noted that the effects of tetanus toxin on spinal reflexes were similar to those of strychnine and proposed that both converted inhibition into excitation. In late 1954, as my introduction to neuropharmacology, I joined Eccles and Vernon Brooks in a study of the effects of tetanus toxin on a number of short latency and duration inhibitions of monosynaptic spinal reflexes by single volleys in a variety of muscle and cutaneous afferent fibers. Recurrent inhibition mediated by Renshaw cells was also examined. The toxin was injected either into a peripheral muscle nerve or directly into the spinal ventral horn in order to initially localize its action so that reflexes and inhibitions on the contralateral side could initially be used as controls. These experiments usually extended for 24 hours or longer. Like strychnine, the toxin enhanced polysynaptic but not monosynaptic spinal reflexes and diminished and eventually abolished all of the inhibitions studied. Because the toxin appeared to have no effect on field potentials generated by interneurons on the “direct” and recurrent inhibitory pathways, it thus appeared to act either preor postsynaptically at spinal inhibitory synapses. This study resulted in my first coauthorship of a letter to Nature and a paper in the Journal of Physiology.

Subsequently in 1955–1956 I showed that IV strychnine also blocked all of the short latency and duration inhibitions that had been shown to be reduced by tetanus toxin, as well as the inhibition of lumbar extensor muscle monosynaptic reflexes produced by stimulating ipsilateral forelimb cutaneous afferent fibers. Another type of “descending” inhibition, the reduction of lumbar monosynaptic reflexes by electrical stimulation of the anterior lobe of the cerebellum, was also blocked by tetanus toxin locally injected into the lumbar spinal cord.

Many years later (see later), whereas strychnine was shown to be a selective postsynaptic antagonist at glycine-mediated (glycinergic) inhibitory synapses, tetanus toxin was shown to reduce transmitter release at both glycinergic and GABA-mediated (gabergic) central inhibitory synapses.

Another neuropharmacological study early in 1955 with Eccles and Rosamond Eccles involved the effects of intra-aortic administered drugs on lumbar dorsal-ventral root monosynaptic reflexes, all branches of the aorta below the renal arteries except the lumbar arteries to the spinal cord having been ligated. The transient reduction of reflexes by nicotine and acetylcholine (ACh), the enhancement of the effect of ACh by IV physostigmine, and the reduction of the actions of both ACh and nicotine by either IV dihydro-B-erythroidine or strychnine indicated that the inhibition was the consequence of the direct excitation of Renshaw cells.

Motoneurons

I was fortunate early in 1956 to join Eccles and Coombs in an analysis of orthodromic, antidromic, and directly excited action potentials recorded intrasomatically from motoneurons in the lumbar spinal cord of the cat and an analysis of the factors determining the generation of an impulse propagating into motor axons. Measurements were also made of the electrical properties of the motoneuron membrane as a means for estimating the time course of transmitter action underlying EPSPs and IPSPs. This collaboration with Eccles was later extended to a study of the amplitude of EPSPs, as a measure of transmitter release, during and after repetitive stimulation of the monosynaptic pathway.

Another project at this time was collaboration with Eccles and Anders Lundberg in recording action and synaptic potentials intracellularly from neurones in Clarke's column, neurones of origin of the dorsal spinocerebellar tract. Both this, and a similar study early in 1975 with Kres Krnjevic and Ricardo Miledi of the shortest latency inhibition of sacral motoneurons by impulses in low threshold contralateral dorsal root fibers, indicated the involvement of an inhibitory interneuron in these types of inhibition.

I submitted my Ph.D. thesis (Synaptic Transmitters in the Spinal Cord) in July 1956 and was admitted to the degree in December, which was awarded in May 1957. In the meantime, in July 1956 I had been appointed a Research Fellow (nontenured) in the Department of Physiology. Promotion to the tenured position of Fellow followed in December 1957.

Neuropharmacology

In January 1957 the Department of Physiology moved into the new JCSMR building. The additional space enabled the expansion of the staff and an opportunity for an increased interest in CNS neuropharmacology and neurochemistry. There were six large laboratories, each with an airconditioned shielded room, studies for each member of the academic staff and research students, mechanical and electronic workshops, a dark room, and a room for histology. Since 1953, despite the somewhat remote location of Canberra, the reputation of Eccles and the high quality and originality of the research being carried out continued to attract numerous distinguished scientists from abroad. By 1966 when Eccles moved from Canberra to the United States, 74 investigators from 14 countries had collaborated in research and published with him.

Microelectrophoresis

Now with my own laboratory, I was able to direct my research toward the pharmacological aspects of central excitatory and inhibitory synaptic transmission. Identification of the transmitter of a particular pathway would enable the rational development of therapeutic agents with specific effects at its synapses, where defects of transmission resulted in human neurological disorders. Additionally, knowledge of transmitters could also provide an explanation of the effects of known drugs and toxic agents on the nervous system.

As an initial step in developing appropriate techniques I chose to make a further study of the cholinergic excitatory synapse between motor axon collaterals and spinal Renshaw cells. This had been investigated in 1953 by Eccles, Fatt, and Koketsu and their findings, as well as the results I had obtained with Eccles and Rosamond Eccles in 1955, suggested that a blood–brain barrier prevented the access of some systemically administered compounds, including ACh, to central synapses.

Additionally, when compounds are administered systemically or topically, difficulties arise in ascribing the effects on central neurons in vivo solely to actions at specific central synapses under investigation. Hence, there was a need to combine extra- or intracellular recording from single anatomically and physiologically defined neurones with the administration of compounds of pharmacological interest directly and in a controlled fashion in their immediate environment. Pressure injection was not suitable because of leakage from micropipettes and the displacement of neurones at the injection site.

Local administration was clearly desirable, and the technique used earlier by William Nastuk, and by Bernard Katz and Jose del Castillo, to investigate the chemical sensitivity of the end-plate of skeletal muscle fibers in vitro was considered to be particularly appropriate. For most compounds of interest a suitable salt can be chosen which dissociates in aqueous solution and for which the complementary anion or cation is pharmacologically inactive. Consequently the diffusional efflux (leakage) of the active ion from the orifice of a glass micropipette containing the solution can be reduced by passing a suitably directed electrical (retaining) current through the pipette, and the active ion ejected by reversing the direction of the current flow (see Curtis 1964).

In these earlier in vitro studies, intracellular recording microelectrodes and extracellular micropipettes were attached to separate micromanipulators. Because such a procedure is impracticable when dealing with single neurons located within CNS tissue in vivo, recording microelectrodes and drug-containing pipettes need to be attached to one micromanipulator. Consequently multibarrel “microelectrodes” were designed and made in Canberra. Extracellular neuronal action potentials were recorded using the central barrel of five- or seven-barrel assemblies. The blanks were manufactured by the JCSMR workshop's skilled glass blowers, and drawn out to the desired shape and length in a vertical “puller.” The tips were broken and ground back to an overall diameter of 4–8 microns. Later, central barrels were also used as stimulating electrodes to excite nerve fibers and unmyelinated axon terminations (see later).

For recording intracellular potentials, pencil or coaxial electrodes were initially used, with a single- or double-recording electrode protruding 60–100 microns through the 8- to 10-micron diameter orifice of the single drug-containing barrel. These proved to be unsatisfactory, and in 1967 separate single- or double-barrel glass recording microelectrodes were cemented along the side and parallel to five- or six-barrel assemblies, projecting beyond their tips by 40–100 microns.

Although the term “microiontophoresis” has been used for this technique of drug administration, the delivery of nonionized drugs in aqueous solution containing sodium and chloride ions can also be controlled by electrical currents. Hence electroosmosis may also be involved, particularly when, as became apparent, dilute solutions of ionized compounds in 165 mM sodium chloride enabled better control of diffusional leakage by retaining currents. Hence the term "microelectrophoresis" seemed to be preferable to describe this microelectrophoretic (ME) procedure of drug administration.

The major significance of the introduction in Canberra of multibarrel microelectrodes was the ability to examine the effects of as many as six different agents on a single neuron or axon. It thus became possible to mimic, enhance, and antagonize the actions of synaptically released transmitters, thereby providing information relevant to transmitter identification. The major limitation of the ME technique is the inability to quantify extracellular drug concentrations, which would be highest close to the site of administration and lower further away depending on distance, diffusion in the complex extracellular space, and inactivating processes in CNS tissues such as enzymes and cellular uptake (see Curtis 1964).

Until 1962 extracellular action potentials of single neurons were photographed on moving film for later calculation of firing frequencies and durations of action. All of the ancillary equipment for switching, timing, measuring, and recording retaining and ejecting currents was designed and made in the Department. By late 1962 rate meters enabled the continuous plotting on ink recorders of firing frequencies of single neurons, and later window discriminators were designed to ensure that, of the action potentials monitored on an oscilloscope, those of only one neuron were counted. Computerized equipment also became available, initially in 1966 with a grant from the Wellcome Trust, for the on-line production of peristimulus histograms of neuronal action potentials and for the averaging of intraand extracellularly recorded potentials and ventral root recorded reflexes.

Acetylcholine and Renshaw Cells

In 1957 Rosamond Eccles and I confirmed the cholinergic nature of the synaptic excitation of lumbar Renshaw cells by impulses in motor axon collaterals: all were excited by ME ACh, nicotine, and decamethonium and synaptic and ACh excitation were enhanced and prolonged by Prostigmine and edrophonium and reduced by dihydro-beta-erythroidine, tubocurarine, and procaine. As at the neuromuscular junction the receptors appeared to be essentially of a nicotinic type. Some of these experiments were carried out while Bernard Katz was visiting Canberra.

In 1960 a study with John Phillis and Jeff Watkins (see later) indicated that apart from the excitation of Renshaw cells by ACh at motor axon collateral synapses, ACh, adrenaline, noradrenaline, 5-hydroxy-tryptamine (5HT), ATP, and histamine were unlikely to function as transmitters influencing spinal neurons. The polysynaptic excitation of Renshaw cells by impulses in dorsal root fibers, however, appeared not to be cholinergic. This latter finding was later confirmed in a more detailed study with Ronald Ryall from 1962. Both nicotinic and muscarinic subtypes of receptor were detected on Renshaw cells, both of which were involved in the excitation of these neurones by non-physiological maximal ventral root stimulation.

In another ME investigation of Renshaw cells in 1964, David Quastel and I found that hemicholinium-3 (HC-3) slowly increased the latency and decreased the number of responses of Renshaw cells to continued 5 per second ventral root stimulation. Because the excitation of these cells and of spinal interneurons by dorsal root volleys was not affected, these observations were consistent with a reduced release of ACh from the cholinergic terminals of motor axon collaterals as a consequence of a reduced synthesis of ACh. In 1975, with Bob Craig and David Lodge, this study was repeated using Renshaw cells, which were excited by volleys in two ventral roots. HC-3 appeared to also have a direct effect on ACh release at motor axon terminals independent of repetitive activity.

Interest in ACh as a transmitter elsewhere in the CNS involved investigations in the brainstem with Kiyomi Koizumi in Brooklyn (see later), in the lateral geniculate nucleus in Canberra with Ross Davis, in the ventrobasal thalamus with Per Andersen, in the cerebellar cortex with Michael Crawford, Paul Voorhoeve, and Victor Wilson, and in the cerebral cortex with Michael Crawford. The excitation of neurons in these regions by ACh involved receptors of a muscarinic subtype, and no evidence could be obtained for an association of these with major excitatory synaptic pathways.

Amino Acids

In January 1958 Jeff Watkins, a chemist with considerable experience in the extraction and characterization of organic compounds from plants and sponges, joined the Department of Physiology as a Research Fellow. Rather than undertaking the extraction and characterization of possible transmitters from mammalian brain and determining their actions on central neurons in vivo, the decision was taken to test some of the numerous compounds already reported in the neurochemical literature, to be present in the mammalian CNS. Thus, we collaborated in examining the central effects of a range of naturally occurring and synthetic amino acids, a project which subsequently resulted in the recognition of amino acids as major transmitters in the mammalian CNS.

Our close collaboration continued to 1965 when Watkins moved to England. From then, while retaining an interest in excitatory amino acids (EAAs), my research was largely centered on the inhibitory amino acids, glycine and GABA. He continued to be involved in the discovery of EAA agonists and antagonists, the recognition and classification of multiple receptors for these excitants and the establishment of the role of L-glutamic acid (L-GLUT) as a major central transmitter (Watkins, 2000). His outstanding contributions in Bristol led in 1988 to his election to Fellowship of the Royal Society of London and the award of the Thudichum Medal by the Biochemical Society in 2000.

GABA had been found in mammals to be uniquely present in central nervous tissues. This amino acid had been reported to have an inhibitory effect in crustacea, and when administered topically to the mammalian cerebral cortex to depress potentials generated by synaptic activation of cortical neurons. Consequently, in March 1958, together with John Phillis, I began a ME examination of the effect of this, and a number of related naturally occurring and synthetic neutral amino acids, on spinal Renshaw cells, inter- and motoneurons in vivo.

Glycine, beta-alanine, and GABA ejected as cations all reversibly depressed the excitability of these neurons, and increased the membrane conductance of motoneurons. Using coaxial electrodes (see previous discussion) to record intracellularly from motoneurons, however, we were unable to detect any increase in membrane potential by beta-alanine and GABA as occurs during synaptic inhibition. Furthermore, IV strychnine, in doses that effectively reduced short latency postsynaptic spinal inhibitions, failed to modify the depression of cell excitability by GABA or beta-alanine. (Unfortunately the effect on the action of glycine was not tested.) Hence at that time we considered that GABA was unlikely to be an inhibitory transmitter in the spinal cord.

In view of the relatively large amounts of L-GLUT in CNS tissue, and its metabolic relationship to GABA, we started in April 1958 an examination of the effects of L-GLUT and related acidic amino acids on spinal neurons. We were not aware at that time of Takashi Hayashi's reports of the convulsant actions of sodium aspartate and glutamate following direct injection into the motor cortex of dogs. Aspartate (ASP), GLUT, and cysteate (CYST) anions excited spinal neurons, and depolarization of the membrane of motoneurons, as occurs during synaptic excitation, was detected with coaxial electrodes.

As had been found with the excitation of Renshaw cells by ACh, extracellular enzymic inactivation was then regarded as important in determining the time course of the recovery following synaptic release or the local administration of central transmitters. The recovery of the excitation of interneurons by L- and D-isomers of these three EAAs, however, had similar time courses. In addition, some specific and nonspecific inhibitors of enzymes likely to be associated with the degradation of the L-isomers did not prolong their effects. Thus, we considered that EAAs were not excitatory transmitters, but we remained interested in finding structurally related agonists and antagonists in order to determine the nature of EAA receptors. An investigation of the excitatory action of calcium complexing agents of the versene group excluded the possibility that EAA excitation was the consequence of sequestration of extracellular calcium ions.

The continuing study of the effects of a large number of natural and synthetic amino acids structurally related to GABA and L-GLUT, in both the cat spinal cord in-vivo and the hemisected spinal cord of the toad in vitro, provided information about the structural features of amino acid receptor sites. One amino group and at least one acidic group were essential for activity, and the close structural relationship between depressant and excitant amino acids led to the proposal that the former interacted with a two-point receptor and the latter with a three-point receptor (Curtis and Watkins 1960).

These findings led to the synthesis by Watkins of numerous analogues of GABA and L-GLUT. Noteworthy were the higher potencies of 3-amino-1-propanesulphonic acid (3APS) than of GABA, and of D-homocysteic and N-methyl-D-aspartic (NMDA) acids than of D- and L-GLUT. NMDA later became a key compound in the classification of EAA receptors. Commercially available DL-homocysteic acid (DLH) was subsequently used in ME studies to maintain constant rates of neuronal firing when studying synaptic inhibition.

In 1961 Watkins and I had examined the effects of amino acids applied in solution on potentials recorded from the surface of the parietal cerebral cortex of cats. Excitant amino acids produced spreading depression whereas GABA and 3APS depressed potentials evoked by transcallosal stimulation. Crawford and I extended this study in 1963 to single cortical neurons, and found no essential differences between the sensitivities of these and spinal neurons to ME depressant and excitant amino acids. In subsequent investigations in Canberra and elsewhere, amino acids having inhibitory or excitatory effects on spinal neurons had the same effects on neurons throughout the cat CNS (see Curtis and Johnston, 1974).

Travel Abroad

In view of the comparative isolation of Australia and delays in receiving journals from Europe and the United States, the ANU had made liberal arrangements for research staff, particularly for those with tenure, to spend periods abroad visiting research institutions, participating in research, and attending conferences in order to keep abreast of major developments in their particular fields of research.

In May 1959 I was invited to a symposium entitled “Inhibition in the Nervous System and Gamma-Aminobutyric Acid” held at the City of Hope Medical Center at Duarte, California and sponsored by the U.S. Air Force Office of Scientific Research. This was my first venture abroad. Gene Roberts was a very welcoming host, and I was able to meet a number of distinguished physiologists and biochemists, including G. Bishop, T. Bullock, K. Elliott, M. Fuortes, J. Folchi-Pi, R. Gerard, H. Grundfest, T. Hayashi, H. Jasper, D. Tower, A. van Harreveld, H. Waelsch, H. Weil-Malherbe, and C. Wiersma. This was also my first meeting with Hugh McLennan, a later collaborator in Canberra in 1970 and 1978. My paper dealt with the effects of GABA, L-GLUT, and related amino acids on spinal neurons, and my negative conclusions related to transmitter functions were unfortunately based on a faulty technique and incorrect assumptions.

I also flew to New York to visit Chandler Brooks, Chairman of the Department of Physiology at the Downstate Medical Center, Brooklyn, who had previously offered me an appointment as a Visiting Professor for 12 months from September that year, and to Washington D.C. to visit Kay Frank and his colleagues at the National Institutes of Health, Bethesda.

Brooklyn

I had been awarded a Fulbright Travel Grant, and on September 22, 1959 my family and I flew to San Francisco enroute to New York. Chandler Brooks had spent a year (1946–1948) in Dunedin with Eccles, investigating excitation and inhibition in the cat spinal cord at a time when Eccles strongly believed that central synaptic transmission was an electrical process. Brooks had wide interests in endocrinology, neurophysiology, and, more recently, cardiac physiology. He and his wife Nelle were extremely hospitable hosts, and had arranged for us to rent an apartment near the Medical Center.

Kiyomi Koizumi and I examined the effects of ME amino acids, ACh, tubocurarine, 5-HT, and noradrenaline on unidentified neurons in the brain stem of decerebrate cats. The resulting paper was published in the Journal of Neurophysiology, despite the comment of a referee, a distinguished neurophysiologist, that the ME technique had a very limited future. I also became involved in lectures to medical students and a postgraduate course in neuropharmacology. While in Brooklyn I had the opportunity to visit and give lectures at a number of centers and to meet distinguished neuroscientists at the Rockefeller Institute including D. P. C. Lloyd, R. Lorente de No, H.K. Hartline, and Victor Wilson who later collaborated with me in Canberra.

My family and I became accustomed to living in an apartment in busy Flatbush. The children attended a public school close by, and Christopher, then aged 7, was regarded by his teacher as somewhat backward in understanding spoken English until Lauri explained that we also had problems with the Brooklyn version of “English.” Subsequently he had no further language problems. A subway station close by provided an opportunity to spend weekends exploring the numerous wonders of Manhattan and enjoying concerts at Carnegie Hall and operas at the “Met.” The purchase of a car early in 1960 enabled us to explore Long Island, Staten Island, Princeton, Washington, and parts of Pennsylvania, and later to travel to Woods Hole (see later) and New England.

In April 1960 I attended the American Physiological Society meeting in Chicago, and in May I was invited to present a paper at the International Symposium on Nervous Inhibition held at the Friday Harbour Laboratories of the University of Washington. Again this provided an opportunity to meet many distinguished neuroscientists from the United States and abroad, including T. H. Bullock, J. Dudel, C. Eyzaguirre, R. Granit, O. F. Hutter, S. W. Kuffler, W K. Livingston, D. M. Maynard, H. Patton, D. P. Purpura, T. C. Ruch, J. Szentagothai, A. L. Tow, and J. W. Woodbury.

This was followed by an invitation to present a paper at the Fourth International Neurochemical Symposium which was held in the Villa Monastero at Varenna on Lake Como from June 12–17. Listening to papers presented by many distinguished neurochemists, I realized that there was a need to apply biochemical techniques at a cellular and synaptic terminal level in the mammalian CNS. Because facilities for this type of complex investigation were unlikely to become available in Canberra, I decided to concentrate on using ME techniques in order to determine if a particular compound present in the mammalian CNS required further investigation as a possible transmitter.

From late June 1960 we spent three summer months at Woods Hole. I had received a U.S. Fellowship in Neuromuscular Physiology to visit Kuffler's group at the Marine Biological Laboratories, and the excellent library provided an opportunity to complete several papers for publication. We were able to rent a Cape Cod cottage in Devil's Lane, close to the Nobska Light and gradually became accustomed to the sound of its fog horn. We met many U.S. biologists and their families, and became aware of their concern about the implications of the nightly passage of the USSR Sputnik across their skies. Visits to New Bedford, Plymouth, Boston, and Mount Washington in early fall, provided an understanding of the beginnings of the European occupation of the North American continent.

Canberra

We returned to Canberra in mid-September 1960. Although I had been impressed by the facilities and funds available in the United States for the development of new techniques for investigating the mammalian CNS, we decided that our family lifestyle in Canberra, and the future opportunities available at the ANU, including the possibility of establishing a Department of Pharmacology within the JCSMR, were preferable.

While I was in the United States, the Australian Physiological Society had been established at the initiative of W. V. Macfarlane, and the first meeting was held in Sydney in May 1960. (In 1967 the word “Pharmacology” was included in the name, to be dropped in 2003.) I joined late in 1960 and served as a member of the Council (1961–1964, 1967–1971, 1975–1979), as Editor of the Proceedings of the Society (1971–1972), as President (1992–1995), and since then I have been an Honorary Member.

Back in my own laboratory, Watkins and I resumed our study of the effects of amino acids on spinal neurons, and I completed an earlier investigation of the effect of ME strychnine on the IPSPs of cat spinal motoneurons. These IPSPs were reduced by strychnine hydrochloride in intravenous doses of 0.1–0.2 mg/kg, and thus by extracellular concentrations of the order of 0.5 microM. In 1958 and 1959 I had used co-axial microelectrodes. The outer barrels contained 90 mM strychnine hydrochloride, and the diffusion of strychnine from the relatively large (8–10 micron) orifice had not been controlled by the retaining currents used. When dilute solutions, 1–2 mM strychnine hydrochloride in 165 mM NaCl, were used the reversible reduction of IPSPs was readily observed.

As a consequence, in subsequent studies depending on intracellular recording from neurons, parallel electrodes were used. A separate but multibarrel assembly attached to the recording microelectrode enabled the controlled retention and ejection extracellularly of as many as six compounds, each barrel having an orifice of 1–2 microns diameter. Care was also taken to select appropriate concentrations of each of the compounds to be used and to determine that diffusional leakage was adequately controlled.

Thalamic Neurones

Systemically administered lysergic acid diethylamide (LSD-25) and some related compounds, many of which were antagonists of the action of 5HT on smooth muscle, had been reported to reduce transmission at optic nerve synapses on neurones in the cat dorsal lateral geniculate nucleus (LGN). Although 5HT had not been detected in this area of the nervous system, this raised the possibility that the transmitter at optic nerve terminals could be a related compound. The blood–brain barrier, however, is relatively impermeable to 5HT. Hence, in 1961, together with Ross Davis who had earlier investigated this synapse with P. 0. Bishop in Sydney, we examined the effects of ME indoles related to 5HT, and derivatives of lysergic acid and of phenylethylamine, on the excitation of LGN neurons by impulses in optic nerve fibers.

Many of these substances depressed transmission, particularly 4-, 5- and 7-HT, psilocin, bufotenine, LSD-25, ergometrine, methylergometrine, dopamine, and mescaline, but did not influence antidromic excitation of LGN neurons by volleys in the optic radiation or excitation by ME L-GLUT. The active depressants thus either blocked the access of the optic nerve transmitter to subsynaptic receptors or reduced its release. Reduced transmitter release was unlikely to result from the activation of postsynaptic receptors at axo-axonic synapses on optic nerve terminals because these terminals appear to be presynaptic at axo-axonic synapses within the LGN (Szentagothai, 1968).

None of these depressants effective in the LGN influenced synaptic excitation of spinal interneurons and Renshaw cells, and, in a subsequent study in 1962–1963 with Per Andersen 4-HT, 5-HT, and dopamine did not reduce the excitation of ventrobasal thalamic relay neurons by impulses in medial lemniscus fibers, although the spontaneous “spindle” activity of some neurons was reversibly reduced.

Conferences Abroad

In October 1962 I presented a paper at the First Asian and Oceanian Neurological Congress held in Tokyo, and on the way to England visited the Instituto Superiore di Sanita in Rome where Dr. D. Bovet and his colleagues had synthesized and provided me with a number of compounds having strychnine-like actions. In England I lectured at the Institute of Animal Physiology at Babraham and the Department of Experimental Neuropharmacology of the University of Birmingham, and visited the Departments of Physiology and Pharmacology in Oxford. Arriving in Boston on October 22, to visit Steve Kuffler and his colleagues at the Harvard Medical School, I immediately became aware of the critical situation that had arisen between the United States and the USSR as a consequence of the latter's installation of missiles in Cuba. President Kennedy's dramatic televised ultimatum to the USSR, and the advice of colleagues in Boston and New York, led me to abandon my intended visit to New York to present a paper by invitation at a meeting of the Manfred Sakel Foundation and to return to Australia with minimal delay. The subsequent removal of the missiles by the USSR avoided further action by the United States.

In November/December 1964 I had been invited to present a paper at a conference “Nerve as a Tissue” held at the Lankenau Hospital in Philadelphia. Prior to this event I visited and lectured at the Department of Anatomy, chaired by John Szentagothai, of the Medical University in Budapest, the Max-Planck Institute for Psychiatry in Munich, and the Department of Anatomy of the University of Oslo. Following the meeting in Philadelphia I attended a Neurosciences Research Program study session at MIT in Boston, and lectured at the Department of Pharmacology of the University of Pennsylvania, the Department of Physiology of the Johns Hopkins School of Medicine in Baltimore, and the National Institute of Mental Health in Washington DC.

Continuing our interest in excitant amino acids, Watkins had obtained a sample of beta-N-oxalyl-L-alpha beta-diaminopropionic acid (OXDAPRO) from P. S. Sarma, and a number of synthetic oxalyl derivatives of amino acids from his colleague D. R. Rao, in India. There was speculation that one or more amino acids, including OXDAPRO, present in Lathyrus sativus could be toxic factors responsible for human neurolathyrism in situations of famine and nutritional deficiencies. OXDAPRO was a potent excitant of cat spinal and cortical neurons, only slightly less effective than NMDA in ME studies. This finding, in 1965 with Watkins and Tim Biscoe, was early but indirect evidence of the later recognized neurotoxicity of EAAs. OXDAPRO did not penetrate the adult blood–brain barrier, but possibly did under extreme nutritional stress.

Chair of Pharmacology

The year 1965 ushered in a period of considerable change in my research group. In April I was elected to Fellowship of the Australian Academy of Science, and a year later was appointed to a personal Chair of Pharmacology within the Department of Physiology. Watkins moved to England in April 1965, and Graham Johnston, a graduate of the Universities of Sydney and Cambridge, and then involved in postdoctoral research at the University of California Berkeley, accepted an appointment to the Department in September. As had been the case with Watkins, he was an experienced organic chemist, and we collaborated closely on the central neuropharmacology of amino acids until he moved to the University of Sydney in 1980 as Professor of Pharmacology.

John Eccles had shared the 1963 Nobel Prize in Physiology or Medicine with A. L. Hodgkin and A. F. Huxley, and in August 1966 he resigned from his Chair in Canberra to take up an appointment in Chicago. I was Acting Head of the Department until September 1967 when P. O. Bishop, a distinguished visual neurophysiologist from the University of Sydney, took up his appointment as Head of the Department of Physiology. In 1968 the title of my Chair was changed to Neuropharmacology, and my colleagues and I were recognized as an independent research group within the Department. Earlier, in 1966, I had received a 2-year grant from the National Institute of Neurological Diseases and Blindness to equip a second electrically shielded neurophysiological laboratory.

In April 1965 I attended a Work Session of the Neurosciences Research Program in, Brookline, and also visited and lectured at the Harvard Neurological Unit of the Boston City Hospital, the Rockefeller Institute in New York, The National Institute of Medical Research at Mill Hill, the National Hospital for Nervous Diseases, Queen Square, the Department of Biophysics, University College London, and the Departments of Pharmacology in Oxford and Cambridge. I was also able to visit SpringerVerlag in Heidelberg to check the page proofs of a book Studies in Physiology, containing essays by previous colleagues of John Eccles in honor of his 1963 Nobel Prize, which I had edited with Archie McIntyre who had been a colleague of Eccles in New Zealand.

Glycine and Strychnine

In September 1966 I was invited to present a paper in Athens at the Twelfth International Meeting of Neuropsychology and to lecture at the Department of Neurology of Athens University. Later that month I presented by invitation a paper “Pharmacology and Neurochemistry of Mammalian Central Inhibitory Processes” at the Fourth International Meeting of Neurobiologists in Stockholm dealing with the “Structure and Function of Inhibitory Neuronal Mechanisms.” Here I heard for the first time the report by Bob Werman and Morris Aprison that the concentration of glycine in the ventral grey matter of the cat spinal cord was higher than that of any other amino acid and that this amino acid was associated with some interneurons. Furthermore, ME glycine hyperpolarized cat spinal motoneurons, increased the membrane conductance, and the equilibrium potential of the hyperpolarization appeared to be identical to that of short latency IPSPs, which result from an increased permeability to chloride ions. This very strong indication that glycine could be an inhibitory transmitter in the mammalian spinal cord was indeed a very significant breakthrough, which subsequently should have been recognized internationally as a major advance in the understanding of mammalian central neurotransmission. I was very aware that we had never examined the effect of ME strychnine on the depression of neuronal excitability by glycine and that this was yet to be examined elsewhere. After visits to Goteborg, Oslo, Amsterdam, Babraham, London, and Vancouver, I returned to Canberra in October.

With Johnston and Leo Hosli, and using parallel electrodes to combine intracellular recording with extracellular ME amino acid administration, the Aprison and Werman glycine results were soon confirmed. We used a range of small anions injected intracellularly to demonstrate the similarity between the membrane permeability change underlying IPSPs and hyperpolarization by glycine. Additionally, however, we found that the effect of ME GABA on motoneurons was identical to that of glycine.

Both glycine and GABA are present in the mammalian spinal cord, and the difference in their pharmacological effects was clearly demonstrated by the selective reduction by ME or IV strychnine of both the inhibitory effect of glycine and short latency IPSPs recorded from motoneurons. The depressant effects of some other alpha and beta amino acids were also blocked by strychnine: L-alpha-alanine, beta-alanine, serine, and taurine. A number of alkaloids and synthetic compounds having the same effect as strychnine on short latency and duration spinal postsynaptic inhibitions were also selective glycine antagonists, including brucine, diaboline, thebaine, laudanosine, dendrobine, morphine, and 4-hydroxy-strychnine (see Curtis and Johnston, 1974b). Later in the 1980s a number of bicyclic 5-isoxazolol derivatives and a steroid derivative (RU5135) were added to this list.

Thus, glycine was the first amino acid to be generally recognized as an inhibitory transmitter in the mammalian CNS, and a number of “glycinergic” spinal neurons were identified, including Renshaw cells and group 1A interneurons of the “direct” inhibitory pathway. We had observed that in comparison with GABA, glycine was a weak depressant of postcruciate cerebral cortical neurons, an effect also blocked by strychnine. Together with Paul Voorhoeve and Victor Wilson we had found in 1963 that the recurrent inhibition of cerebral Betz cells evoked by pyramidal tract stimulation, and the basket cell inhibition of cerebellar Purkinje cells evoked by local cortical stimulation, were not affected by IV strychnine in doses that considerably reduced short latency and duration inhibitions of spinal motoneurons. Later in 1965 Biscoe and I found that neither the recurrent inhibition of Betz cells following a pyramidal tract volley nor the inhibition produced by exciting nearby inhibitory interneurons with DLH were reduced by ME strychnine. Thus, glycine appeared to be of minor significance as an inhibitory transmitter in these supraspinal regions, in which strychnine-insensitive inhibitions we later found to be mediated by GABA.

Amino Acid Uptake

Johnston and his colleagues had been investigating glycine metabolism and uptake in the spinal cord in vitro, and it seemed very probable that the actions of two mercurial compounds which enhanced and prolonged the depression of spinal neuron firing by glycine, generally without affecting the action of GABA, was related to the inhibition of membrane transport processes rather than to enzyme inhibition. There was at this time increasing in vitro neurochemical evidence for the presence in CNS tissues of specific and high affinity, sodium-dependent uptake processes for particular amino acids, including those of interest as central transmitters.

Such transport, essential for maintaining intracellular intermediary metabolism, including transmitter synthesis, came to be regarded as more important than extracellular enzymic inactivation for the rapid removal of synaptically (and ME) released amino acid transmitters. Differences were apparent between postsynaptic receptors and membrane sites associated with transport, and we were interested in finding specific antagonists of the in vivo transport of individual transmitter amino acids that had no effects on postsynaptic receptors (see Curtis and Johnston, 1974a).

Tetanus Toxin Revisited

Another convulsant agent of neuropharmacological interest is tetanus toxin, shown earlier to block the types of spinal postsynaptic inhibition by now recognized as mediated by glycine. In 1968 Chet de Groat and I found that when injected into the spinal cord this toxin suppressed the synaptic inhibition of lumbar Renshaw cells by volleys in hind paw afferent fibers but did not diminish the depressant actions of ME glycine and GABA. Johnston had not detected any significant reduction by tetanus toxin of spinal levels of these amino acids, although there was a marked increase in the level of L-ASP. Consequently we proposed that tetanus toxin interfered with the synaptic release of glycine.

A later study in 1971 with Dominik Felix, Christopher Game, and Roy McCulloch of the effect of tetanus toxin on bicuculline-sensitive GABA-mediated “presynaptic” inhibition of spinal reflexes, and basket cell postsynaptic inhibition of cerebellar Purkinje cells, indicated that tetanus toxin also reduced the synaptic release of GABA.

Colorado Springs

In 1968 I spent three short periods abroad. In February, at the invitation of the U.S. National Institute of Neurological Diseases and Stroke (NINDS), I went to a meeting held in Colorado Springs to plan a symposium to be held in November on the topic “Basic Mechanisms of the Epilepsies.” Late in September I visited the CIBA Company in Basel, gave an invited paper at a Mechanisms of Synaptic Transmission Symposium held at Einsiedeln under the auspices of the Swiss Society of the Natural Sciences and later visited Jeff Watkins, then a member of the staff of the MRC Neuropsychiatric Research Unit at Carshalton in England.

I returned to Colorado Springs in November, and presented a paper in which I reviewed the then current evidence for the involvement of ACh, norepinephrine, dopamine, 5-HT, L-ASP, L-GLUT, glycine, GABA, and some other compounds present in the mammalian CNS as synaptic transmitters. This 3-day event was an excellent opportunity to meet many basic and clinical neuroscientists internationally recognized for their expertise. On my return journey I spent 2 days with John Eccles who had by then moved to Buffalo.

Excitatory Amino Acids

In Canberra, Johnston and I continued to investigate depressant and particularly EAA analogues, the latter as a means for establishing L-ASP and L-GLUT as transmitters. He had become very interested in the possibility of making use of L-GLUT and GABA analogues of restricted conformation as agonists and antagonists of amino acid receptors. This followed our finding in 1968 with Arthur Duggan and Chet de Groat that ibotenic acid excited and muscimol inhibited spinal neurons, the latter effect at strychnine-insensitive receptors. These two isoxazoles, isolated from mushrooms of the genus Amanita, are structurally similar to L-GLUT and GABA. Their opposite effects were consistent with earlier findings with Watkins regarding the structural requirements for excitatory and inhibitory amino acid actions, and that alpha-decarboxylation of an EAA produced an inhibitory amino acid.

The inhibitory action of muscimol was later shown to be blocked by the GABA antagonist bicuculline. In 1978 David Lodge, Hugh McLennan and I observed that the excitation of spinal neurons by ibotenic acid was followed by a prolonged depression that was blocked by bicuculline. Hence ibotenic acid was presumably converted in-vivo to muscimol or a related compound. As a consequence of the effects of ibotenic acid and muscimol, Johnston began collecting and synthesizing further related compounds.

In addition to our interests in EAA receptors and selective antagonists we continued to investigate the mechanism of EAA depolarization and its relation to synaptic excitation. In our earlier studies (1958–1962) using coaxial electrodes with single- or double-barrel intracellular microelectrodes, ME NMDA, L-ASP, L-GLUT, and L-CYST depolarized motoneurons, and the reversal potential of this depolarization was consistently observed to be at a lower membrane potential than that of monosynaptic EPSPs.

A number of factors, however, need to be taken into consideration when interpreting observations of this type as indicating a difference between the ionic events underlying ME amino acid and synaptic depolarization. Given the complex morphology of motoneurons, the probable intrasomatic location of intracellular microelectrodes, and the distribution of excitatory synapses on somas and dendrites, it is probable that perisomatic concentrations of EM amino acids were higher than those at distal dendrites, as were changes in membrane potential produced by passing current through the intracellular microelectrode.

In a later study (1968–1971) using parallel micropipettes, depolarization of motoneurons by ME DLH was not affected by increasing the intracellular chloride concentration, which readily converted hyperpolarization by glycine into depolarization, or by EM tetrodotoxin in a concentration adequate to suppress neurone action potentials. Hence, when taken into consideration with the then accumulating neurochemical evidence related to the CNS distribution of EAAs, the ionic basis of amino acid excitation was considered to be probably identical to that accounting for EPSPs, an increase in membrane permeability to sodium and potassium ions.

By 1969 we had not been able to find selective antagonists of excitation by either L-ASP or L-GLUT or of the cellular uptake of these EAAs. The different distributions of these amino acids in dorsal and ventral roots and in the spinal grey matter, however, suggested an association of L-ASP with intraspinal excitatory interneurons and of L-GLUT with primary afferent fibers. Consistent with this proposition, from 1970 Duggan found that interneurons excited monosynaptically by afferent impulses were more sensitive to EM L-GLUT than to L-ASP whereas Renshaw cells, which respond polysynaptically but not monosynaptically to such impulses, were more sensitive to L-ASP than to L-GLUT.

Later, in 1974 with Game and McCulloch, Johnston and I found a greater difference in the sensitivity of these two types of neurons to kainic acid (KAIN), a conformationally restricted analogue of L-GLUT, and NMDA, considered to be too small a molecule to interact with L-GLUT receptors.

Oxford

In May 1969 my wife and I traveled via Vancouver, Washington D.C., and New York to Oxford where Charles and Cynthia Philips had arranged for us to rent a flat overlooking Oriel Square until late August. In addition to enjoying Oxford and its environs, which we explored by bicycle, this enabled me to complete the writing of several papers and to visit and lecture at a number of University Departments in Oxford, London (three Special University Lectures at the Middlesex Hospital Medical School), Birmingham, Paris (a lecture at the College de France), Basel (a main lecture at the Fourth International Congress of Pharmacology), Zurich, Freiburg, Heidelberg, Frankfurt, and Oslo. We returned to Canberra in mid-September via Milan (a paper at the Second International Meeting on Neurochemistry), Pisa, Rome, Athens, and Madras.

GABA and Bicuculline

Reports in the late 1950s that picrotoxin blocked the action of GABA at invertebrate inhibitory synapses, and the observations in the early 1960s by Eccles and his colleagues of the reduction of the “presynaptic” inhibition of monosynaptic reflexes by this convulsant but not by strychnine (see later) suggested that in addition to glycine GABA was also a transmitter in the mammalian spinal cord.

I had not been able to demonstrate, however, that IV or ME picrotoxin, and picrotoxinin later prepared by Johnston, influenced the effect of GABA on spinal neurons. Because these convulsants are poorly soluble and not ionized in water, local concentrations achieved by ME administration were presumably too low, as also were those concentrations achieved after IV administration (1–2 mg/kg), to significantly reduce the effects on neurons of relatively high and localized concentrations of ME GABA. In a series of papers published in 1970, Masao Ito and his colleagues reported that IV picrotoxin blocked the synaptic inhibition of Deiters' neurons in the cat lateral vestibular nucleus by impulses in Purkinje cell axons, thus supporting strong neurochemical evidence for GABA as the inhibitory transmitter of these axons.

A study by Johnston and several colleagues of the structure of strychnine, some related alkaloids and synthetic compounds, all of which were selective glycine antagonists, provided an understanding of how these interfered with the action of this particular amino acid at receptors on central neurons. As a consequence, he was then able to propose the possible structure of selective GABA antagonists, and suggested that a number of convulsant isoquinoline alkaloids be tested. Of particular interest was bicuculline, a phthalide isoquinoline alkaloid isolated from Dicentra cucullaria and Corydalis species, and found in the 1930s to be a potent convulsant when administered IV to rabbits (see Curtis and Johnston, 1974b).

Beginning in March 1970, and in a study with a number of colleagues including Johnston, Duggan, Dominik Felix, and McLennan, we found that ME bicuculline, ejected from a solution of the hydrochloride, reversibly blocked the inhibitory action of ME GABA but not of glycine on spinal interneurons and Renshaw cells, cerebral pyramidal cells, cerebellar Purkinje cells, hippocampal pyramidal cells, Deiters' neurones, thalamocortical relay neurones in the ventrobasal thalamus and lateral geniculate nucleus, and olfactory bulb mitral cells. Furthermore, IV bicuculline hydrochloride (0.2–0.5 mg/kg) reduced presynaptic inhibition of spinal reflexes and the accompanying primary afferent depolarization (PAD). In addition, bicuculline reduced the strychnine-insensitive postsynaptic inhibitions of Deiters' cells, Purkinje cells, pyramidal cells in the cerebral and hippocampal cortices, and thalamocortical relay cells.

Our first paper reporting bicuculline as a GABA antagonist was a letter to Nature, received on May 19 and published on June 27, 1970. These observations provided strong support for increasing neurochemical evidence of the association of GABA with particular inhibitory pathways in the mammalian CNS. In addition, McLennan found that bicuculline blocked the inhibitory effect of GABA and the picrotoxin-sensitive synaptic inhibition of stretch receptor neurones of the Australian freshwater crayfish Eustacus armatus.

In contrast with strychnine, the central effects of IV and ME bicuculline were of relatively short duration. The low aqueous solubility, and rapid conversion of bicuculline in neutral solution to inactive bicucine, led to Johnston preparing bicuculline methochloride (BMC), a more soluble, stable and potent GABA antagonist for ME studies. As expected from its quaternary structure, BMC did not readily penetrate the mammalian blood-brain barrier. Other selective GABA antagonists found in the initial and later studies included (+) but not (–) bicuculline, corlumine, bicucine methyl ester, coriamyrtin, and benzyl penicillin. Bicucine and bicuculline diol were inactive, and N-methyl bicuculline was a glycine antagonist (see Curtis and Johnston, 1974a,b).

In 1983, Richard Malik and I, in collaboration with S. J. Enna and his colleagues in the United States, found that securinine and dihydrosecurinine, indolizidine alkaloids from the shrub Securineqa suffructicosa, were selective antagonists of mammalian CNS GABA receptors. In the same year, in collaboration with the French investigators C. G. Wermuth and K. Biziere, Bruce Gynther and I found that 2-(carboxy-3'-propyl)-3-amino-6-paramethoxyphenylpyridazinium bromide, a pyridazinyl derivative of GABA, was also a selective GABA antagonist in the cat spinal cord.

Taken in conjunction with our earlier observations of the antagonism between strychnine and glycine, these results with selective GABA antagonists confirmed our earlier classification of inhibitory amino acids as either glycine-like (glycine, L-alpha-alanine, beta-alanine, and taurine) or GABAlike (GABA, beta-hydroxy GABA, muscimol, and 3-APS). Antagonism by bicuculline was subsequently the basis for identifying GABA-A subtype receptors and inhibitory processes, as distinct from receptors later defined as GABA-B, which were insensitive to bicuculline and activated by baclofen (see later).

Bicuculline: A Postscript

In 1982 we learned of an earlier but unfortunately unpublished investigation of the convulsive activity of bicuculline. In the early 1960s Dr. K. Tsou in the Department of Pharmacology of the Shanghai Institute of Materia Medica had obtained from colleagues a sample of an alkaloid isolated from Corydalis humosa Migo, which was later identified as bicuculline. He found this to be an extremely potent convulsant when applied to the cerebral cortex, and studied its interaction with similarly applied GABA. The alkaloid also reduced strychnine-insensitive “presynaptic” inhibition of spinal reflexes, and he wondered about its possible use in studying other central inhibitions, including those possibly mediated by GABA. He had no facilities, however, for further investigations at a cellular level.

These results were presented at a Congress of the Chinese Society for Physiological Sciences in the summer of 1964. Subsequently, a full-length paper submitted to Acta Physiologia Sinica in 1965 was never published, since in 1966, with the beginning of the Cultural Revolution, the publication of all Chinese scientific journals was suspended. Dr. Tsou's research ceased, and he was assigned initially to screen antifertiliy drugs, then to take care of animals and eventually to be a farm laborer. He was aware of our 1970 Nature article, but was unable to return to his own research until 1976. In that year he and his colleagues were able to publish a paper about the CNS effects of bicuculline as a possible GABA antagonist in a new Chinese language journal Diseases of the Nervous System.

In Canberra we became aware in 1982 of his observations and subsequent problems from Zhi-Qi Zhao, a visiting scientist from Shanghai. Tsou's attendance at a meeting elsewhere in China prevented my meeting him in Shanghai in September 1984, but later that year Johnston was able to meet him and to discuss their mutual interests in bicuculline and GABA.

Amino Acid Analogues, Agonists, and Antagonists

Johnston and Philip Beart had continued to synthesize isoxazole and amino acid analogues of glycine, GABA, and L-GLUT having restricted conformation. The finding that 4-aminotetrolic acid activated GABA-A receptors on spinal neurons indicated that GABA, a flexible molecule, acted in an extended rather than in a folded conformation. This was consistent with the structural similarities of bicuculline and muscimol. Supporting evidence came later using trans- and cis-aminocrotonic acids, the former an extended and the latter a folded analogue of GABA, and a series of cyclopropane, cyclobutane, cyclopentene, and cyclopentane restricted analogues of GABA.

Together with Duggan and Felix, Johnston and I continued to test the effects of a large number of L-ASP and L-GLUT analogues, and drugs known to depress the excitability of central neurons, particularly to find specific antagonists of either EAA. Tests were carried out on spinal, thalamic, and cerebral cortical neurons. Renshaw cells were particularly useful, because further investigation was not warranted if a potential EAA antagonist also reduced excitation by ACh. Compounds warranting further interest included L-glutamic acid diethyl ester (GDEE), L-methionine-DL-sulphoximine, 2-methoxy-aporphine, and l-hydroxy-3-amino-pyrrolidone-2, but all reduced excitation by both EAAs.

In 1973 we found kainic acid (KAIN), a conformationally restricted analogue of L-GLUT, to be a more potent excitant of spinal neurones than NMDA, DLH, and ibotenic acid. An analysis of molecular models suggested that KAIN and ibotenic acid, and L-GLUT in a partially extended conformation, interact with the same receptors. L-ASP would not be able to interact with these sites, although L-GLUT in a partially folded conformation would be able to interact with L-ASP-preferring receptor sites. The possibility of finding selective antagonists for each of these two EAAs present in the mammalian spinal cord, based on our experience with strychnine and bicuculline as selective antagonists of glycine and GABA, respectively, thus seemed to be remote.

In the 1970s there was increasing evidence, mainly from the investigations of John Olney and his colleagues, that EAAS were also neurotoxic. KAIN proved useful experimentally as an excitotoxin for producing localized lesions in the CNS, because histological evidence suggested that only neurons and not axons were destroyed. Malik and I provided physiological evidence for this in 1984: ME KAIN, in concentrations that destroyed lumbar motoneurons in vivo, did not affect nearby primary afferent fibers, their unmyelinated synaptic terminations, or axo-axonic GABA-releasing synaptic terminals upon them.

Australian Neuroscience Society

In July 1971 I attended the Third International Meeting of the International Society of Neurochemistry in Budapest, the XXV International Congress of Physiological Sciences in Munich, and contributed to a Satellite Symposium on Physiology and Pharmacology of Synapses in Basel. I also lectured at the University of Vienna, and, as a member since 1959, attended a meeting in Oxford of The Physiological Society. Lectures were given at the National Hospital for Nervous Diseases in London and the National University in Athens.

In Budapest I had an opportunity to discuss with Lawrie Austin, a neurochemist from Monash University in Melbourne, the idea of setting up an Australian Neuroscience Society. The purpose was to stimulate discussions and cooperative interactions between basic scientists and clinicians in view of the increasing interests in basic neuroscience by neurologists and neurosurgeons in Australia. Later that year a large majority of those we had identified as possibly being interested clearly favored this proposal, and a 1-day meeting was held at Monash University in November 1972. As the majority of attendees favored an informal structure, further 1-day meetings were held annually until February 1980 when a more formal structure was established with officers and representatives from each Australian state and New Zealand. A constitution was adopted in 1981, and thereafter the Society has continued to grow and flourish.

Conferences Abroad

In November 1971 I participated in another NINDS symposium in Colorado Springs concerned with Experimental Models of Epilepsy. I was also able to visit Winnipeg, St. Louis, New York, Vancouver, and Duarte. The visit to John Olney at the Department of Psychiatry at Washington University, St. Louis, was important in view of his increasing interest in EAAs as neurotoxins.

In November 1972 I was invited to visit and lecture at the Merck Frosst Laboratories at Pointe Claire, Quebec, and also visited The Rockefeller University New York, the School of Medicine of the University of Pittsburgh, the Health Sciences Centre of the University of Western Ontario, and John Eccles and his colleagues in Buffalo.

Department of Pharmacology

The establishment of a Department of Pharmacology within the JCSMR had been considered for many years, but it was not until the retirement of Adrien Albert in 1972 that the top of four floors of laboratory space occupied by his Department of Medical Chemistry became available. For some years he had provided space for Watkins and then Johnston on this floor, at the same level as my laboratories in the Department of Physiology. In January 1973 the University Council established a Department of Pharmacology within the JCSMR, and in March I was appointed Foundation Head and Professor.

Several years elapsed before building operations enabled us to occupy three large electrophysiological/pharmacological laboratories, each with an electrically shielded room, several chemical laboratories, and electronic and mechanical workshops. From 1957 I had continued to use the stimulating portion of the ESRU, which had been designed early in the 1950s by Coombs and based on the use of thermionic tubes. In 1985, the need for additional timing facilities led to the design and construction by Alex Saeck of a more compact and entirely solid state stimulating unit that I used until 1995.

The availability of more laboratory space enabled new lines of research to be developed, including those dealing with peptide transmitters, opioids and transmission in nociceptive pathways (Arthur Duggan), nerve growth factors controlling the development of neurons (Ian Hendry), and autonomic neurotransmission (Caryl Hill). In 1985 Duggan and Hendry developed an antibody-coated microprobe technique for detecting the sites of release in the CNS of neuropeptides.

Baclofen

In late 1972 Johnston and I became interested in a lipophilic derivative of GABA, baclofen (4-amino-3-(4-chlorophenyl)-butyric acid). This had been synthesized in 1962 by H. Keberle at Ciba in Basel as better able to pass the blood–brain barrier than GABA. Monosynaptic and polysynaptic spinal reflexes of cats were reduced by IV baclofen, and oral baclofen alleviated spinal spasticity in humans in the absence of clinically significant effects on supraspinal centers and the peripheral autonomic nervous system.

In our initial 1973 investigation with Game and McCulloch, ME baclofen depressed the spontaneous and EAA-induced firing of spinal interneurons, cortical pyramidal tract neurons and cerebellar Purkinje cells, but had little effect on Renshaw cells. This depression, of longer duration than that produced by GABA, was not blocked by bicuculline or strychnine. We also observed a prolonged reduction by ME baclofen of intracellularly recorded EPSPs and IPSPs from motoneurons, indicative of an increased membrane conductance.

Following suggestions by others that baclofen had a presynaptic action reducing transmitter release at the terminals of spinal primary afferent fibers, in 1979 Lodge, Joel Bornstein, Martin Peet, and I reinvestigated the spinal effects of baclofen. Monosynaptic spinal reflexes and dorsal root potentials evoked by afferent volleys were considerably reduced by IV baclofen (2–3 mg/kg). Two effects of ME (–)-baclofen became apparent, the (+) isomer being inactive. The monosynaptic, but not polysynaptic, excitation of spinal interneurons by impulses in low threshold muscle and cutaneous afferent fibers was reversibly reduced. Baclofen, however, had little or no effect on the cholinergic monosynaptic excitation of Renshaw cells by ventral root impulses and the polysynaptic excitation of these cells by primary afferent impulses.

This selective presynaptic reduction in transmitter release was apparent even when the background firing rate of the cells was maintained at the control level by ME EAAs. The reduction in sensitivity to EAAs indicated a postsynaptic depressant effect of baclofen, which generally required higher extracellular concentration than those influencing transmitter release.

By that time I had developed techniques for investigating the physiology and pharmacology of primary afferent unmyelinated terminations in the ventral horn (see later). Without altering the electrical excitability of these structures, or their depolarization by ME GABA, (–)-baclofen reduced the synaptic GABA-mediated and bicuculline-sensitive depolarization (PAD) produced by tetanic volleys in flexor muscle group la afferent fibers. Later the same results were obtained with muscle group 1A and 1B primary afferent terminations in Clarke's column of the cat spinal cord.

Meanwhile, Norman Bowery and his colleagues had shown that (–)-baclofen and GABA reduced transmitter release in the peripheral autonomic superior cervical ganglion, an effect not blocked by bicuculline. The possibility of a novel receptor for GABA, activated by baclofen, was proposed, and in 1983 they reported the detection on rat brain crude synaptic membranes of two distinct binding sites for radiolabeled GABA: GABA-A sites blocked by bicuculline and GABA-B sites which also bound (–)-baclofen but were not blocked by bicuculline. Selective baclofen antagonists, which would enable the physiological significance of GABA-B binding sites to be determined, were not available.

A number of in vitro studies had shown that (–)-baclofen and GABA reduced the influx of calcium ions through voltage-activated channels of dorsal root ganglion cells and decreased the duration of the action potentials of these neurons. In an investigation that began in 1987, with Gynther, David Beattie, and Gary Lacey, we found that ME baclofen also reduced the duration of the action potentials of intraspinal primary afferent unmyelinated terminations in vivo. This effect, blocked by baclofen antagonists (see later), was most likely produced by a reduction of the relatively small and late calcium influx associated with transmitter release rather than by an enhanced influx of potassium ions. Baclofen, however, did not reduce the duration of the action potentials of motor axon collateral unmyelinated cholinergic terminations.

Our observations were consistent with the reduction by low concentrations of (–)-baclofen of the calcium-dependent release of excitatory transmitter from the intraspinal terminals of primary afferent fibers, and of GABA at axo-axonic synapses upon these terminals (see later). The selectivity of baclofen for reducing transmitter release from primary afferent fibers was subsequently confirmed in 1984 when Malik and I found that IV baclofen had little or no effect on the monosynaptic excitation of interneurons in the spinal intermediate nucleus by impulses in rubrospinal, corticospinal, and descending propriospinal fibers. Additionally, IV baclofen in doses as high as 6 mg/kg did not modify excitatory or inhibitory transmission in the cat cerebellar cortex, a region rich in GABA-B binding sites, for which physiological significance remains to be established.

Our findings thus suggested that the mechanism of transmitter release at central excitatory synapses of axons of peripheral dorsal root ganglia differed from that of neurons having cell bodies within the CNS. This may reflect the presence of both GABA-A and GABA-B receptors only on primary afferent terminations and possible differences in intracellular processes related to transmitter release and the voltage activation of calcium channels.

Baclofen Antagonists

On the basis of structural considerations, and the central effects of a large number of GABA analogues, including 3-aminopropylphosphonic acid (Curtis and Watkins, 1965), in 1986 David Kerr, Rolf Prager, and their colleagues in Adelaide prepared phaclofen, (3-amino-2-(4-chlorophenyl)-propylphosphonic acid). This phosphonic analogue of baclofen reversibly blocked the depression by baclofen of cholinergic twitch responses of guinea pig gut in vitro, and in the cat spinal cord ME phaclofen blocked the reduction of primary afferent transmitter release by ME (–)-baclofen. Phaclofen was subsequently used to demonstrate GABA-B receptor-mediated effects in a number of in vitro CNS preparations, but this compound did not penetrate the cat blood-brain barrier.

Later, in 1988, we found that 2-hydroxy-saclofen (3-amino-2(4-chlorophenyl)-2-hydroxy-propyl-sulphonic acid), also synthesized by the Adelaide group, reduced the presynaptic effect of (–)-baclofen on primary afferent transmitter release. The postsynaptic depression of cell excitability by baclofen was also reduced, but not that by GABA. In 1987 P. Berthelot and his colleagues in Lille had reported that 3-(5-methoxybenzo [b]furan-2-yl)-GABA inhibited baclofen binding to rat brain membranes, and we subsequently showed this to be a baclofen antagonist, blocking pre- and postsynaptic effects in the spinal cord. We also demonstrated that three thienyl-GABA derivatives, shown in Lille to block baclofen binding to rat brain synaptic membranes, were baclofen agonists in the spinal cord.

In this latter study, Lacey and I were able to use one of the synthetic phosphinic acid analogues of GABA, which were selective GABA-B antagonists. These, together with a number of related GABA-B agonists, had been generously provided by Helmut Bittiger, Wolfgang Froestl, and Stuart Mickel and their colleagues at Ciba-Geigy AG in Basel (CGP series, see Froestl et al., 1996). From mid-1992 Lacey and I compared the effects of a range of CGP GABA-B agonists with those of (–)-baclofen in the cat and rat spinal cord in vivo and examined the selectivity of a number of antagonists. Our findings essentially confirmed published results of other in vivo and in vitro studies regarding agonist and antagonist activity (see Lacey and Curtis, 1994).

In particular, ME 3-aminopropyl-methyl-phosphinic acid had effects identical to those of (–)-baclofen on spinal neurones and synaptic terminals but was effective at considerably lower concentrations. All of the antagonists tested, which were effective in much lower concentrations than those required in our earlier tests of phaclofen and 2-hydroxy-saclofen, selectively blocked all spinal effects of baclofen and no convincing evidence was obtained of any antagonism of the effects of GABA on neurones and afferent terminations. Those antagonists reported to pass the blood-brain barrier in rats did so in cats, and we chose two for a further study of the possible role of GABA-B receptors in spinal “presynaptic” inhibition, my last neuropharmacological study (see later).

An unexpected finding was that 3-aminophosphinic acid, established as a potent baclofen agonist on the basis of binding data and in vitro pharmacological studies using rat supraspinal CNS tissues, was neither a baclofen agonist nor an antagonist in the cat spinal cord in vivo. The heterogeneity of GABA-B receptors was further demonstrated by the finding with Kerr and his colleagues in Adelaide that the nitropropane analogue of GABA, a GABA-B antagonist in the guinea pig gut preparation in vitro, was neither a GABA-B antagonist nor agonist in the rat isolated neocortex and was a GABA-A agonist in the cat spinal cord in vivo.

The Copenhagen Connection

In February 1974, Povl Krogsgaard-Larsen from the Royal Danish School of Pharmacy (now the Danish University of Pharmaceutical Sciences) joined the Department as an Honorary Fellow. This first of four visits (later visits in 1977, 1981, 1987) began a highly successful and productive collaboration which continued for 18 years. He and his colleagues had become interested in the structural features of excitatory and inhibitory amino acids, and were providing us with a large number of new and novel compounds synthesized in Copenhagen to add to those already being prepared by Johnston and his colleagues. Conformationally restricted analogues of GABA and L-GLUT, including chiral analogues of fully established stereochemical conformation, were of particular interest, especially isoxazoles related to muscimol and ibotenic acid. There was a very close collaboration between Krogsgaard-Larsen and Johnston with his considerably smaller number of chemical colleagues in Canberra.

Compounds related to GABA were tested in vivo in the cat spinal cord by ME techniques and by in vitro ligand binding techniques as possible agonists or antagonists at GABA-A and glycine receptors, in addition to being tested as antagonists of sodium-dependent uptake of GABA by rat brain slices and as inhibitors of enzymes associated with GABA metabolism. Excitants related to L-GLUT were compared with ME L-GLUT, NMDA, and ibotenic, quisqualic, and kainic acids. Use was also made of an increasing number of antagonists of EAA excitation, which we and others were investigating to assess the degree of specificity towards central “aspartate-” or “glutamate-preferring” receptors.

Krogsgaard-Larsen and his colleagues introduced too many new compounds for studying the nature of central amino acid receptors to enable the inclusion of details of all of our findings in Canberra. These were reported in 27 papers coauthored by colleagues in Canberra and Copenhagen from 1975 to 1993. Some compounds were potent GABA-A agonists, including isoguvacine, 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), dihydro- and thio-muscimol, and piperidine-4-sulphonic acid (P4S), a cyclic analogue of 3APS and poorly taken up by spinal tissue. Others, such as nipecotic acid (piperidine-3-carboxylic acid), blocked the cellular uptake of GABA in vitro, enhanced the effect of GABA on spinal neurones but blocked that of glycine. Some isoxazole derivatives were also glycine antagonists. Confirmation was also obtained that the conformation of GABA to activate GABA-A receptors differed from that associated with the carrier responsible for the in vitro cellular uptake of this amino acid.

The therapeutic potential of THIP was recognized in 1977–1978, and this compound is now (2005) in advanced phase III clinical trials as an analgesic and hypnotic. The lipophilic derivative of nipecotic acid, Tiagabine, is marketed as an antiepileptic.

A number of ibotenic acid derivatives were potent excitants, including 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), which later was a key compound in the classification of L-GLUT receptors, and 4-bromo-homoibotenic acid. Using GDEE and alpha-aminoadipic acid (aAA) as antagonists of glutamate- and aspartate-preferring receptors, respectively (see later), excitation by AMPA and 4-bromo-homoibotenic acid were reduced by GDEE. In contrast, aAA was an antagonist of excitation by ibotenic acid and NMDA.

Royal Society of London

In 1974 I was elected to Fellowship of the Royal Society of London, and during a period of study leave from late June to late October I signed the Charter Book at Carlton House Terrace during a meeting of the Society's Council. My wife, daughter, and I spent 2 months living in Cambridge at Churchill College, and 1 was able to visit colleagues having similar research interests in Cambridge, Oxford, London, and Bristol, to attend meetings of The Physiological Society and the British Pharmacological Society, and to attend the IX Congress of the International College of Neuropsychopharmacology in Paris and a NATO Advanced Study Institute concerned with Metabolic Compartmentation in Relation to Structure and Function of the Brain in Oxford.

Returning to Canberra via Copenhagen, Munich, Basel, and Zurich, at which I lectured about our research in Canberra, I also contributed to a Symposium on Neurotransmitters at the 26th International Congress of Physiological Sciences in Delhi. This was followed by the presentation of the opening Review Lecture at a Satellite Symposium on Drugs and Central Synaptic Transmission held at the Indian Central Drug Research Institute in Lucknow.

GABA Uptake

From 1975, continuing our interest in the influence of cellular uptake on the action of amino acids on neurons, we investigated the effects on the depression by EM GABA and other inhibitory amino acids on the firing of spinal, cerebellar and cerebral cortical neurons by a number of inhibitors of the in vitro uptake of GABA. These included in 1975 ( + )-2-4-diaminobutyric acid (DABA), (–)-nipecotic acid, and 2,2-dimethylbeta-alanine, and in 1976 arecaidine and guvacine, constituents of the betel nut Areca catechu. Although there was some degree of selectivity in the enhancement of the effects of GABA in vivo, this was not high. Furthermore, we were not able to demonstrate any prolongation of the GABA-mediated basket cell inhibition of cerebellar Purkinje cells by EM nipecotic acid or DABA. It is possible, however, that these inhibitors are also taken up by tissue elements during ME administration and hence do not gain access to many GABA-ergic synapses.

An unexpected finding in 1975 with Johnston and Lodge was the enhancement of the action of muscimol by nipecotic acid and DABA. Subsequent in-vitro studies confirmed the presence of a relatively inefficient sodium-dependent transport process for muscimol in rat cortical slices.

Benzodiazepines and Barbiturates

Our interest in these clinically used agents stemmed from reports of the enhancement of spinal GABA-mediated “presynaptic” inhibition of spinal reflexes by pentobarbitone and by diazepam. We found in 1976 that IV diazepam also prolonged basket cell GABA-mediated inhibition of cerebellar Purkinje cells but did not influence the effect of EM GABA on these and spinal neurons.

In 1977 Lodge and I reported that in cats anesthetized with alphachloralose and urethane or barbiturates, ME pentobarbitone enhanced the depression of the firing of spinal interneurons by GABA more than that by glycine. Furthermore, in decerebrate cats we found IV pentobarbitone enhanced and prolonged the inhibitory action of GABA, but not that of glycine, on spinal neurons. Relevant in vitro studies suggested that barbiturates enhance the binding of GABA to postsynaptic receptors.

Later, in 1982, John Leah, Malik, and I reported that midazolam, a benzodiazepine effective as an anesthetic in humans at IV doses of the order of 0.3 mg/kg, was relatively less effective in cats. In animals anesthetized with pentobarbitone sodium, however, IV midazolam in doses as low as 0.1 mg/kg enhanced and prolonged “presynaptic” inhibition of reflexes. Furthermore, ME midazolam enhanced the inhibitory effect of GABA, but not of glycine, on spinal neurons and the depolarization of primary afferent terminations by ME GABA and P4S. These effects, which were blocked by a benzodiazepine antagonist, R021-3981, were thus consistent with an enhancing action of benzodiazepines at or near central GABA-A receptors.

GABA and Inhibition in the Spinal Cord

In 1976 I began an investigation of the role of GABA as an inhibitory transmitter in the cat lumbar spinal cord, which continued until 1995. In 1960, Eccles and numerous colleagues began a comprehensive investigation of the mechanism and organization of the prolonged inhibition of extensor muscle monosynaptic spinal reflexes by impulses in flexor muscle afferent fibers. Unlike relatively short duration “direct” inhibition of motoneurons by impulses in low threshold afferent fibers of muscles of opposing function, they were unable to record intracellular IPSPs from motoneurons. Monosynaptic EPSPs were reduced in magnitude but not in time course, and hence there appeared to be no associated increase in motoneuron membrane conductance (Eccles, 1964).

This inhibition of monosynaptic reflexes was accompanied by central depolarization of the extensor group 1A primary afferent fibers. This PAD was detected by recording dorsal root potentials or by determining the electrical excitability of afferent fibers within the cord. Accordingly, the inhibitory process was considered to be essentially presynaptic in nature. Eccles postulated that a synaptically generated increase in ion conductance, and the consequent depolarization of primary afferent boutons, would reduce the amplitude of terminal action potentials and thus diminish transmitter release. PAD was also detected in primary afferent fibers of cutaneous origin and to accompany the inhibition of impulse transmission through the dorsal column nuclei.

In 1962 George Gray had provided morphological evidence for axoaxonic synapses on spinal primary afferent boutons, and subsequent investigators found that the presynaptic elements of these synapses were also in contact with motoneurons in a triad arrangement. Later GABA and the GABA synthesizing enzyme glutamic acid decarboxylase were detected in the presynaptic elements of many spinal axo-axonic synapses.

Eccles, with Robert Schmidt and Bill Willis, found in 1961 that both the presynaptic inhibition of spinal reflexes and PAD were enhanced by IV barbiturates and chloralose. The inhibition and PAD were usually increased by strychnine in doses that considerably reduced “direct” inhibition but were reduced by picrotoxin, which did not decrease “direct” inhibition. Additionally, the effects of GABA and 3APS applied topically to the surface of the spinal cord on PAD were interpreted in terms of a depolarizing action of these amino acids on primary afferent terminals. Because picrotoxin blocked both inhibitory synaptic transmission and the effect of GABA in a number of crustacean preparations, these pharmacological findings were regarded as strong evidence that GABA was the depolarizing transmitter generating PAD and “presynaptically” reducing transmitter release from primary afferent boutons in the cat spinal cord. A role for GABA as a “postsynaptic” transmitter hyperpolarizing spinal neurons appeared to have been excluded.

At that time we had not yet demonstrated that GABA hyperpolarized motoneurons and had not been able to show that picrotoxinin was a GABA antagonist in the cat CNS. It was not until 1970 that we demonstrated bicuculline to be a specific GABA antagonist, which reduced “presynaptic” inhibition of spinal reflexes, PAD, and the hyperpolarization of motoneurons by GABA.

In late 1962 Ryall and I had attempted to provide direct evidence that GABA depolarized the intraspinal terminals of muscle and cutaneous primary afferent fibers. Brief current pulses (max 12 microamps) passed through the central barrel of five-barrel microelectrodes were used to excite fibers near ventral horn motoneurons or dorsal horn interneurons excited monosynaptically by afferent volleys. In retrospect our technique of measuring changes in the amplitude of summed potentials recorded peripherally of impulses in a number of fibers before, during, and after ME GABA was quite inadequate to be interpreted in terms of changes in terminal excitability. Our results suggested that GABA decreased rather than increased fiber excitability, an effect later shown to reflect changes in the composition of the extracellular fluid rather than in the excitability of afferent boutons (see later).

In addition to finding that GABA hyperpolarized motoneurons, in the 1970s we were obtaining evidence that the polysynaptic inhibition of dorsal horn interneurons by impulses in cutaneous afferent fibers had two components, early glycinergic followed by GABA-ergic. Based on the selective effects of ME strychnine and bicuculline, the same result was observed when cutaneous afferent volleys were used to inhibit the firing of Renshaw cells and ventral horn group 1A inhibitory interneurons by volleys in high threshold cutaneous afferent fibers. In the case of Renshaw cells, both components of this afferent inhibition were blocked by tetanus toxin.

Because the firing of neurons in these three studies had been maintained by ME DLH, the synaptic and ME GABA depression of excitability was surely largely the consequence of the activation of neuronal postsynaptic receptors. Furthermore, by then there were several reports of the detection of increases in motoneuron membrane potential and conductance associated with “presynaptic” inhibition, suggesting that a postsynaptic component of predominantly dendritic origin was also involved in this type of inhibition of motoneurons.

Primary Afferent Terminations

My return in 1976 to a study of the effect of GABA on primary afferent terminals was stimulated by two reports that ME GABA enhanced the excitability of these structures in the dorsal and ventral horn of the mammalian spinal cord. Furthermore, GABA had been reported to depolarize mammalian dorsal root and autonomic ganglia in vitro at nonsynaptic GABA-A receptors.

Lodge, Stephen Brand, and I recorded monophasic action potentials of single group 1A afferent fibers within an extensor muscle peripheral nerve in response to just-threshold 0.3 msec cathodal pulses of less than 2 microamps passed through the central barrel of seven barrel microelectrodes. With the tip of the electrode within the extensor muscle motonucleus, and by controlling the pulse amplitude manually, we found terminals, the thresholds of which were reduced by brief tetanic (4 at 320 Hz) stimulation of low threshold afferent fibers of flexor muscles 50 msec earlier. These were conditions known to depolarize primary afferent fibers (PAD) and “presynaptically” inhibit extensor reflexes. ME GABA and EAAs reversibly reduced terminal thresholds, but only PAD and the effect of GABA were reduced by ME BMC. Glycine had no consistent effects on terminal excitability.

This technique was subsequently refined in order to continuously monitor the threshold of a terminal. The frequency of single action potentials recorded peripherally, and identified by shape, amplitude, and latency, controlled a feedback circuit to regulate the amplitude of 10 Hz stimulating pulses (0.2–0.3 msec, <1 microamp) to maintain a 50% firing index. The multiplying factor in this circuit was plotted on a multichannel paper recorder, together with stimulating pulse amplitude, latency of response, percentage changes in termination threshold, microelectrophoretic currents, and other parameters including time, arterial blood pressure, and end-tidal carbon dioxide levels. There was also a need for continuous oscilloscopic monitoring of the recorded action potentials.

From early 1978 we used a simple electrophysiological test to assess whether the central fibre stimulated was myelinated or unmyelinated. The anodal blocking factor (BF) of a nerve fiber is the reciprocal of the ratio between the amplitudes of the threshold stimulating current and the higher current which blocks the transmission of impulses by hyperpolarizing the fiber adjacent to the site of excitation. Measurements of this factor for myelinated fibers in the dorsal horn and dorsal column, and our experience with low threshold ventral horn afferent structures depolarized by GABA and P4S at BMC-sensitive GABA receptors, led to our accepting an upper figure of four as an indication that the structure stimulated was unmyelinated. Thereafter, unmyelinated preterminal axons and terminal boutons were referred to as “terminations."

In the late 1980s we also made use of the time course of the recovery of the central excitability of afferent myelinated fibers and terminations following a centrally generated or an orthodromic impulse as an indication of action potential durations and rates of repolarization. As expected, GABA-sensitive terminations had faster rates of repolarization and briefer action potentials (APs) than did myelinated fibers.

Termination GABA Receptors

Lodge, Bornstein and I used a number of GABA-A agonists to demonstrate that termination GABA receptors were similar or even identical to those on spinal neurons. In a more detailed study with Lodge of primary afferent fibers and ventral horn terminations, ME GABA and BMC had no effect on either the PAD or the excitability of myelinated fibers. BMC readily blocked PAD and depolarization by GABA of terminations but not depolarization by ME potassium or L-GLUT (see later), and occasionally increased termination thresholds, presumably by decreasing background PAD.

During depolarization by GABA, and other GABA-A analogues including 3AP, P4S, and muscimol, synaptically generated PAD, measured as a percentage change in threshold, was decreased. As this did not occur when terminations were depolarized by ME potassium or L-GLUT, activation of termination GABA-A receptors appeared to increase the membrane conductance, presumably to chloride ions. Such an increase had been established in vitro to account for the depolarization by GABA of dorsal root ganglion cells, cells that have a higher intracellular chloride concentration than neurons located within the CNS. That the equilibrium potential for ion fluxes generating PAD was at a more depolarized level than the resting membrane potential was supported later by demonstrating that PAD and depolarization by ME GABA and P4S were all enhanced during the hyperpolarization of a termination that followed prolonged tetanic excitation of its peripheral nerve.

The prolongation of termination but not fiber APs by ME tetraethylammonium (TEA) and 4-aminopyridine (4AP) indicated that voltage-activated potassium channels contributed to the repolarization of termination excitable membranes. Depolarization of terminations by GABA-A agonists and during PAD also prolonged termination APs, changes which did not occur during equivalent depolarization by an EAA (see later). Thus an increase in termination membrane conductance could be the major factor in the reduction of transmitter release during activation of presynaptic GABA-A receptors, rather than mere depolarization.

In 1985 with Gynther and Malik, GABA-A receptors were also shown to present on groups 1A and 1B muscle afferent terminations in the lumbar intermediate nucleus and in Clarke's column. I was unable, however, to find any BMC-sensitive effects of GABA agonists or any evidence of synaptically generated PAD on the lumbar spinal terminations of the vestibulospinal tract (with Wilson and Malik), the rubrospinal tract (with Malik), and motor axon collaterals (with Gynther). In contrast with dorsal root ganglion cells which are depolarized by GABA at nonsynaptic receptors, the neurons of origin of all of these three types of termination, in the lateral vestibular nucleus, the red nucleus, and spinal motoneurons, respectively, are all hyperpolarized by ME GABA at receptors related to BMC-sensitive postsynaptic inhibitions.

Fundamental differences thus became apparent between the central spinal terminations of neurones located within the CNS and those with peripheral cell bodies. In addition to differences in embryological origin, there are differences in intracellular ion content and pharmacological properties and possibly also in the process of transmitter release at axon terminals. This latter difference was suggested by the differing effect of (–)-baclofen on transmitter release from the axonal terminations of these two types of neurons (see previous discussion). Another difference between central and peripheral neurons was the finding with Gynther that a number of divalent metal cations, including cadmium, magnesium, and calcium, reduced the depolarization of primary afferent terminations by ME GABA and P4S, and synaptic PAD, yet did not influence the depression of spinal neurone firing by these GABA-A agonists. Hence there also may be differences in the manner by which GABA-A recognition sites activate chloride ionophores of central and peripheral neurons.

Nonsynaptic Amino Acid Effects on Afferent Fibers

When relatively large ME currents were used to eject GABA, the initial reduction in termination thresholds was often not sustained and was occasionally followed by an increase in threshold that either was not affected or was enhanced by BMC. In a later more extensive study with Lodge, Peet, Bornstein, and Leah, we examined the effects on afferent myelinated fibers and terminations of a large number of GABA-like and unrelated amino acids about which direct or indirect information was available concerning their sodium-dependent uptake by mammalian brain preparations in vitro.

Our findings indicated that observed increases in termination and fiber thresholds most likely resulted from alterations in the ionic constitution of the extracellular fluid near the tip of the stimulating microelectrode as a consequence of the ouabain-sensitive cotransport of amino acids and sodium ions into neurons and glia. GABA-A agonists, which were poor substrates for such uptake processes, such as muscimol, P4S and 3APS, reduced but did not increase termination thresholds and had no effect on myelinated fibers.

Lodge, Max Headley, and I reinvestigated an earlier observation that EAAs, including L-GLUT, L-ASP, QUIS, KAIN, and NMDA, reduced the threshold of muscle and cutaneous afferent terminations. In addition myelinated fibers stimulated in spinal grey matter were also depolarized but, unlike ME potassium, these EAAs had no effect on myelinated afferent fibers stimulated in the dorsal columns. The insensitivity of depolarization by EAAs to ME BMC, and its reduction by selective EAA antagonists, suggested that this also was a consequence of alterations in the extracellular medium, in these conditions resulting from the depolarization and firing of neurons.

GABA-A and GABA-B Inhibition of Spinal Reflexes

By the early 1990s there were a number of reports that, under in vitro conditions, relatively short latency and duration biculline-sensitive postsynaptic hyperpolarizations of neurons within supraspinal regions of the mammalian CNS were accompanied by a longer latency and duration GABA-B receptor-mediated hyperpolarization. Accordingly, from 1992 until 1995, Lacey and I compared the effects of IV bicuculline and several CGP baclofen antagonists on the “presynaptic” inhibition of lumbar spinal reflexes in cats anesthetized with pentobarbitone sodium (Curtis and Lacey, 1998).

Two forms were studied of this inhibition of monosynaptic extensor reflexes, recorded from transected ventral roots, by twice-threshold tetanic stimulation of flexor muscle afferent fibers: that following a brief tetanus of four volleys at 333 Hz, as in the 1960s investigations by Eccles and his colleagues of “presynaptic” inhibition and that during and after continuous 333 Hz stimulation for 10 to 60 seconds.

On the basis of the effects of IV administered selective GABA-A and -B antagonists, two components of brief tetanus inhibition were detected: early GABA-A associated with PAD and a later GABA-B component of more prolonged duration. Inhibition during and after continuous tetanic stimulation of flexor afferent fibers, however, appeared to be predominantly associated with GABA-B receptors. Although GABA hyperpolarized neurons and depolarized primary afferent terminations at postsynaptic receptors in the mammalian spinal cord, we were unable to determine the relative roles in the inhibition of spinal reflexes of GABA-A and GABA-B receptors at either of these sites. The presence of GABA-B receptors on spinal and other neurons would account for our earlier observed depression of neuronal excitability by ME baclofen.

Conferences Abroad

In the meantime, to return to 1976, in March, at the invitation of the Houston Neurological Society and the Department of Neurobiology and Anatomy of the University of Texas at Houston I was one of two invited overseas speakers at a Neurological Symposium concerned with the Basic and Clinical Aspects of Neurotransmitter Function. I also gave lectures at the Department of Neurobiology and Anatomy, to the Houston Chapter of the American Neuroscience Society, at the University of Texas Medical Branch at Galveston, and at the University of Pittsburgh.

In July 1977 my wife and I, as guests of the USSR Academy of Sciences, visited research institutes in Moscow, Leningrad, and Kiev over a period of 2 weeks during which I delivered a number of lectures. In Moscow I had the opportunity to meet Dr. Y. S. Sverdlov whose paper in 1975 with S. N. Kozhechkin reporting the depolarization of ventral horn afferent fibers by ME GABA led me resume my interest in reinvestigating the role of this amino acid in spinal “presynaptic” inhibition. Unfortunately Sverdlov was no longer involved in neurophysiological research. In Kiev at the Bogomoletz Institute of Physiology I renewed my acquaintance with Platon Kostyuk, who had spent 6 months in Canberra in 1961 working with Eccles, and in Leningrad at the Sechenov Institute I met Alexander Shapovalov who was later to visit Canberra.

Before returning to Canberra I attended the XXVII International Congress of Physiological Sciences in Paris, contributed to a Satellite Symposium held in Cambridge concerned with microelectrophoretic methods for investigating central transmitters, and, as an invited speaker and a member of the Faculty, participated in a NATO Advanced Study Institute held in Norway dealing with amino acids as chemical transmitters.

EAA Antagonists

In 1978 we resumed our interests in EAA antagonists following published reports that D-alpha-aminoadipic acid (DaAA) acted preferentially at spinal aspartate-preferring receptors, as did GDEE at glutamate-preferring receptors. Lodge, Headley, and I confirmed this for DaAA, which antagonized excitation of interneurons and Renshaw cells by NMDA and L-ASP to a greater extent than that by L-GLUT. Additionally, DaAA reversibly reduced the polysynaptic noncholinergic excitation of Renshaw cells, which earlier we had considered could be mediated by L-ASP.

Subsequently, these findings were confirmed with McLennan and Lodge in Canberra, using DLaAA, which Watkins and I had earlier found to be a weak excitant. Excitation by NMDA and ibotenic acid was most readily reduced by DLaAA and least by GDEE; that by L-GLUT and quisqualic acids (QUIS) were most reduced by GDEE and least by DLaAA; that by L-CYST, L-ASP, and D- and L-homocysteic acids were reduced to some extent by both, and excitation by kainic acid (KAIN) was relatively insensitive to both antagonists. Additionally both DLaAA and particularly GDEE reduced the excitation of Renshaw cells by ACh. Later we found that D-5-aminohex-2-enedioic acid, a conformationally restricted analogue of DaAA prepared by Rob Allen, also reduced excitation by NMDA to a greater extent than that by L-GLUT.

These results raised questions as to whether either D-aAA or GDEE were sufficiently selective for distinguishing between L-GLUT and L-ASP as synaptically released central excitatory transmitters in vivo. Furthermore, KAIN, structurally a L-GLUT analogue, appeared not to activate glutamate-preferring receptors.

By this time there was increasing acceptance that EAAs chemically related to L-ASP and L-GLUT interacted with a number of different types of receptor. In the early 1980s at least three EAA receptors had been proposed: NMDA, selectively antagonized by D-aAA and 2-amino-5-phosphonovaleric acid (2AP5); QUIS, selectively antagonized by GDEE; and KAIN for which no antagonist had been found. Some receptors were activated by more than one class of EAA. The simple classification of aspartate- and glutamate-preferring receptors clearly required revision to take into account new information from in vivo and in vitro studies of the effects of an expanding range of EAA agonists and antagonists of various degrees of specificity.

We in Canberra were very familiar with the readily demonstrable high degree of specificity of ME strychnine and bicuculline as glycine and GABA antagonists, respectively, at inhibitory synapses in the mammalian CNS. Accordingly, we considered that a similar high degree of specificity was required of antagonists for identifying in vivo the EAA transmitter at particular central excitatory synapses, for which L-ASP and L-GLUT were likely candidates.

In 1982 Peet, Leah, and I compared the effects of a number of compounds, reported by others to be EAA antagonists, on the excitation of lumbar spinal interneurons by ME NMDA, QUIS, and KAIN with those on mono- and polysynaptic excitation by volleys in cutaneous and muscle afferent fibers. Antagonists which reduced excitation by NMDA and L-ASP depressed polysynaptic excitation, thus supporting the role of L-ASP as the transmitter of excitatory spinal interneurons. We were unable, however, to find any selective antagonism of the monosynaptic excitation of spinal interneurons by impulses in primary afferent fibers by antagonists somewhat more selective for QUIS receptors, evidence that would support the transmitter role of L-GLUT.

EAA Uptake Inhibitors

Early in the 1970s Johnston and V. J. Balcar had screened a large number of amino acid analogues and other compounds as inhibitors of the high affinity uptake of L-GLUT and L-ASP by rat brain slices. Threo-3-hydroxy-DL-aspartic acid, which we had found some years earlier to excite spinal interneurons, was a potent inhibitor, and the subsequent preparation of the two isomers indicated that the L-isomer was approximately twice as effective as the D. In in vivo tests on spinal neurons, in subthreshold concentrations for excitation, both isomers enhanced excitation by L-GLUT, L-ASP, and QUIS and had much less effect on excitation by NMDA, KAIN, and ACh. Similar in vivo results were found using dihydrokainic acid, a very weak excitant, which was twice as effective as KAIN as an inhibitor of the high affinity uptake of L-GLUT and L-ASP in vitro.

These in vivo and in vitro observations strongly supported the importance of cellular uptake in determining the duration of action of ME excitant amino acids present in the mammalian CNS. Because L-GLUT and L-ASP, however, appeared to share the same transport process, the use of uptake inhibitors in vivo seemed to be unlikely to be useful in distinguishing between CNS pathways using either as an excitatory transmitter.

Further EAA Investigations

Following Johnston's move to the Chair of Pharmacology at Sydney University in January 1980, and the need to provide more support for other lines of research within my Department in the JCSMR within funding of decreasing value, I decided to reduce my interests in EAAs. A major factor that led to this decision was the expanding complexity of the field of EAA research, including the ever increasing number of individual EAA binding sites revealed by in vitro investigations (see Watkins, 2000), the physiological significance of many of which had yet to be established. Additionally, numerous large research groups abroad, particularly those associated with pharmaceutical companies, were becoming interested in specific EAA antagonists active in vivo, and hence considered to be of potential clinical and financial benefit.

To return to 1978, when in May I presented the opening lecture “Gabergic Transmission in the Mammalian Central Nervous System” at an Alfred Benzon Symposium in Copenhagen, which had been organized by Povl Krogsgaard-Larsen and his colleagues. This covered virtually all aspects of current research related to GABA, including the possibility of designing useful drugs for the management of GABA-related neurological disorders. I was also able to visit Sandoz Ltd. in Basel and to present a paper “Problems in the Evaluation of Glutamate as a Central Nervous System Transmitter” at a Symposium organized by the Mario Negri Institute in Milan. In July 1978 I made a brief visit to Paris to attend the VIIth International Pharmacological Congress.

Multiple Sclerosis

From 1978 I also became involved with the National Multiple Sclerosis Society of Australia as Chairman of its Scientific Research Advisory Board, which advised the Society on the allocation of research grants. This was the consequence of my earlier experience as a member of a number of NHMRC grant-allocating committees, and the fact that I was not directly involved in MS-related research, rather than, like the other members of the Board, from my having an intimate knowledge of this disorder. I continued as Chairman until 1983 and was reappointed from 1993 until 1996.

Animal Experimentation

In view of my experience in using fully anesthetized or decerebrate cats in neurophysiological and pharmacological investigations I was invited in 1979 by the NHMRC and the Commonwealth Scientific and Industrial Research Organisation (CSIRO) to chair a committee to revise the NHMRC booklet Code of Practice for the Control of Experiments in Animals. This had been prepared in 1969 by a committee chaired by Professor A. K. McIntyre. The 1979 version was subsequently revised a number of times, and the 1983 edition included the requirement for research institutions or organizations to establish Animal Experimentation Ethics Committees. The 7th edition, Australian Code of Practice for the Care and Use of Animals for Scientific Purposes was published in 2004.

Conferences Abroad

In March 1982 I attended the IBRO Congress held in Lausanne and gave lectures at the Max-Planck Institute for Biophysical Chemistry in Gottingen, the Institute of Physiology at the University of Aarhus, the MRC Clinical Pharmacology Unit in Oxford, the Departments of Physiology at the University of Bristol and University College London, and the Department of Psychiatry of the Athens University Medical School.

In July 1984 I briefly visited Krogsgaard-Larsen in Copenhagen, participated in a Symposium “GABA Mechanisms and Their Clinical Significance” at Cambridge, and attended the IXth International Congress of Pharmacology in London and a Satellite Symposium “Electrophysiology of the In Vitro Synapse” in St Andrews. At the Faculty of Medicine of the University of Tokyo I gave a lecture “The Micropharmacology of Spinal Terminals” and then with my wife spent 2 weeks as guests of the Academia Sinica visiting the Shanghai Brain Research Institute, where we met the distinguished Chinese physiologist H-T. Chang, and the Institute of Biophysics in Beijing.

In April 1987 I attended a symposium “Excitatory Amino Acids in Health and Disease” held at the Royal Institution in London, and in August delivered a plenary lecture “Amino Acid Neurotransmitters” at the Xth International Congress of Pharmacology in Sydney, my one and only “performance” on the vast stage of the Concert Hall of the Sydney Opera House.

In August 1988 I had been invited to a Swedish-Australian Scientific Symposium “Neural and Hormonal Mechanisms in Circulatory Homeostasis” held at Wenner Gren Centre in Stockholm. This enabled me to visit and lecture at the Department of Physiology of the University of Goteborg and to meet Anders Lundberg with whom I had collaborated in Canberra in 1957, the Nobel Institute for Neurophysiology of the Karolinska Institute in Stockholm and Krogsgaard-Larsen's Department in Copenhagen. At the invitation of the President of the USSR Academy of Sciences, my wife and I then spent 2 weeks visiting and lecturing at research Institutes in Moscow and Kiev. It was a great pleasure to see Platon Kostyuk in Kiev and to meet Dimitri Kharkevich and his colleagues in Moscow.

We returned home via Oslo to visit Per Andersen and London to attend a Royal Society Dinner. I also participated, in my then role as President of the Australian Academy of Science, with Sir George Porter, President of the Royal Society, in unveiling a memorial plaque to Sir Joseph Banks at the new Banks Building at the Royal Botanic Gardens at Kew. This plaque was jointly sponsored by the Royal Society and the Academy. Earlier in April 1988, Australia's Bicentennial Year, Sir George had unveiled a bust of Banks at the Australian National Botanic Gardens in Canberra.

Australian Academy of Science

I had been elected to Fellowship of the Australian Academy in 1965, and had been a member of the Council (1974–1977) and a Vice-President (1975–1977). I also served on a number of Standing, Sectional, and National Committees, and, as recipient of the Academy's Burnet Medal, delivered the Burnet Lecture in 1983. This, the Academy's major award for research in the biological sciences, honors the contributions to science in Australia of Sir Macfarlane Burnet OM, KBE, MD, FAA, FRS, Nobel Laureate, the Academy's fourth President (1965–1969).

In May 1986 I was elected as President for a 4-year term. Fortunately the location of the Academy very close to the JCSMR considerably reduced the impact that this appointment could have had on my research program. I am currently a member of the Academy's House Committee and Chairman of the Editorial Board of “Historical Records of Australian Science."

JCSMR Administration

In 1988, following a major ANU review of the School's research activities and structure, the departmental organization was replaced by four divisions, and from January 1989 I was invited to be Head of the Division of Neuroscience. This incorporated my Pharmacology (later Neuropharmacology) Group, the Physiology Group (Peter Gage), the Experimental Neurology Group (Steven Redman), and the Visual Neurosciences Unit (Bill Levick).

This appointment, however, was very brief as in March 1989 Robert Porter, who had been Director of the School and Howard Florey Professor of Medical Research since March 1980, resigned to take up the position of Dean of the Faculty of Medicine at Monash University in Melbourne. I was invited by the ANU Council to accept the Directorship and the Howard Florey Professorship from March 1989 until my retirement in December 1992. For the first year of this appointment I was also President of the Australian Academy of Science.

In 1989 the JCSMR had 73 full-time research staff, 56 PhD students, 125 technical support staff, and 66 administrative, general, and animal support staff. The total annual expenditure was A$14.6 million, 90% of which was derived from the School's allocation of the University's block grant from the Federal Department of Employment, Education, and Training. Members of the research staff were not able to apply for research grants awarded by the major Government grant-giving bodies, the NHMRC and the Australian Research Council (ARC), except in a few areas of research specified as being of special interest.

This appointment was in fact a “caretaker” role, because in 1987 the Federal Labor Government had announced its intention to bring about radical changes in the Australian tertiary education sector. An external committee was appointed by the Government in January 1990 to review the standing, role and funding of the ANU Institute of Advanced Studies (IAS) in the Australian higher education and research system. This included consideration of the then seven individual Research Schools: Biological Sciences, Chemistry, Earth Sciences, Pacific Studies, Physical Sciences, Social Sciences, and the JCSMR. Each had been reviewed in the past by committees, appointed by the University Council, and consisting of experts in the appropriate disciplines from Australia and abroad. The research activities and structure of the JCSMR had been reviewed in 1978 and 1988, the second led to the abolition of the departmental structure and the creation of four divisions.

Only one of the eight IAS Reviewers had experience in biomedical research, and although their recommendations, received by the Government in October 1990, could be regarded as generally favorable for the Institute, those specifically related to the JCSMR were far from welcome. Some research activities were suggested as being more appropriate for transfer to Biological Sciences or Chemistry, some to be discontinued and then the School to be “detached” from the ANU as an institute with its own governing body and management, funded for research by the NHMRC but affiliated with the ANU for academic purposes.

These recommendations were not acceptable to the University Council, and to the large majority of the JCSMR staff who strongly asserted that as one of the four Foundation Research Schools of the ANU the JCSMR should remain a formal component of the IAS. As Director I had spent considerable time in preparing a submission for this review. Then there was the need to respond to the report as it affected the JCSMR, and to participate in numerous discussions and negotiations with NHMRC representatives about future funding and administrative arrangements for the JCSMR. The NHMRC was then within the Department of Health, Housing, and Community Services (DHHCS), and in March 1991 funds considered appropriate for the JCSMR were transferred from the Department of Higher Education to DHHCS for a period of 5 years.

The details of the resultant complex bureaucratic saga are not relevant to this autobiography (see Fenner and Curtis, 2001). The School's precarious situation was referred to a Standing Committee of the parliamentary Senate, and in the meantime the School continued to receive its block grant from DHHCS. By this means, rather than transferring funding for the School directly to the NHMRC, the Government had accepted that the School should remain part of the University, which would then be responsible for its overhead costs. In August 1992 a liaison Committee was established with representatives of the ANU and DHHCS to consider policy and administrative issues related to the JCSMR. This arrangement continued until December 1996 when, following a change in government, funding for the School was restored as part of the ANU block grant from the Department of Education.

It is of historical interest that by the late 1990s, with the decreasing value of the government block grant to the IAS, there was an increasing need for the JCSMR to obtain additional funding from commercial interests and nongovernment research granting bodies. By 1998 approximately 78% of the JCSMR expenditure (A$19 million) was covered by the block grant. In 2001, however, the School's research staff gained access to the NHMRC and ARC for project grants. This access, increasingly staged over 3 years, was accompanied by a reducing block grant. The school's success in obtaining project and other grants resulted in a considerable increase in total annual expenditure, approximately A$36 million in 2004, of which only 57% was derived from the government block grant.

Retirement

In the meantime, well aware that the JCSMR required a long-term director, and more than anxious to return to hands-on research rather than to continue dealing with ministers, reviewers, and administrators, I resigned as Director in March 1992 and returned to the Division of Neuroscience. During the rest of that year until my retirement on December 31, and then for 3 years as a University Fellow, with an ANU grant for research expenses and travel, and with the financial support of the JCSMR, I was able to complete several research projects with the assistance of Gary Lacey. My last experiment was on December 21, 1995, in the laboratory that I had occupied since February 1975, and for which I had designed, and even constructed, much of the special items of equipment.

In 1987, in recognition of my contributions to medical science, I had been invited to become a Fellow of the Royal Australasian College of Physicians. My contributions to medical sciences, particularly in the fields of research and administration, were also recognized in January 1992 by my appointment as a Companion in the Order of Australia, Australia's highest award for eminent achievement. Later in December 2002 I received a Centenary Medal for “Service to Australian society and science in neurophysiology."

With financial assistance from the Academy of Science, the JCSMR and the Department of Pharmacology of the University of Sydney, Graham Johnston and Steven Redman organized a 1-day symposium on Neurotransmission at the School on February 3, 1993 to mark the occasion of my retirement. I was indeed honored by the presence of many of my previous colleagues from Australia and abroad who attended, including Jeff Watkins, Graham Johnston, Povl Krogsgaard-Larsen, Victor Wilson, Hugh McLennan, Per Andersen, Dominik Felix, Bruce Gynther, and David Kerr.

Conferences Abroad

In late May 1990 I had presented a paper “GABA and Presynaptic Inhibition” at a symposium in Vancouver on the occasion of Hugh McLennan's retirement. My wife and I then briefly visited the Rockefeller University in New York, and then spent 18 days in the UK visiting London, Oxford, and Bristol. Then to Zurich to present a paper “Micropharmacology of Presynaptic Terminals” at the Brain Research Institute before delivering the opening lecture “Early Excitement About Amino Acids” at a meeting held at Flims. Finally, I delivered a Plenary Lecture dealing with amino acid transmitters at the IUPHAR Congress in Amsterdam.

In September 1992 I attended the Second International Conference on GABA-B Receptors in Interlaken. I returned to Europe in May 1993 to present a paper at a gathering of ex-colleagues of John Eccles, held at the Max-Planck Institute for Brain Research in Frankfurt, to celebrate his 90th birthday and his outstanding contributions to neuroscience. I was also able to visit Ciba-Geigy AG in Basel to discuss our results with a series of baclofen agonists and antagonists, which had been provided earlier by Helmut Bittiger and his colleagues.

My final science-related period abroad was from October 1 to mid-November 1994 and included Vancouver, Ottawa, lectures in Edinburgh, Goteborg, and Tampere, a Plenary Lecture at the FAOPS Congress in Shanghai, and lectures at the Institute of Biophysics in Beijing and the University of Hong Kong.

Post-1995

From December 1995 until late 1998 I occupied a small office in the JCSMR Division of Neuroscience to complete a number of manuscripts, and then decided to work from home, visiting the school occasionally as a Visiting Fellow. With a small word processor I learned to type and prepared a number of obituaries of John Eccles who died on May 2, 1997 at the age of 94. Per Andersen and I authored his biographical memoirs, which were published in December 2001 by the Academy of Science and the Royal Society. I was also invited by Frank Fenner, who in 1948 had been the Foundation Professor of Microbiology, subsequently Director of the School from 1967 to 1973, and a Visiting Fellow since 1979, to join him in preparing a book The John Curtin School of Medical Research. The First Fifty Years, 1948–1998. This was published locally in August 2001 by Brolga Press, the manager of which was Robert Kirk, a former Head of the School's Department of Human Genetics. Our book, of 565 pages, included a detailed and illustrated history of the school and its staff, together with 85 invited essays covering highlights of many of the school's research achievements.

From 1998 until 2001, largely because of my experience on grantallocating committees, I was a member of the Panel of Advisors of the National Institute of Forensic Science. I now enjoy a busy retirement, totally free of any involvement in laboratory research. I remain deeply concerned, however, that although the relevance of the increasing number of in vitro biophysical and molecular biological discoveries to the complex operation of the mammalian CNS and its disorders clearly requires in vivo confirmation, very few neuroscientists are currently receiving training in techniques appropriate to research using whole animals. I am practically free of administrative responsibilities, apart from those associated with several Standing Committees of the Academy of Science, and now can enjoy adequate time for nonscientific reading, listening to music at home and at concerts in Canberra, visiting relatives and friends, gardening, wombling, learning new techniques for turning wood, and making the appropriate tools.

I was extremely fortunate in having had John Eccles as my scientific mentor, which led to my holding full-time research positions in the JCSMR from 1954 until 1995. Jack Coombs had an important influence on my ability to design and make electronic equipment, and collaboration with Rosamond Eccles in 1955 and 1957 resulted in the choice of Renshaw cells with which to initiate ME techniques. I was also particularly fortunate in having Jeff Watkins and later Graham Johnston as collaborators, because, without their expertise as organic chemists and their acquisition of a considerable understanding of the mammalian CNS, neuropharmacology and neurochemistry may not have been developed as research disciplines in the school.

I have been extremely fortunate, living in a somewhat remote region of the world, to have had numerous opportunities to travel abroad and to meet so many scientists with interests in the nervous system in the UK, United States, Canada, Denmark, Norway, Sweden, Finland, Holland, France, Germany, Switzerland, Italy, Hungary, Russia, Ukraine, India, China, and Japan.

My interests in the CNS were broadened by collaboration with David Kerr and his colleagues in Adelaide, and with a number of distinguished neuroscientists from abroad, including Anders Lundberg, Per Andersen, Paul Voorhoeve, Victor Wilson, Tim Biscoe, Hugh McLennan, and Povl Krogsggard-Larsen. I am also grateful to the many Research and Postdoctoral Fellows, and PhD Scholars, who contributed so much in the JCSMR Departments of Physiology and Pharmacology and the Division of Neuroscience. Many later occupied senior academic or administrative positions in Australia and abroad, including John Phillis, Ron Ryall, Michael Crawford, Chet de Groat, Arthur Duggan, Dominik Felix, Christopher Game, Roy McCulloch, David Lodge, Max Headley, Joel Bornstein, Martin Peet, John Leah, Richard Malik, Bruce Gynther, David Beattie, and Gary Lacey.

My research would not have been possible without skilled technical assistance from numerous members of the school's and departmental support staff, particularly Gerry Allen, Bob Ayling, Pam Blower, Arthur Chapman, Geoff Cohen, Arlene Daday, Lionel Davies, Don Geary, Laurel Graham, Barbar McLachlan, Beth McNaughton, Bryan Maher, Margaret Rodda, Alex Saeck, Pat Searle, Helen Taylor, Les Tranter, Toyne Van Arkel, Helena Walsh, Les Wells, and Gerry Winsbury.

Finally, without the support of the Australian National University, John Eccles and particularly that of my wife Lauri and our children, who survived our move to Canberra in 1954, I would not have been in a position to have been invited to prepare this autobiography.

Selected Bibliography

Beart PM, Curtis DR, Johnston GAR. 4-Aminotetrolic acid: A new conformationally restricted analogue of γ-aminobutyric acid. Nature 1971;234:80–81.

Bowery NG. GABA B receptor pharmacology. Annu Rev Pharmacol 1993;33: 109–147.

Coombs JS, Curtis DR, Eccles JC. The interpretation of spike potentials of motoneurones. J Physiol (Lond) 1957;139:198–231.

Curtis DR. Microelectrophoresis. In Nastuk WL, ed. Physical techniques in biological research, Vol. 5. New York: Academic Press, 1964;144–190.

Curtis DR. A method for continuously monitoring the electrical threshold of single intraspinal nerve fibres. Electroen Clin Neurophysiol 1979;47:503–505.

Curtis DR, Andersen P, Sir John Carew Eccles, AC. 27 January 1903–2 May 1997. Biog Mems Fell R Soc Lond 2001;47:159–187.

Curtis DR, Bornstein JC, Lodge D. In vivo analysis of GABA receptors on primary afferent terminations in the cat. Brain Res 1980;194:255–258.

Curtis DR, de Groat WC. Tetanus toxin and spinal inhibition. Brain Res 1968;10: 208–212.

Curtis DR, Duggan AW, Felix D, Johnston GAR. GABA, bicuculline and central inhibition. Nature 1970;226:1222–1224.

Curtis DR, Duggan AW, Felix D, Johnston GAR. Bicuculline, an antagonist of GABA and synaptic inhibition in the spinal cord. Brain Res 1971;32:69–96.

Curtis DR, Duggan AW, Felix D, Johnston GAR, McLennan H. Antagonism between bicuculline and GABA in the cat brain. Brain Res 1971;33:57–73.

Curtis DR, Duggan AW, Felix D, Johnston GAR, Tebecis AR, Watkins JC. Excitation of central neurones by acidic amino acids. Brain Res 1972;41:283–301.

Curtis DR, Duggan AW, Johnston GAR. The specificity of strychnine as a glycine antagonist in the mammalian spinal cord. Exp Brain Res 1971;12:547–565.

Curtis DR, Eccles RM. The excitation of Renshaw cells by pharmacological agents applied electrophoretically. J Physiol (Lond) 1958;141:435–445.

Curtis DR, Felix D. The effect of bicuculline upon synaptic inhibition in the cerebral and cerebellar cortices of the cat. Brain Res 1971;34:301–321.

Curtis DR, Felix D, Game CJA, McCulloch RM. Tetanus toxin and the synaptic release of GABA. Brain Res 1973;51:358–362.

Curtis DR, Gynther BD. Divalent cations reduce depolarization of primary afferent terminations by GABA. Brain Res 1987;422:192–195.

Curtis DR, Gynther BD, Beattie DT, Kerr DIB, Prager RH. Baclofen antagonism by 2-hydroxy-saclofen in the cat spinal cord. Neurosci Lett 1988;92:97–101.

Curtis DR, Gynther BD, Beattie DT, Lacey G. An in vivo electrophysiological investigation of Group 1A afferent fibres and ventral horn terminations in the cat spinal cord. Exp Brain Res 1995;106:403–414.

Curtis DR, Gynther BD, Lacey G, Beattie DT. Baclofen: reduction of presynaptic calcium influx in the cat spinal cord in vivo. Exp Brain Res 1997;113:520–533.

Curtis DR, Headley PM, Lodge D. Depolarization of feline primary afferent fibres by acidic amino acids. J Physiol (Lond) 1984;351:461–472.

Curtis DR, Hosli L, Johnston GAR. A pharmacological study of the depression of spinal neurones by glycine and related amino acids. Exp Brain Res 1968;6:1–18.

Curtis DR, Hosli L, Johnston GAR, Johnston IH. The hyperpolarization of spinal motoneurones by glycine and related amino acids. Exp Brain Res 1968;5:238–262.

Curtis DR, Johnston GAR. Amino acid transmitters in the mammalian central nervous system. Ergebn Physiol 1974a;69:97–188.

Curtis DR, Johnston GAR. Convulsant alkaloids. In Simpson LL, Curtis DR. eds. Neuropoisons, Vol 2. New York: Plenum Publishing, 1974b;207–248.

Curtis DR, Lacey G. Prolonged GABA B receptor-mediated synaptic inhibition in the cat spinal cord: an in vivo study. Exp Brain Res 1998;121:319–333.

Curtis DR, Lodge D. The depolarization of feline ventral horn group 1A spinal afferent terminations by GABA. Exp Brain Res 1982;46:215–233.

Curtis DR, Lodge D, Bornstein JC, Peet MJ. Selective effects of (-)-baclofen on spinal synaptic transmission in the cat. Exp Brain Res 1981;42:158–170.

Curtis DR, Lodge D, Bornstein JC, Peet MJ, Leah JD. The dual effects of GABA and related amino acids on the electrical threshold of ventral horn group 1A afferent terminations in the cat. Exp Brain Res 1982;48:387–400.

Curtis DR, Lodge D, Brand SJ. GABA and spinal afferent terminal excitability in the cat. Brain Res 1977;130:360–363.

Curtis DR, Malik R. The effect of GABA on lumbar terminations of rubrospinal neurones in the cat spinal cord. Proc R Soc B 1984;223:25–33.

Curtis DR, Malik R. The differential effects ofbaclofen on segmental and descending excitation of spinal interneurones in the cat. Exp Brain Res 1985;58:333–337.

Curtis DR, Malik R. A neurophysiological analysis of the effect of kainic acid on nerve fibres and terminals in the cat spinal cord. J Physiol (Lond) 1985;368:99–108.

Curtis DR, McIntyre AK. Studies in physiology. Presented to John C Eccles. Berlin: Springer Verlag, 1965.

Curtis DR, Ryall RW. The acetylcholine receptors of Renshaw cells. Exp Brain Res 1966;2:66–80.

Curtis DR, Ryall RW. The synaptic excitation of Renshaw cells. Exp Brain Res 1966;2:81–96.

Curtis DR, Watkins JC. The excitation and depression of spinal neurones by structurally related amino acids. J Neurochem 1960;6:117–141.

Curtis DR, Watkins JC. The pharmacology of amino acids related to gamma-aminobutyric acid. Pharmacol Rev 1965;17:347–392.

Davidoff RA, Graham LT, Shank RP, Werman R, Aprison MH. Changes in amino acid concentrations with loss of spinal interneurones. J Neurochem 1967;14: 1025–1031.

Duggan AW. The differential sensitivity to L-glutamate and L-aspartate of spinal interneurones and Renshaw cells. Exp Brain Res 1974;19:522–528.

Eccles JC. The neurophysiological basis of mind. Oxford: Clarenden Press, 1953.

Eccles JC. Presynaptic inhibition in the spinal cord. Prog Brain Res 1964;12:65–91.

Eccles JC, Schmidt RF, Willis WD. Pharmacological studies on presynaptic inhibition. J Physiol (Lond) 1963;168:500–530.

Falch E, Jacobsen P, Krogsgaard-Larsen P, Curtis DR. Gaba-mimetic activity and effects on diazepam binding of aminosulphonic acids related to piperidine-4-sulphonic acid. J Neurochem 1985;44:68–75.

Fenner F, Curtis DR. The John Curtin School of Medical Research. The first fifty years, 1948–1998. Gundaroo: Brolga Press, 2001.

Foster SG, Varghese MM. The making of the Australian National University. St Leonards: Allen and Unwin, 1996.

Froestl W, Mickel SJ, Schmutz M, Bittiger H. Potent, orally active GABA B receptor antagonists. Pharmacol Rev Commun 1996;8:127–133.

Gynther BD, Curtis DR. Post-tetanic influences on primary afferent depolarization in the cat spinal cord. Exp Brain Res 1989;74:365–374.

Johnston GAR. The intraspinal distribution of some depressant amino acids. J Neurochem 1968;15:1013–1017.

Johnston GAR. Neurotoxic amino acids. In Simpson LL, Curtis DR. eds. Neuropoisons, Vol 2. New York: Plenum Publishing, 1974;179–205.

Johnston GAR. Neuropharmacology of amino acid inhibitory transmitters. Annu Rev Pharmacol Toxicol 1978;269–289.

Johnston GAR, Curtis DR, Davies R, McCulloch RM. Spinal interneurone excitation by conformationally restricted analogues of L-glutamic acid. Nature 1974;248:804–805.

Johnston GAR, Curtis DR, De Groat WC, Duggan AW. Central actions of ibotenic acid and muscimol. Biochem Pharmacol 1968;17:2488.

Kerr DIB, Ong J, Prager RH, Gynther BD, Curtis DR. Phaclofen: a peripheral and central baclofen antagonist. Brain Res 1987;405:150–154.

Krogsgaard-Larsen P, Brehm L, Johansen JS, Vinzents P, Lauridsen J, Curtis DR. Synthesis and structure-activity studies on excitatory amino acids related to ibotenic acid. J Med Chem 1985;28:673–679.

Krogsgaard-Larsen P, Falch E, Schousboe A, Curtis DR, Lodge D. Piperidine-4-sulphonic acid, a new specific GABA agonist. J Neurochem 1980;33:756–759.

Krogsgaard-Larsen P, Hjeds H, Curtis DR, Lodge D, Johnston GAR, Dihydromuscimol, thiomuscimol and related heterocyclic compounds as GABA analogues. J Neurochem 1979;32:1717–1724.

Krogsgaard-Larsen P, Honore T, Hansen JJ, Curtis DR, Lodge D. New class of glutamate agonist structurally related to ibotenic acid. Nature 1980;284:64–66.

Krogsgaard-Larsen P, Johnston GAR. Inhibition of GABA uptake in rat brain slices by nipecotic acid, various isoxazoles and related compounds. J Neurochem 1975;25:797–802.

Krogsgaard-Larsen P, Johnston GAR. Structure-activity studies on the inhibition of GABA binding to rat brain membranes by muscimol and related compounds. J Neurochem 1978;30:1377–1382.

Krogsgaard-Larsen P, Johnston GAR, Curtis DR, Game CJA, McCulloch RM. Structure and biological activity of a series of conformationally restricted analogues of GABA. J Neurochem 1975;25:803–809.

Krogsgaard-Larsen P, Johnston GAR, Lodge D, Curtis DR. A new class of GABA agonist. Nature 1977;268:53–55.

Lacey G, Curtis D. Phosphinic acid derivatives as baclofen agonists and antagonists in the mammalian spinal cord: An in vivo study. Exp Brain Res 1994;101:59–72.

Lodge D, Curtis DR. Time course of GABA and glycine actions on cat spinal neurones: Effect of pentobarbitone. Neurosci Lett 1978;8:125–129.

Lodge D, Curtis DR, Brand SJ. A pharmacological study of the inhibition of ventral group 1A-excited spinal interneurones. Exp Brain Res 1977;29:97–105.

Lodge D, Headley PM, Curtis DR. Selective antagonism by D-α-aminoadipate of amino acid and synaptic excitation of cat spinal neurones. Brain Res 1978;152:603–608.

Lodge D, Johnston GAR, Curtis DR. Effects of the Areca nut constituents arecaidine and guvacine on the actions of GABA in the cat central nervous system. Brain Res 1977;136:513–522.

McCulloch RM, Johnstone GAR, Game CJA, Curtis DR. The differential sensitivity of spinal interneurones and Renshaw cells to kainate and N-methyl-D-aspartate. Exp Brain Res 1974;21:515–518.

McLennan H, Lodge D. The antagonism of amino acid-induced excitation of spinal neurones in the cat. Brain Res 1979;169:83–90.

Obata K, Ito M, Ochi R, Sato N. Pharmacological properties of the postsynaptic inhibition by Purkinje cell axons and the action of γ-aminobutyric acid on Deiters' neurones. Exp Brain Res 1967;4:43–57.

Peet MJ, Leah JD, Curtis DR. Antagonists of synaptic and amino acid excitation of neurones in the cat spinal cord. Brain Res 1983;266:83–95.

Szentagothai J. Synaptic structure and the concept of presynaptic inhibition. In von Euler C, Skoglund S, Soderberg V, eds. Structure and function of inhibitory neuronal mechanisms. Oxford: Pergamon Press, 1968;15–31.

Werman R, Davidoff RA, Aprison MH. Inhibitory action of glycine on spinal neurones in the cat. J Neurophysiol 1968;31:81–95.

Watkins JC.L-glutamate as a central transmitter: Looking back. Biochem Soc Trans 2000;28:297–310.

Watkins JC, Curtis DR, Biscoe TJ. Central effects of B-N-oxalyl-α-Bdiaminopropionic acid and other Lathyrus factors. Nature 1966;211:637.

Ennio De Renzi

BORN:

Cremona, Italy

December 18, 1924

EDUCATION:

University of Pavia, M.D. (1950)

University of Pavia, Specialty in

Neurology and Psychiatry (1953)

APPOINTMENTS:

University of Pavia (1951)

University of Modena (1956)

University of Milan (1958)

University of Trieste (1969)

University of Milan (1971)

University of Modena (1974)

HONORS AND AWARDS (SELECTED)

President of the Brain and Behaviour Society (1971–1973)

Carlo Riquier Award, University of Pavia (1988)

Honorary Degree in Psychology, University La Sapienza of Rome (1993)

Member of the Academia Europea (1994)

Honorary Member of the American Neurological Association (1995)

Honorary Member of the Academy of Neurology (1995)

Honorary Member of the British Neuropsychological Society (1996)

Professor Emeritus, University of Modena (2002)

Ennio De Renzi pioneered the development of neuropsychology as a scientific discipline in Italy. He carried out early work on hemispheric specialization in patients with unilateral brain lesions and made fundamental contributions to understanding the nature of virtually every neurological condition that affects higher functions: aphasia, apraxia, agnosia, amnesia, disorders of spatial cognition, and frontal lobe syndromes. In 1964 he founded the international journal Cortex and served as Editor for more than 25 years.

Ennio De Renzi

I was born in Cremona in December of 1924. Situated in Northern Italy, in the heart of the Po valley, Cremona is an agricultural center, renowned as the birthplace of such unsurpassed lute makers as Stradivari and Guarnieri. This is not, however, the greatest source of pride among its inhabitants, who instead boast of the three Ts that characterize the city. T represents the first letter of the dialect names turun (a sort of nougat), Turaz (the 111-meter-high bell tower of the cathedral) and tetaz (an augmentative form pointing to the generous bosom of the Cremonese women). I can vouch for the deliciousness of turun and the beauty of the Turaz; as to the referent of the last T, I must have appreciated it, having been put out to a Cremonese wet nurse, but honestly I do not cherish any memory of this experience.

In those years, Italy was an apparently quiet and peaceful country that many Italians and a good few distinguished foreign statesmen (among them Winston Churchill) praised for having warded off the Reds and having at last become well-disciplined and respectful of law and order. As a matter of fact Italy was heading into the tunnel of Fascist dictatorship, from which it would emerge only 20 years later at the end of a ruinous war. A few months before my birth, Mussolini's hired killers had murdered Giacomo Matteotti, one of the opposition leaders. In the aftermath there had been a wave of protests, which had given way to a feeling of helplessness and eventually of acquiescence when in January 1925 a parliament of sheep and a pusillanimous monarchy passed the laws that wiped out any trace of political freedom. The first 20 years of my life were spent in a society ruled by a form of government that, although incomparably less bloody than those set up by the other two big dictators of the 20th century, was repressive, untruthful, and boring. Yet, in spite of the endless political jokes it inspired and the tiresome ritual of its parades, the Fascist regime was largely accepted by the middle classes, which were sensitive to the nationalist and populist topics of its propaganda: a poor country like Italy must be prepared to fight, if she wants to conquer a place at the banquet of rich countries. The atmosphere was somewhat different in my family, mainly thanks to the attitude of my father who could not stand the clownish aspects of fascism and, being a staff officer, was painfully aware of the great bluff underlying the representation of Italy as a great military power.

He used to comment upon the negative aspects of the regime with two sarcastic refrains: “fatal degenerations of tyranny,” referring to the deleterious consequences of barring freedom of speech and “our doomed to defeat army,” referring to the pitiful conditions of the armed forces. Yet he also harbored strong patriotic feelings and thought that he had to be present in the battlefield, where the future of his country was at stake. Consequently, I received a double-bind message and had mixed feelings about the goals pointed out by Fascist propaganda.

My decision to study medicine was neither early nor prompted by scientific interests or humanitarian aims; it came as a result of my having second thoughts. In my family there was no tradition of scientific studies. The influential figure for my cultural development was my maternal grandfather, a fine Latin scholar, who was rightly proud of being the first Italian translator of Tacitus' Complete Works in the modern age. When the volumes of his translation were published, a copy of them was sent to my family and was received with great respect, although I do not think it was ever actually read. He influenced my reading matter, which he guided with advice and by supplying me with 19th-century novels from both Italian and French literature (the former I found rather boring, the latter fabulous, and I learned to read them in the original language). I was an avid and precocious reader, and I still remember being angered by the skeptical smile of a family friend when, at the age of 12, I declared that I had read Crime and Punishment by Dostoevski. At the very least I must have understood very little of it, he commented, and I long wondered what hidden meaning of the novel I had missed and how I could find it out. At any rate, whatever the comprehension level achieved, there is no denying that my voracious reading did little to improve my performance at school, which, until the last years of "liceo," was by no means outstanding, possibly due to the continuous relocations to which my father's military career obliged his family. In the early 17 years of my life, I had lived in 14 different cities and, as a result, I found it hard to establish firm relations with either teachers or classmates.

Throughout high school the sciences never really gripped me. Whether this was due to the teachers not being particularly stimulating or to my overwhelming interest in literature and history, I cannot say. Consequently, when the time came to enroll at the university, none of the scientific faculties was taken into account and I chose law. In the meantime war had broken out. Initially it seemed that its unfolding events were confined to distant parts and had a marginal impact on everyday life, but as the years went by, its threatening waves rumbled closer and came to shake our consciences with the warning of an impending catastrophe. If I try to recall my feelings in the war years, it seems that at first I was captivated by patriotic propaganda and that it was only under the pressure of events that I became progressively aware of its falsity and the abyss into which the country was about to fall. After the Nazi occupation I had various adventures in occupied Italy and eventually reached the free part of the country where I enlisted in the Italian army that fought alongside the allies. It was in this climate of precariousness and overturning of values that I made up my mind to abandon the faculty of law, in spite of the seven examinations I had passed and to matriculate in medicine, a profession that in the wartime turmoil appeared to maintain its dignity and profile whatever the circumstances in which it was practiced. I had just read with great interest a book on the functioning of the brain and one day while talking with my father I expressed regret at not having the possibility to pursue this subject. We were taking a walk in the hills surrounding the encampment, where we were training, just before being sent to the front on the Gothic line, he as colonel and I as private. He did not miss the chance to back up the change of faculty and suggested that I enroll in law and medicine in two different universities, with the intention of keeping both doors open and of postponing the decision until the end of the war. This was a rather unlawful procedure, which, however, was very unlikely to be discovered in a period of utmost administrative chaos when Italy was split in two.

The Ghislieri and the Faculty of Medicine of Pavia

A few months later peace returned. After my discharge from the army, I finally made up my mind and took the definite decision to abandon law and to prepare for the exams of the first year of medicine: physics, chemistry, histology, and part of anatomy. I must confess that I found these matters boring and mnemonically demanding, as they indeed are, to the point that I came to miss the speculative breadth of law studies.

In the fall 1945, I passed an entrance examination to the Ghislieri College in Pavia. It was, along with the Borromeo College in Pavia and the Scuola Normale in Pisa, one of the three Italian foundations that offered deserving students from less affluent families the chance of a university education in optimal study conditions and free of charge. It was founded in the 16th century by Antonio Michele Ghislieri (1504–1572), a Dominican friar who, after having shown great zeal in fighting against heretics and infidels as Grand Inquisitor of the Holy Office (as Waldensian refugees in Calabria had come to learn at their cost during the persecution he set off against them), was elected Pope under the name of Pius V. In this capacity, he had achieved remarkable successes (as in the battle of Lepanto) as well as painful defeats, as with his decree of deposition and excommunication of Queen Elizabeth, which resulted in the worsening of the English Protestant persecution against their fellow country people. At any rate his undertaking was greatly praised by the church, which a century and half later consecrated his memory to the devotion of Catholics, making him a saint. The extent to which believers turned to Pius V's intercession to gain heavenly protection is unknown, but surely his decision to allocate the rents of his fertile landed properties to support university students won for him the gratitude of several generations of students, who were not too overly worried by the blood and tears that the benefits they enjoyed cost. All the more as any trace of religious norms had disappeared from the college rules and all that was expected of students was that they attained good grades.

The academic year of many young men of the same age (obviously girls had not been considered as possible students by Pius V and his successors and had to wait another 20 years before being admitted to the college) began with a month devoted to “freshman re-education,” a time of abuse and humiliation, to which freshmen were submitted by senior students with the declared aim of ridding them of any intellectual smugness they might harbor. This period ended with the “rain season,” during which freshmen were incited to take their revenge, staging a show in which senior students were subjected to merciless jibes and put-downs. The remaining days were filled with many hours of hard work, sometimes alternating with tomfoolery and revelry and with nights spent recounting past experiences and sketching out future hopes. It is little wonder that this atmosphere fostered the beginning of deep friendships, some of which were destined to last a lifetime. I took advantage of this chance and found friends particularly among people on different courses, who gave me the opportunity to widen my cultural horizons and sharpen my wits.

Students of the early years of medicine were encouraged by the college authorities to attend laboratories and wards, even if the time spent in doing so clashed with lecture attendance, which in principle was mandatory but not actually supervised. I soon realized that good textbooks could easily make up for academic lectures. Moreover, teaching skills, as well as other mental abilities, were distributed among university professors according to a Gaussian curve, which made only few of them irreplaceable. Therefore, I attended only lectures whose content was otherwise inaccessible, e.g., those of dermatology and radiology, or those which were given by stimulating lecturers. One of them was Carlo Berlucchi, the neuropsychiatrist, who stood out from the generally dreary crowd for the meaty content of his lectures. Although not as clear as they might have been, they were the fruit of wide reading and original reflections and not the mere repetition of standard textbooks. At first hearing they could leave you with a feeling of frustration. I still remember one of them on neurosis therapy, which after having outlined the many treatments proposed, subjected each of them to radical criticism and ended up without coming to any positive recommendation. The audience was bewildered and left with the impression of being lost in a forest without a guide. It was only a few years later that I realized just how realistic a view the lecture provided of an area where the challenge was not to memorize notions of questionable validity but to assess the evidence supporting them. Berlucchi's personality and the thought-provoking nature of his lectures piqued my old interests in the enigma of mind and led me to ask him to propose a subject for my thesis.

The Neuropsychiatric Department of Pavia

Under the influence of the German model, neurology and psychiatry were taught in one course at the undergraduate level and in one 3-year specialty at the postgraduate level. There was a certain asymmetry between the clinical importance and the scientific prestige of the two disciplines. Neurology had developed around firm anatomical and physiological notions, whereas the conceptual framework underlying the interpretation of mental disorders rested on a frailer basis. On the other hand, psychiatrists had been the first to gain autonomy from the core of medical matters and nobody would dispute their area of competence, all the more because mental patients were feared and were left willingly to their care. It had been harder for neurologists to win visibility. The most common pathology, vascular diseases, was still considered province of internal medicine and Alzheimer disease was rarely diagnosed and only in patients younger than the age of 65. In addition, there was a common and not totally unjustified belief, both among practitioners and patients, that very few effective weapons against the diseases of the nervous system had been developed and that, on the whole, neurologists' intervention was of little use. To put it bluntly, neurology provided prestige, psychiatry money.

In Pavia the Institute for Nervous and Mental Diseases was set apart from the general hospital. There were two neurological and two psychiatric wards with a total capacity of 100–150 beds. The medical staff was amazingly small: in addition to the director, Prof. Carlo Berlucchi, there were just four assistants. One of them, Prof. Gildo Gastaldi, was Berlucchi's aiuto (something like his deputy director) and was waiting for a competition that would earn him full professorship. The hospital could only run with the aid of the specializing doctors, who gave their services as unpaid volunteers (in actual fact they had to pay their own school fees). In those days, the exploitation of medical graduates as unpaid labor was a feature common to every clinical department and was accepted without (open) complaint. Some of these doctors also spent part of their time in research, attending the well-equipped lab of histology or those of biochemistry and clinical neurophysiology, which were still rather rudimentary, but were destined to be remarkably developed in the coming years.

Berlucchi did his rounds everyday. This was not usual practice in other clinical departments. For instance, when I attended the two main internal medicine departments, Patologia medica and Clinica medica, I never saw their chiefs in the wards discussing difficult cases with other doctors. They were hidden gods we sometimes met and greeted in the corridors, without being recognized and to whom nobody but a member of the staff would dare raise queries. With Berlucchi it was different. First of all, every doctor could make remarks and ask questions during the round or knock on the door of his office to discuss a problem. In the latter case, it was not exceptional for him to be so engrossed by the question the person raised that he interrupted the neurological exam he was carrying out on a private patient and left the room looking for a book in the library, forgetful of the half-undressed client and his or her problems. I still remember one of them—a cousin of mine for whom I had asked a consultation—questioning me with a look of puzzlement: “Is he supposed to come back?” His approachable nature did not necessarily imply an exhaustive answer to any question, either because he was not in the mood for a pressing talk or because his reply appeared to avoid the core of the question and to address a secondary aspect of it. Eventually we realized that the gist of his comments could be hidden in an apparently irrelevant remark, maybe dissembled under the form of a bibliographic reference that we soon learned to remember and later look up in the department's well-stocked library. He had the tendency, I cannot say how much malice was involved, to declare himself poorly informed on a topic somebody had raised and to feign interest and curiosity for what was being said. It was embarrassing for the young doctor to discover after attempted explanations and much confident enthusiasm that the very same topic had already been analyzed and criticized by Berlucchi himself in one of his papers. By and large a prevalent trait of his personality was the skepticism with which he viewed the latest conceptual and therapeutic developments. He did not discourage attempts to validate them, but had probably learned throughout his career how easy it is for a novelty to kindle enthusiasm and to dull critical skills. Admittedly, some of his recurrent questions—what is the normal subject's behavior and are we sure that we are dealing with a specific effect?—were anticipating the methodological requirements that in few years would become mandatory for any research on human behavior.

Early Steps in Research

Looking back at the early years of my scientific life, I cannot help regretting that my research lacked a leading theme and jumped from one topic to another under the impulse of casual observations. In a way this is a risk inherent to clinical research, which must be ready to follow new directions suggested by observing patients. However, this flexibility must be reconciled with the need to cultivate personal lines of investigation to be pursued in depth and with tenacity. In my case, among the many subjects addressed, one looked promising. Berlucchi had remarked that our knowledge of sensory syndromes and their anatomical correlates was grounded on a relatively scanty number of cases. For instance, the evidence supporting the Déjerine-Roussy thalamic syndrome, reported by every neurological textbook and characterized by typical pains, had actually been verified in only a few patients. In Milan, there was a home for aged poor people, which, in case of disease, also served as a hospital and was equipped with necropsy facilities. Paolo Borghi and I decided to take advantage of this opportunity and went there weekly to carry out sensory testing of stroke patients, whose names were forwarded to the necropsy service in case of death. There were many dropouts, but in 3 years we were able to collect 15 brains, albeit none of them were of patients with Déjerine-Roussy syndrome. The autopsy findings of three cases contradicted well-established notions on the vascularization and functional anatomy of the central nervous system and were worth publishing. However, we had miscalculated the energy and time we could spend in this enterprise and, when Borghi decided to become a neurosurgeon and left the department, it came to an end.

My Experience with the Rorschach Test

Eventually I found in the Rorschach test an instrument that looked promising for the assessment of psychic life and that permitted wide-ranging applications in clinical diagnosis. Different lines of psychological thought converged on the amazing idea that inkblot interpretation could open a route to understanding the human mind and character: gestalt psychology, behaviorism, and psychoanalysis. What made it particularly attractive for the study of personality traits was that their assessment no longer relied upon the examiner's insight but on objective data provided by the responses. These could be analyzed from different viewpoints (part of the inkblot selected, the role played by form, color, and movement, the content of the interpretation, etc.) and transformed into quantitative data suitable for statistical analysis. Rorschach himself had sketched the patterns of responses typical of various psychiatric disabilities, but obviously he was not familiar with the concepts of variability and probability level and it was up to the next generation to ground his intuitions on firm findings.

On this occasion I was lucky enough to avail myself of the advice of Giulio Maccacaro, a college fellow, who had just spent a year in the lab of Sir Ronald Fisher, one of the founders of modern statistics. He had acquired a good command of the discipline and was eager to divulge its principles in the medical research milieu, whose cultural backwardness in this area he knew well (the Faculty of Milan eventually rewarded his sensitivity to didactic problems by giving him the first chair of medical biometry in Italy). He was happy to accept Berlucchi's invitation to hold an elementary course in statistics at the Department of Nervous and Mental Disease and in 1953 this was indeed an event. I owe to his lessons and the discussions that followed them my understanding of the principles of inferential statistics in an era when they were generally unknown in Italy. Knowledge of this tool was of great help to me when I addressed neuropsychological issues.

In an early study on adolescent psychology, carried out with the Rorschach test, it was my impression that several of the variables underlying the responses were related to demographic factors, such as education, age, and sex. These, however, were overlooked in studies that referred to the control group's performance, which tended to be based only on university students. With Mario Isotti and Anteo Saraval we undertook the task of collecting Rorschach data from 300 normal subjects, subdivided for years of schooling, age, and sex, according to a factorial design that allowed us to weigh the influence of each factor. The analysis highlighted the import of education on performance: it increased not only the number of responses and their originality but also the percent of global, movement, color, and shade responses, i.e., those features that Rorschach had interpreted as affective life indicators. It was amazing to see how the influence of education was not confined to the development of intellectual skills but also to the wealth and variety of emotional experiences with which the subject reacted to external stimuli. This finding had implications that went beyond the scientific horizon and offered hints for reflecting on the responsibility of the ruling classes, which had so long neglected to improve the level of education of the Italian population and still made access to secondary school a privilege of middle classes.

Other research aimed at assessing the Rorschach test's contribution to the psychopathology and diagnosis of mental diseases. In one study, 105 schizophrenic patients were tested before the illness became chronic and classified into the hebephrenic, paranoid, and simple subgroups, established by Kraepelin. In a second paper, schizophrenics were compared with 70 neurotics (divided into anxious, phobic, and obsessive patients) and 50 normal subjects. Finally, in a third study, carried out with Bianca Gatti, we used the Rorschach, Rosenzweig, Minnesota, and Wechsler tests to investigate 23 subjects committed to a criminal lunatic asylum because the circumstances of their crime had led to the diagnosis of sociopathic personality. I will not go into the details of the single studies, and I will limit myself to a few general reflections on the Rorschach test's (and other projective tests') contribution to psychiatry. It was my conclusion that the additional knowledge it brought to the understanding of patients was too often meager and disappointing, especially in subjects with low education, whose poor and sometimes constrained records (as, for instance, when almost every response had anatomical content) precluded any indepth inquiry into their personality. It is true that in a few cases one is struck by the new vistas that inkblot interpretation opens on hidden aspects of the personality, but if the time and effort required to master the test and the uncertainties that still plague its interpretation are considered, one cannot escape the question of whether they would not have been employed more fruitfully in directly interviewing patients and their families.

The Academic Power: Strengths and Weaknesses

After having attended the wards for 3 years, I obtained the specialty in nervous and mental diseases and had to make up my mind about which way to go. My preference was for staying in a hospital, possibly affiliated to a university, where clinical activity could be joined with research, while leaving the door open to an academic career. My need was also to earn a living and this was ensured by a small fellowship granted by the university on Berlucchi's recommendation and a free accommodation in the department building. Any expense beyond subsistence had to be covered by the money earned during the summer holidays, when I stood in for country doctors on leave. It was an exciting experience, because of the seemingly high earnings (at least in comparison to those to which I was accustomed) and the variety of work it offered. A minor drawback was that the area I was supposed to cover professionally was hilly with some of its country roads not asphalted and steep. This was not a real problem, if one could drive a car or a motorbike, but my only transport was a bicycle and sometimes, to get the top of the climb, I had to carry it by hand. However, what represented a persistent nightmare, which hounded me, was the risk of being called to a remote country place to assist a difficult delivery. At that time women in labor were not hospitalized systematically and the general practitioner was expected to be able to use forceps. My knowledge of obstetrics was gleaned entirely from textbooks and I still remember with a shudder the stormy night in which the midwife's shout “He's coming out” crowned with success my pushes on the woman's belly, just as her own mother was announcing that the forceps put on the fire was coming to a boil. The sigh of relief I breathed was as deep as the risk I had run of committing manslaughter.

My meager income notwithstanding, I managed to marry Rita, the woman who agreed to share her destiny and wealth with mine and who a year later gave birth to the first of my three children. She was a biologist and received from the Institute of Genetics, in which she worked, a fellowship that was as small as my own, but the consumer society was not yet in sight and we were content with what we had (along with a little help from our families).

People willing to pursue an academic career aimed for the title of libera docenza, inspired by the German Privat Dozent, which rewarded the candidate's scientific and clinical maturity. This was ascertained through the discussion of their research, a lecture on a subject drawn by lots 24 hours earlier, and the testing of clinical skills. In principle the title simply qualified the winner to give a free course to students. Actually it attested to the high level of scientific and professional know-how and was, in addition to its academic value, of benefit to its holder in two more pragmatic ways: It justified a honorarium increase in private practice and was an appreciated qualification for head positions in general hospitals. The system had its own logic, because it indicated a career path that persuaded at least some of the most brilliant graduates to resist the lure of immediate financial gains in favor of long scientific and clinical training, with the prospect of later entering well-paid top positions. At the same time it ensured the dissemination of knowledge to hospital doctors. It did little, however, to improve university-hospital relations. A professor would be placed in the position of becoming “indebted” to people who had passed several years working in his institute with little or no remuneration and would be expected to pay them off when he chaired the board of examiners that was entrusted with the choice of head physicians. This team spirit collided with the requirements of a rigorous selection. The system was also blamed for encouraging the mere piling up of the number of papers needed to be admitted to a competition, instead of a genuine interest in research. In truth the poor selection of to-be-published articles was also due to the editorial policy of most medical journals, which was to accept papers approved by department directors, without requiring an independent evaluation by anonymous referees. The lenient selection criteria made it relatively easy to publish papers and led to an upsurge in the number of journals in print: In the 1960s, there were around 10 devoted entirely or partially to neurology. This number dropped dramatically when libera docenza was abolished (now we have just one national journal of neurology, although such an extreme reduction also reflects the preference to submit papers to international journals). The price we paid was that research published in Italian journals was all but ignored by the international literature, in part for linguistic reasons but also because their general standard was rather low. To remain at the periphery of the scientific community was frustrating and gave young researchers a sense of futility and a parochial view of their own work, because its aim seemed to be confined more to winning the Italian academic hierarchy's approval than to capture the interest of a wider audience of international scientists.

Veering to Neurology

I spent 6 years in Pavia, 3 in neurological and 3 in psychiatric wards. My original enthusiasm for psychiatry had waned somewhat: I still found the encounter with psychic misery emotionally involving and noetically intriguing, but was put off by the difficulties in studying it with scientific methodology. The investigation of its biological foundation was still at sea, while psychological approaches either remained at a descriptive level or set up their theoretical constructs on psychoanalytic quicksand where different phenomena are interpreted with the same repetitive formulas, which are not liable to refutation. In those years, there was also in Europe a growing interest in approaching psychiatric troubles from an existentialist perspective, which was thought to offer more comprehensive insight into the role of humans in the world. It was not easy to follow these students' philosophical jargon and to my shame I must confess to having failed to understand what profit a doctor might gain from their speculations, however stimulating they were theoretically. As a result of these perplexities, I was slowly turning to neurology as a more promising field of investigation, although still uncertain about what subject to choose for my research.

In 1956, Prof. Gastaldi invited me to join his group in the Department of Nervous and Mental Disease of the University of Modena. I was happy to accept his offer, as I had already had the opportunity to work with him and to appreciate his acumen and the friendly and generous rapport he cultivated with his coworkers. I stayed in Modena for 1 year and in 1957 I followed Gastaldi in Milan, where he had been called to hold the Chair of Nervous and Mental Disease. Both disciplines were taught by him to medical students, but only neurological patients were hospitalized in the wards. Moreover the faculty had already called another professor just for psychiatry, thus prefiguring the separation between the two specialties that was to be formalized nationwide in a few years. These circumstances concurred to strengthen my decision to devote myself entirely to neurology. Eventually I was given a stable position along with a regular stipend, which, added to that earned by my wife as a high school science teacher, put an end to my economic worries, even though the size of my family increased (by the end of the 1960s we had three children).

Neuropsychology in the Early Sixties

The interest I developed for neuropsychology (this name became popular only later, the term we used then was “higher nervous function disorders") had been first aroused by the encounter with a few patients who presented a conspicuous impairment in the cognitive area. I still remember the amazement with which I listened to the speech of a typical Wernicke's patient, who showed a striking dissociation between her firm belief that she was communicating and the lack of meaning of her jargon. Other patients, whose behavior I spent several hours trying to define, were a patient with a post-traumatic Korsakov and an autobiographic delusion, one with spatial disorientation, and a third one with multisensory neglect. They interested me, because their conditions gave insights into the architecture of the mind, established a strong link with the brain and were hopefully less convoluted than affective disorders. Also a factor that militated in favor of carrying out research in this area was that it did not require strong financial support, which would not have been available in those days. Yet it was not easy to wade through the literature and the controversies that arose from it.

The method that prior to the First World War had provided an opportunity to gather a large body of information on how mental skills were organized in the brain was based on single-patient study of the anatomical substrate underlying the derangement of a given ability. It required a shrewd clinical investigator and the possibility of performing the autopsy. In the course of the 20th century the latter condition had become more difficult to meet, mainly because customs had evolved and relatives had become reluctant to give their consent. Also hospitalization had become shorter and it was no longer possible to keep patients in the hospital indefinitely, waiting for their death (as was the case for Broca's patient Tan-Tan who had been hospitalized for 10 years). As a result, anatomical information on the locus and extent of damage was limited almost exclusively to neurosurgical patients. Nobody would have predicted that within a few years technology would fulfill the dream harbored by generations of neuropsychologists, i.e., the in vivo localization of the lesion responsible for the symptom investigated. Twenty years later the question of localizing the anatomical correlates of a symptom was put between brackets by the introduction of a new method of symptom analysis, which rested entirely on the identification of cognitive modules. This approach required, however, the development of an information processing theory and the construction of cognitive models.

In the 1960s, the autopsy impasse was overcome by group studies, which had the double advantage of using a standardized method of evaluation and having criteria of localization that were not dependent on necroscopy findings. They were based on a comparison between the mental test performance of two or more groups of patients, defined on the grounds of an easily ascertainable feature, either anatomical (hemispheric side of lesion, cerebral lobe damaged) or clinical (aphasia, visual field defect). Care was taken to avoid selection biases and to have a normal control group. The tasks used were often constructed ad hoc with the aim of testing a specific ability and of yielding a score that could be submitted to statistical analysis. This methodology permitted active research planning and the testing of a priori defined hypotheses and it was no longer dependent on the chance of finding an interesting patient.

It is only fair to acknowledge that there was a turning point in this research area when its doors were opened to experimental psychologists, who brought a methodological rigor in treating psychological data that neurologists were not familiar with. In between the two World Wars there were indeed psychologists who had worked with neurologists (e.g., Gelb and Weigl worked with Goldstein in Germany) or who had developed their own line of research in the study of cognitive disorders (e.g., Weisenburg and McBride in the United States and Ombredanne in France), but their participation had been occasional and had not substantially influenced research methodology, as it did now that they were present in various centers.

Among the earliest contributions to be remembered are those of Brenda Milner from the Montreal Neurological Institute on the psychological effects of epileptic patients' temporal lobectomy and those of Hans L. Teuber and coworkers in New York on the consequence of Korean War veterans' missile cerebral injuries on a wide range of sensory and cognitive functions. Group studies were also carried out by Hécaen and coworkers at the Saint Anne Hospital in Paris predominantly in neurosurgical patients and by Oliver Zangwill and coworkers at the National Hospital in London in patients selected for the presence of a symptom rather than for the locus of lesion. With the partial exception of England, in the early postwar period European research in this area was still in the hands of neurologists. In Italy, there was only a small number of faculties of psychology and the few psychologists interested in patients were concerned mainly with those affected by psychiatric difficulties. Then the situation progressively changed and a group of young physiologists and psychologists (Berlucchi Jr., Marzi, Rizzolatti, and Umiltà) began to investigate the issue of hemispheric differences of function in normal subjects. As the number of psychology faculties increased, teachers and researchers with a solid neurobiological and neuropsychological background were in great demand and that favored the passage of neurologists to the new faculties.

Classifying patients based on the damaged lobe was not an easy task and, with few exceptions (e.g., Milner's studies), its accuracy was questionable. For instance, Teuber and coworkers were satisfied with the radiological information provided by the missile entrance holes, which were far from being waterproof. Benton and other authors preferred to group patients by the damaged hemisphere, a criterion that could be inferred directly from clinical signs (the side of motor, sensory and/or visual field deficits, language impairment, etc.) and, therefore, was ascertainable in practically every patient. The emphasis on the hemisphere dimension received impetus from Sperry and coworkers' studies on patients submitted to commissurotomy for the relief of epilepsy, which allowed them to investigate the functional competence of each hemisphere, free from the influence of the other. The rekindled interest in the issue of hemispheric dominance focused mainly on the right hemisphere, whose contribution to cognitive skills had been dismissed in the past, by being defined as “mute,” but which now, if properly tested, were revealed to play a critical role in an array of mental performances.

This was the subject of my research throughout the rest of my working life. For the first decades the emphasis was on group studies. Then the pendulum swung back to single case studies, which took advantage of cognitive psychology models and the possibility of localizing the lesion in vivo by imaging techniques. I will not report my work in a strict chronological order to avoid a disjointed and confused narrative. I will summarize together studies that addressed the same general topic, even if they were carried out at intervals of several years, and I will put in here and there news about my life and the academic environment.

Early Studies on Aphasia

My early studies were on aphasia and they were carried out with Luigi A. Vignolo, who had graduated in 1959 with a thesis on aphasia and had spent some time with F. Lhermitte at the Centre du Langage of La Salpétrière, in Paris. We decided to address the question of whether aphasics' comprehension deficit also involves nonverbal information, such as that transmitted by miming. We were lucky enough to have the help of the Piccolo Teatro della Città di Milano mimes, who prepared short sketches in which everyday actions (hammering a nail, putting a valise on the luggage rack of a train, etc.) were mimed. Findings were in keeping with the aphasics' impairment hypothesis and we prepared a communication for the 7th International Congress of Neurology, which was to be held in Rome and had a plenary session devoted to aphasia. There were also two free communication sessions, chaired by Hécaen and Benton, and our paper was assigned to Benton's session. We sent it to him for a preliminary screening and received warm words of encouragement, but also the query as to whether we had tested normal subjects' behavior. We had not, on the naïve assumption that it ought to have been flawless. The dialogue, which began by correspondence, went on throughout the Congress and has never stopped since. Indeed it heralded the beginning of a special lifelong friendship. Arthur Benton is now 95 years old and is still remarkably lucid. In 1964, he spent 2 months in Milan, giving a series of lectures on neuropsychology, in which the history and state-of-the-art of the main symptoms were analyzed and the methodological requisites for their investigation underlined in his own plain and persuasive manner. They were translated into Italian and published as a book that was widely read and helped rekindle attention to disorders of cognition among Italian neurologists. In 1965, I spent some time at his lab in Iowa City and then devoted the last fortnight to visiting the places where neuropsychological research was being actively pursued in the United States. There were few of them, and people were delighted to meet someone else who shared the same area of interest. Thus, I struck up a friendship with a number of colleagues.

Of all the papers I had published in those years the one on the Token test was the most resonant. What prompted its development was a paper by George Miller, which, by emphasizing how redundant verbal communication is, gave me the idea that a way to enhance the sensitivity of a sentence comprehension test to aphasic impairment was to reduce to a minimum the redundancy of its word order. By doing so, each word had to be decoded individually, no cue being available from the other components of the sentence, while the intellectual and syntactic complexity of the message remained low. The test principles and its early findings were communicated in the first post-war joint meeting of the British and Italian neurological societies and were then published with Vignolo in Brain. The sensitivity and specificity of the Token test were definitely confirmed a few years later by Boller and Vignolo. They found that, although right brain-damaged patients performed as well as normal controls, the test was failed not only by left brain-damaged patients in general but also by a subgroup that had been screened for the ability to pass demanding comprehension tasks. A shortened version of the test was prepared by Faglioni and myself and given to a large normal sample, providing the correction for age and education and the score discriminating normal from pathological performance. The test was translated into many languages and gained great popularity as an aphasia severity index.

The Birth of the Milan Group

Group studies are expensive in terms of time and energy, as they often imply testing between 100 and 200 subjects, if normal controls are included. At that time, grants for research were scarcely available and I had to arrange on my own for patients to be tested. The only way was to look for coworkers among doctors specializing in neurology, asking them whether they were willing to devote to research the time they had free from clinical duties, in the knowledge that the only reward would be their name on the paper. There was never a dearth of people eager to participate and I could easily assemble a number of enthusiastic and bright young colleagues, ready to spend hours and hours in data collection and analysis and who came to be known as the Milan group. On my part I dare to credit myself for having something of a talent scout ability and the bent for fostering a relaxed and friendly atmosphere. Some of these colleagues eventually followed other routes (Mario Savoiardo and Giuseppe Scotti became neuroradiologists of some repute) or went abroad (Francois Boller); others carried on their own line of research as leaders of new groups and crowned their career becoming full professors and chiefs of neurology departments. Among them I wish to remember, in addition to Vignolo: Pietro Faglioni, Hans Spinnler, and Anna Basso. Faglioni developed a degree of interest and competence in statistics, which is rare to find among clinicians, and became our guide and expert in the use of parametric and nonparametric analyses, freeing us from the slavish dependence on standard programs. Spinnler had a tireless working capability, great critical insight, and a good command of German, a quality that unfortunately is getting rarer and rarer and that helped him (and indirectly us too) access the ancient literature, avoiding the risk of rediscovering what had already been published. Basso pioneered aphasia rehabilitation in Italy and her painstaking assessment of language disorders and their evolution was of invaluable aid to our studies. The bond with these colleagues soon went beyond professional interactions and took on all the features of friendship, also fostered by the many cultural and political interests we shared.

Apraxia

Ideomotor Apraxia

The next subject I investigated was ideomotor apraxia (IMA), a disruption of gesture execution, which Liepmann had identified as an autonomous symptom, not attributable to paresis, incoordination, or other elementary neurological disorders. It is worth remembering that apraxia was the subject of the first and probably the only group study carried out in the classic era with the aim to ascertain its relation to the hemispheric side of damage. Relying on the side of paresis, Liepmann divided 83 patients with cerebral disease into two hemispheric groups: 41 patients were classified as left-hemisphere damaged, because they had right paresis, and 42 patients as right-hemisphere damaged, because they had left paresis. Apraxia was tested in the healthy upper limb and found in 20 patients of the former group and in none of the latter. It was time to recheck these data on larger samples, submitted to quantitative assessment under rigorous testing conditions. We took care to give test items by imitation and not verbally, to avoid mistaking errors due to comprehension for those due to apraxia. A series of variables were controlled, namely, whether the tobe-imitated movements were meaningful or nonmeaningful, whether they were carried out with the whole limb or with fingers only, and whether they required the imitation of single positions or of motor sequences. None of them was influential. We confirmed the association between IMA and left hemisphere damage: In this group apraxia was more frequent and severe. However, we could also identify a moderate impairment in a few right brain-damaged patients.

Having borne out the left-hemisphere prevalence for gesture production, we addressed the question of the role played by the left parietal and frontal lobe in executing gestures with the left hand (which was the hand left brain-damaged patients used in carrying out the test). Following Liepmann, orders should travel from the left parietal lobe to left prefrontal areas, cross the corpus callosum, reach the right prefrontal lobe, and finally end in the right premotor area. In this view, left hand apraxia is expected to occur with the same frequency and severity in patients with left parietal and left frontal injury. This prediction was not supported in a study in which patients with lesion to either lobe, identified with imaging techniques, were tested on the imitation test: apraxia was found in 75% of parietal patients versus 38% of frontal patients, and in the former group it was remarkably more severe than in the latter. This finding suggests that left parietal information can be transmitted to the right prefrontal area through other pathways, in addition to that involving the left premotor area, although heterologous transhemispheric connections have not yet been identified.

The interpretative schema proposed by Liepmann conceives of apraxia as a disconnection between the areas of the brain where gestures are programmed and those where they are executed. The pathways connecting them differ depending on the modality used to transmit information and thus it is likely that, in some patients, the lesion is so placed as to produce apraxia when the order is transmitted in one modality and not in another. In a large sample of 150 left brain-damaged patients, Faglioni, Sorgato, and I required the use of the same series of objects on command, by visual presentation, and when they were handed to the blindfolded patient. In agreement with the hypothesis, there were patients who showed wide discrepancies in the scores obtained in the three modalities.

ldeational Apraxia

The defective movement organization underlying IMA must be kept distinct from defective recall of the spatial configuration of the gesture with which an object is used. This kind of impairment was reported at the beginning of the 20th century by Pick under the name of ideational apraxia (IA) and was apparent when patients were requested to show how they would use single objects that they were handed or, better, more than one object. However, the symptom autonomy was accepted with some hesitancy, because most of the patients investigated by Pick were demented or confused. Another knotty issue was the independence of IA from IMA, which, when severe, might so impair movement execution as to make it unrecognizable. The group studies I carried out first with Pieczuro and Vignolo and then with Barbieri showed that IA is even more closely linked to left-brain damage than IMA and cannot be accounted for by intellectual deficit, because patients with IA were not more impaired on the Raven test (a nonverbal intelligence test) than patients without it. Neither could IA be attributed to severe IMA, as there were patients that showed a strong dissociation in both directions, those with very poor scores on IA and normal performance on the IMA test were particularly convincing.

Fifteen years later I revisited IA in a study with Lucchelli, seeking in the qualitative analysis of errors, insights into the nature of the disorder. We were led to stress its independence from other movement disorders and to conceive of it as a specific form of semantic amnesia, characterized by the loss or inaccessibility of the use of object representations and similar, in a way, to the amnesia for other object attributes (their sound or color) reported in a few left brain-damaged patients.

The Birth of Cortex

As already mentioned, the only way to expose one's research to the scrutiny of a wider audience and to contribute to the scientific information circuit was to have papers published in journals with an international circulation rather than burying them in Italian journals, which nobody read abroad. The choice may appear obvious today, but it was not that easy 40 years ago, because it implied the acquisition of not only a language but also a style in which to report data, which were unfamiliar to most of us. As a matter of fact publishing in English was then exceptional among Italian neurologists and entailed a high risk of rejection. We concurred that it was a risk worth taking.

More hazardous was the initiative to promote the birth of a journal entirely devoted to the relation of brain to behavior. It started as a local undertaking, but soon gained the support of colleagues from other countries, who shared the idea that it was time to develop a sounding board for the increasing number of people who were interested in neuropsychology. Initially we thought of carrying out the project with the aid of a minor publisher, then we gathered up courage and tried to interest a major one, initially with some success. Then it all went awry, because our man changed his mind and began attributing more importance to being a urban guerrilla than to publishing books or journals (in a few years he would blow himself up on a high-voltage electricity pylon he was trying to fill with dynamite on the periphery of Milan). We had to begin our search for a solution to our problem all over again. In the meantime we learned that Hécaen had taken a similar initiative, which reached its goal a year before ours and was called Neuropsychologia, derived from the term used by Lashley to define the new discipline. Finally our project came to fruition and in June 1964 we were able to publish the first issue of the journal, for which we chose the Latin name Cortex that, in addition to pointing to the part of the brain most involved in higher mental activity, had the advantage of being readily understood and pronounced in different languages. The editorial board included some of the most prominent neuropsychology scholars, among whom I wish to remember those who in the early days gave the most active contribution to the selection and editing of submitted papers: Arthur L. Benton, George Ettlinger, Norman Geschwind, Harold Goodglass, and Klaus Poeck. The editor in chief was Gastaldi, who also made a financial contribution to enable us to meet early expenses, but the bulk of the editorial work was on Vignolo's and my own shoulders. In 1973, on Gastaldi's death I took over as editor in chief, a position I held until 2000, when Sergio Della Sala succeeded me.

Year after year the circulation and prestige of Cortex, as well as the number of submitted papers, increased. It is worth recalling that when Hécaen learned about our initiative, he expressed the understandable concern that there would be insufficient scientific production to supply both it and Neuropsychologia. Yet within a few years the number of journals exclusively devoted to cognitive disorders doubled and then tripled and has now exceeded 10. I found editing a journal an exciting, although exacting job, which requires assiduity, competence, and tact. One of the risks a wise editor should beware of is a blind reliance on referees' opinion, especially when a dispute arises between one of them and the author. The possibility that the referee is wrong should not be discarded, even if he or she is an authoritative scholar and the author young and unknown. This may seem an obvious and trivial warning, but it is easy to forget that at times overly strict adherence to previous personal findings or views can dim the perspicacity of even the most competent referees.

Spatial Disorders

An issue soon addressed by group studies was constructional apraxia (CA), the inability to reproduce a drawing or a block model, respecting its size and the spatial relations among the elements that make it up. The impairment of constructional skills had always enjoyed a certain popularity among neurologists, because of the ease with which it could be demonstrated at the bedside with the mere aid of paper and pencil. Yet its mechanism and relation to the side and locus of lesion had not been clarified. Both Hécaen in Paris and Zangwill in London investigated constructional disorders in hemispheric samples and found that they could follow damage to either side of the brain but were more frequent and severe when associated with a right lesion. Also based on qualitative differences, they drew the inference that CA differed in nature depending on the side of injury: It reflected a defective space perception (spatial agnosia) in right brain-damaged patients and an executive disorder (apraxia) in left brain-damaged patients. We took up this question in several studies and came to the conclusion that hemispheric differences were less neat and replicable than was assumed by other authors, probably due to the fact that too many skills concurred in the constructional performance and made it difficult to disentangle those differently represented in the two hemispheres. My feeling was that constructional tasks would be better abandoned in favor of those that more directly assessed discrete spatial abilities, an area that in the past had been studied only occasionally in few patients showing devastating deficits and that needed a systematic investigation with sensitive procedures. I distinguished four levels in the processing of spatial information and made each of them the subject of a series of studies that spread out in several years: exploration, perception, memory, and conceptualization. I will summarize them in this order, without minding the chronological order.

Head and Eye Forced Deviation

This is a symptom that neurologists are well acquainted with in patients showing the sudden onset of a hemisphere disease (mostly vascular). Their head and eyes are deviated towards one side, which is opposite to the paresis, i.e., they look at the lesion. Although known from the 19th century, the symptom had never been the subject of a systematic investigation. We surveyed its presence and graded its severity in all the patients admitted to the wards for the recent onset of a stroke. Out of 436 patients, gaze paresis was found in 120 and showed a striking hemispheric asymmetry, being more frequent, severe, and long-lasting in those with right brain damage. Also the underlying lesional pattern differed: It corresponded preponderantly to post-Rolandic damage when the injury was on the right side and to the involvement of the entire territory of distribution of the Sylvian artery when it was on the left side. This suggests that oculomotor centers have an asymmetrical organization in the two hemispheres, focalized on the right and diffuse on the left.

Neglect

A less blatant manifestation of defective space exploration is the tendency to disregard stimuli occurring in the space contralateral to the lesion, which is observed in some right brain-damaged patients, in spite of their preserved ability to move their head and eyes in any direction. It is amazing how little attention this symptom drew before the 1940s, even though its effects on a patient's behavior are so remarkable that we now consider it second only to aphasia in terms of clinical and rehabilitative impact.

In our investigation of neglect, we started from Kinsbourne's hypothesis that neglect results from the disruption of the balance between the mechanisms controlling in each hemisphere the shift of attention to contralateral space. According to this view the emphasis is not on the lack of attention to the left space but on its focus on the rightmost space. To test this hypothesis we projected a four-letter horizontal string in the patient's right field and measured the time it took the patient to decide whether a target letter, whose position varied from trial to trial, was capital or small. In controls and right brain-damaged patients without neglect, reaction time was unaffected by the target position, whereas in patients with neglect it was shortest for the rightmost letter and progressively increased as the target was displaced to the center of the screen. This apparent paradox—longer reaction time for stimuli closer to the fixation point—provides evidence that in neglect patients, the rightmost stimulus exerts a sort of magnetic attraction, which traps their attention in the space ipsilateral to their lesion.

If neglect reflects a disorder of attention, it is supposed to affect other modalities, in addition to the visual one, in which it is almost exclusively investigated. First, we tested the tactile modality, by asking blindfolded patients to explore a symmetrical maze engraved in a board with the hand ipsilateral to the lesion. The exploring hand started from the central position of the maze and then traveled through its alleys in search of a marble, which was put in one of the four ends (upper and lower left and upper and lower right). In both hemisphere-damaged groups, the search time was longer when the marble was in the space opposite to the lesion, attesting that exploration was steered by the contralateral hemisphere. However, failure to find the marble in 90 second was only present in patients with right-sided injury and visual field defects, the same brain-damaged subgroup usually impaired in the visual modality. Analogous findings were obtained in a similar test, in which blindfolded patients were seated in front of a computer keyboard and informed that 10 keys, symmetrically arranged to the left and right of the midline, emitted a sound when pressed. Their task was to find the sounding keys, pressing whatever key they wanted in 10 successive trials. Right brain-damaged patients with visual neglect showed a clear-cut tendency to avoid entering the left space. The question raised by this and the previously discussed experiment is what kind of information guides the movements of the exploring hand in space. It springs neither from vision, as the patient was blindfolded, nor from tactile perception, as the stimuli processed by the finger only concerned the point where it was and contained no spatial information. Searching movements have to be steered by the maze or keyboard mental representation the patient is building on the basis of the kinesthetic input, possibly transformed in visual images. Accordingly we conceived of the patients' tendency to neglect the contralateral space as secondary to a “dimidiated” space representation. This was the first hint at the existence of a representational neglect, the role of which was to become the focus of Bisiach's astute clinical remarks and ingenious experiments.

Hints that neglect can also play a role in the auditory modality are suggested by the behavior of patients who answer questions from an examiner placed at their left by addressing a second examiner placed at their right, even if their voices are supposed to sound quite differently, being the voice of a man and a woman, respectively. We also developed a purely acoustic test, in which the patient was requested to detect the interruptions occurring in a continuous sound delivered to either ear through earphones. In the monaural condition, the sound was sent to one side only and, consequently, patients knew in advance the ear on which they had to focus; in the binaural condition, the sound was received by both ears and could be interrupted in either of them, obliging patients to keep both under surveillance. The task was easy to perform for control or left brain-damaged patients, none of whom failed to detect any interruption, but turned out to cause leftear omissions in one third of right brain-damaged patients, especially in the binaural condition. Their lesion was located in the parietal lobe or the thalamus, areas that are also implicated in visual neglect. Yet visual and auditory neglect cannot be viewed as an expression of the same phenomenon in two sensory domains, as there are patients who show the former but not the latter and vice versa.

Disorders of Space Perception

It is extremely rare to encounter patients with unilateral brain damage who are impaired in judging object space orientation in everyday life or who fail to recognize an object, because of its inclination. However, if space perception is assessed with graded, quantitative measures, a deficit emerges clearly, provided we use elementary tasks, which minimally involve other cognitive skills. The test we found most sensitive required only reproduction of the orientation in space of a segment. A model was presented, made up of a pair of rods, connected vertically at one end by a hinged joint, with the lower rod mobile on the horizontal plane and the upper on the vertical plane. This made it possible to orient the upper rod in any position in space. The patient was also given another pair of rods and requested to manipulate them in such a way as to put the upper rod in the same position as that of the model. In one condition, the task was carried out with the aid of vision, in the other with the patient blindfolded. In both conditions, a defective performance was found only in right brain-damaged patients with visual field defects; all other brain-damaged groups were indistinguishable from normal controls. It is worth mentioning that at a time when the intrahemispheric locus of lesion could not be determined, we used the presence of visual field defects (VFDs) as a marker for damage extending posterior to the Rolandic fissure. If right and left brain-damaged patients with VFD performed poorly on a visual test, it was impossible to state whether the impairment was due to defective vision or to injury to posterior areas; if, however, only one of the hemispheric groups with VFDs had poor scores or both were impaired, but the task did not involve vision (e.g., it was a tactile task), then we interpreted the results as pointing to the specialization of posterior areas for the skills we were testing.

In another study, unilaterally brain-damaged patients were given a more complex tactile perception test, in which they had to run the extended forefinger of the hand ipsilateral to the lesion along the raised outline of a meaningless block, without viewing it, and were then requested to identify visually its shape on a multiple-choice display. Presumably this task is more difficult than the rod test, as block recognition is dependent on the ability to integrate in one spatial pattern the successive changes of orientation made by the moving finger. In support of this hypothesis we found that all hemispheric groups, with or without visual field defects, performed more poorly than normal controls. Also the hemispheric side of lesion was an influential factor, right brain-damaged patients being more impaired than left brain-damaged patients, whereas the posterior location of lesion did not cause an additional impairment, as was the case for the rod test. In another study, we contrasted the performance of unilaterally damaged patients on intelligence tests involving spatial skills, such as the Raven test and the Block Design and Picture Arrangement subtests of the Wechsler, and found no difference associated with the side and site of lesion, the only significant variable being the presence of brain damage. Intelligence tests had been the first to be used to detect hemispheric differences in spatial performance, but they yielded inconsistent results, probably because the many abilities they involve make them sensitive to lesions in different areas.

Spatial Memory

We studied the relation of this form of memory to hemispheric damage with the tests devised by Brenda Milner and her coworkers, Corsi's test and a maze learning test. The former presents the subject with cubes glued to a board, which are tapped by the examiner in a pseudo-random sequence of increasing length. The patient is requested to reproduce the tapping pattern either immediately after the examiner (short-term memory) or after a filled delay (long-term memory). Our studies confirmed that these two forms of spatial memory are separately organized in the brain, in agreement with what is know for verbal memory: Not only can a double dissociation be found in their performance but they are differently associated with the lesion site and side. Although no hemispheric effect emerged with short-term memory, a definite impairment of right posterior patients was brought out by the long-term memory procedure. The sensitivity of the maze learning test to long-term memory deficit found support in the performance of a patient who suffered from topographical amnesia, the inability to find one's bearing in unfamiliar or, in the most severe cases, even familiar surroundings. In spite of the fact that our patient's difficulty was limited to learning new pathways, she was still unable to master a simple version of the maze, after 250 trials, given in blocks of 25 trials a day for 10 days

Balint's Syndrome

An impressive syndrome, which represents an epitome of spatial disorders, is that reported by the Hungarian neurologist Balint in 1909 following bilateral damage to the parietal lobes. It consists of gaze apraxia, misreaching, and extreme narrowing of visual attention. In a patient of this kind whom I had the opportunity to observe, the spatial disruption was not limited to vision, as is the rule, but extended across all modalities. He was not only completely unable to direct his gaze and to reach out for an object presented in any part of his visual field but also failed when the stimulus location depended on tactile or acoustic information, e.g., when he was requested to direct his gaze or to grasp with his hand the thumb of the other hand or a ringing bell.

Career Moves

In 1959 I gained libera docenza and became Gastaldi's "aiuto". In 1967, the Italian Society of Neurology chose hemispheric dominance as a topic for one of the main sessions of its Congress and I was invited to give a talk. In the world of academia, the role of speaker at the national congress was much longed for, as it gave the selected person the chance to be in the limelight and to show the quality of his or her research. My lecture focused on the findings my colleagues and I had been collecting during 6 years of research on a wide range of neuropsychological topics and was supported by slide projection, an uncommon practice at that time, which allowed me to speak and not read a long and tedious text. Nowadays it may be difficult to imagine how boring a conference could be in those days when lectures were not pepped up by data presentation and when the long and sometimes involved sentences of the text were read hastily, for fear of running out of time. Initially I too made these kinds of mistakes, but soon learned that, no matter how many rehearsals you need, your speech should never be read. The approval of the audience was due not only to the wealth of data I had to offer but also to the flavor of novelty of the statistical approach employed, even though a few old clinicians turned up their noses at the suggestion that only differences associated with a given probability be accepted.

Meanwhile neuropsychology was becoming a popular topic in a number of neurological departments, where young students gathered around Guido Gainotti, Gianfranco Denes, Dario Grossi, and other researchers whose names were beginning to spring up in the international literature. Other centers blossomed in neurophysiological departments and in the psychological departments that were developing in a number of universities, with Carlo Umiltà, Luigi Pizzamiglio, and Carlo A. Marzi as leading figures.

My time was largely taken up by research, but I was not deaf to forewarnings from the society. By the late 1960s, students all over the world were staging protests against the manifold manifestations of power abuse in international and national relationships. Vietnam and the nightmare of the atomic war were sensitive issues, which stirred up the hearts of millions of people and gave rise to public demonstrations and rallies. From time to time I joined them. More domestic themes were the fight against old privileges and social injustice and the incongruity between the economic growth after the war, which had brought Italy closer to the model of the most advanced European countries and the delay with which a few obsolete institutions were reformed. Among these were our universities.

There were insufficient facilities to cope with the growing number of students coming from all social layers and the teaching methods had to be thought over again, in view of changed requests. Especially in big cities, like Milan, university life was upset by students protests, which I supported at least in part. In particular I thought that a few good steps could be taken toward a reform of medical studies and that we, young researchers, had to stand by students and add credence to their demands. For instance, we could show our solidarity by proposing a new methodology of teaching, with students divided into small groups and assigned to a tutor, who reduced formal lectures to a minimum, emphasized bedside teaching, and at the end assessed the students' preparation first directly on the patient and then with a questionnaire. This model was tried for a few months, with the approval of Gastaldi, who contributed to putting it into effect. However, this was not the opinion of most of his colleagues, who were horrified at the prospect of seeing their subordinates performing the duties that qualified their own role at the top of the career ladder and spoke of a coup d'état. Actually what they considered little less than a preliminary to the assault and seizure of the Winter Palace in St. Petersburg, 1917, was the teaching system adopted by several American schools of medicine. I also took part in the activity of a group of young lecturers, who strongly believed in the need of a reformation in medical studies and sought to settle its principles and to outline the guidelines for a reform bill. Our efforts resulted in a booklet, which we tried to distribute among people working for the university and Members of the Parliament, hoping that it would receive some attention. Just one of the latter acknowledged its receipt. Unfortunately I did not keep a copy of the booklet and so I am not in a position to say what I would think of it today. I strongly suspect that we were guilty of levity and overconfidence, as always happens when a problem is solved by looking at a theoretical model, without considering the social forces at work. Even if this episode was a little farcical, it does bear witness to an atmosphere of hope and commitment that was typical of 1968 and represented a high point in democratic participation. I must add that neither students nor full professors showed any appreciation for our initiative. The former seemed more interested in a palingenetic process of rebirth and did not care about practical trivialities, the latter considered it as an inadmissible and offensive attack on their powers of authority. A few years later I was to learn that their resentment was still very much alive.

In 1969 I was called to hold the Chair of Nervous and Mental Diseases by the School of Medicine, which had been recently set up in the University of Trieste. My position was that of Professor on an annual contract and not yet that of Full Professor. However, the fact that it entitled me to hold the ward direction stood me in good stead in the next Chair competition, which in fact I won in 1971. Surrounded by Carso stony hills and reflected in the crystal clear water of the Adriatic sea, Trieste was a charming city, molded on a middle European rather than an Italian model and rich in traditions inherited from the time it had been at its most prosperous as the Hapsburg empire's main harbor. Its recent history had been marked by ethnic conflicts, which had left bloody wounds destined to only heal with the passage of time and generations, as in fact it did. My family and I liked the city and I would have been delighted to stay on for good, had the working conditions been adequate. Unfortunately they were not: The hospital was an overcrowded building of the 19th century, research facilities were practically nonexistent, and the staff was inadequate. Fearing to have little chance of overcoming these drawbacks and of creating a vital research center in Trieste, I decided to go back to Milan, even if this choice implied at least for a time a step back in my career, because it meant renouncing Full Professorship. With the benefit of hindsight one might say that what the future held for Trieste was the flourishing of several scientific centers and in particular of a branch devoted to cognitive neuropsychology, which was to be guided by Tim Shallice. This development occurred, however, several years later and I was reluctant to waste time, in the absence of clear indications. Back in Milan, I collaborated with Gastaldi in teaching neurology and got involved in research again with the members of our group.

As our research grew and its results were published and known, the opportunity to get into touch and establish personal relations with foreign colleagues increased. At first this demand was met by the initiative taken by Hécaen since the early 1950s to invite neurologists from different countries to convene in one of the beautiful resort places or art sites, which make Europe so attractive, to discuss subjects of common interest in an informal and relaxed atmosphere. As the years went by, the meetings were opened to a larger number of continental and overseas participants and their schedule became more rigid, but they maintained a well-balanced distribution of time for talking and time for discussion. It is no wonder, therefore, that several people agreed to reserve one of their holiday weeks (precisely the last week of June) to attend the International Neuropsychology Symposium, as it came to be known. Their format was certainly suited for developing more intimate relationships among scientists and for favoring their exchange of information. In the 1960s a more formal society was created, the European Brain and Behaviour Society, with the aim to bring together scientists from different sources who were interested in the biological underpinnings of behavior. I participated in the preliminary discussions to create the Society and had the honor to be nominated as its president for the biennium 1971–1973. Approximately at the same time, a comparable initiative was taken in Italy, where a branch of the Italian Neurological Society was devoted to the study of cognitive disorders and was open not only to neurologists but to anyone qualified in research and wishing to participate. Formal requirements were kept to a minimum and from then on meetings have been held twice a year and from time to time have been organized in conjunction with other national societies.

Disorders of Object Recognition

A theme that repeatedly attracted my attention and was the subject of group studies as well as of single case analyses was agnosia, which represents along with aphasia and apraxia one of the three broad areas of cognitive impairment identified by neurologists before the First World War. It designates disorders of recognition and is classified according to the stimulus type (object, face, color, sound agnosia) and the sensory channel through which information is transmitted (visual, tactile, or auditory agnosia). Lissauer, a 26-year-old student of Wernicke, who reported the first clearly documented case of visual agnosia, stated that there are two main forms of the deficit, depending on the stage at which the visual information processing breaks down: apperceptive agnosia when the patient fails to achieve the three-dimensional structural representation of a stimulus and associative agnosia (such as that of the patient he described) when the stimulus is perceived correctly but is not associated with its meaning. Few cases of either type had been published since and for some of them the interpretation remained contentious (see Goldstein and Gelb's patient Schnee, who was suspected of being a malingerer), so that the very existence of agnosia was questioned.

To overcome the stalemate produced by the apparent rarity of agnosic patients, Faglioni, Spinnler, and I devised the strategy to tackle recognition disorders by investigating the contribution made by the two hemispheres to the processing of visual information. To this end we gave patients, with unilateral brain lesions, visual tasks that were either demanding in terms of perceptual discrimination or were calling for a semantic association, e.g., matching similar meaningless stimuli vs. matching objects of different shape but with similar functional meaning (a traditional key with a Yale key). Right brain-injured patients failed the perceptual tests and left brain-injured patients the associative tests, in keeping with the findings of other experiments, in which non-object stimuli or even nonvisual stimuli were used to assess perceptual and associative skills. For instance, rightsided patients were impaired in hue discrimination (Farnsworth's test) or in judging whether pairs of meaningless sounds presented in succession were the same or different, and left-sided patients were impaired in selecting the color typical of an object (red for cherries) or in matching a meaningful sound with the corresponding picture (mewing with cat). By and large these data are compatible with the hypothesis that the right hemisphere plays a dominant role in perception and the left hemisphere in semantics, a specialization that, when disrupted, gives rise to apperceptive and associative agnosia.

The theme of agnosia returned in studies undertaken a few years later, which benefited from the introduction of imaging techniques that were able to localize in vivo the lesions of the great majority of patients. Thus, we could gather patients with computed tomography (CT) scan evidence of left posterior cerebral artery (PCA) infarct, which is held responsible for a typical visual-verbal disconnection syndrome, due to the interruption of the fibers linking the undamaged visual area (right occipital lobe) with the undamaged language center (Wernicke area in the left temporal lobe). As a result, patients suffer from alexia and color anomia, being unable to associate graphic signs with their linguistic value and colors with their names. In contrast with this deficit, patients are claimed to show a preserved ability to name visually presented objects, a discrepancy that represents a challenge for the disconnection hypothesis. Geschwind speculated that object visual images avoided the block by activating tactile images in the ipsilateral parietal lobe, whence they would reach the left language center via the fibers crossing the corpus callosum, anterior to the lesion. A further reason of perplexity is that a left PCA infarct had also been found in the patients reported by Freund (1899) and Lissauer (1900), the former complaining of an object naming inability limited to the visual modality (optic aphasia) and the latter of object associative agnosia. Thus, what are the consequences of a left PCA infarct? Alexia with color anomia, optic aphasia, or associative agnosia? There was clearly a need to marshal new data. We collected 16 cases with CT scan evidence of left PCA infarct and tested their reading and color naming ability along with that of naming objects presented visually, tactually, and through a verbal definition. The claimed divergence between letters and colors vs. objects did not exist. The majority of these patients was alexic, color anomic, and object anomic, of comparable severity in both the visual and tactile modality. These findings deserve a few comments. First, the failure to associate visual stimuli with their verbal code, far from representing an exception, is the rule following left medial occipital lobe damage. Second, naming objects does not differ substantially from color and letter naming and, therefore, does not require an ad hoc interpretation. Third, the boundaries between visual agnosia and optic aphasia require further investigation. As mentioned previously, optic aphasia is assumed to affect visual naming but not recognition. The evidence provided by Freund in support of this statement were the patients' claim to have recognized the object they failed to name or the circumlocutions they used, which contained clues pointing to a successful identification. Nowadays, one is supposed to assess stimulus recognition with stricter criteria, using nonverbal tasks calling for category grouping, semantic matching, miming object utilization, etc. However, even one patient who qualified for the diagnosis of optic aphasia, having passed these tests, was found to be problematic by Alphonso Caramazza, in that he revealed an inadequate knowledge of the object's semantic properties. The same occurred in a patient I investigated with Saetti. His semantic recognition was correct according to all of the criteria set out for the diagnosis of optic aphasia, but turned out to be flawed when task difficulty was further increased, e.g., when in a matching to sample task all of the stimuli bore a semantic relation to the target and he had to choose the one that showed the strongest association (select the object most closely connected with a thimble among scissors, a threaded needle, a button, reels of thread). Also on miming, his performance depended on the nature of the task: He passed when the gesture was evoked verbally, but failed when it was evoked visually or when the examiner himself carried out the miming and he had to point to the corresponding object. These findings prompt two conjectures on the nature of visual recognition disorders. First, associative visual agnosia and optic aphasia are not two discrete symptoms, but lie on a continuum of impairment and share a common mechanism, characterized by a defective and a compensatory component. The former is the failure of visual information to gain access to the left hemisphere, due to the lesion interrupting of information transfer from the right occipital cortex to the left temporal lobe. As a result, the patient not only is deprived of the ability to attribute to the perceived stimulus its name (optic aphasia) but cannot or can only imperfectly avail himself of the wealth of semantic knowledge stored in the left hemisphere (agnosia). The compensation factor is conditioned by the extent to which the recognition deficit can be made up by the semantic potential of the right hemisphere, which varies across subjects but does not usually match that of the left hemisphere. This hypothesis is in agreement with the dominant role of the left hemisphere in semantic processes, demonstrated by our group studies. Thus, optic aphasia and visual agnosia share the same lesion and the disruption of the same mechanism and differ depending on the right-hemisphere semantic capability the patient had acquired premorbidly.

Tactile agnosia was the subject of the last research I carried out before retiring. Disorders of recognition have rarely been reported in the tactile modality, because they usually affect one side of the body (contralateral to lesion) and, therefore, their detection is obscured by the concomitant presence of sensory deficits. The patient I studied with Saetti had suffered from repeated occipital infarcts, which had caused cortical blindness and tactile agnosia. The parietal primary and secondary somatosensory cortices were undamaged and the patient showed no deficit of either elementary sensations or the ability to perceive the so-called intermediate tactile qualities (texture, weight, size, and length discrimination). We had, therefore, to assume that the severe impairment of object and letter recognition we found in both hands was attributable to a deficit not related to tactile information processing. We held that its source was the striking failure in tactile spatial performances the patient showed at both the perceptual and imaginative level. He made a lot of errors in judging line spatial orientation and, when given the rod orientation test, described earlier, he was unable even to conceive of how the task could be carried out, a failure I had never found in patients with damage limited to the right hemisphere. The imaging impairment was highlighted by his inability to estimate the spatial relation between two elements of a conjured up object (Is an ox's tail above or below its horns?). We posited that in the tactile modality, severe spatial disorientation could result in a recognition deficit, while the same does not occur in the visual modality, as suggested by the absence of object agnosia in patients with Balint's syndrome, i.e., the utmost form of spatial disorientation. We speculated that, in visual perception, a global apprehension mode prevails, which permits one to analyze the stimulus shape straight-away, while when information is gathered through palpation, stimulus recognition is critically dependent on the ability to make a piecemeal reconstruction of how adjacent parts are oriented and related spatially.

Modena

In 1973 Gastaldi died. As his "aiuto," I was supposed, according to academic rules, to receive from the faculty the temporary appointment to direct the department, until a new director could be selected. The fact that I was totally ignored, in spite of having been qualified as a Full Professor in a national competition, came as a warning to me that the faculty had not forgotten my commitment to the 1968 movement and did not welcome my staying on in Milan. Thus, when the faculty of Modena offered me the Chair of Nervous and Mental Diseases the following year, I was pleased to accept.

Clinical duties were exacting in Modena, as I was the chief of a department with 70 neurological beds and 40 psychiatric beds. The first thing I did was to entrust the psychiatric beds to a colleague who taught psychiatry without having patients and to devote all my time to neurology. There were a few unfilled positions in the team, which I offered to young doctors who were specializing in Milan or Modena. Thus, I could rely on the cooperation of enthusiastic colleagues, eager to learn, carry out research, and assist me in teaching students. Their clinical experience was necessarily limited and, at least in the earlier years, called for my continuous supervision and advice at the bedside, but eventually they became skilled clinicians and experts in their own area of specialization. That gave me the opportunity to learn a lot from the discussions about patients I had with them during the rounds.

Throughout my career I have enjoyed the variety of activities and duties, associated with the role of clinical professor, which are somewhat different from those accomplished by other neuroscientists. Looking through the list of the contributors to the previous volumes of this series it would seem that I am the first to represent this category—clinicians; it might, therefore, be appropriate to discuss the extent to which patients' treatment, research, and teaching interact and interfere.In the present context, I assume that clinical activity is limited to that carried out as a consultant in the wards and outpatients' clinic and does not involve private practice, because profit has its own psychological dynamic, which tends to dominate over other engagements. By and large, my feeling is that the medical profession is more akin to that of a judge than of a lawyer, in that the needs it is supposed to meet are entitled to receive an answer proportionate to their nature and not to the subject's status. This right is not guaranteed if the client must pay the doctor's honorarium.

The issue of the extent to which clinical duties are compatible with those entailed by research and teaching can be addressed from a subjective or an objective standpoint, namely, in terms of personal satisfaction or of proficiency. Subjective evaluations are obviously dependent on personality and circumstances, and I can only cite my own experience. I always felt that the opportunity to shift from patient examinations to research and teaching, far from causing loss of concentration and dissipation of energy, is an asset, because it keeps your mind open and inquisitive on a wide range of practical and theoretical aspects of reality and can be immensely gratifying. In the latter respect, the medical profession is unique. Perhaps people are less familiar with its intellectual appeal and do not realize how much it has in common with the work of detectives, as they sift their way through heaps of irrelevant information in the search for the small clues that allow the formulation of hypotheses on the culprit. Doctors have to display similar skills in their endeavor to pick out the thread that leads to the correct diagnosis, identifying it from among the often hazy and sometimes downright misleading descriptions patients provide of their ailments. Learning to bridge the gap between theory and practice is a requisite for all professional activities, but in none is the distance so wide as in medicine. Books and formal lectures teach students a rational tale, where and what the illness causes, the somatic changes it produces, and the deriving signs and symptoms reported according to a logical and self-explanatory plan. Doctors, however, are faced with a different task: They must learn to discard accounts that miss the point, to raise questions that often are not obvious and to combine apparently unrelated bits of information, namely, an array of procedures that are only mastered when experience is coupled with shrewdness and knowledge. This is a combination that remains crucial even in times, like ours, when technology is claimed to be able to solve any problem, a dangerous belief that we, as teachers, are supposed to discourage, if young doctors are to resist the temptation to rely on machines instead of their own brains.

The other side of the coin is whether having to attend to three different activities helps or hinders your performance of each. There is agreement that at least in principle teaching improves both clinical and research activity, as nothing helps more in clarifying one's own thought than having to explain it to other people. That is not to say that being a clever doctor or researcher guarantees success as a teacher, because neither logic nor insight are a safeguard against the risk of being boring when speaking on a well-known topic. A more delicate question is the competition for time between clinical practice and research, a subject of a recurring polemic against clinicians heavily engaged in research, who are sometimes accused of having a narrow circle of acquaintances and of being more familiar with test tubes and centrifuges than real patients. The point at issue is the extent to which the expertise acquired in one's own field of research is transferable to daily bedside activities and can enhance diagnostic skills across a wide range of diseases. I hope I will not be accused of being biased, if I claim that neuropsychology is an area of great synergy between research and clinical neurology. First of all, at least some of the cognitive disorders we study are frequently encountered, being present in a large gamut of diseases of different etiologies, practically all of those encroaching on the hemispheres, and have a definite localizing value. The ability acquired in detecting and testing them gives the neurologist a wider perspective on an array of signs and symptoms, which, if not properly investigated, may escape the standard examination and give the false impression of its negativity. Alternatively, they can be mistaken for the manifestation of a psychiatric disorder and lead to wrong measures, as it happens when the jargonaphasia patient's speech is attributed to mental confusion or hysteria and treated accordingly. I remember feeling great professional satisfaction when I was able to reverse an ophthalmologist's diagnosis of hysteria in a patient, whose inability to recognize familiar faces dated back to more than 3 years. The diagnosis had been accepted by the general practitioner and shared by his relatives, but not by the patient himself, who was delighted when I told him that the name of his disability was not hysteria, but a long Greek name that seemed a tongue twister, prosopagnosia. Yet it must be recognized that the ophthalmologist's sin was venial, because in the 1960s this strange deficit was unknown even to most of neurologists.

Prosopagnosia

The inability to recognize familiar faces, or prosopagnosia; represents a special case of agnosic deficit, which does not extend usually to other stimulus categories and is often associated with a lesion confined to right hemisphere areas, which is not found in other forms of agnosia. These are notions acquired following a debate that dragged on for several years and was also made harder to settle because of the rare occurrence of these patients. For instance, in the course of a 50-year experience with neuropsychological patients, I could count the number of prosopagnostics I saw personally on the fingers of my hand.

Faced with this drawback, Spinnler and I devised to circumvent it by giving face recognition tests of graded difficulty to hemisphere-damaged patients. This procedure allowed us to study milder and clinically silent forms of the deficit and at the same time to test the hypothesis of its association with right brain damage, which Hécaen had suggested on the basis of the few cases with autopsy available in the literature. Because familiar face knowledge differs from person to person, we used unfamiliar face snapshots and administered them in matching and short-term memory tasks. The data from this and subsequent studies pointed out that right braindamaged patients, especially those with posterior injury, performed poorer than left brain-damaged patients and extended, therefore, the generality of Hécaen's hypothesis to unfamiliar faces. The hemispheric asymmetry found with them was analogous to what we had discovered with other types of visual stimuli (meaningless figures, colors, etc.) when the patients' perceptual abilities were tested with exacting tasks and suggested that prosopagnosia may be just an aspect of a more general deficit in discriminating subtle perceptual differences (remember how similar are human faces). However, it is unclear whether this account also holds for familiar face recognition, which represents the gist of prosopagnosia and can be due either to a perceptual deficit or the disruption of the known face semantic store or both mechanisms. This is a question that can only be answered by examining prosopagnostic patients, as we did with three of them 20 years later. The method devised with Faglioni was to give to 100 normal subjects unfamiliar and familiar face recognition tests, assumed to assess perceptual and semantic memory abilities, respectively. On the distribution of the difference between the unfamiliar and familiar test scores, we computed the thresholds that corresponded to the internal and external tolerance limits and allowed the identification of subjects who were outliers for an exceedingly poor performance on perceptual or semantic memory tests. Thus, we had a measure that permitted us to classify prosopagnostics as predominantly apperceptive, predominantly associative-semantic, or failing in both dimensions. When we gave the battery to our three patients, we found that they were distributed among the three categories, one failing predominantly on familiar faces, one on unfamiliar faces, and one being equally impaired on both. It would appear, therefore, that the relation of prosopagnosia to the right hemisphere reflects the preeminent role of this side both in processing perceptual information and in storing human face representations.

Is the poorer performance of right brain-damaged patients in face tests, combined with the outcome of Hécaen's review, to be taken as evidence that prosopagnosia depends critically on injury to the right side of the brain? Or does a clear-cut deficit in recognizing familiar faces always have to be associated with bilateral damage? In favor of the latter hypothesis, one can cite the extreme rarity of the disorder: Although dyslexia follows with a certain regularity left PCA infarcts, most right PCA infarcts are not associated with prosopagnosia. Even more supportive of bilateral damage was an early review of the autopsied cases of prosopagnosia, made by Damasio, who inferred that lesion to both hemispheres was a feature of all of them. Their small number, however, cautioned against drawing definite conclusions. Twelve years later, I addressed the issue relying on the much larger number of cases submitted to imaging techniques (CT and MRI), which are accessible nowadays. With respect to autopsy findings, they enjoy the great advantage of being available in practically every patient who complains of the disorder and not only in those who die (obviously a subsample biased for its severity) and of coinciding with the time of the clinical examination and not with the end of disease (during which new damage may have occurred). The survey of the literature yielded the retrieval of more than 30 cases of prosopagnosia with lesion confined to the right hemisphere (confirmed by autopsy in two patients) and thus produced conclusive evidence that a right-sided injury is sufficient to produce prosopagnosia.

In carrying out this research I had the generous help of Dr. M. Kawamura, who kept me abreast with the cases published in Japanese journals, a source of information unavoidably ignored by the western literature. I had met him during a scientific trip made in Japan at the invitation of the local neurological society to lecture on prosopagnosia at its Congress. Thanks to his warm hospitality, my stay in Tokyo was pleasant and relaxing and I was delighted to discover that he was a bibliophile, an enviable owner of a collection of 19th century neuropsychology books that he had managed to find in antique bookshops. Incidentally, if one is curious about what happens in the world, visiting foreign countries and getting to know colleagues in their own environment is one of the most attractive aspects of our work, as it gives us an intimate knowledge of the heart of a country. There are many facets of the way of life and thinking of foreign people and of the social issues they face that one comes to know better and to appreciate while chatting over a good bottle of wine, whiskey, or (as in the case of Kawamura) sake. Conversely, it has always amazed me to meet colleagues of high scientific standard and intelligence who show very little interest and ask few or no questions about countries they visit for the first time, as if events, habits, and feelings of foreign people were somehow beyond their mental horizons.

A central and recurring issue of prosopagnosia is its specificity, namely, whether it reflects the disruption of an anatomo-functional apparatus devoted to faces or is but an aspect of a more general visual recognition impairment, which extends to other stimulus categories, provided either of the following conditions occurs: (1) The category exemplars share the same degree of figural similarity as faces do and thus can be compared to them in terms of perceptual difficulty. This argument is supported by the finding that there are patients, whose errors involve, in addition to faces, other categories, such as car makes or some kinds of animals, which have the previously mentioned features. Particularly impressive was the case report of an ornithologist, who lost the ability to discriminate birds of different species and to discriminate faces. A possible account of these cases is that they suffer from a minor form of apperceptive agnosia, affecting any perceptually demanding task and apparently preeminent with faces, because these stimuli are so relevant socially. (2) Object and face recognition is tested with the same kind of tasks. Lhermitte was the first to point out that we raise different questions to assess object and face recognition. When presented with objects, patients are supposed to say the name of the category to which they belong (it is a hammer); when presented with faces, the name of the exemplar (he is Bob Dylan). The assumption is that, were objects assessed with the same test used for faces, they too would be found impaired in these patients. The remark is pertinent; whether it also is valid is worth testing. In order to verify it, I requested two associative prosopagnostic patients to identify their personal belongings (e.g., their own wallet, glasses, electric razor, etc.) from among objects of the same category and their own handwriting from among other handwritings. Neither patient showed the slightest uncertainty in choosing his own belongings. Thus, there is evidence that, at least in prosopagnostic patients with an associative defect, the deficit is specific for faces.

At the end of the 1970s a model of investigating cognitive disorders was introduced, which placed new emphasis on single case study but adopted a new conceptual framework for their interpretation. Unlike the traditional approach, the focus was no longer on anatomic-clinical correlations, but on the identification of the module that was damaged, in the chain of those involved in processing incoming information. The module sequence and its disruption is reconstructed by comparing patients sharing a broad functional disability (e.g., dyslexia) but who perform differently according to the nature of the task (e.g., reading meaningless or meaningful words). These studies represented the extension to brain disorders of the principles of cognitive psychology, but they also took advantage of the progress made by behavioral psychology in improving test construction and their quantitative assessment. They provided a wealth of information on the architecture of the mind and opened new paths to disentangling the cognitive disorder's fine-grained structure, although the cogency of the inferences they draw is somewhat weakened by the absence of any reference to the biological level.

After all, differences in function must correspond to different patterns of lesion.

I was impressed by cognitive models and appreciated their power to improve our skill to discriminate disorders and to disclose dissociations that, amazingly, had been completely neglected in the past. However, they should be viewed as complementary and not alternative to group studies, which retain their heuristic potential in tackling issues relevant to clinicians and, when addressed to the right questions, provide definite answers. An example are frontal signs.

Frontal Signs

The frontal lobe has paradoxical features that have long puzzled neuroscientists: In humans, the size of its anterior areas has increased more than that of any other brain region and there is consistent evidence that they play a role of paramount importance in controlling behavior; yet their damage does not result in signs or symptoms that stand out enough to capture the observer's attention. It is true that some of these patients show amazingly queer behaviors, but they almost always ensue bilateral damage, whereas unilateral injury is associated with subtler deficits, interesting theoretically, but of questionable diagnostic value in the single case. In view of these limitations, we set out with the idea of focusing on a few stereotyped and forced behaviors, easy to elicit at the bedside, which had been occasionally pointed out following unilateral frontal injury, but whose frequency, specificity, and localizing value had not been established definitely.

The first symptom to be investigated was grasping, the reflex closure of the patient's hand on the examiner's fingers when they exert a pressure on his or her palm. It is physiological in the early months of life, but then is progressively inhibited by frontal neuronal networks, whose damage is claimed to cause its reappearance. We tested grasping in 151 patients with disease not involving the brain, who were all negative and 340 patients with hemispheric damage, 26 of whom were positive. In most of the latter, the lesion was localized by CT scan in the medial frontal lobe. Among patients with damage to this area, 70% were positive, an amazingly high percentage, whose weight for diagnostic purposes is enhanced by the absence of grasping in patients with retro-Rolandic damage.

Two other peculiar behaviors, pointing to frontal lesion, were highlighted by Lhermitte: imitation and utilization behavior. In the former, patients repeat compulsorily whatever gesture or vocal expression (words or other sounds) the examiner makes when he is looking at them from a frontal position. In the latter, they use objects, which happen to be on the table within their reach, independently of any request or need. I studied both, following a fixed procedure, in a sample made up of 52 patients with frontal lesions and 26 with damage to other hemispheric areas. Imitation was observed in 39% of frontal patients and in none of the nonfrontal ones. When present, it was always a massive phenomenon, consistent through repeated sessions, which the patient could inhibit if strongly requested by the examiner but that reappeared inexorably after a short interval, the embarrassed justification being “I thought you wanted me to imitate.” Differently from Lhermitte, I found it following lateral and medial, but not orbital, frontal lesions. Compared with imitation, utilization is a much rarer (present in two frontal patients only) but very impressive phenomenon: It is astounding to see a patient so intensively absorbed in the use of objects, simply because they are present and beyond any request and purpose.

Amnesia

Memory disorders are probably the cognitive symptom most often complained of by patients and observed by doctors, even though usually they are but the earliest and most striking aspect of general mental deterioration. More rarely they occur in isolation, linked to damage to specific limbic and diencephalic structures and characterized by the predominance of anterograde over retrograde amnesia and by sparing of semantic and procedural memory. Following Milner's seminal papers, the symptomatic pattern of so called global amnesia is well known, but from time to time patients are reported who differ from the classic syndrome in terms of etiology, evolution, or symptom patterns. Among those I have encountered, the following are worth mentioning.

A 22-year-old young man had been complaining ever since his childhood of memory weakness, manifest in remembering both episodic events (he had to write down errands when he went shopping) and schooling (he failed to learn historical and geographic facts, mathematical formula, poetry and songs, and even the most common verbal series, such as alphabet letters and month names). Pregnancy and delivery were uneventful and he did not suffer from any disease in childhood. The neurological exam and other investigations were negative, except for a mild dyslexia. The syndrome remained unmodified throughout his life and was confirmed by his defective performance on a battery of memory tests, while no evidence of other cognitive defects emerged. With Lucchelli, we proposed to consider him an example of developmental dysmnesia.

Following an episode of encephalitis, a 44-year-old lady showed an amnesic pattern, which was the mirror image of that found in classic amnesia, namely, preserved autobiographic memory (thoroughly comparable to that of her husband) and severely impaired semantic memory. Word meaning as well as the stock of acquired knowledge, inclusive of nonverbal notions, such as monuments and recipe ingredients, were no longer retrievable. The episodic-semantic dichotomy receives strong support from the evidence of double dissociation.

Their peculiarities notwithstanding, these and comparable cases fall by full right within the province of organic amnesia and do not call into question its conceptual scaffolding. Much more contentious and difficult to reconcile with the current body of knowledge on amnesia are patients who show a striking retrograde memory deficit with integrity of anterograde memory, in the absence of any evidence of brain damage. They have been repeatedly reported over the last 25 years and I had the opportunity to investigate three of them. The most common event associated with the onset of amnesia is a minor head trauma, not accompanied by loss of consciousness. It leaves the patients bereft of their past episodic and sometimes even semantic memories for a variable period of time (up to the entire span of life), without, however, impairing their ability to retain new information. The first idea that occurs to doctors, when they are confronted with patients complaining of a loss of function having idiosyncratic features and lacking evidence of a somatic lesion, is to look for events or conditions that may justify a psychological block. Sometimes they are easy to find and suggest either a voluntary mechanism that leads the patient to feign a morbid state to evade responsibility in a difficult state of affairs or an involuntary functional inhibition that relieves the patient from distressful emotions. It has rightly been recommended not to stop at the early negative evidence but to pursue with great tenacity a careful psychological investigation on the patient's history and present condition. However, what should be done if no direct or indirect support is gathered for a voluntary or involuntary psychic mechanism, as has happened with most reported cases? A few authors warn us never to yield to apparently negative findings, because a psychological cause must be there and its discovery is simply a question of time and determination. I am unconvinced by what seems to me a petitio principii that begs the question and I would plead for a more flexible approach, keeping a wait-and-see attitude, to collect new cases and for the time being to label these patients' amnesia functional, an adjective that stresses the loss of function but leaves its cause uncommitted.

When I reached 70, I retired from clinical and teaching commitments and for the next 5 years I devoted my time to research and the job as editor of Cortex. In 2000, this phase also came to an end and the role of chief editor of Cortex was handed over to the skillful hands of Sergio Dalla Sala, whose energies and spirit of enterprise have been decisive in renewing and enriching the journal.

As it sometimes happens, the end of my career was celebrated by the awarding of a few academic titles and honors. I was particularly flattered by the honorary degree in psychology awarded to me by the University La Sapienza of Rome. I saw it as an acknowledgment of the contribution that, profiting by the openings made by disease, other neurologists and I gave to penetrating the recesses of mind, joining psychologists in what remains their main task. I see no competition between the two specialties, especially in a country, like Italy, where many of the psychologists now engaged in neuropsychological research have a neurological background.

Last December I celebrated my 80th birthday, in good health and with a mind, which has not, as far as I can judge, deteriorated beyond the physiological norm. I still wish to be kept abreast of what is happening around me and in the world, although I am not sure to always understand all of its implications. At my time of life people indulge in taking stock of their life and reconsidering its pros and cons. My survey is positive, not so much because of my merits but because fortune has protected me against what are called the blows of destiny, those unpredicted and uncontrollable events that upset the development of your projects and force you to make deleterious choices. I might even go as far as to say that I have been a lucky person, who has led the life he has wished and has drawn elements of satisfaction and comfort from his family and his job. That the kind of work I was doing was rewarding must be an impression I transmitted firmly to my children, because all of them chose to undertake an academic career, although not in the medical area.

As I mentioned at the beginning, the decision to study medicine was not my first choice, but came at the end of a period of uncertainties and second thoughts and was at least in part the fruit of a particular historical climate. It might have turned out to be a choice unsuited to my aptitudes or not completely up to scratch with respect to my aspirations. With the benefit of hindsight, I can say that it was wise and gratifying both intellectually and emotionally. I was able to combine the satisfaction of investigating one of the most intriguing areas of research, the structure of mind, with the wealth of social and emotional experiences linked to the medical profession. Yet precisely because my work was so absorbing, I had to neglect subjects outside the natural science area, which had attracted me so keenly in my youth when I thought they would have sharpened my understanding of what humans represent in the world. It is for this reason that when I retired, I opted for a complete change of cultural horizons, turning from science to history and poetry, mainly of the 20th century. My passion for history springs from different sources. Admittedly one of them is the well-known tendency of elderly persons to recall and ponder on their own past, inclusive of the experiences connected with public events. There is also the curiosity to know the truth and details about events that had made a huge impact on contemporaries and were the subjects of ongoing questions. However, a deeper and more enthralling motive is to gain a comprehensive view of the chain of events and underlying forces that have marked the great and terrible century (especially its first half) we have gone through. It is not that I expect my reading about the recent past to improve my understanding of the mechanism steering history or the design imminent to it (which I believe does not exist), but because memory of what happened and of how we and our fathers behaved in those terrible contingencies should never be forgotten, if coming generations are to live in a decent world. Among the several warnings to emerge from the history of the past century, two seem to me particularly important. One is that, considering the present development of technology and the fierce awareness people have of their own rights, neither social conflicts nor disputes between nations have the least probability of being settled by using the force of weapons. All that will result is blood, mourning, and hate, with a dire incongruity between aims and results. The other is that whenever we become aware that a minority is abused in the name of majority's common feelings, we ought to voice our unyielding disapproval.

As to the charm of poetry, any comment on my part would be conceited. I only wish to point out that, however different the attitudes with which poets and scientists look at the world, they share the same will to bring to light aspects of reality that are concealed beneath the surface of things. To define the work of poets, Nafisi said that what they depict is not reality but an epiphany of truth. I like this distinction if truth is taken as a term referring to how the outer world is echoed by our sentiment and imagination and reality to the external world in its objective terms.

Selected Bibliography

Barbieri C, De Renzi E. The executive and ideational components of apraxia. Cortex 1988;24:535–543.

Borghi G, De Renzi E. Contributo alla conoscenza delle sindromi vascolari da rammollimento nell'ambito della silviana profonda. Neurone 1953;1:32–49.

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John S. Edwards

BORN:

Auckland, New Zealand

November 25, 1931

EDUCATION:

University of Auckland, NZ, B.Sc. (Zoology/Botany, 1954)

University of Auckland, NZ, M.Sc. (Zoology, 1956)

Cambridge University, UK, Ph.D. (Zoology, 1960)

APPOINTMENTS:

University of Auckland (1954)

Cambridge University (1960)

Western Reserve University (1962)

University of Washington (1967)

Director, Biology Program

University of Washington (1982–1987)

Director, Honors Program

University of Washington (1994–2001)

HONORS AND AWARDS (SELECTED)

John Simon Guggenheim Fellow (1973)

Humboldt Research Award (1980)

Fellow AAAS (1981)

Jacob Javits Neuroscience Investigator award, NIH (1986)

University Liberal Arts Professor, University of Washington (1989)

Visiting Fellow, Gonville and Caius College, Cambridge (1990)

John Edwards has worked throughout his career on aspects of insect physiology and ecology and especially on neural development. He pioneered the use of an insect system, the cercus-to-giant interneuron connectivity, in the analysis of sensory regeneration. He also discovered the pioneer role of insects in ecosystem regeneration after the 1980 eruption of Mount St. Helens.

John S. Edwards

The invitation to contribute to this autobiographic series was as intimidating as it was tempting. Intimidating because of the eminence of so many contributors, beside whom my own contributions seem, without false modesty, rather trivial. Tempting because I had often spoken with colleagues about the value of putting on record our lives in science during the second half of the 20th century, a period that will surely come to be seen as the coming of age of biology in general and of developmental neuroscience in particular, but perhaps also the zenith of science as a profession if we are indeed living in the twilight of the Enlightenment, a possibility raised recently by a distinguished invertebrate neuroscientist (Kennedy, 2005). It is all too easy to procrastinate the act of writing, no matter how many ideas swirl through one's cortex, until senility creeps on and it is too late. The editor has provided a deadline for that effort, and I thus offer my thanks at the outset to Larry Squire.

My life in science was best characterized early on by the admonition leveled at me by my dreaded undergraduate adviser: “Mr. Edwards, you suffer from responding to an excessive diversity of stimuli.” I have never quite mastered that defect, so I must preface my story with the warning that my neuroscience will be studded (or stunted) with diversions and tangents. It is said that moles know one big thing, whereas foxes know lots of little things. I am vulpine. If there is a theme in what follows, it stems from Wigglesworth (1939) that “Insects provide an ideal medium in which to study all the problems of physiology.”

Origins

I was born in Auckland, New Zealand on November 25, 1931, in the shadow of the worldwide Great Depression that hit New Zealand hard. Neither of my parents had more than primary schooling but they were avid readers; my father could recite Shakespeare and Wordsworth at great length and enjoyed word play. Their love of music left its mark on me. My mother, a second- or third-generation New Zealander, whose pre-antipodean ancestry we do not know, was born in Waikino, a small town in the gold fields of the North Island where her father owned a chain of butcher shops and the first model T Ford in the region. She was an able pianist and for some years worked in a music store as a sight reader of sheet music for prospective buyers. She later moved to Auckland where she worked as a stenographer and met my father. His father emigrated to New Zealand from Iffley, near Oxford, where he was a champion sculler and a skilled woodcarver. He created many elaborate ornaments in the Victorian style for churches and public buildings in Auckland. His father, my great-grandfather, was a servant at Balliol College Oxford. My father's apprenticeship as a pharmacist was interrupted by the First World War, for which he traveled to England as a cellist in the New Zealand Army Band. He never saw action, unlike his elder brother who was a victim of gas in the trenches of France from which he never fully recovered. On his return to New Zealand my father took a job in a retail business in Auckland, rising there over the years to general manager. In the 1920s he played cello 3 nights a week in a silent movie theater pit to pay the mortgage on their modest suburban home where I was born and spent my first decade. Several years of my early schooling required a long bicycle ride because the local school was taken over by the American military as a recuperation center for U.S. forces in the Pacific theater. Three memories stand out from schoolboy views of the GIs: We never found a real cowboy despite persistent questions, the women did not look at all like Hollywood beauties, and they were all so generous with candy and gum to pestering kiwi kids. Boy Scouts played a key role in nurturing my love of field biology. My parents were resolutely suburban and the “bush” was to them a hostile place. My happiest days were on Scouting forays (however tame in retrospect) into the native forest and that joy in wilderness has remained with me throughout my life. I am sure that my current activities with the North Cascades Conservation Council aimed at protecting what little remains of northwest wilderness springs from those early experiences. During much of my childhood my parents and younger brother suffered from various illnesses that occupied most of their attention. I think I learned to be self-sufficient during those years.

School and College

Early childhood memories are few, but one that I am reminded of these days on regular visits to my dermatologist is of the association of appallingly painful sunburn with midsummer antipodean Christmases at the seaside, for which 60– 70 years later my dermis is paying.

The Auckland Boys Grammar School was modeled on strict English traditions. Uniforms and strong discipline, with a stout cane to the backside for even minor infringements, was the rule. I did not excel in school but I found my niche as a lab assistant, paid a pittance to prepare materials for the next day's lessons. There I met some of my life-long friends, fellow refugees (nerds in today's parlance) from the macho rugby football hierarchy of the school. Most of those school pals went on to distinguished careers in science in New Zealand or overseas. We were culpably free to use the lab equipment unsupervised after school hours and there were some miraculous escapes from disaster, for example a rocket that went off prematurely through the school roof, and the successful x-ray photography of a lizard, using an ancient x-ray tube from a museum cabinet, which we connected to a chain of military surplus high-tension batteries. It was a relief years later, when my offspring were born apparently normal.

An early fascination with insects and with growing plants was fostered during school years by sympathetic teachers and by the Curator of Birds and Insects at the Auckland Museum where Graham Turbott, a respected ornithologist, gave me the run of the insect collection and its care. Science as a research career was unknown to my parents who urged me to choose a practical profession. My dream then was to practice veterinary medicine in a dairy farming area. I worked as a farm hand during school holidays, milking cows, delivering calves, making hay, and castrating hundreds of piglets and that framed my ambitions. Having survived grammar school I began university studies in Auckland, majoring in Zoology and Botany. Zoology was my first love but the head of the small department was a pompous tyrant (or so it seemed) who concealed his incompetence behind a glowering, humorless presence. Failure to take dictated notes (we had no textbooks) was met with a reproachful eye and, other than his clipped dictation, sepulchral silence was to be maintained—no questions asked. I once won a dare by eating a raw carrot in the front row during his exposition of the skeletal anatomy of some obscure fish.

Botany on the other hand was a lively place under V.J. Chapman, an ebullient new arrival from Cambridge. Animals, for all we were taught, had only anatomy and fossils but plants had thrilling physiology, genetics, and ecology. Peer learning played a major role through the activities of the student-led Field Naturalists Club that organized expeditions to offshore islands to collect and record and live camp life with a zeal that endowed us as graduates with a thorough knowledge and love of the New Zealand flora and fauna. Despite our total innocence of much of the science that was current in those immediately pre-Watson-Crick days, I believe that our thorough organismal training served us well. In my senior year I was awarded the Botany Book Prize, for which I chose, to the consternation of the Botany faculty, the newly published Insect Physiology edited by Kenneth Roeder (1953).

Plans for a career in veterinary medicine faded partly for financial reasons and partly from the epiphany of finding V.B. Wigglesworth's newly published studies (Wigglesworth, 1959) on the insect nervous system. A Masters in Zoology then seemed to be the alternative track. I was advised against attempting it under W.R. McGregor, the head of the mausoleum-like Zoology Department, but the return to Auckland of two Imperial College entomological PhDs Tom Woodward and Jim Pendergrast made graduate work feasible and in the end McGregor graciously supported my next step overseas to Cambridge. My master's work focused on the reproductive biology of a large native longhorn timber beetle that was thriving on the dead wood of extensive exotic Pinus radiata plantations. The thrill of discovery came early when I found evidence that the female beetles had an olfactory sex attractant. That thrill was short-lived when I found the literature on pheromones that dated back to Fabre, but it primed the pump.

Graduate School on the Other Side of the World

The Master's thesis was almost done when I read invitation notices to apply for Research Studentships at several Cambridge colleges. Having scant hope of success, and unwilling then to take a technical position in New Zealand entomology, I began planning to travel in Canada, attracted by both forest entomology and mountains to climb. At that time, New Zealand was so anglocentric that graduate study in North America was rare. But the improbable happened and I was accepted by Gonville and Caius College, to do my PhD with V.B. (later Sir Vincent) Wigglesworth, whose papers, models of clarity, so elegant in style and so beautifully illustrated, had become my beacon. Appointed Quick Professor in the Department of Zoology and author of The Principles of Insect Physiology, he became known as the founder of the field (Edwards, 1998). The 6-week trip to England in 1956 as a steerage passenger on the Tamaroa, a wallowing frozen meat ship, gave me some time to cover my nakedness in insect physiology. In these days of easy flight it is hard to believe that England was then so far away and at the same time so much a foundation of all our myths. Arriving in London was like stepping into reality after a quarter century on vacation in the colonies. I was finally in history, in the nursery rhymes, and among the symbols of Britain that had loomed so large in our early education, especially through the war years of my childhood that were so filled with pro-British, anti-Nazi, and later anti-Japanese propaganda.

Life as a graduate student in Cambridge was at first overwhelming. My congenital response to an “excessive diffusity of stimuli” proved insurmountable. Who could not leap at the opportunity to attend lectures on nerve and muscle from Hodgkin and Huxley, respiratory enzymes from David Keilin, Chinese science from Joseph Needham, or architecture from Nicholas Pevsner? I had hoped to combine field study with bench physiology but I was dissuaded by Wigglesworth who cautioned that seasonal field work dependent on Britain's fluctuating weather was too risky a project. Instead he proposed that I work on a predatory insect in the assassin bug family (Reduviidae), a relative of Rhodnius prolixus, the blood-sucking insect made famous through his pioneer work on the hormonal basis of insect development.

The first few months at the bench were troubled. Wigglesworth expected his students to find their own question and pursue it; he regarded his advisory role as inhibitory, “to help students avoid making fools of themselves.” But my assigned animal seemingly raised no experimental potential until I began to closely observe their predatory behavior. They were fed on moth larvae that could outweigh the predator a hundredfold and yet succumb in seconds. The mouthparts of assassin bugs, as with all in the order Hemiptera, are modified from chewing units to form a hypodermic needle. Saliva is injected through one barrel, while fluid food is ingested through the other. When a prey is captured, the injected assassin bug saliva causes immediate convulsive thrashing followed within seconds by flaccid paralysis. Their saliva had obvious analogies to that of neurotoxic snake venoms. The composition of insect saliva was known at best superficially for very few species and was certainly quite unknown for assassin bugs, so I decided to explore this vacant frontier. It soon became clear however that “my” animal, Rhinocoris carmelita was a poor source of pure saliva. Only minute quantities could be harvested and, given analytical techniques then available, there was little to be learned. But serendipity struck while I was summoning the resolve to take my case to Wigglesworth for a change of topic. Thumbing through an economic entomology journal I found an account of a large African assassin bug that attacked chestnutsized rhinoceros beetles in the coconut plantations of Zanzibar. Rhinoceros beetles were destructive pests and Platymeris was considered a potential biological control agent, but it was also notorious for causing disabling pain in bitten coconut harvesters. Not only did it bite, but it also could spit, using its saliva as a defense against would-be predators. Inquiries to the author F.L. Vanderplank in Zanzibar led to the delivery by mail of a small batch of eggs from which I started a colony. These evil-looking insects with adults the size of a large cockroach, black with two menacing red spots on the wings, were raised on cockroaches from the departmental culture. Their spitting behavior enabled me to collect tens of milligrams of dried saliva. The technique of starch gel zone electrophoresis had only recently been introduced by Smithies (1955) and having found a source of DC current in the basement of the Zoology building I was, to my delight, able to separate six protein bands. Hydrolyzing starch and pouring a layer on a sheet of glass was a delicate art but persistence paid off and, armed with data, I managed to convince Wigglesworth, who was famed for his “string-andsealing wax” approach to experimentation, that I needed a controllable DC supply unit and that gave me the springboard for my thesis work. I isolated three endopeptidases comparable in specificity to trypsin and chymotrypsin, hyaluronidase, and weak phospholipase (Edwards, 1961). None of these, according to work then published, could account for the rapid lethality of the whole saliva, and the mystery of the mode of rapid neurotoxic action remained when I submitted my thesis. By that time I had become intensely allergic to the assassin bugs, probably from careless handling of the saliva powder, and I could no longer work with them.

I cannot leave an account of my graduate student time in Cambridge without a comment on the Agricultural Research Council's Insect Physiology Unit headed by Wigglesworth on the top floor of the Zoology Department. The staff included John Treherne who was to become a leader in insect neuroscience, A.D. (Tony) Lees, whose brilliant experimental work on photoperiodic control of aphid polymorphism involved piping light through fine polystyrene threads to different regions of free-living aphids' brains, and John Kennedy, a pioneer in the analysis of aphid migratory flight behavior and a resolute mechanist who was skeptical of ethological metaphors. Lees and Kennedy did not have graduate students but were always ready to listen to the woes of graduate students too intimidated to take their problems to Wigglesworth who was perceived by the student mind as somewhat remote and of the “sink or swim” persuasion. He presided over the ritual Monday afternoon tea, a time for discussion of latest developments and publications after which students and some of the staff adjourned to the Bun Shop, a neighboring pub, where the discussion became less inhibited and where we learned so much about the sociology and politics of research in the UK.

Unlike United States practice, the PhD thesis was submitted for examination as a bound volume and the award decision was “up or down.” My external examiners were Sir Rudoph Peters, an eminent Oxford biochemist known for his synthesis of dimercaprol or “British anti-Lewisite,” an antidote to a very potent arsenic-based chemical warfare agent, and David Keilin, the discoverer of the cytochrome respiratory chain system. Weeks went by without an appointment for the final oral exam and my apprehension grew exponentially until I learned that Keilin had been ill. Eventually the exam went well, again thanks to serendipity. I had bought a copy of Scientific American to read on a train trip to London the previous day. It carried an article with all the latest on the actions of biological toxins, so by chance I appeared to be fully au fait, and I enjoyed the afternoon-long discussion with these two remarkable men.

The next move had been looming: where to go and what to do? The university system in New Zealand at that time was in a lamentable state, with limited research and travel opportunity, heavy teaching, and meager salaries. The opportunity to spend a couple of years in the School of Agriculture in Cambridge postponed the decision. I joined an aphid research unit directed by Claude Ribbands, better known for his honeybee studies at Rothamstead, in which my task was to find a technique for plucking a migrating aphid from the air and determine which of many potential plant hosts it had sprung from. The question had immediate significance for British agriculture because the aphids in question are notorious vectors of debilitating plant viruses that affect the productivity of crops such as sugar beet and potatoes. What was the source of virus bearing aphids that infested each new spring crop? Immunological techniques had recently been used to determine the hosts of tsetse flies in areas of Africa ravaged by sleeping sickness. Perhaps a similar technique could be used to identify the plant hosts of migrating aphids and thus the source of overwintering virus. Neither immunology as then practiced nor plant phenolics, both of which offered a potential fingerprint, proved applicable because they are not transported in measurable quantities in the phloem vessels of plant that are tapped by aphids. But all was not lost in this venture for in the process of dissecting countless winged aphids I found that those that had fed on sugar beet or other members of its family, the Chenopodiaceae, were pot-bellied; their guts were stuffed with an insoluble mass whereas those from cabbage, for example, had mere traces of solid material in their crop. This observation in itself raised interesting questions that are still to be addressed for phloem is thought to transport only small soluble molecules such as sugars and amino acids. Standard agricultural practice was to store harvested sugarbeets through the winter in “clamps” (earth-covered piles in the field), and these clamps provided refuge for aphids. It was thus important to know how many aphids among the spring migrants had come from this virus reservoir. (This was the nearest I ever got to clamping studies.)

A byproduct of my experience with aphids was the demonstration that their defense mechanism against parasites was based on the release of supercooled liquid wax that is stored within the body in special cells (oenocytes). When extruded it instantaneously solidifies on contact with a solid surface thus enveloping a would-be parasite (Edwards, 1966; Chen and Edwards, 1972).

To the New World

Further field testing with spring migrant aphids and the nature of their gut contents were left unresolved when the opportunity to work in the United States arose during a sabbatical visit of Howard Schneiderman from Cornell to Wigglesworth's lab. His ferocious enthusiasm was infectious and the added prospect of working with Tom Eisner on chemical ecology led to plans for a move to Cornell. I had secured a National Institutes of Health (NIH) post doc on the limited New Zealand quota that was generally reserved for MDs, when news came from Schneiderman that he was moving to Western Reserve University in Cleveland along with Marcus Singer, to head the Biology and Anatomy Departments respectively and to found a Developmental Biology Center. I was given the option of going to Cleveland or to Cornell. The decision was difficult. It was tempting to pursue some aspect of chemical ecology with Tom Eisner at a renowned university and continue the theme of insect venoms, but I opted for the unknown Western Reserve University whereupon Schneiderman advised me to get immigration visas for the family in case the Developmental Biology Center should prove attractive as a faculty position. An ecological and climbing expedition to North East Greenland and then the usual bureaucratic wait for immigration visas ensued and we were finally on board the Queen Mary to arrive in a bedecked New York on March 2, 1962, where we were happy to share the tickertape festivities for John Glenn on his return from orbit.

The renaissance of Biology at Western Reserve proved to be an exciting process. Schneiderman had attracted able new faculty, including Boris Ephrussi, Bob Josephson, and Michael Locke. Singer had brought Ted Voneida to the Anatomy Department. I met him through Colwyn Trevarthen, a friend since undergrad days who had been with Ted in Roger Sperry's lab at Cal Tech. That meeting proved to be providential for although I had intended to join the frenzied search for the identity of the insect juvenile hormone in which Schneiderman was a front runner I had doubts about being a late arrival in what Schneiderman himself described as “a mighty crowded frontier.” In the end the prize for that race went elsewhere but by then I had read Singer's papers on amphibian neural regeneration (Singer, 1965), Ted had shown me Sperry's seminal paper on neural specificity (Sperry, 1963), and I knew where I wanted to go. Growth and regeneration of insect nervous systems has been a preoccupation ever since.

Adventures with the Insect Nervous System

I had found an empty frontier—almost. Dietrich Bodenstein had looked en passant at regenerating insect nerves and Hans Nuesch had published his beautiful studies showing the trophic necessity for motor nerves in the development of adult muscles during metamorphosis of giant silk moths, but the issue of specificity had not been directly examined. Given the difference between vertebrates and arthropods in the origin and organization of sensory neurons it seemed that insects could provide a simpler system for the analysis of sensory regeneration. I started out with the so-called American cockroach Periplaneta americana (in fact an import in slave ships from Africa). They regenerate appendages well during immature stages but their development was too slow for my impatience and when, by chance, a marketing sample of house crickets sent from Fluker's Cricket Farm in Louisiana, as potential teaching material, arrived in the lab I found my animal. They proved easy to keep, they bred prolifically, they developed relatively rapidly, and they regenerated lost appendages vigorously during immature stages. Franz Huber in Cologne had already shown the value of crickets in his pioneering brain stimulation studies. And further, unlike cockroaches and assassin bugs, which elicit responses of disgust and fear from colleagues, no one objected to the pastoral song emanating from the garbage cans where the crickets lived happily on a diet of cat chow.

Crickets and their orthopteroid relatives have abdominal cerci, sensory appendages that project from the posterior end of the abdomen. The many mechanosensory hairs on their surface function as warning systems for impending predatory or parasitic attack; they are in effect antennae a posteriori. The mechanosensory neurons arise during embryonic and postembryonic development from a monolayer of epidermal cells that underlie the cuticle. They both transduce the mechanical stimulus and project to the central nervous system (CNS) where they synapse with a small population of giant interneurons. Their giant axons traverse the abdominal ventral nerve cord to synapse with motor systems in the thorax and in the brain. They elicit rapid evasive movements, the so-called startle reflex made famous by Kenneth Roeder's studies of the cockroach nervous system (Roeder, 1967). The cereal startle system is widespread among orthopteroid insects and their evolutionary ancestors such as silverfish and bristle tails gave the potential for comparative and phylogenetic studies. Cricket cerci can be simply amputated with a flick of fine forceps. During immature stages (but not in adults) the cerci regenerate from epidermal cells, becoming more complete through successive molts. The new sensory neurons, associated with each sensory hair, are derived from epidermal cells. They grow to the CNS where they reestablish central connections with arborizations of the giant interneurons. They fully restore the startle reflex behavior even, as I later showed with John Palka, after prolonged absence of regenerates (Edwards and Palka, 1971). Then, with post doc fellow Tara Sahota we tried transferring a cereal regenerate to a leg stump, thus testing whether an ectopic cercus could regenerate functional central connections in different central territory. We asked, in the context of Sperry's chemospecificity hypothesis and Singer's ideas about amphibian neural generation, whether the transplanted cereal sensory axons, now far from their familiar territory in the terminal ganglion, could find their targets. Our criteria were crude by present day standards, but we did show that the ectopic cerci elicited characteristic giant interneuron spikes in response to airpuffs, as in normal animals. We concluded that the ingrowing axons had found their target cells at a site far removed from normal (Edwards and Sahota, 1967). This was,. I believe the first exploration of specificity in an invertebrate system. The crudity of those experiments is laughable by present day standards; it surely illustrates the extraordinary technical advances since then. Later work by Rod Murphey and his students greatly refined this experiment, but the general finding held. I returned later, with colleagues, to the problem of sensory input from ectopic appendages using a homeotic mutant of Drosophila and homeotic regenerates in a stick insect Carausius and concluded that the pathway to the center is specific for a given ganglion, so that antennapedia “legs on heads,” both as mutants and as regenerants, obey the same guidance rules that are intrinsic to the segment, irrespective of sensory modality. At about that time, two other approaches to neural regeneration and growth were getting underway in my lab. To look at the capacity for central neurons to regenerate I chose another “white rat” of insect labs that was already in use in the Schneiderman lab for hormone assays: Galleria mellonella, the wax moth larva. It has a rugged larval stage that can take a lot of abuse. I severed the ventral nerve cord in larvae that were ready to undergo a molt to the pupal stage. To my surprise segments anterior to the cut, wherever it was made along the length of the larva, resulted in a tonic contraction of body wall musculature anterior to the cut while the posterior segments relaxed and expanded. I found no evidence for central neural regeneration, but, again to my surprise, these larvae never made the molt to the pupal stage. They remained alive, slowly metabolizing themselves away long after the controls had completed metamorphosis to the adult. Cuts to the CNS made well clear of any possible damage to the endocrine glands that regulate molting, prevented the molt, while small control epidermal incisions that did not sever the cord had no significant effect on the timing of the molt. It seemed possible that a proprioceptive input was involved in the release of the molt cycle. There seemed to be a parallel with the demonstration by Wigglesworth (1934) that proprioceptive input in response to the stretching of the integument by a blood feed activated the neuroendocrine release of the molting sequence in Rhodnius. Accordingly I developed a straitjacket technique using adhesive tape to constrict various regions of the body. Such animals did not pupate until they were released from constraint (Edwards, 1966). My conclusion from these experiments that proprioceptive input was one parameter, among others such as adequate nutrition and time of day, that must signal “go” to release the brain hormone and the subsequent train of endocrine events that induce the molt, was supported in later experiments with Frantisek Sehnal, a visitor from Prague (Sehnal and Edwards, 1969).

Another point of departure in setting out on neural developmental studies concerned brain changes during neural metamorphosis, the pattern of profound changes that accompany the transformation of a rudimentary larval brain to a large and complex adult structure. The chosen animal for these studies was the Monarch butterfly Danaida plexippus, a favorite animal of mine since childhood in New Zealand, that was common in the milkweed fields of Ohio where the larva, a vegetative feeding machine, contrasted with the long-lived migratory adult. My first graduate student, Ruth Nordlander, took on the Herculean task of sequential tritiated thymidine labeling animals throughout postembryonic development and by means of radioautography to trace the events of cell proliferation and migration. Brain metamorphosis had been described in broad outline in work from the late 19th and early 20th century but the cellular events were then unknown. The series of papers that came from that study (Nordlander and Edwards, 1968a, 1968b, 1969a, 1969b, 1970) became classics of insect development. At the same time a Master's student, Anne Gymer, looked at glial cell growth during postembryonic development of the house cricket. We showed for the first time that, although the number of neurons in ganglia of the CNS remains constant throughout postembryonic development, increasing only in volume, the glial cell population increases twentyfold, in synchrony with the molt cycle (Gymer and Edwards, 1967). Glial cells hear the signals to epidermal cells to divide, but neurons do not.

Cleveland at that time was an exciting place, not only for biology but also for music. The Cleveland Orchestra was brilliant under the baton of George Szell, the Cleveland and Guanieri String Quartets were starting out on their illustrious careers, and James Levine was emerging as a prodigy. As well the Cleveland Museum of Art's magnificent collections, especially of Asian art, were a treasured resource for wet weekends. All of us who were in Biology at Western Reserve during the late 1960s remember it as a time of intense and buoyant intellectual ferment. It was the crucible in which I learned to do science the American way. Growth was the flavor, grant money flowed, and faculty numbers swelled in the postsputnik boom. It felt good to be part of it but it was not to last. There were unsettling tensions within the Biology Department, and I became aware that my eclectic proclivities might stand in the way of tenure. Echoes of undergraduate admonitions about diffusity of effort returned, but thanks to Boris Ephrussi, who “adopted” me and who insisted that I concentrate my efforts and publish, tenure came shortly before my move West.

Summer expeditions to the Teton Range and winter climbs in New England's White Mountains kept a love of mountains alive and the call of the Cascades became irresistible when the University of Washington advertised for Zoology faculty. I visited, gave a seminar, we liked each other, and their offer was airdropped to me in Base Camp during the first winter ascent of Denali (Mt. McKinley, Alaska) (Davidson, 1986). So, later in 1967, now with four small boys, we traveled west to Seattle.

Across the Cascades to Seattle

Although I was sorry to be leaving such wonderful colleagues as Ted Voneida, Bob Josephson, and Jim Weston, I can only write with enthusiasm about my years in Zoology (now Biology) at the University of Washington. The collegiality, open doors, and broad coverage of population, organismal and later molecular biology achieved by unusual disciplinary altruism made it a great environment for such as myself with eclectic interests that could not be ignored and with tenure in hand. I had picked up on my cereal regeneration work when John Palka joined the faculty. We began a rewarding collaboration that lasted many years with NIH support, the last 7 of them on a Javits Award. John brought the electrophysiology and I the developmental background to an analysis of neural regeneration in the cricket. We worked on decoding the rulebook for postembryonic regeneration (Edwards and Palka, 1974; Palka and Edwards, 1974; Edwards, 1980, 1988). I like to think that our demonstration of the potential of the cricket cercal system attracted others such as Rod Murphey and his students who took the system to higher levels of refinement.

A Year in Basel

In 1973 a sabbatical leave supported by a John Simon Guggenheim Fellowship took the family to Basel and the Zoologisches Institut, then co-directed by Hans Nuesch who was my host there. My room at the Institute overlooking the Rhine was said to be where Miescher first isolated nucleic acids from sperm of migrating salmon netted from the river below and may also have housed Paracelsus, a 16th century father of modern medicine. Research in progress there was not exactly cutting edge, but Nuesch and his wife were wonderful hosts and Basel remains a magical place to all the family. And for frontier science a short walk across town took me to the Biozentrum where big things were happening. My objective in Basel was to get to know the embryo of the house cricket. I first needed to become familiar with the timeline of developmental events and learn the microsurgery that would enable me to remove embryonic cerci before they had neural connections with the CNS. I further hoped to resurrect the ultraviolet (UV) lesion equipment that Geigy had used in Basel for his embryo studies but that did not prove practicable. However, an hour away by autobahn in Freiburg was Klaus Sander and his Institute devoted to mechanisms of insect embryogenesis. I found a welcome there and by extraordinary good fortune Klaus Kalthoff was using a focussed UV beam for his lesion studies and was willing to let me use his equipment. I hoped to remove the embryonic cercus rudiment before it sent afferent fibers to the CNS, then later challenge the “naïve” ganglion with a transplanted cercal regenerate. Simple surgery having failed to yield cleanly deafferented embryos, I hoped that the UV beam would work. Many attempts later I concluded that, at least in my hands, the lesions were not localized enough to be useful. Success would await later laser studies described later. A delicious memory of those visits to Freiburg is of eating spargel with excellent Riesling in the town square after days at the microscope.

Crickets: Embryos Again and Responses to Deafferentation

Back in Seattle I set about refining, with my long-suffering electron microscope technician SuWan Chen, the timeline of neural development in the cricket egg (Edwards and Chen, 1979). We were slow to realize what the montages of embryonic cerci at successive stages were telling us, and we had just concluded that there must be a set of initial axons that reach the embryonic CNS before the circus elongates and that these provide the pathway for the functional sensory afferents that grow to the center later in embryogenesis when Michael Bate published his elegant paper showing the role of pioneer fibers in locust embryos (Bate, 1976). It became clear that this was a general mechanism by which the periphery makes contact with the center. It was also immediately clear that the relatively large locust embryo, where axons could be seen in the light microscope, was the material of choice for studies of neurogenesis and in the hands of Corey Goodman, David Bentley, and their students the locust embryo became the object of ground-breaking studies of sensory, motor, and CNS development.

It remained to be shown that pioneer fibers were indeed necessary and sufficient for the orderly development of the functional nervous system. Our earlier attempts to prevent the formation of pioneer fibers by mechanical and UV lesions not having been productive, we did at last achieve success in collaboration with Michael Berns at Irvine, using his laser beam microlesion system (Edwards, Chen, and Berns, 1981). We were able to show that after ablation of the source of pioneer fibers in the apex of the cercal rudiment, the later developing functional afferents grew in a disorganized looping fashion. We concluded that in the cricket cercus, the dorsal and ventral pioneers are essential to normal development and that after detaching from the epidermis they fuse to form the pathway to the center for the late-developing sensory axons. The successive additions of new axons in each instar between molts follow this pathway to the center by contact guidance.

Along with embryo studies we were also pursuing questions of metabolic effects of deafferentation. We had made a start in Cleveland at looking at the cricket terminal ganglion as a potential model for the analysis of trophic processes in showing the presence of three membrane-bound acetylcholinesterases (Edwards and Gomez, 1966), but it was Mark Meyer's neurochemical know-how that enabled a targeted approach to the effects of deafferentation on the metabolism of the terminal ganglion. First he showed that the ganglion had high levels of muscarinic binding sites, in contrast to the generally reported nicotinic binding sites in insects (Meyer and Edwards, 1979), and we went on to show with quantitative radioautography that the suppression of growth in target giant interneurons deprived of their cercal sensory input was reflected in depressed uptake and incorporation of tritiated leucine after chronic deafferentation, although not in short-term deafferentation (Meyer and Edwards, 1982). That led to an analysis of the effects of deafferentation on the density of cholinergic binding sites and acetylcholinesterase (Meyer, Reddy, and Edwards, 1986) in which we showed changes in the turnover of three macromolecules associated with cholinergic transmission in the cercal sensory-giant fiber system. We thus demonstrated trans-synaptic effects on the synthesis and turnover of specific molecules.

Franz Huber and Huberhaus at Seewiesen

In 1980 a Humboldt Award enabled the entire family to take a year in Germany thanks to Franz Huber, whose section at the Max Planck Institute for Behavioral Physiology at Seewiesen centered on the neuroethology of crickets. Seewiesen is famed for the ethologists led by Konrad Lorenz, who set it in the idyllic landscape of Bavaria near Munich. Later members included Dietrich Schneider whose group broke new ground with anatomical and experimental studies of insect olfaction and Franz Huber. Among the first scientists to cross the Atlantic at the close of World War II, Franz had worked with Ted Bullock and he maintained an international perspective both in his research and his hospitality at Cologne and then at Seewiesen. That visit was a wonderful time for the family, a year to savor the rich history of the area and to live on the beautiful Starnbergersee, half way between the music of Munich and the snows of the German Alps. My research plan was to explore the cercal system of primitively wingless insects, silver fish, and firebrats with the aim of extending the comparative and evolutionary history of the cercal system. I posted a note in my most polite German on the Institute notice board requesting silverfish or firebrats. The meager result was an occasional anonymous specimen in a vial left on my desk. When I commented to Franz on the paucity and anonymity of the offerings Franz replied, “Oh, no German housewife would ever let it be known that there were insects in their home!” I felt that I should distribute Karl von Frisch's beautiful book Twelve Little House Friends that gives a lyrical account of our insect cohabitants. I did get enough material to get to know the neuroanatomy and something of their development. That work laid the foundation for later studies in Seattle. A memorable feature of life at Seewiesen was the seminars from visitors or sometimes from a resident in rapid-fire German only intermittently intelligible to me. Questions after the seminar would begin with technical details and end, sometimes hours later, with discussions by that time dealing with such things as “What is life?” I recall also abstaining from the massive farmers' lunches served in the mensa, conducive only to a prolonged but reluctant afternoon nap. Instead I took bread and cheese on crosscountry skis, sometimes with Ali Steinbrecht, through the local countryside (which I likened to frozen Schubert), to lunch on a viewpoint where we talked science.

On one of those forays I noticed snowfleas, so named because these minute wingless members of the insect order Mecoptera can make flea-like leaps even at near-freezing temperatures on the snow surface as a predator evasion tactic. Here began another tangent: I found that the length of their long-jumps was independent of temperature over quite a wide range and that the power for the jump came from energy stored in an elastic protein, resilin, derived from a wing hinge that was distorted by muscular action then rapidly released. The detailed microanatomy proved to be indeed a prototype of the resilin-powered jump of the true fleas and this finding added data to the view that the true fleas were derived in phylogeny from Mecoptera rather than the true flies (Diptera). This project remains a work in progress and has become yet another project waiting in the files for further high speed movies of the jump.

Another tangent: I had to admit that I knew nothing about Alexander von Humboldt when I received my Award from the Humboldt Foundation. Who was he? What did he do? The more I read of his life the more I became intrigued by his extraordinary accomplishments. His name is everywhere, an ocean current, a glacier, a county, a college, but his science has been lost to all but historians. His was the last great sweeping view of the Cosmos as a great piece of eternal clockwork before Darwin swept the world of Biology and Geology with a dynamic evolutionary view of life on earth. Ironically it was Humboldt's writings on his South American journey that persuaded Darwin to join the Beagle. But a different facet of Humboldt's impact led me on another quest that stemmed from my interest in the history of landscape painting. Humboldt's writings were greatly admired by painters of the Hudson River School, and one of their leaders, Frederick Church, followed Humboldt's exhortation to go to the tropics and paint the tropical scenery, so well described by Humboldt, for all to see. Church's epic landscapes from the Andes were a sensation and I believe that there is a causal pathway to be traced from those paintings and those of contemporaries such as Bierstadt to the political will to create the first national parks and thence the modern conservation movement (Edwards, 1999). I had the opportunity to present these ideas at a symposium held in connection with a major show of Hudson River paintings at the Metropolitan Museum in 1989. I have yet to commit a detailed study to scholarly print.

Firebrats and Flights of Fancy

On my return from Seewiesen to Seattle I resumed work with firebrats and invited a visiting post doc, Rajarami Reddy, to work with me on the project. We found that, as with the silverfish I had worked on at Seewiesen, the central projection of the median terminal appendage split to left and right halves, joining the neighboring cercal nerves. The central projections of these combined nerves closely resembled that of the cricket, the cockroach and other orthopteroid insects. And, as judged by segmental position and detailed pattern of arborization, the giant interneurons of the firebrat appeared to be directly homologous with those of the cricket (Edwards and Reddy, 1986). Later work with the most primitive living insects, the bristle tails, revealed the same general pattern and this led me to some speculations (flights of fancy, as one reviewer said) on the origin of insect flight. Arguably one of the major innovations in evolutionary history with profound consequences for terrestrial life (not to mention human ecology), the evolutionary origin of insect wings and the pressures that led to flight, have been debated ever since Darwin. The dominant theory through most of the 20th century was based on the development of lateral extensions of the thoracic segments that would act as passive gliding wings when the proto-flier jumped out of trees. Some of the sparse fossil material then available, analogous to ideas about Archeopteryx, and later a nice biomechanical analysis (Kingsolver and Koehl, 1985) lent support to the gliding hypothesis. But the rival view, that the wing originated as an active structure, gained support from newer fossil discoveries (Kukalova-Peck, 1990) and the finding in Drosophila that the embryonic origin of the wing was from a leg-base rudiment, called for an alternate view of the selection pressure that led to active flight. Our work with the ancient startle reflex comes in here. It is known that various arachnids, some of them now extinct, colonized the land at the same time as the first insects. It must have been a jungle back there. That those early insects devoted about 30% of the volume of their abdominal nervous system to their mechanosensory predator evasion system based on the startle reflex surely reflects the predation pressure for which running then jumping served as the escape. A jump requires symmetrical motor patterns, as does flight. Any palaeoneuroethological reconstruction is just a story but the known facts seem to fall into place and become a plausible hypothesis. The first land-dwelling insects faced diverse predators. Startle mechanisms arose, based on abdominal giant interneurons, that responded to the air movements made by incipient predators. The response of prey was to run, then to leap away from danger. Extensions from basal leg segments found in early fossils provided stabilizing glide surfaces, then active flight. Flight then opened up new adaptive space, allowing exploitation of a spatiotemporally patchy environment and that in turn led to their unparalleled diversification of species and ecological function (Edwards and Palka, 1991). We concluded that an important operating principle in insect neural evolution seems more like a fugue than that of an opera. Richness of variety has been generated by the combination and recombination of a small number of themes rather than the invention of new melodies to suit the appearance and disappearance of characters as the plot evolves. At the same time we were learning that the insect nervous system is by no means a rigid hardwired device in its development and the behavior that it mediates.

Are Insects Relevant?

Relevant to what? The late 1960s through the 1980s was a time when the long-held notion that insect (and other invertebrate) behavior was rigidly stereotyped and that their nervous systems were parsimonious and hardwired, inflexible, and therefore ultimately irrelevant to most of mammalian/human neurobiology on which research support was focused. As Greenspan (1981) commented: “Insects may be tolerated in neurobiology, but they are rarely admired. More often they are disdained by students of higher organisms for their lack of relatedness to mammals.” There were those who discounted invertebrates, such as Roger Sperry and Pasko Rakic. There were also public defenders of invertebrate work, Graham Hoyle militantly so, others less provocatively, such as Rod Murphey (1986) and Ian Meinertzhagen (2001) among many others. Times have changed. Increasingly, even before genomic studies began to emphasize similarities rather than differences, invertebrate studies found plasticity and modulatory systems and that endowed them with more respectability. At that time also interest was growing in the developmental and modulatory role of glia and we began to address the question of insect glial diversity in the house cricket Acheta. My long-time colleague Mark Meyer, a man of infinite resource, made a series of monoclonal antibodies to preparations of cricket glia (Meyer, Reddy, and Edwards, 1987). The set of glial types that emerged from that immunohistological study, proved to fit remarkably well with the glial classification made by Wigglesworth (1959) on the basis of light microscopy, and subsequent work with Drosophila also conforms to the same general pattern. One of our monoclonal antibodies, 5B12, recognized a high molecular weight glycoprotein associated with central and peripheral glial cells that we named glionexin. Its expression proved to be developmentally and spatially modulated. It was widely expressed on the basal lamina of embryonic epithelia along which developing neurons grow (Meyer, Brunner, and Edwards, 1988) but is later confined to the glial lacunar system surrounding ganglionic neuropile. In the periphery of postembryonic and adult crickets it is retained in sensory nerves at much higher levels in mechanoreceptor sensilla than elsewhere (Field, Meyer, and Edwards, 1994). Thus, a transient embryonic adhesive component involved in guidance serves in the adult in a role that is consistent with ion homeostasis.

Bergen

Seattle is the sister-city of Bergen, Norway, and the University of Washington has a sister relationship with the University of Bergen. The long-running faculty exchange program provided me with the opportunity in 1989 to visit the place where Fridtjof Nansen, the famous explorer and statesman began his career. A hero since boyhood for his stories of Arctic exploration, I had been incredulous at finding in the newly published Bullock and Horridge (1965) a reference to Nansen's PhD thesis on the structure of the invertebrate nervous system. A beautiful study, illustrated with his own lithographs, he reached the plainly stated conclusion, on the basis of comparative studies of numerous invertebrates, that nerve cells touch each other but do not fuse. In this he clearly presaged Ramon y Cajal's famous formulation of the Neuron Doctrine. I found no relics of Nansen's time in Bergen, but my continuing interest in his work led to contact with Nansen's latest biographer, Roland Huntford (1997), with whom we reached the conclusion that Cajal must have been aware of Nansen's work but chose to ignore it, Nansen having left for his remarkable first crossing of Greenland immediately after defending his dissertation, never to return to neuroscience (Edwards and Huntford, 1998). Our idols are not lightly dethroned and Nansen's neuroscience will surely remain an obscure footnote to Cajal's fame.

A Return to Cambridge

In 1990, thanks to another sabbatical leave and a Visiting Fellowship from my old college, Gonville and Caius, I had a sparkling year back again in Cambridge where I lived in Stephen Hawking's delightful little rowhouse overlooking the garden of Little St. Marys, its vertical structure being no longer accessible to the great cosmologist. I often had the opportunity to lunch with Sir Vincent Wigglesworth who was then 91 and still engaged in research. He commented on one occasion: “I am working on difficult problems now because I don't feel the pressure to publish.” It is telling that he was asked to give up his lab shortly after my visit and he died within months. My research interests having turned again to glial cells, I had planned to work with John Treherne and his Agricultural Research Council Unit on glial regeneration. But to my dismay and profound sorrow John died of a heart attack just days before I arrived. I was there in time to attend his funeral in Downing College Chapel where, following a moving service, there were floods of tears when, following his request his favorite jazz band struck up “The World is Waiting for the Sunrise” as his coffin left the classical portico of the chapel. John's group was left in utter disarray and rather than intrude into their mourning I was able to join Michael Bate's group with whom I had also hoped to work during my time in Cambridge. Mike had done pioneer (literally) work with locust embryos but was now a drosophilist. So once again a sabbatical offered another opportunity for a change of course. I was soon immersed in his dynamic group with Helen Skaer and others working on neural development in Drosophila. I found myself in a whirlwind learning process. Questions in the back of my mind since Cleveland days concerning the source and diversity of glia had floated to the front on reading Treherne's (Treherne, Smith, and Howes, 1988) remarkable series of papers showing that excitability was lost in cockroach ventral nerve cords after chemical lesions to the surrounding glial sheath cells. The action proved to be reversible; glia grew back to replace the lost cells and conduction in the cord was restored. The beauty of these experiments using the cockroach ventral nerve cord is that the cell bodies of all neurons are distant from the lesion sites so that the integrity of axons is not affected. There were questions, however, about the identity and terminology of the cell layers that enclose the nerve cords. Discussions with Mike and Helen raised the possibility that the identity of the cell layers surrounding the nerve cord might be determined using mutant Drosophila. Nancy Lane had used electron-opaque lanthanum ions to explore the establishment of the blood–brain barrier in blowfly (Lane and Swales, 1978) and this approach seemed feasible with mutant Drosophila embryos. The mutant twist is an embryonic lethal in which no mesodermal structures form but the CNS that is derived from ventral ectoderm does develop. After learning the fine art of embryo dissection, 20-hour embryos of wild type and twist were opened and exposed to saline containing lanthanum. With the help of Lesley Swales' superb microscopy we were able to show that the overlying neural lamella and its formative cells were absent in twist mutants, but as in wild type embryos the CNS was impermeable to lanthanum due to the formation of a superficial layer of glial cells, the perineurial glia that in Treherne's work had provided the permeability barrier and which were killed with chemical lesion. In contrast, similar experiments with Delta mutant embryos in which neuroblasts excessively proliferate, an outer perineurial layer was formed, but both it and the underlying glial sheath occurred as discontinuous islands, having been forced apart by neurogenic cells, and the core of the neural mass was in this case permeable to lanthanum (Edwards, Swales, and Bate, 1993). This work resolved continuing ambiguity concerning the investing layers of the insect CNS and vindicated the work of Berta Scharrer (1939), whose intuition based on light microscopy recognized the distinction between the mesodermal sheath forming cells and the underlying glial layer. It became clear too that there are striking parallels between neural repair and gliogenesis in insects (Smith, Shepherd, and Edwards, 1991). Later I was delighted to have the opportunity to join with Leslie Tolbert, who has done magnificent work on the role of glia in the development of the olfactory lobe in the moth Manduca, to write a review of the diversity and classification of insect glia (Edwards and Tolbert, 1998).

One of the joys of High Table at Caius College was the opportunity to meet people from different disciplines. During the year I got to know Bob Butcher, a physicist and agile rock climber, and with him I finished the sabbatical year devoted to glia on a high point literally by climbing all of the peaks of the High Atlas Mountains of Morocco where we shared the experience of standing on summit snow and looking down to the sands of the Sahara.

National Science Foundation

A year at the National Science Foundation (NSF) as Program Director for Developmental Neuroscience in 1996 stands out as perhaps the busiest, but certainly one of my happiest, years in science. The workload was enormous, especially for a new recruit (a second year would have been a piece of cake) but the insights into the currents of neural development and the attractions of Washington D.C., galleries, museums, and great music too, gave little chance for down time. As for so many other transient directors in the neuroscience fields, staffer Christopher Platt made it all endurable with his guidance and support especially during the rapid learning phase. I was there during the infamous shut-down of Congress when the budgetary standoff reached its climax thanks to Newt Gingrich and government departments closed down. Orders came to leave the NSF building in Balston within 10 minutes, taking only personal effects. Attempts to re-enter the building during the crisis would be a federal offense we were told. Like some other program officers who were worried about delays in informing anxious applicants, I smuggled out my awards book and made “anonymous” calls from my apartment to those for whom such things as tenure or set-up hung on the news. During the year I became aware that Neuroscience was no darling of Mary Clutter, Assistant Director for Biological Sciences at NSF, who saw it as a province of NIH. My exit interview with her was one long argument for the place of Developmental Neuroscience at NSF, recounting the track record of innovative studies, especially those on invertebrates that would not have prospered at NIH, at least at the outset. I doubt that my argument carried much weight, but I felt good for having tried.

Full Circle

Much as I admired the world of Drosophila and enjoyed my brief encounter with it in Cambridge, I did not feel the urge to join the ranks on its crowded frontier. So I returned full circle to my dissertation work, acquired a colony of assassin bugs, found that my immune system seemed to have forgotten them (or that I had learned to be more careful), and joined with my colleague Mark Meyer in a new assault on the neurotoxic mechanism. Starch gel in 1956 had yielded six proteins, polyacrylamide revealed at least 14 bands. Enzyme activities were confirmed but the exciting step forward came when we found that the neurotoxic component of the saliva survived 3 minutes at 100°C, a treatment that denatured and precipitated all the hydrolytic enzymes. A neurotoxic peptide was isolated from the supernatant. At that stage we sought the advice of Michael Adams, a spidervenom specialist at Riverside. We have since collaborated on a work in progress. We know that the peptide(s) rapidly depolarize muscle and nerve cells die after a brief volley of spikes. The simplest explanation is that the venom knocks holes in cell membranes, rather like the blood-borne antibacterial agents in most insects that knock holes in bacterial membranes. The precise mode of action proves to be a difficult problem for which I am glad that I no longer feel the pressure to publish but I expect to solve the challenge. The peptide led en route to brief flirtation with a big-time biotech company. It led nowhere but it did provide a glimpse of a facet of modern biology with which I am glad not to tangle.

The Other Side of the Mountain

It may seem out of place in the context of neuroscience history to write of volcano ecology, but it has loomed large in my activities in recent decades. The pursuit grew from a hobby to a professional activity when Mount St. Helens blew up in 1980. I had for years been fascinated by the life of invertebrates at high altitudes and latitudes, a seeming paradox in habitats where homeotherms were better equipped against the cold. But arthropods and other heterotherms thrive in these arid places, variously using tricks such as antifreeze and/or behavioral ways of coping with extremes. With students I had looked at the biology of one of the northwest's insect treasures, grylloblattids, a rare group, some of which live high on such mountains as Mt. Rainier. They spend their lives in a thermal window close to 0°C. They go into heat convulsion above about 12°C, and they freeze lethally at about –6°C, lacking antifreeze. Their giant interneurons respond with spikes to stimulation of their abdominal cerci down to about –5.8°C, just above their lethal temperature (Morrissey and Edwards, 1979). Their behavior patterns are such that they never need see lethal cold for they are sheltered in rock fissures, where they are insulated by deep snow during winter extremes.

So much for their thermal biology, but what do these alpine dwellers eat in a habitat devoid of plants? The answer we found, to quote Bob Dylan, is “blowin' in the wind.” We measured the quantity of organic fallout, composed mainly of derelict arthropods carried from productive lowlands on the winds, and showed that it was the source of sustenance for the diverse alpine invertebrate fauna and was also significant for alpine birds that rely on arthropod derelicts laid out on the white tablecloth of the snow as their principal protein source in the breeding season. In the context of years of study of arthropod fallout on snowfields around the world, the eruption of Mount St. Helens, just 25 years ago as I write, proved to be an irresistible temptation. Here was a naked mountain cooked to several hundred degrees, a moon landscape only 3 hours drive from Seattle. NSF recognized the opportunity to follow the biological events following the eruption and supported a multidisciplinary approach. Here we had the opportunity to observe Act 1, Scene 1 of the succession play, at first by helicopter visits, and later on reconstructed roads. Just as we predicted, the standard story of primary succession was turned upside down. Most ecology texts give plants the pioneer role on bare land, followed by herbivores, and then the scavengers and predators. But on Mount St. Helens, and we suspect on most other such newly devastated sites, the pioneers are predatory and scavenging insects, specialists in exploiting the ubiquitous windborne organic fallout (Edwards, 2005).

Teaching

Some are born teachers, some have teaching thrust upon them, and some should never teach. I started my teaching career somewhere between the latter two. I know that my early attempts must have been as pathetic as they were excruciating. It is painful to remember and I pity those early students. But I worked at the art over the years and I found that two things, conviction and enthusiasm, were paramount and outweighed all the psychobabble and technology that professional pedagogues love to promote. My most challenging but exciting teaching was a bold attempt at Case Western Reserve in 1967 to team up for a Comparative Neurobiology of the Animal Kingdom, with Bob Josephson and Ted Voneida. Bob did the squishies (to use Graham Hoyle's terminology), I did the crunchies, and Ted the bonies. From sponges, coelenterates, and mollusks (Bob) to arthropods (JSE), we had the help of the newly published Bullock and Horridge (1965) volumes and we learned what a storehouse of information they were. The course was well received and could have become a staple had not I left right away for Seattle, Bob a little later for Irvine, and Ted to help found a new medical school in North East Ohio. I taught the wonders of insect biology with emphasis on their physiology, development, and ecology for many years at the University of Washington and enjoyed it, having become reasonably skilled in the later decades. I have been energized over the years by the sheer fascination of insect life and by a sense of the value of an organismal biology perspective in these reductionist times. I like to quote E.O. Wilson to the effect that if primates were suddenly removed from the globe, terrestrial ecosystems would revert to prehominid conditions within a relatively short time, whereas if the insects were to be abolished all terrestrial ecosystems would quickly subside into chaos.

A stint as Director of the Biology Program at the University of Washington during the 1980s involved putting together Introductory Biology courses that were taught by faculty gleaned from the separate Departments of Biochemistry, Botany, Genetics, and Zoology. It held little joy, with struggles for shares of declining budgets, and the constitutive resistance of faculty to change anything, especially course content and sequence. In contrast I gained great satisfaction from directing the University Honors Program during the 1990s. Small classes of highly able undergrads who were eager to learn and to be challenged made the chore of persuading chairs to release their best faculty for Honors courses a worthwhile if strenuous exercise in diplomacy. I looked forward each year to teach in the Honors core a course that I called Human Ecology, a subject that comes in many flavors, but which I used to impart some general biological literacy to nonmajors, many of whom entered the course wary of science and suspicious of its implications. I hope it left some future leaders among the incipient lawyers, business people, teachers, and legislators with a more rational perspective on the place of Homo sapiens on Planet Earth. At least they know what the Laws of Thermodynamics tell them about sport utility vehicles (SUVs) and compost heaps, and that the gas bubbles in their beer are the same stuff that leaves the SUV tailpipe to warm the globe.

Family

I met my future wife, Ola Shreeves, when we were undergraduates on a student expedition with the Auckland University Field Club to Mayor Island, an offshore island near the coast of the North Island, one of many extinct volcanoes. We shared a strong interest in field ecology, her interests centering on Botany and mine on Zoology. We were engaged in New Zealand and married in Cambridge, England in 1957 where she taught high school biology while I struggled with my thesis work. Summer vacations were spent traveling Europe on a heavily laden Lambretta scooter and midwinter took us to icy Scottish mountains with fellow grad students Hugh Rowell and Thelma Giles. Two boys, Richard and Duncan, were born in Cambridge, the latter only weeks before we left for Cleveland. Two more boys, Marten and Andrew, were born in Cleveland. All of them have accompanied their parents on mountain forays, sometime as willing (more or less) field assistants. One of them, Marten, has followed in my footsteps and is now a mosquito molecular biologist at Muhlenberg College. Richard is immersed in the world of computer programming far beyond my level of comprehension. Duncan is a jet aircraft engineer in Fairbanks who, with his family, lives the Alaska life to the fullest. The youngest, Andrew (Zack) works with a government archives office in Seattle. By the time the boys reached adulthood, our marriage, which had worked pretty well for 30 or so years, was no longer sustainable and in 1987 we divorced. Later, at a Society for Neuroscience meeting, Ruth Nordlander and I met over lunch and in the course of conversation we compared loss by divorce with bereavement by death, her husband, an organic chemist turned Dean, having died of cancer. That led in due course to our marriage in 1999, after which Ruth left her faculty position in the School of Dentistry at Ohio State University, where she worked on spinal cord development in Xenopus, and moved to Seattle where she expected to continue her Xenopus research and we talked of returning to the insect neural development work that had been so fascinating back in Cleveland long ago. The prospect of our sharing research and travel into retirement was however taken from us with the realization that Ruth, then aged 62, had early symptoms of Alzheimer's disease. It is hard to put on paper how our hopes were dashed when that new reality intervened. After several years during which I cared for her at home, Ruth is now in an excellent Adult Family Home that specializes in the care of advanced Alzheimer's victims. Retirement now gives me the opportunity to re-open old files of variously unfinished manuscripts (finding that what was obvious 10 years ago is now a challenge to decipher). I have time to study harpsichord; to travel, especially to enjoy European music festivals with my antipodean brother, Graeme; and to collect more mountain ranges, from Siberia to Tasmania. Carpe diem.

Acknowledgments

I recall Don Kennedy saying at a Snowmass Winter Brain Research Conference many years ago: “When I say I, I mean we and when I say we I mean they.” I have used the same code in this chapter. I thank all the students, graduate and undergraduate, who helped make the science in this chapter and made life in the lab and in the field so full of adventure and fun. I especially thank my enduring colleague John Palka and my long-time loyal technician Su-Wan Chen, for their tolerance of my inability to stay on target, and Mark Meyer whose try-anything spirit propelled much of our work together. A scientist by day and a serious, accomplished graphic artist by night, I could never figure out when Mark slept. Of course, most of the neuroscience could not have been done without some 35 years of support from NIH. I am restricting my thanks here to my partners in neuroscience, but we all know that it would not have been possible without the forbearance and support of family and friends. Finally, thanks to my sister-in-law Roberta Abbey for untangling the computer problems that dogged my work on this chapter.

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Mitchell Glickstein

BORN:

Boston, Massachusetts

July 13, 1931

EDUCATION:

Bucknell University (1948–1949)

University of Chicago, B.A. (1951)

University of Chicago, Ph.D. (1958)

APPOINTMENTS:

Research Fellow, California Institute of Technology (1958)

Research Fellow, Stanford (1960)

University of Washington (1961)

Brown University (1967)

MRC, London, England (1980)

University College London (1987)

Mitch Glickstein began his studies with Garth Thomas and Roger Sperry.

Using mainly neuroanatomical methods, as well as physiology and behavior, he studied the organization of the cortical visual pathways in mammals and found that the lateral geniculate nucleus projects widely beyond what had been thought to be its sole cortical target. Subsequently, he identified projections from visual cortical areas to the pontine nuclei and from visually driven pontine cells to the cerebellum. His work has illuminated the role of the cerebellum in the sensory guidance of movement.

Mitchell Glickstein

Although I began writing this preface on the day after my 73rd birthday, I feel that I must be no more than 30 years old.Well, maybe 40. I have been around for a long time, been to a lot of places, and met many people. I hope that my chapter might be of as much interest to those that read it, as it was to me to write it.

In addition to the usual stuff of autobiography “I was born...,” I want to talk about the schools and universities that I attended and the places that I worked. I want to describe the people—teachers, bosses, colleagues, and students—whom I have been privileged to know. Some were inspirational teachers and remarkable bosses. I hope that I can convey some of my gratitude for the gifts that they gave me.

Universities are, I think, the finest institution that people have conceived and built. What a magnificent idea! A place for scholars to study and teach and for students to learn. I feel lucky to have been attached to one or another university or research institute in four countries for most of my life. I know something of how subjects are taught, academic appointments are made, and students are examined in those places. Although the idea of a university is a magnificent one, all real universities have flaws and limitations. I am sometimes surprised at how little some of my colleagues know about higher education in systems other than their own. My personal history might help others to know a bit more about institutions other than those they grew up with.

I love universities, even though I was often a mediocre student in high school and early years in college, scraping by and sometimes in danger of dropping off the educational ladder. In this brief autobiography, I propose to describe my early education, the teachers, colleagues, and students I have known, and the research I have done. I focus principally on my earlier years, although I still maintain as active an interest in neuroscience and its history as I did when I began.

Early Life

I was born on July 13, 1931 in Roxbury, a lower middle class district in the south of Boston. My neighborhood at the time was almost entirely Jewish. In Boston at the time the ethnic borders were clearly drawn, although they shifted from decade to decade. Roxbury had once been an upper middle class suburb; first of Yankees and then Irish immigrant families on the way up. John F. Kennedy's grandfather, “Honey Fitz” Fitzgerald had once lived in the house next door to the one that I grew up in on Warren Street. That house had since been divided into six flats, my own house into three, with another little apartment tacked on at the back. Roxbury, Dorchester, and Mattapan are three contiguous regions of greater Boston. Jews occupied much of Roxbury. Black people lived to the north and west of my neighborhood. Malcolm X, in his autobiography, described that area of Roxbury as sugar hill, where successful black people lived. Further east, in South Boston, the Irish lived, and remotely, in the North End and in East Boston, the Italians. The Jewish neighborhood stretched from Roxbury, southward through Dorchester, to Mattapan. There was little mixing with the other ethnics, except, of course, for the fights at the borders. Blue Hill Avenue, the artery that ran through all three of the contiguous Jewish districts could have passed for a pre-war Polish ghetto; small kosher butcher shops, a synagogue, and a pushcart whose proprietor sold needles, thread, and shoelaces and called continuously “anything at all, I've got any kind you want.”

My father was the cantor at the large synagogue Mishkan Tefilla (house of prayer). He was a wonderful tenor, recruited by the reasonably well-to-do congregation from his post at the principal Conservative Jewish Synagogue in Budapest where he had grown up. My mother was born in Newark, New Jersey. She had many brothers, whom we visited often. Downstairs in our house lived my father's sister, Aunt Esther, her husband, Uncle Philip, and their two boys Eddie, whom everybody called Sonny, and his brother David. My father's mother, a matriarch, lived downstairs with Aunt Esther, where she continued to dominate the family until she died when I was in the second grade. I had two older sisters: Helaine (whom everybody called Honey), 5 years older than me, and Judy, 4 years older. The only boy, I was loved by my mother and indulged by my sisters.

Early Schooling

From kindergarten to the sixth grade, I was a pupil at the Garrison School. William Lloyd Garrison was a 19th century abolitionist, an early campaigner against slavery. As a byproduct of the almost complete segregation of Boston neighborhoods, the school's pupils were 99% Jewish. There might, on occasion, be one non-Jewish kid in a class of 30 or so, mostly not. The teachers at that time reflected the Boston school district's rules. Spinsters all, they could not be married, although widows were acceptable. There was only one male teacher in the school, but I do not know whether the same rule against marriage applied to him. I did not like school and did rather poorly in all the subjects. Some absurdities of the methods of teaching remain unexplained to me today. We were taught that we must write using the “Palmer method.” The technique involves holding the pen firmly but writing by moving the arm from the shoulder NOT using your fingers. I suspect that maybe through some murky subconscious route, my interest in the motor control of the fingers may have had its root in that absurd technique. As a kid I would note, secretly, that the teachers did not use the Palmer method. They moved their fingers when they wrote. Do as I say, not as I do. I have only the faintest recollection of what was actually taught, but I do recall that the only reasonable question I can remember asking in 6 years of elementary school failed to elicit a sensible reply. The teacher had solemnly explained to us that rain came about because the winds, as they traveled over the ocean, picked up moisture, which later fell over the land as rain. “Why,” I asked, “isn't rain salty?” In retrospect I think that the teacher did not have any idea of why. She dismissed the question as a silly one.

With changes in the people living in the Roxbury/Dorchester neighborhood from predominantly Jewish to predominantly black, the Garrison School reflected that change with a nearly all black set of pupils. Jonathan Kozol later taught at the Garrison School, and it became the subject of his angry book about the deficits in the teaching of black kids by the Boston School Department.

Every day after school for 6 years, I went to the nearby Hebrew school. We had about a half-hour from the time that the Garrison School let out until the Hebrew School began. That half-hour was almost always devoted to playing marbles ("aggies” in our argot) on the sidewalk across the street from the Hebrew School. Most of the play involved bowling aggies along the pavement. The practice was to set up a string of marbles and offer a certain number of marbles if you could hit the string from two paving stone distances away. Alternatively it could be “hit the penny and keep it.” I devised a winning system. I set out a very long string of marbles; “hit the marbles and get two.” Because the probability of hitting the string of aggies was less than .5, I acquired a vast collection of marbles.

Compared to the traditional ghetto cheder, in which boys learned to read the Hebrew alphabet and to recite the prayers, the Hebrew School was modern. Girls as well as boys learned not just to read Hebrew but also grammar and to translate the Bible into English. In Hebrew School, as in the Garrison School, I did not shine as a pupil. I never could settle down at either school to work. Later in the school—I think it was my last year there—we had an exam on translating Second Samuel. (Shmuel Bais in the Ashkenazi Hebrew we learned.) My father, having been told by my teacher of my generally poor performance, encouraged me with a bit of wordplay. “If you get a bad grade on Shmuel Bais, Yitzchak (My father) will be bais, Yiddish for angry. I got one of my only Bs and ran home to tell my father the good news.”

Boston Latin School (Founded 1635)

Boston Latin School is the oldest school in the United States, outdating Harvard College by 1 year. I am not clear on how its selective admission policy worked. Clearly it could have not been related to my performance in elementary school. Maybe there was a test, but I do not recall. My sister Honey had gone to Girl's Latin School. I applied to and was accepted at Boys' Latin. The school lasted from the seventh grade to senior high school, 6 years in all. The incoming students were called the sixth class, and you worked your way through the classes to the first, or graduating class. Many, if not most of the graduates of Boston Latin School went on to Harvard. I failed in the second class, and never graduated.

I squeaked along through the successive years. Even though it was wartime, the teachers were all men, often elderly or strange. In the sixth class (the seventh grade) we had as a homeroom teacher Mr. Sullivan, who also taught us introductory Latin. “You can work out whether a phrase is in the passive voice, by thinking; 'by Mickey mouse' after it.” A kindly, elderly man with silver hair, he was also a fount of great wisdom. “I think it's a good policy in life not to ask questions if you can find out the answer for yourself.”

In the sixth class, and all subsequent classes, I remained a mediocre student. I could, when required, memorize conjugations of verbs or declensions of nouns, usually on the evening before a test. I never shone. Each year three prizes were awarded within each homeroom group: the classical prize (Latin and Greek), the modern prize (French, German, etc.), and the “fidelity prize,” whose function I still do not know. My friend Sumner Kirshner won the fidelity prize one year. I never came close to any prize.

The fourth class (first year of most high schools) was no better. I managed to keep a low profile, to survive, but never to excel. Our Latin teacher that year, Mr. Roche, was known throughout the state. A short man, he delivered a never-ending stream of invective at the class, alternatively reproaching us for sweating (we came to Latin after gym) or wondering why we came at all; “Latin is for the amusement of the rich; you are neither rich nor amused. Why don't you all learn to do something with your hands.” Most of us had an illicit translation of Caesar, the text for the year. Most of us were skilled at simulating a halting translation, not Doherty. He read his translation directly from the book he had bought and duly received a reprimand and a misdemeanor mark. A certain number of misdemeanor marks netted you a censure. Three censures and you were expelled.

Latin school was politically incorrect. What now might be the subject of angry letters to the school by a parent, and perhaps a reprimand to a teacher, was a routine occurrence. In the 10th grade Mr. Brickley, our homeroom teacher and English master called the roll on the first day. “William Stone.” “Here sir.” “William I see that you come from the West End. Tell me William, have you ever seen a tree?” Military drill was a required part of the curriculum. Our drill teacher, called the roll alphabetically. When he got to David Yee, he stopped. “David, does your father have a restaurant?” “No sir.” “He must have a laundry. Pity, I thought I might go and get me some chop suey.”

Sailing

I love boats. My best friend for most of my years at Boston Latin School was Sumner Kirshner. In the summer we would sometimes take the subway and buses to Revere Beach, just north of Boston. On one afternoon when we were 13 years old, we watched a sailboat in the water off the beach, and both of us became infected. That winter we shoveled snow to earn money, keeping our earnings hidden in a glass jar in Sumner's house. In the spring we had saved $60, enough to buy a boat, a Swampscott Dory, which we found in a boatyard at the mouth of the Neponset River just south of Boston. We learned about boats and about sailing by making mistakes, many mistakes. We knew that dry seams between the planks had to be filled. We used Webtex, a roofing compound to fill them. We could figure out no way in which the boom fitted onto the mast and were too embarrassed to ask anyone. We finally overcame our shame and asked. We bought the appropriate fitting, a gooseneck, and managed to put it on the mast. Dory sterns are not easily adapted to fitting a rudder. Our boat had a peculiar arrangement in which a yoke on the rudder was connected to a yoke on the tiller by a pair of wires. The wires would snap easily under tension, which they did routinely. Our ignorance of hardware was matched by our ignorance of sailing. We took along Eddie Stoller on our first sail in the river mouth, just off the boatyard. Eddie shouted, “Head er up.” Not knowing what that meant, we did nothing, and the boat capsized. It almost always capsized, but someone would usually come out and tow us and the boat back to the boatyard's shore. The next year we sold the dory (called Salty) and bought a larger boat with a tiny cabin, a Massachusetts Bayer, built, we were told, by a Mr. Shivrick on Cape Cod. We were not much more skilled at repairs or sailing, but we did manage to get it out of the mouth of the Neponset River, to tie up briefly, unwelcome, at the Dorchester Yacht Club. Boats were my salvation from a complex home life and mediocre school performance.

Dropout Year

My father died when I was 15. A chronic smoker, he died of cancer that probably originated in his lungs but was billed as cancer of the pancreas. I knew he was ill, but I had no idea of how ill. The only death in the family that I had experienced before was that of my grandmother some years earlier, to whom I was not attached. The year after my father died, I fell apart. I was truant most days. Scollay Square in Boston is now sanitized as Government Center. When I was 15 it contained two burlesque houses: the Old Howard and the Gayety. The Old Howard burlesque was a wonderful alternative to school. It began at the same time and ended at about the same time as the school did each day. For the price of admission you could see two movies, a sequence of strippers, a chorus of would-be strippers, several comics, and sometimes a trick dog act. All infinitely more appealing than school. On days that I did not go to the Old Howard, I wandered the length of Atlantic Avenue looking at boats. The fishing boats came in from the Grand Banks of Newfoundland loaded with cod in the hold and covered with ice. My schoolwork reflected my truancy. That year I managed to achieve the lowest grade in some subjects ever recorded in the school. My mother was copeless. My sisters arranged for me to go to Cheshire Academy that summer, where there was a remedial program for the lost year of high school. My sisters came to tell the teachers at Boston Latin that I was going to a private school. The Latin master said; “I think that he should go to reform school.”

Cheshire Academy

Cheshire, Connecticut and Cheshire Academy are located about 14 miles north of New Haven. It was a good choice. The structure was what I needed. Each evening you went to your room and were meant to study until lights out. In the summer I made up the lost year, thanks to being required to stay in my room in the evening. Cheshire Academy was cosmopolitan. About 10% of the class were Latin American boys. A lively lot, we had a good soccer team and some great fellow students. They came from all of Latin America, from Mexico to Argentina. Gus Aguero was from Camaguey in Cuba. He had a sign over his bed that said “Gus, the great.” He was. So were Santiago Flores, Esteban Rock, and Louie Uncein, whom we quickly designated Louie Insane.

Classes were small, and the work was easy. My father had left an insurance policy for educating his children, and there was enough money to support me at Cheshire for another term. After repairing the lost year in the summer term, I stayed on in the fall term, which gave me enough credits for a high school diploma. I graduated midyear first in my class, for the first time an academic success.

For the first months of 1948 I lived at home. I had a job at a soda fountain in the Parkway Pharmacy in Milton. Each morning I took the trolley car as far as Mattapan Square and walked across the bridge up to the drugstore. I learned to make the ice cream sodas and drinks that were asked for, and I learned the beginning of a foreign language. A milkshake in Boston was a pallid thing of syrup and milk mixed and frothed in the mixer. If ice cream, was added, it was called a “frappe.” The Parkway Pharmacy was on one of the main routes from Boston to Providence. Rhode Island people would stop in asking for a cabinet, Rhode Island-speak for frappe.

University

When I graduated from Cheshire Academy I applied to Yale but was not admitted. I also applied to Bucknell University, which shared Lewisburg, Pennsylvania with a fine federal prison. Once again I backslid. I did minimal work. Although I did very little work, my life was enriched by friends I met there and by my ownership of an absurd vehicle. A Chevy of dubious vintage circa 1929, it had a sheet metal body and no top. My sister, Honey, bought it for me in Connecticut where she was a teacher in the Cherry-Lawn School. The car retained its Connecticut plates (registered to one Kenneth O'Connor, whom I never met).

Bucknell's administration basked in their Baptist heritage. “We think Baptists are better than anyone else or we wouldn't BE Baptists!” Except for one bland mixed fraternity, all were segregated. We Jews had our own chapter of Sigma Alpha Mu, “Sammy.” I duly 'pledged' for a few months. A silly business, I soon quit. I still feel guilty about not working at all at Bucknell. Manning Smith taught chemistry. A kindly professor, he gave me my deserved very low grade in chemistry but then turned up to visit me at home on his way through Boston.

Despite my mediocre performance at Bucknell, I was accepted as a transfer student at the University of Chicago.

University of Chicago

My high school friend Sumner Kirshner had been at the University of Chicago for a year. We loaded my old topless Chevy and drove the thousand miles or so to Chicago. For the first few weeks, we boarded in the home of a kindly old German-Jewish couple but soon moved out in search of livelier student life. We found it. I joined Whitman House, a coop. Unusual for its time, Whitman house had both men and women as members. Twenty-five people lived in the house. Ten more, in the food-group, were full members, but only ate there. Most of the people in the house were students, but it was not technically a student cooperative. We members of the house owned it. Whitman was one of four houses, jointly called “United Cooperative Projects.” Whitman House was what I came to Chicago for. The membership was opposite in character to Bucknell's fraternities. Where each fraternity was structured so as to include the narrowest of backgrounds among its members, Whitman house had all sorts of people: every variety of socialist, anarchist, and democrat. We even had one Republican member. At Bucknell, Jews joined the Jewish fraternity. The few black people at Bucknell could join only the one non-nationally affiliated fraternity. Whitman house had black people and white people, Jews, a few practicing Christians, southerners and northerners. Almost everyone was studying something or doing something. One of our members, Mickey Frank, was the cook, and we all ate dinner together. The food was pretty awful, but it did not matter. Mickey was among the most lovable of people, so no one cared much about her standards of cooking. Food was available in the refrigerator for breakfast or lunch; you signed up for what you used. One of our members was the work manager, and jobs rotated among the members. I have never known a more tolerant, interesting, or congenial group of people. Why study when there was so much to talk about, and so many good people to talk to? Evenings we might listen to Marlene Dietrich or Edith Piaf records, drink cheap wine, and drive to the Indiana dunes just before dawn to watch the sunrise. If anyone had some money we might get up a group to go to Granato's, a pizza restaurant west of Halstead where the pizza seemed wonderful and the company great. Although McCarthyism was in full swing around the country and state, Robert Maynard Hutchins, the chancellor of the university, publicly affirmed his policy that “No University of Chicago professor would be dismissed for any offense short of rape or murder committed at high noon with three witnesses.”

Politics was everywhere at Chicago. One of the factions of the U.S. Trotskyist movement was led by Max Schachtman. Schachtman's followers had an active group on the campus. They organized a debate between Max Schachtman and Alexander Kerensky (yes THAT Kerensky; leader of the provisional government in Russia just before the Bolshevik revolution) on the topic; “Was the Bolshevik revolution democratic?” Schachtman; “Yes"; Kerensky “NO!”

The university never noticed if you turned up for class ("discussion groups") so mostly I did not. Each course had a single comprehensive exam at the end of the academic year. In the last few weeks of the academic year I read the assigned material continuously and managed to scrape by, yet again. Two of my friends, Bill Donaho and Dave Stevens, shared a room on Woodlawn Avenue in the house of a lady who kept student boarders as well as 30 or so cats. They gave me their room to study in. Bill moved into my room at the coop. Dave moved onto the beach on the Lake. For 3 weeks I read almost continuously, just about completing all of the years assignment. I passed without distinction but well enough to repeat the process in my second year at Chicago.

The University of Chicago remained a great place to be. I supplemented my modest income from my father's will with a job as a relief night clerk in The East End Park, a local residential hotel. The manager of the hotel stood in some awe of the hotel's bookkeeping. A relative anumerate, he was convinced that it took years of training and experience to cope with hotel bookkeeping (called “transcript"). There were a few residential hotels on the south side of Chicago near the university, and a number of students had jobs as relief night clerks. We taught one another transcript in about an hour or so. Because the manager of the East End Park could not believe that we could know transcript unless we had experience, we gave as a reference Mike Nichols' mother who ran a Hotel in New York State called the Continental House. In addition to doing the day's bookkeeping, the night clerk manned the desk, ran the elevator, and operated the switchboard. All three took very little of the 10 or 12 hours. Some studied. Some held long discussions with other student night clerks on the nature of truth or the correct interpretation of a passage in Dostoyevsky.

Chicago's undergraduate college at the time offered 14 undergraduate courses. When you arrived you took a placement exam. If you passed one of the placement exams, you were exempted from 1 of the 14 courses. I passed seven exams, so I needed to take seven courses for the degree. I took four courses the first year and three the second. The third-year humanities course was offered in a variety of options. I took the Latin option along with three other students. Mr. Clarke, the teacher, was English. A superb teacher, his hobby was translating poetry from English into Latin. It often did very well indeed, translating T.S. Elliot's “When Mr. Apollinax Visited the United States ....” into "Ad civitates foederes dum Apollinax ….”

My second-year exam results were only marginally better than my first-year results, but I passed, and got the curious B.A. that Chicago awarded. “But what did you major in?” It was useless to try to explain.

When I finished the undergraduate course at Chicago, I applied to the psychology department to be a graduate student. I had a somewhat vague interest in becoming a clinical psychologist. I was politely refused. The secretary kindly suggested that my undergraduate grades were not high enough. So I traveled.

Weltreise

I went back to Boston in the fall of 1951 to stay with my mother. I found the very cheapest way to go to Europe: $125 for a ticket on a Panamanianregistered, Greek-owned ship, the Olympia, from Canada to Europe. The ticket was from Quebec to Cherbourg. Most of the passengers were Canadian soldiers, bound for Germany, where they were to relieve some of the British occupying forces.

There were only a very few civilian passengers, so we were treated with great indulgence by the ship. Five meals a day and a small German ship's orchestra playing "Du bist die schönste am Strandkaffee" or a maudlin song about a boy whose mother had just died: "Mamati, schenke mirein Pferdchen; Ein Pferdchen wär mein Paradis ... “ One of the other young people on board was a Cypriot, Andy Georgiades, on his way from McGill to medical school in Paris. Andy had recently seen Ingrid Bergman as a psychiatrist in the movie Spellbound and was planning to be a psychoanalyst. Although my ticket said Cherbourg, the ship decided not to call there, and off-loaded us passengers in Southampton, providing us with a ticket on the night ferry to Le Havre. Six hours in Southampton, and I became an authority on England and all things English.

We left for France late that night. There was a deep thrill in closing the French coast in the morning. I was, at last, in a really foreign place. One of the other passengers taught me how to say “matches” in French, and I asked for “des allumettes” at a kiosk at the train station in Le Havre. Magic. She understood! Andy Georgiades and I roomed together at a pension in Paris while he found a permanent place to live, and I prepared to move on. I was scheduled to meet a friend, Dave Padwa, in Paris. We had arranged three sequential times and locations to meet: 3 PM at the Palais Dorsay on the Quai Dorsay, failing that 9 PM that evening under the Arch of Triumph, and if he was not there under the arch, we were to meet at 3 PM the next afternoon at the American Express office. Dave never showed up. I struck out on my own.

There was an easy camaraderie at the youth hostels and ready companions to travel with. We would hitchhike together or maybe beg a meal on a ship in a harbor. I worked my way first south to Nice and then to Genoa and Naples, then across Italy to Brindisi and a boat to Piraeus, where I arrived on New Year's Day 1952. Aside from the Parthenon, I never saw much of Greece. After 3 days in Athens, I left aboard the Abazia, an Italian passenger liner for Israel.

I spent 2 months in Israel working at various kibbutzim. In one kibbutz, there was an American friend. In another, I fished for the same fish as Jesus' disciples on the Sea of Galilee, with bright lights as lures and nets to catch them. I spent 2 weeks at Urim, a Kibbutz on the edge of the Negev desert in the south of the country. At the time our diet consisted mostly of bread, oranges, and yogurt. At Urim, I opened and shared the contraband tin of ham I had smuggled into the country in contravention of the Israeli laws at that time against importing pork. We ate the ham at a small party one evening.

Israel was a fantastic place at the time. All of us were cousins. I asked a soldier directions at the train station in Haifa. We rode on the same train, and I ended up staying the weekend at his sister's kibbutz.

In February, I learned that there might be a chance for a job on an American ship in Haifa. The chief steward of a C2 freighter had become ill and was flown back to the States. Everyone in the steward's department moved up one, leaving a space at the bottom. I signed on the Pacific Far East Line ship, the Indian Bear, as saloon pantryman. The job involved making salads and coffee and washing the dishes in the officer's mess. Light duty except in the 132°F that we encountered in the Red Sea. The ship loaded chemical fertilizer, 10,000 tons of it in Savona Italy, and then proceeded eastwards briefly stopping in Cyprus, through the Suez Canal, Aden Arabia, Colombo Ceylon, and Singapore. When the ship was safely anchored in the outer harbor at Singapore, I asked (respectfully of course) the beefy-faced British pilot if it was safe to swim off the small platform next to the ship in the harbor or were there sharks. “It's not the sharks you have to worry about, sonny, it's the crocodiles wot eats them.” He may have been joking, but I did not test it. We offloaded the fertilizer in Pusan, Korea, then still a war zone, and proceeded to Yokohama where we loaded dishes and took on as passengers two families of missionaries that had been evicted from China, who were enroute home. In Yokohama, I saw a tiny bit of Japan. On the way back to the States we encountered a typhoon—high winds and very high seas. One of the old able-bodied sailors, a northern Italian who had been shipping out most of his life, attributed the storm to the fact that we were carrying missionaries. “Dey all Jonahs; you always git dis wedder wit dem on board.” We headed east from Yokohama to our homeport in San Francisco. It was thrilling to see a faint glint of gold in the far distance that got larger and larger as we approached the American coast. The ship passed under the Golden Gate Bridge into San Francisco harbor. I had never been west of the Mississippi river before. Here I was in California.

I left the ship with a magnificent $1000 in cash. I bought an old car for a $100 and headed east. The car died in Bakersfield. I carried on by “travel bureau,” an office where you could arrange to pay for a ride with someone driving in your direction, to Amarillo and then by bus to Houston, where my sister Judy was living, and from Houston by bus to Chicago, where I checked back in briefly at my co-op house and then on to New York.

New York

I arrived in New York in June of 1952 and proceeded to settle in. My old Chicago friend, Bill Donaho, and I found a precious rent-controlled flat in the old Spanish Harlem at First Avenue and 107th street, $24 a month with the bathtub in the kitchen. I still had a few hundred dollars left from my payoff on the Indian Bear, and I spent most of it paying for summer courses in math and psychology at NYU. The psychology courses were deeply boring. The math I found wonderful. Ignorant, I started with a course in analytic geometry and then a continuation night school course in calculus. Calculus was marvelous. I did all of the problems in the book. My sister Honey was married and living in nearby Bayonne, New Jersey, pregnant with my niece, Martha. Honey taught Latin in the Bergen School, a small private girl's school in Jersey City, but she was leaving to look after Martha. I was offered her job, teaching Latin and history at $1900 a year. My Latin schoolteachers would have been appalled. I found the job pleasant and easy. I gave an inspired lecture to my eight students in second-year Latin on the passive periphrastic. Miss Wood, the headmistress, had her office next door, and she said she would stop and listen to my history classes because she enjoyed them. So did I. That summer I had a job as a sailing counselor at a camp on Lake George. My duties consisted of sailing all day with campers and teaching about the nature of winds and boats. Evenings, the other sailing counselor and I would take his sailing canoe out, overrigged with a massive mainsail and a cut-down tent for a jib, and fly over Lake George until we capsized.

My grades at NYU were good, and so I reapplied to the University of Chicago graduate school in psychology. This time they accepted me.

Graduate School

Bill Donaho and I divided our joint possessions. He got my half of the furniture. I got full possession of our 1942 Chevrolet station wagon. I arrived in Chicago with a half tank of gas and $2. The universal advertising spot was then the tree in front of Woodworth's Bookstore on 57th Street. There was a job listed as a home-helper with the MacFadyens, who lived in a big house about a mile north of the university. The main responsibility was to ferry their adolescent son to school in the morning. They were a delightful couple; Mrs. MacFadyen taught piano at a local college. They let me come down to listen in the evenings when she played chamber music. My other job was as a night emergency worker with the Red Cross. My main responsibilities were to arrange emergency leave for servicemen or to alert the disaster team when there was a fire. The Red Cross job paid enough so that I could afford to rent a place of my own and I left the MacFadyens in good graces. The Red Cross job lasted for 5 years. I was sacked in my last year of graduate school for sleeping through a five-alarm fire—a warehouse, no one was injured or needed shelter. I was offered the chance to shift to the day work, which I politely declined.

First Year in Graduate School; The Core Curriculum; Roger Sperry; Austin Riesen and Ekhard Hess

Chicago's psychology department had a fixed course in the first year, centered on a Proseminar in General Psychology. The proseminar dealt with all experimental psychology. At the end of the academic year we took prelims. You could pass the prelim exams at a doctoral level or a master's level, or you could fail. In the latter two cases, it might be with or without permission to retake the examination.

For the second time in my life I worked very hard at my studies. I attended and took notes in every class. I read and summarized all of the assigned readings in my notes. Three people lectured us in the first part of the proseminar: Austin Riesen, Eckhard Hess, and Roger Sperry. All three taught us about vision. We were ignorant, but we could tell that all three could not be right. Riesen spoke about his dark-raised chimps, Snark and Alfalfa who, he said, slowly learned to see after being raised for several months in complete darkness. Vision, he argued, must be learned. Hess told us about his experiments on prism displacement in chicks. Newborn chicks were fitted with a rubber mask containing laterally shifting prisms. Over the first 3 days of their little lives, the chicks pecked more and more accurately at exactly the wrong spot to pick up a single bit of grain. Vision, Hess argued is innate. Sperry told us about his experiments on rerouting nerves. The nervous system, Sperry argued, is fixed, with little chance for its functions to be modified. He had a memorable clinical example of a woman who had a nerve that normally controls salivation shifted to a tear duct. She wept when she saw an apple.

We students were ignorant, but we recognized that at least one of our teachers must be wrong. A similar challenge was presented by the “transposition experiment.” Rats were trained to choose one of two triangles; one was 2 cm high and the other 4 cm. When tested with a pair of triangles 4 and 8 cm in height, they chose the taller, 8-cm triangle. They had learned a relationship: “the larger triangle” not an absolute size. The only theory that seemed to offer an explanation for the transposition experiment and for Riesen's data was in a book recently published by Donald Hebb, The Organization of Behavior. In the argument between nativism and empiricism in vision, empiricism was saved by Hebb. I was a Hebbian for about a year. The following year I began working at Michael Reese Hospital where Jack Orbach, a physiological psychologist, worked. Jack had been Karl Lashley's last post doc at the Yerkes lab, when it was still in Jacksonville, Florida. Orbach also admired Hebb, but he gave me a 100-page monograph by Gordon Walls to read: The Problem of Visual Direction (Walls, 1951). I became, and remain, a nativist.

I took the readings and the concepts we were taught in the first year of the psychology course seriously. Along with my classmates, I read Hull and Spence, and I found them underwhelming. Learning theories that taught me little or nothing about learning. I was particularly put off by reading Miller and Dollard—an attempt to blend Freudian ideas with learning theories, to the benefit, I thought, of neither. We were assigned, and I read, 300 pages of Kurt Koffka's book on the principles of Gestalt psychology. I took 30 pages of notes, but I also found many of Koffka's principles hard to accept. Koffka's notion of “good gestalt” seemed especially arbitrary when it was used to account for the appearance of the constellations. The Gestalt psychologist had put forward vague ideas about a role for electrical fields in the functions of the cerebral cortex. Sperry had directly challenged the postulated electrical fields as the basis for form perception. Sperry inserted gold, which would have shorted them; mica, which would have insulated them; or cross hatching, which would have interrupted short cortico-cortical connections. None of these assaults on the visual cortex abolished form vision.

We took prelims in the late spring of the first year of graduate school—29 of us. There was a fine tradition of older students serving drinks, coffee, etc. while you took the exams. I had worked hard, and my notes and memory were both intact, so I did not worry. The day before the prelims I tried to bring one of my fellow students over to Billings Hospital with me to hear a lecture on the adrenal cortex. He refused to leave the library; an unfortunate choice, because one of the questions was on the material of the lecture. I was one of the fortunate nine students that passed at the doctoral level. The department made it clear that there would be no more hassle. Take whatever courses you choose. Write the dissertation you wish to, and you will get a Ph.D. degree.

Second-Year Graduate Student

Having passed the prelims, I could carry on at Chicago; I planned to be a clinical psychologist. The clinical psychologists in the department organized their own second-year program. Hedda Bolgar taught us personality theory, with a serious amount of Sigmund Freud. Soskin taught us Jung. We had courses in Rorschach testing from Sam Beck and a course on the TAT test with Bill Henry. Sam Beck gave me a job as a research assistant; an easy enough task, writing short precis of the literature on schizophrenia. My high school German was sufficient for the task. I also helped by translating one chapter of Ewald Bohm's text on the Rorschach test. I translated the chapter on “The Special Responses” in which I learned that “white shock,” or a slowed response to a white space on the card, always meant fear of the female genitalia—maybe. I also started seeing two clients in Carl Rogers' counseling center, a responsibility I liked. Forget the theory. In one of my two clients, I was convinced that the opportunity to talk to a neutral, but interested and sympathetic person, was helpful.

By now I was convinced that I did not want to be a clinical psychologist. I liked the work, but I wanted to be in a field that made orderly progress—one in which the small grain of sand I might add to the pile was based on what had gone before and would be of interest, and perhaps even of importance, for those that followed. My clinical psychology teachers were intelligent and insightful, but there seemed little chance that knowledge would become cumulative.

Third- and Fourth-Year Graduate School

Michael Reese Hospital was about half way between the loop and the University of Chicago. It had attached to it a relatively new Institute of Psychiatric and Psychosomatic medicine, headed by Dr. Roy Grinker. Grinker came from an old German Jewish family in Chicago. His father, Roy Grinker Sr., had been a neurologist. As a young physician, Roy Jr. was a neurological wunderkind. He wrote an excellent textbook of neurology, rare for someone so young. The medical school at the University of Chicago had a checkered history in hiring a head of psychiatry. The hot area of the time was psychoanalysis. They would hire a psychoanalyst to head the department, but he would soon leave, feeling undervalued by the real doctors. The higher-ups had a great plan. Send Roy Jr., a real doctor, to Vienna for analysis by Freud, and bring him back as Chairman of the Psychiatry Department. They sent him. He went and had a fast psychoanalysis with the master himself. Grinker came back to Chicago, but he too soon left the university to found his own empire attached to Michael Reese Hospital. As a psychiatrist and director of the Institute at Michael Reese in the 1950s, there was still much of the rigor of a neurologist in Dr. Grinker. He wished to study psychiatric problems in a rigorous way and set out to study anxiety. Patients would spend a period of time in a testing room, where a sequence of biochemical and psychological procedures and interviews would be carried out. Heart rate and blood pressure were monitored continuously. Heart rate was measured by electrocardiogram (EKG) written onto a Grass penwriter. My job in those precomputer days was counting heartbeats. The plan of the experiments seemed straightforward—several procedures, each preceded and followed by a rest period, then a stressful interview with Dr. Grinker, designed to elicit anxiety, followed by a repeat of the procedures prior to the interview. Did heart rate go up after the interview?

I had been studying and was obsessed at the time with factor analysis. Because L.L. Thurstone had recently left Chicago, Lyle Jones taught the factor analysis course. In the first lectures, Lyle Jones introduced us to two unsolved problems: how many factors to extract from a correlation matrix, and how should the factors be rotated. In the precomputer time, we did our factor analyses using a desk calculator. Because it was relatively simple for hand calculation, the major technique we used was Thurstone's centroid method for factoring. We also were introduced to Thurstone's semiintuitive criterion for rotation: to “simple structure.” I began immediately trying to develop a more rigorous mathematical solution for both problems. I developed some possible solutions, including significance testing of the factors. I also developed a unique solution for the worst rotation, which I thought would be 45 degrees away from the best rotational solution; I could rotate a solution to the least simple structure. I never published either, but I applied factor analysis to the data I had collected at Michael Reese. Factor analysis was not known by my senior colleagues, so I developed a teaching device to illustrate its use. Suppose you had a simple test of measuring a patient's heart rate. You could, for example, ask the patient to exercise briefly by stepping up and down on a chair and measure heart rate before and after the exercise. If you averaged the data from 100 subjects you would doubtless find the trivial result that heart rate on average goes up significantly with exercise. But suppose that a subset of the 100 subjects, say 10, had a paradoxical decrease in heart rate. The data would be lost in the group measurement. A matrix of the correlations between all pairs of subjects would preserve the average data but also allow you to identify the aberrant response. I applied this logic to the data I had collected and showed that the Michael Reese patients could be divided easily into two groups with grossly different patterns of response. The work on heart rate and blood pressure formed the basis for my doctoral thesis and was published along with the other members of the Michael Reese group as coauthors in the Archives of Neurology and Psychiatry—my first publication (Glickstein et al., 1957).

In my last year in graduate school I was drifting away from factor analysis, but I remained painfully aware of the pitfalls and limitations of the method. My last effort in clinical psychology was a negative one. J. Wittenborn (1950) had published a factor analysis of Rorschach scoring categories. The Rorschach Test is open-ended. You can say as much or as little as you choose in response to each card, which seriously influences the factor solution. Wittenborn had published the original correlation matrix in his paper, so it was possible to use partial correlation to evaluate the influence of this open-ended aspect of the test. I showed that the number of responses accounted for almost all of the variance in the test. Removing this factor revealed another statistical artifact of the factor analysis. Response categories are mutually exclusive. If you give, for example, a “whole” response, you cannot give a “detail” response. In the limiting case of a true-false test, there must be a correlation of minus one of true with false answers. The reduced matrix of partial correlations reflected the imposed negative correlation between categories. There seemed little more in the data than randomness. Brash, I published my analysis as a “Note on Wittenborn's Factor Analysis of Rorschach Scoring Categories” (Glickstein, 1959).

In my fourth year in graduate school I spent two nights a week in the lab of Nathaniel Kleitman. Eugene Aserinsky and Kleitman (1953) had discovered and described the phenomenon of rapid eye movement sleep (REM) and its association with dreaming. Bill Dement was both a medical and graduate student in physiology at the time, continuing the sleep research. I was happy to work there. I would typically sleep in the lab one night as a subject or run the experiment on another night with Bill Dement or some other student as sleeper. Good fun, we studied the possible effect on the electroencephalogram (EEG) of hypnotic suggestion on the perceived brightness of light. In other studies, we tried to influence dreams by external stimuli. Mostly we could not, but in a few cases we could clearly do so. In one subject we played a series of low, bass notes from a sound generator at an irregular interval. The student dreamed that he was in his cousin's house, learning guitar. His cousin would play a low bass and interleave it with high melodies between bass cords. In another experiment we sprayed the room during REM sleep with a cheap perfume we had bought that afternoon in Steinway's drugstore. The subject dreamt that he was a male prostitute, waiting for his next client.

Chicago seemed a place where everybody made an important discovery. Eugene Aserinsky had discovered REM sleep; Ronnie Myers, a medical and Ph.D. student working with Roger Sperry, had shown that it is possible to establish two nonconflicting memory traces in the two hemispheres. Myers cut the corpus callosum and optic chiasm of cats in the midline. He taught the cats to choose one of two visual patterns for a food reward with one eye masked. When tested using the opposite eye, the animals were naive. They could easily learn to choose the formerly negative cue. Cats with the corpus callosum cut, and with visual information restricted to one or the other hemisphere, had no difficulty maintaining two opposite memory traces. Depending on which eye was open, the cat would choose the cue that had been learned on that side of the brain. With Aserinsky and Myers as examples, it seemed that every graduate student at the University of Chicago had made a fundamental discovery. I was jealous.

Final Year of Graduate School

By now I was convinced that the answer to any of the questions I had lay in the study of the brain. I knew very little about the brain, so I asked three people for a job so that I could learn more about it. K.L. Chow, Jim Toman at Michael Reese Hospital, and Garth Thomas, who had been one of my teachers at the University of Chicago and was now working in the basement labs at the Illinois Neuropsychiatric Institute (INI). My job as a research assistant for Garth Thomas was mainly to train rats in a shuttlebox avoidance task, testing the effect of hippocampal lesions on acquisition and retention. We ran many subjects. My other jobs were to assist in stereotaxic surgery and to perfuse the animals after testing was completed. I also removed the perfused brains for sectioning. The INI lab had several active research groups working on various aspects of neuroscience. Ralph Gerard and Gilbert Ling had worked there in the past and had developed the use of microelectrodes for single unit recording.

Garth Thomas was a splendid boss. He was newly converted from psychophysics to neuroscience, and he shared his knowledge and his enthusiasm with me. When the smelt run on Lake Michigan was in full force, I would go with Garth to the lakeshore in the evening with the appropriate net, a small alcohol stove, and a bottle of whiskey to greet the incoming fish that arrived in the millions.

Two of my acquaintances from the university were medical interns working upstairs at INI. We jointly decided to study the effect of temperature on the EEG. We reckoned that the natural choice for a subject for our experiment was a cold-blooded animal, so we bought a small alligator for the purpose. We discovered that alligators have a low threshold for barbiturates. When our first subject died from an overdose, we abandoned the project.

I had the use of an EEG. I collaborated with another group who wanted to study electrical activity in mealworms. One of that group had devised a cunning plastic holder for the mealworm. A pair of metal of plates was connected to lead wires and was adjustable on either side. Fantastic. We placed a mealworm in the restraining apparatus and recorded low-voltage activity, which slowed when we cooled the mealworm. Then someone suggested a control. Take out the mealworm. The electrical activity persisted, so we abandoned that project.

Others in the lab included Dr. Meduna who had previously discovered Metrazol shock therapy for psychiatric patients. Meduna's reasoning had been a bit fallacious. He said that although he had seen many epileptic patients and many schizophrenics he never had seen a patient suffering from both. Epilepsy and schizophrenia, he suggested, are the opposite of one another. The solution would then be to give a schizophrenic an epileptic fit. In Meduna's first attempts, he produced the fit using the convulsant drug, Metrazol. The technique of producing seizures was later modified by Cerletti and Bini in Rome who used electrical stimulation to produce the seizure. Meduna's original thinking was a bit flawed. If the random probability of a person being epileptic is, say 1 in 100, and the random probability of someone being schizophrenic were also 1 in 100, and if the two conditions are independent of one another, the joint probability would be 1 in 10,000. No matter. Meduna was now studying the effects of inhaled CO₂ on psychiatric patients.

A good colleague in the lab was K. Koketsu who had worked previously with John Eccles in Australia and was actively studying spinal reflexes with another Japanese colleague, S. Nishi. Working with them was a very pretty technician called Yoko. Koketsu taught me and the others in the lab how to hold and use chopsticks. Another one of the senior colleagues in the lab was Alexander Geiger. Geiger was from an earlier era when physiology and biochemistry were still united. He had developed a preparation for studying brain metabolism by isolating the cerebral circulation. Geiger made replacement blood from ox blood, substituting the normal circulation with his made-up solution. He could then measure the concentration of substances going into the cerebral circulation and compare it to that in the venous outflow. Active neurons use more oxygen and absorb more glucose. Before the development of the 2-deoxyglucose technique for studying glucose uptake, Geiger had the idea to use tritiated glucose in order to study active sites in the brain. I collaborated by making test rats anxious, fearing the onset of a foot shock. The first cases that we looked at seemed promising. The hippocampus and entire limbic system were lit up in the very first rats we tested but so were the controls. Geiger was one step away from the optimal method of using a form of glucose that would remain in the cell. Perhaps a better-controlled behavioral study might have shown up the difference between rats in our study.

Geiger's method had another use for me. There was at the time some speculation that the EEG might have nothing to do with neuronal activity but was simply a mechanical artifact, a sort of jiggling of the brain pulsed by a flood of blood and shaking within its cerebrospinal fluid (CSF) bath. The perfused brain was an easy way to evaluate the idea that the EEG is a mechanical artefact, because the pump that perfused the brain was a smooth one. The EEG appeared to be entirely normal.

By now I was committed to a career in neuroscience. I had not completed my qualifications as a clinical psychologist, but I was encouraged by Howard Hunt, the Chairman of the Psychology Department at Chicago, to accept a clinical psychology internship at Billings Hospital: “We would very much like to have one of our people in that internship.” I agreed to a one-third-time internship and rather liked it, although I was not deflected from my plans to be study the brain. One person that I was asked to evaluate was a middle-aged lady of rather limited intellect. The woman had been living with her brother's family. Could she survive on her own if a caretaker were to share a flat with her? Was she just of limited intellect, or was she also psychotic? The tests convinced me that she was just mentally slow, not psychiatrically ill. In a sentence completion test I began “I want to know ... “; she said “What's news?” As part of the intelligence test, I asked her “Why should people pay taxes?” She said, “I don't know; my brother takes care of all that.”

I was faced with the good question of where to go to continue to study the brain. One possibility that Howard Hunt suggested was to apply to work at National Institute of Health (NIH) with Mort Mishkin and Hal Rosvold. Roger Sperry had moved to Cal Tech, where he was now the Hixson Professor of Psychobiology. I remembered Sperry's lectures and wrote to him. He agreed to have me.

Cal Tech

Cal Tech was a marvelous choice. When I arrived I knew very little about the brain but was eager to learn. I also knew little or nothing about what was going on in Sperry's lab. Sperry himself was in a sanitarium when I arrived, recovering from a bout of tuberculosis. Norma Sperry, his wife, relayed messages from Roger to us in the lab. I had some vague acquaintance with Ronnie Myers' thesis research at Chicago, but I can clearly remember my own confusion when Norma kept talking about “split brains.” I had no understanding of what she was talking about.

Sperry's lab had attracted some excellent people, and Cal Tech was a lively place for biology. When I arrived, Colwyn Trevarthen and Chuck Hamilton were both graduate students with Sperry. Harbans Arora was a post doc. That summer Mike Gazzaniga, whose parents lived in the Los Angeles area, worked in the lab between his junior and senior years at Dartmouth. He became a lifelong friend. Gilbert French had left recently and Al Schrier was just leaving for Brown. Later, Ted Voneida came after working with Marcus Singer and Walle Nauta. The technicians were equally excellent. Lois MacBird trained monkeys, as did the animal caretaker, Mike Saxlund. Mike confided in me that he would sing while training the animals and that they liked it. I am sure they did. Others came while I was there. Domenica (Nica) Attardi arrived in Pasadena with her husband and 8-year-old son, Luigi ("My name is Louie!"). Her husband had come to work in the virus lab of Renato Dulbecco. Nica wanted a part-time position during the hours that her son was in school. At the same time as Nica appeared, Sperry's histology technician, Octavia Chin, apologized to him that despite her best efforts she could not get the regenerating fibers to stain the same color as the normal fibers. Sperry put the two people together and the result was a beautiful study of regeneration of the fish optic nerve (Attardi and Sperry, 1962). Nica made regional ablations in the fish retina and cut the optic nerve. She showed that the regenerating fibers came to three successive choice points. All of the optic fibers decussate, but as they approached the tectum, half proceeded medial to it, half lateral. As they traveled along the edge of the tectum they would choose the appropriate point to turn along its surface. There was a third choice point when they stopped at a point on the surface of the tectum to synapse.

The lab had two foci. One was the study of nerve regeneration, a continuation of Sperry's brilliant earlier work. The other was on the functions of the corpus callosum. I knew very little about either. I spent the first weeks in the lab looking for an appropriate source to help me to learn about the callosum. I found it in Bremer's Physiologie et Pathologie du Corps Calleux (1956). That was the good news. The bad news was that it was in French. I bought a dictionary and plodded through it, writing out all 50 pages in English—a good move. At the end, I knew a lot more about the callosum, and I could read French.

Ronnie Myer's discovery of the role of the corpus callosum in interhemispheric transfer had been made while he was a graduate student with Sperry at Chicago. He had continued those studies with Sperry at Cal Tech for a short while before being called up in the doctors' draft, where he was assigned to Walter Reed Hospital. There was more to do. Sperry suggested that I test the generality of the failure of interhemispheric transfer in callosum-sectioned animals by studying tactile learning. I trained monkeys to reach out of a training box and feel two objects that they could not see, placed over wells in front of the box. My monkeys readily learned to displace one of two three-dimensional objects for a food reward; for example, a high vs. a low cube or a cone vs. a pyramid. In order to rule out a trivial deficit caused by a brain lesion, I arranged the testing situation so that it was an advantage to have no corpus callosum. I would train the monkey to use one hand to select one of two paired objects. When I tested the second hand, I reversed the positive cue. If the cone had been positive with the first hand, the pyramid was now correct. Normal monkeys start at 0% correct with the second hand, because they know the problem. Callosum-sectioned monkeys start at 50% correct. When the animals were retrained using the second hand, I tested the original hand with the original values. The cone would again be correct. Now there was an even clearer advantage in not having the callosum. The normal monkey again performed at 0% correct. The callosum-sectioned monkey remembered the training on the original hand and remained at the criterion level of performance (Glickstein and Sperry, 1960).

Although the knowledge of which of two stimuli was correct did not transfer, the habit of testing did. The callosum-sectioned monkey did not know which of the two objects was correct, but he did know that there were two objects. He would reach out to feel the two from the outset, when first using his untrained arm and hand. I believe that I later found an explanation for this puzzling form of interhemispheric transfer, when I began to study the anatomical connections of the cerebellum.

I did another experiment with Sperry and Harbans Arora in my second year at Cal Tech (Glickstein et al., 1963). Since Jacobsen's work it was known that monkeys with bilateral lesions of the dorsolateral prefrontal cortex are profoundly impaired in performing tasks involving delayed response or delayed alternation. Both tasks require immediate memory. Monkeys with unilateral lesions are relatively unimpaired. In order to analyze the anatomical circuits involved, I followed a procedure that Mort Mishkin had devised to study functional connections between the striate and the inferotemporal cortex. I made a unilateral lesion of the frontal cortex combined with a section of the ipsilateral or contralateral optic tract. Vision was now restricted to one hemisphere, with the intact prefrontal cortex either on the same or opposite side of the brain. When I cut the corpus callosum in animals in which the two areas were on opposite sides of the brain, they were impaired in performing the delayed response task.

Sperry's lab was enriched by people coming to learn techniques or collaborate in experiments. I remember Michael Gaze coming in the summer after I arrived. He later told me that he had been alerted to Sperry's work by David Whitteridge, then professor of Physiology at Edinburgh, who later became my close friend.

Although he had a natural tremor, Sperry was a skilled surgeon. His model for experimental surgery was not human surgery but zoological dissection. He sterilized the dissecting table. He made irregular-shaped wooden blocks that he would wrap in a sterile towel and weighted inside with lead to stabilize his wrists. He routinely operated using a dissecting microscope. Sperry was an excellent lab director. He was completely supportive of any research plans of mine or of others in the lab. He was, however, often angry about any claims for priority made by his students after they left the lab.

Cal Tech's biology department had no assistant or associate professors at the time, only full professors. The biology lab had been founded by the great geneticist Thomas Hunt Morgan, originally from Columbia. Among the full professors there were nine geneticists, several of whom, like Sperry, went on to win the Nobel Prize. Sperry was one of three neuroscientist professors when I arrived. The other two were Anthony Van Harreveld and Kaas Wiersma. Van Harreveld was a kind and generous man. At the time he was interested in the mechanism of spreading depression and the distribution of fluid and ions in the brain. Controversial at the time, Van Harreveld questioned the conclusions of many electron microscopists on the amount of intercellular space in brain. Van Harreveld was most helpful to younger colleagues. I knew very little anatomy when I arrived. He lent me a copy of Winkler and Potter's beautiful 1912 Atlas of the Cat Brain, a fixed cat brain, and a knife. At his suggestion, I made cuts roughly in the plane of the atlas and studied the structures I could see. Van Harreveld had three postdoctoral students working with him when I arrived. Johannes Schade had been at the Brain Research Institute in the Netherlands and was studying spreading depression. Joe Bogen was training as a neurosurgeon, that year working in the lab with Van Harreveld studying the pharmacology of an awful drug called bulbocapnine. Nico Spinelli was also with Van Harreveld, interested in the physiology of spinal reflexes. An imaginative electronic designer, Nico made his own stimulator, which had dozens of switches and dials. None of the dials or switches had labels, but the apparatus worked, and it did what he wanted it to do.

Wiersma was the third neuroscience professor. Wiersma studied invertebrates, particularly crayfish. A pioneer in invertebrate physiology, Wiersma developed some of the concepts that were later taken up and elaborated by others in the field. Eric Kandel credits Wiersma as being the pioneer.

The introductory biology course at Cal Tech was designed to be a showpiece. Cal Tech undergraduates were among the most highly selected high school kids of any institution in the United States. Most came planning to study physics or engineering. The introductory biology course was meant to convince these very bright young people that biology is as exciting and rewarding as any science. Most of the lectures were given by the full professors. Sperry never really liked lecturing and designated me to deal with his part of the course. There was an informal popularity contest among the lecturers for student ratings. The first year I came second after James Bonner, an outstanding and articulate plant geneticist. The second year I had the highest student ratings for my lectures on the brain. The students were not passive. I used a lot of slides in my lectures. One of their clever tricks was to invert the optics of the projector, so that the image was minified, a tiny postage stamp, rather than a full screen.

Cal Tech's geneticists were world leaders. George Beadle was abroad the first year that I came. While at Oxford, Beadle learned that he had been awarded the Nobel Prize for his studies of yeast genetics. The graduate students promptly sent him a congratulatory telegram in DNA code.

When I arrived at Cal Tech I was told that I must give a talk; a Cal Tech tradition for new people. I felt that I knew nothing of any interest, so I declined. But further encouraged, I agreed to speak on REM sleep, then still recently discovered. I began my talk by drawing a 2 x 2 table on the blackboard to illustrate the probability of people reporting a dream while their eyes were moving, as opposed to when their eyes were still. I had barely finished putting the table on the board when Max Delbriick got up to say; “Oh no that's wrong!” I said, “No, it's right.” He thought a bit, and said “Oh yes, that's right."—lively seminars always.

Cal Tech attracted scientific visitors. In an early thaw with Eastern Europe, Jan Bures came and spoke. A charming and most intelligent visitor, I liked him enormously, enough to discuss the nature of politics in his country. At the time Jan was a member of the party in Czechoslovakia. Somewhat drunk in the faculty club that evening, I said, sympathetically, that Czechoslovakia had been betrayed in 1938. He agreed and told me that at the height of the German occupation a large number of Czech citizens were in forced labor or concentration camps. I sympathized but asked him, “How many are there now?” He said, “None; but it is unsafe to criticize my government or your government.”

The next day when Jan Bures came by the lab again, he admired some of the wire that Colwyn Trevarthen and I had bought to record EEGs. Very thin and flexible, 12 of the wires would fit into a quarter-inch laboratory tube. “Take one,” I told Bures. “I must pay.” “No just take one and put it in your luggage.” Jan said, “I must choose the red wire, no?” Some years later, after the Russian invasion of his country Bures reminded me of the incident with the wire some years earlier and said, “If you were to test me again with the wires, I'm not sure which color I would take.”

Sperry did not suffer fools gladly—two occasions come to mind. One was a talk by a young woman who had an elaborate, almost incomprehensible, learning-theory approach to avoidance training. Sperry snorted and said “Oh I could do it much better than that. All you have to do is throw a rock at a cat. He will avoid you forever.” Another time a visitor came with a theory of how the cortex works. Tiny magnetic domains circle around continuously and constitute the basic mechanism of cortical function. I kept looking at Sperry, whose previous work ruled out any such mechanism. He passed me a note, saying, “Why are you looking at me?” Someone asked, “What would be the consequence of inserting conductors or insulators into cortex?", experiments Sperry had done and published. “Oh that would be equivalent to decortication!” As we left the seminar room Sperry said quietly “I wonder if he's crazy.”

Although we had speakers from time to time, Cal Tech did not have as active a neuroscience seminar series as UCLA, so we would arrange to invite many of the UCLA lecturers to speak at Cal Tech. I had the dubious joy of being in charge of the seminar one year, snagging people from the UCLA list. The Long Beach lab where I picked up the speakers was about 50 miles from Pasadena, much of the driving on city streets. Returning them to their motel in the evening I clocked 200 miles of city driving, but I had a good chance to ask questions of the speaker and learn more neuroscience.

On the occasions when we went to UCLA to hear a seminar, Joe Bogen, Nico Spinnelli, Colwyn Trevarthen, and I might stop at Taix, a cheap country-style French restaurant on our way. Jim Olds' pleasure centers were new, and the surgeons were not far behind, stimulating the human brainstem on their way to making a basal ganglia lesion for Parkinson patients. They would stimulate at a subcortical site and ask the patient how it felt. One surgeon reported that his patient said, “I feel great pleasure; it is 'appiness; I feel 'appy on one side of my body.”

The Los Angeles coast is not a particularly rich one for sailing, but Catalina Island was a favored goal for weekend trips. I remember a fine voyage on a Chinese junk with Jennifer Buchwald, Carlos Guzman, and Henry Lesse.

Stanford

I had spent 2 years, from 1958 to 1960, with Sperry at Cal Tech. I was eager to learn new techniques and to work in a new lab. I wrote to Karl Pribram at Stanford and arranged to work there in the following year, 1960 to 1961. Karl was based in the psychiatry department of the Stanford Medical School. Jean Koepke, an Iowa Ph.D., Jim Dewson, and Tony Deutsch were attached to Pribram's lab, as was Muriel Baghaw, a pediatrician. I remain grateful to Karl for teaching me surgery and to Miriam for teaching me how to look after a monkey after surgery. Pribram was an excellent surgery teacher. At first, I would do the initial incision and final closure in an operation. The next step was to do the first two procedures, and the final two closures, and so on, until I was doing the entire operation on my own. Sometimes we would operate on two monkeys simultaneously, with Karl at one end of the surgical table and with me at the other. If I wanted to ask a question, or needed help, he was available and gowned. Karl also knew and taught the thalamus. At the time the standard work on the monkey thalamus was Earl Walker's book The Primate Thalamus (1938). Karl would hold seminars in the lab or in his house, teaching major thalamic groups and their subdivisions. I also learned from Karl how to do careful reconstructions of a cortical lesion and the associated retrograde degeneration in the thalamus.

While at Stanford one of my old teachers, K.L. Chow came to join the neurology department. It was good to see him again. He took me and my wife to a local Chinese restaurant, saying that it served the best Peking duck he had eaten since he left Peking. Sadly, it had gone down from an A minus to a B plus on the night we ate there.

Seattle

It was time to look for a real job. I turned up three possibilities. One was to join one of the giant soft-money pyramids at Harvard Medical School, a second was to become an Assistant Professor of Psychology at Wesleyan University in Connecticut, and the third possibility was a joint appointment in physiology and psychology at Seattle. A happy choice, I opted for Seattle. The job was supported by a training grant held jointly by the two departments for a joint Ph.D. in physiology and psychology. The major force behind the plan was Theodore “Ted” Ruch, who had been Chairman of the Physiology Department at Seattle since the medical school was founded about 10 years earlier. Ruch had brought with him from Yale several of the promising young people to join him in the new department. Under Ruch's leadership it was generally rated as one of the best in the United States. Professor Ruch's brother, Floyd Ruch, was a psychologist, which may have influenced T.C. Ruch's view that the two sources of outstanding young physiologists were from psychology and physics, hence his enthusiasm for the joint program. Seattle is an attractive city, and the job was an attractive job. There were many applicants narrowed down to a short list of three. I have no illusions about the reason for my appointment. It seemed from late informal discussion after I was appointed that the two departments had opposite ratings of the three short-listed candidates. I was offered the job because I was not unacceptable to either department.

My responsibilities were to teach in both departments and to look after the students who were enrolled for the joint Ph.D. degree—a pleasure. The five students who were in place when I arrived were Ron Adkins, Harry Carlisle, Chris Davis, Joe Miller, and Gene Taylor. The physiology department also had a grant for training post docs, many from psychology, to learn neurophysiology. In the first years I was at Seattle, the post docs were Bill Stebbins, Bob Reynolds, Dwight Sutton, and later Dick King. These were among the best years of my academic life. Each of us knew something different. Each of us came to Seattle with a strong wish to learn neurophysiology. We all got on well. Daily informal seminars in the bull pen knocking Skinner out of Bill Stebbins and a residual Freudianism out of me. The following year Karen (Greene) arrived from Brown University as a graduate student, and the next year her fiance, later her husband, Mark Berkley joined the department as a post doc. Mark became one of my closest friends.

Seattle was a magnificent opportunity but paradoxically limiting. While at Cal Tech and Stanford I had haunted electronic surplus stores and built a most rudimentary physiological lab: an electronic stimulator, a restored old amplifier, and an oscilloscope from a Radio Shack kit. My aim was to do physiology as a hobby, perhaps studying the giant nerve cord of earthworms. My enthusiasm for physiology was dampened by the offer of state of the art equipment, with professional level stimulators, amplifiers, oscilloscopes, and a Grass camera. I stayed with my behavioral and, later, anatomical experiments.

I had only minimal knowledge of anatomy when I arrived. Seattle and its people taught me much more. Ide la Bossiere was a superb technician in the histology lab. She had been taught to do degeneration staining by Orville Smith, who was a fellow Assistant Professor. Orville taught me how to read Ide's Nauta-stained sections. My first attempt with the method was controversial. I had been aware from the old German literature that there might be a crossed thalamo-cortical pathway. Although thalamic projections were thought to be strictly to the ipsilateral cortex, there was some behavioral evidence that there might be a weak projection from the thalamus to the contralateral side of the brain by way of the corpus callosum. The existence of such a pathway would bear on the anatomical basis of interhemispheric transfer. My first attempt at using degeneration staining was to look for a crossed geniculo-cortical pathway. With Joe Miller who had become my graduate student, I made lesions in the geniculate of cats, waited an appropriate length of time, and with the help of Orville Smith, studied the distribution of degenerated fibers in the cerebral cortex. The results were surprising. Most striking, was the very widespread distribution of geniculo-cortical fibers on the ipsilateral side of the brain. We also found degenerating terminals at the border of Vl and V2 on the contralateral cortex. We published a note in Science on “The Lateral Geniculate Nucleus and Cerebral Cortex; Evidence for a Crossed Pathway” (Glickstein et al., 1964). The finding was questioned by another group; they attributed our findings to direct damage to the corpus callosum.

Although we had varied the trajectory of the injections to avoid the caudal corpus callosum, the widespread ipsilateral geniculo-cortical projections seemed of far more importance. Rather than pursue the argument, Dick King, Joe Miller, Mark Berkley, and I followed up the more striking features of our result. In addition to the expected projection to area 17, we saw a massive geniculate input to area 18 of Otsuka and Hassler, V2 of Hubel and Wiesel, and to the lateral suprasylvian cortex “The ClareBishop area” (Glickstein et al., 1967). The physiological implications of our anatomical findings seemed important. The dominant view of the way in which visual receptive fields are constructed was that neurons with simple receptive fields in Vl project to neurons with complex receptive fields in V2. But if geniculate cells have only center-surround receptive fields, and if there are no simple cells in V2, there had to be another way in which complex receptive fields are formed.

Some time later, Mark Berkley, Ellen Wolf, and I studied the problem in more detail. We published a study that the three of us were proud of, but which, we felt, nobody ever read. Mark and I had become close friends as well as colleagues. We enjoyed working together. As a part of our joint study of the geniculocortical projections in cats, Mark mapped gross evoked potentials to flash in several cats. Otsuka and Hassler (1962) had described the variations in the morphology of the cat visual cortical areas: their types I, II, III, and IV. The major distinction among them was the depth of the lateral fissure. In some cats, the fissure is represented as only a slight depression on the surface of the lateral gyrus. Bob Doty (1958) had earlier described a “high amplitude strip,” a large evoked potential he recorded to flash on the surface of the lateral gyrus. Mark showed that the highamplitude strip corresponds exactly to area 18 of Otsuka and Hassler. The highest amplitude evoked potentials are in area 18 not in area 17.

In other cats, we made a small stereotaxic lesion in the geniculate under sterile operative conditions. Several days after we made the lesion, we reanesthesized the cat, and Mark mapped the distribution of gross flashevoked potentials on the cortex and then prepared the brain for studying degenerating fibers. I charted the distribution of degenerating fibers in the cortex. We worked independently on the physiology and the anatomy. We compared the two maps; my map of the degenerating fibers in area 18 and Mark's map of the “holes” in the expected gross potential to flash. The match was perfect. Where there were degenerated geniculo-cortical fibers in area 18, the high-amplitude response was abolished. In other experiments we showed that the high-amplitude response was unaffected if the corresponding region of area 17 was removed. Mark Berkley, Ellen Wolf, and I published the results in Experimental Neurology (Berkley et al., 1967), where it languished, unread and unloved except by its authors.

I had not abandoned my interest in interhemispheric transfer. With J. Secrist, I started to study whether more complex rules could be transferred between the hemispheres as well as simple visual discriminations (Glickstein and Secrist, 1972). We studied interhemispheric transfer of a learning set. I first cut the optic chiasma in the midline. We trained the monkey with one eye open in a reversal learning set. The monkey learned to choose one of a pair of two-dimensional patterns. When he reached criterion, we reversed the value of the stimuli. The former positive cue, was now negative, and the animal was now at 0% correct. Eventually he relearned to choose the formerly negative cue. Once again, when he reached criterion we switched the value of the two patterns. Over time the monkey takes less and less time to reacquire the correct choice. Fully trained, he is almost always correct by the second try. He has learned a rule “win stay; lose shift.” When the monkey was tested on the formerly closed eye, the learning set was immediately available. Either the set was present in the second hemisphere, or it could be accessed by way of the callosum. I cut the callosum after only a few trials, and the animal still knew the set when tested with the formerly closed eye. The evidence suggested that the learning set had been stored in both hemispheres.

Bill Stebbins had studied reaction time in rats while he was on the faculty of Hamilton College, before he came to Seattle. He had developed a simple and effective behavioral technique to teach rats to respond as quickly as possible to a stimulus as soon as it was presented. Monkeys could also be trained using Bill's methods. Joe Miller, Bill Stebbins, and I (Miller et al., 1966) added an additional rule to ensure rapid responses. We set an initially long time within which responses would be reinforced. If the monkey responded in a time that was shorter than the setting, it was rewarded. If it took longer than the preset time, it was not rewarded. After every trial the minimal time was shortened if it succeeded and lengthened if it failed to go as fast as required. We adjusted the ratio of increases and decreases, so that the monkey never quit working and never got into a lazy habit of accepting 50% reward. The monkeys performed the task rapidly to either light or sound stimuli. The same behavioral contingencies worked well for us humans in the same apparatus. Helped by Chuck Stevens, Joe Miller designed an optimal configuration for bipolar stimulation of a restricted region of the striate cortex. We placed a bipolar stimulating electrode permanently over foveal striate cortex in a monkey that had previously been trained to respond rapidly to the onset of a light. It took only three trials before the monkey would respond rapidly either to a light or to a short train of bipolar stimulation of visual cortex. We then tested systematically the latency of reaction time to lights of different intensities and to electrical stimulation at different current levels. At the shortest asymptotic speed of performance, stimulation of visual cortex gave us average reaction times that were about 40 milliseconds shorter than responses to light. The savings were about equal to the evoked latency of the light (Miller and Glickstein, 1964, 1967).

The lateral geniculate nucleus is prominently laminated in humans and the Old World primates. There are other animals in which the geniculate is also laminated but in which the input to the layers was unknown. The literature assured us that the large parvocellular mass of the squirrel monkey geniculate had only two layers. In an attempt to clarify the inputs, Bill Calvin, then a graduate student in the physiology department, and I made a unilateral enucleation of a squirrel monkey, waited for a year, and studied the resultant long-term transneuronal degeneration in the geniculate. Rather than a four-layered geniculate that had been postulated by previous authors, we found that the lamination is similar to the inputs in humans and the Old World primates. The contralateral eye projects to layers 1, 4, and 6; the ipsilateral eye projects to layers, 2, 3, and 5. Unlike humans and the Old World primates, there are no prominent interlaminar fiber layers within the parvocellular LGN. When we had this result, we heard that Bob Doty had done a similar experiment with the same conclusion, I wrote to him, suggesting that we publish the results jointly, which he agreed to do (Doty et al., 1966).

I did a similar study on the tree shrew, Tupaia, an animal that also has a prominently laminated geniculate (Glickstein, 1967). Like monkeys and humans, the individual laminae receive segregated input from the ipsilateral and contralateral eye. A puzzle presented itself, still unexplored. The tree shrew eye is placed far laterally in its head. Consistent with the Newton-MÜller-Gudden principle, which states that it is the contralateral visual field that is represented in the geniculo-cortical pathway, the optic nerve arising from each retina is almost entirely crossed. There is very little overlap in the visual input from the two eyes, with only a tiny representation in the ipsilateral optic tract. But the territory occupied by the inputs from the left and the right eye are of roughly equivalent volume in the geniculate. There are, I believe, only two possible explanations for this apparent paradox. One possibility, which I do not believe, would be that there is massive convergence onto geniculate laminae from the contralateral eye and divergence from the ipsilateral eye. A more plausible explanation is that the geniculo-cortical pathway is virtually restricted in this animal to the representation of the binocular field.

I have always been blessed with technically skilled students. Erich Luschei had been an undergraduate in psychology at the University of Washington. Erich was accepted as a joint program graduate student, and he chose to work with me. At the time, Evarts had recently developed techniques for recording single unit activity in behaving monkeys. Erich developed a technique for single unit recording on his own. We set out to study the will. Erich found a two-channel tape recorder that would play backwards. He recorded a monkey's lever press on one channel and cell firing in the motor cortex in the other channel. With Bob Johnson, then a medical student, we studied performance in a reaction-time task. We could tell whether the response of a given unit was more closely linked to the stimulus or to the response by summing unit responses forward in time from the stimulus or backward in time from the response. The results seemed promising. We published a short account of the work in Nature (Luschei et al., 1968).

At the time it seemed that it would be a straightforward task to track neural activity from primary sensory cortex to motor cortex by recording from structures along the way. We never got quite that far. What appeared to be the simplest of behavioral tasks is not so simple. In order to study the muscle activity in reaction time performance, we sanded our own arms to get low-resistance electromyograms (EMGs) from agonist and antagonist muscles. With Carol Saslow, we studied muscle potentials while we performed the same reaction time task. The task of withdrawing our arms from a telegraph key turned out to be a more complex act than we had envisaged. The first response we detected was a diminution in the activity of the major antagonist muscle. This was followed by a burst of activity in the agonist, which brought our arms and finger off the key. Finally, we recorded a braking activity in the antagonist muscle that slowed and then stopped the movement. There was an 80-millisecond spread from the first sign of the response to the final end of the movement. Thus, it was hard to relate individual cell activity to specific aspects of the movement (Luschei et al., 1967).

The Zoo Connection

Seattle had a modest-sized zoo. The zoo had an occasional problem. Animals are shown only if they are normal-appearing and in good physical health. In order to extend our study of the cortical representation of vision, Mark Berkley and I were able to study the visual cortex of large cats that were scheduled for killing by the zoo. We studied the morphology of the cortex in a leopard, jaguar, and a young lion. In all three, the brain was entirely cat-like. Where there is a usually only a hint of a fissure in most domestic cats, there is a deep fissure on the lateral gyrus of the great cats.

The Other Faculty

T.C. Ruch was head of the physiology department, universally addressed as “professor” by all of us juniors in the department. When I first arrived in the Seattle department, I was scared. Here I was in one of the major physiology departments in the United States, and I knew very little physiology. Only a matter of time before they find me out. Within the first week of my arrival, T.C. Ruch suggested we go to have a coffee together. Here it is, I am done for! Now is when he finds me out. Rather than interrogate me on my knowledge of physiology, T.C. asked my opinion on woven wire vs. hardware cloth. “For what?” I bravely asked. “For monkey cages.” Ruch was ordering more cages, and his habit was to sound out his own ideas with a younger colleague. After a monolog on the advantages and disadvantages of the two types of cage, he changed the subject, and addressed me directly. “You don't know any physiology; don't worry, you will learn it here. We will start you as an assistant in the nurse's course. You will be lecturing in the medical school course in three years.”

I have never known a more effective chairman. Entirely selfless, he worked for the good of his department. When an NIH study section was due to make a site visit, the visit was announced well in advance with the coda, “Don't let the presence of the site visitors interfere with any plans you may have made to do an experiment on that day.” A typical Ruch three-line whip.

Ruch's chairmanship influenced the other members of the department to be supportive of one another. If you needed help in understanding a problem, designing apparatus or building equipment, the other members of the department were always ready to assist. In my second year at Seattle, Chuck Stevens arrived as an Assistant Professor. Much of my education in neurophysiology began with his help and his excellent Primer of Neurophysiology. Among the memorable colleagues was Art Brown. A converted physicist, Art is as intelligent as any colleague I ever knew and as skilled. He also set a high moral standard for the department. I remember when we were considering whether we should accept someone as a student who came with a reputation of being difficult, perhaps a political dissident. The sense of the department meeting was to adopt a vague “We don't have room” solution. Art was not having it. He insisted that if we reject someone for his politics, we must be explicit and tell him so. We accepted him, but he did not come.

When I first got to Seattle, the university was completing the construction of a Primate Center whose director was Professor Ruch. The dean of the medical school gave him an ultimatum, “You cannot manage two big jobs at once; physiology or the primate center, choose.” Ruch chose the primate center, and he was succeeded in the Chair of Physiology by Harry Patton.

Pat was a marvelous lecturer. His lectures to the medical students were models of clarity. They were much more than that. Pat taught, among other things, the neurophysiology of reflexes. Not just what we know about spinal mechanisms but how we know. He taught physiology in a historical context. What was the sequence of experiments and clinical observations that led to current understanding? Pat was a major influence in my own thinking about how to teach.

Isolated in the northwest corner of the United States, we relied on one another for interaction. One of the best programs was the “Neurological Study Unit.” Every 2 weeks a topic was selected that had both clinical and basic science relevance. A member of the clinical and of the basic science departments would each present about a half-hour talk, followed by discussion. Through the Neurological Study Unit, I got to know some of the clinical problems and several of the outstanding people in the clinical departments.

One of my favorites was Elsworth (Buster) Alvord, the Professor of Neuropathology. We disagreed once on the interpretation of macular sparing after lesions of the visual cortex. The disagreements did not make us enemies but good colleagues. Alvord was a most helpful source of advice on how to deal with artifacts in histological sections, for example, how to get rid of an annoying reddish contaminant in our Nissl stains.

The Psychology Department

My appointment was as an Assistant Professor in two departments. As a member of the psychology department, I taught courses and seminars in my first years at the university. The psychology department was neither as successful nor as supportive as physiology, so I spent most of my time in the medical school. Shortly after I arrived in Seattle, the university appointed a new Chairman of the Psychology Department. His proposals for revising the structure of the department's teaching and hiring policy soon were vigorously opposed by two thirds of the members of the department. About a third of the members thought the new chairman's ideas were excellent and supported him. So did I. The administration listened to the complaints of the majority, and the chairman left.

I was put up for promotion to Associate Professor by the Physiology Department. By university rules, my promotion had to be supported by both departments. One of the members of the psychology department had been a physiological psychologist before becoming a dean many years ago. No longer the dean, he was back in the psychology department. In order to become familiar with current issues, he had taken my seminar on association cortex. When my name came up for promotion, I had unanimous support from the tenured members of the physiology department but not from psychology. I was opposed by the former dean on the grounds that my position was not needed, “What would he teach?” Happily, his influence was insufficient to block my promotion.

Ben Everett Buys My Other Half

I was put off by my experience in psychology. I was pleased when Ben Everett, the Chairman of the Anatomy Department, offered to take up the other half of my appointment. I cheerfully left the psychology department and devoted my full time to teaching and research in the medical school.

Seattle is set in one of the most beautiful regions of North America—paradise, but it rains a lot. Sometimes, even in midwinter, the rain would stop. Very rarely, the sky would be completely clear. The mountains on all sides would become visible—the Cascades to the east, Mt. Baker to the north, “The Brothers” to the west in the Olympic Peninsula, and, best of all, Mt. Rainier would also appear in the southeast. On those rare winter days, we stopped work in the lab and went out on my little 19-foot sailboat to experience the joy of the place we lived in. The waters around Seattle are protected. Happy times with friends were when we took my sailboat up Puget Sound. A fine voyage with Bill Stebbins and Dwight Sutton, catching fish, anchoring in pleasant little harbors, and arguing about the brain.

The Move to Brown

My wife was unhappy in her job in Seattle and saw brighter prospects in the East. We had been married in 1955, when she was a resident in psychiatry and I was a graduate student. She had been following me through three successive places, so when the Brown University psychology department offered me a job, I accepted it. We moved from Seattle to Providence in 1967. Two of the people that I worked closely with in Seattle came with me. Ide La Bossiere was an outstanding histology technician. Erich Luschei was my graduate student. Both helped me set up a lab at Brown. One of the pleasant surprises was finding Ford Ebner in an adjacent building. Ford had studied interhemispheric transfer at Walter Reed with Ron Myers. Ford was a fine colleague and has remained a close friend. Brown had a collection of excellent undergraduate students, several of whom worked with me in my lab or assisted in a tutorial course. Dennis Butcher studied reaction time and Barbara Brown studied finger use in monkeys with cerebellar lesions.

Lorrin Riggs and the Vision Group

My closest colleagues in the Brown Psychology Department were in the vision group: Lorrin Riggs, Dean Yaeger, and our students. Two of Lorrin Riggs' students, Mark Hollins and Kay Fite, spent a postdoctoral year with me. Sylvia Thorpe, Dean Yaeger's student, worked with me on a translation of Cajal's monograph on the retina (Cajal, 1972). Lorrin Riggs is the best professor I have ever known. A quiet scholar, he had made fundamental discoveries on vision and on its relation to eye movements. Lorrin was also a superb teacher, not as a lecturer but as a guide for younger people. Under his care, average students became good scientists. Excellent graduate students became outstanding scientists. Lorrin's students and post docs loved him rather than liked him. He was kind in his dealings with others, but somehow managed to remain incisive and clear in his scientific judgments. When a new student arrived, a typical scene would ensue. Most had been excellent undergraduates, and most talked fast. In their first interview with Professor Riggs, they would often ask him a question. Lorrin never shot from the hip. If you asked him a question, he thought about your question. While he was thinking he did not say anything. The student would then fill the silence by asking him another question. Lorrin would now think about that question. Aware of the danger, older students began to give new students advice on how to proceed. If you ask Lorrin a question, wait! He would answer it, but only after he has thought about it.

Retinoscopy and Eye Size

With Ide La Bossiere, I continued to add to a collection of sections of eyes and brains that I had started in Seattle. The collection of eyes proved useful for solving a puzzle in interpreting the literature on refraction in animals. Every week or so Lorrin, Dean Yager, and I and our students would have an informal vision lunch, where we would discuss vision, sports cars, or anything else. One of Lorrin's students, Ross Beauchamp, was using the retinoscope for refraction. Ross raised the question in the vision lunch, “What would the consequences be if the moving shadow seen in the retinoscope were to be reflected from a layer other than the receptors?” No one knew. Because retinas are thin, it did not seem to matter much. It does. To a good approximation, all mammalian retinas are about the same thickness. Myotis, the little brown bat, whales, and elephant's eyes are vastly different in volume, but the retinas are about the same thickness. The retina of the baleen whale, Ballaenoptera physalis is more than 15,000 times the volume of the bat eye, but the retina of each is about a quarter of a millimeter in thickness. Because the retina has a roughly constant thickness in all mammals, the error in retinoscopy can be calculated for a simplified eye. The dioptric power of a simplified eye is equal to one over the square of the focal length times the refractive index: D = uf¹. Differentiating this equation: dD/ df = –uf⁻². Thus, the error in diopters should be proportional to the inverse square of the focal length of the eye. Michel Millodot, who was a graduate student with Lorrin at the time, and I began to assemble published data from the literature and to refract the eyes of various creatures. We plotted measured refractive state against corneo-retinal length. The plot in log-log coordinates is linear with a slope of −2, suggesting that the argument about a possible source of error in the measured refractive state was correct. We could now calculate where the reflection comes from. We concluded that the shadow seen in retinoscopy is due to a specular reflection from the retina-vitreous surface. Contrary to the literature, rats are not 7 diopters hypermetropic, and rabbits are not 2 diopters hypermetropic. Both are probably emmetropes. We published the results in Science (Glickstein and Millodot, 1970).

Paul Yakovlev's Lesson

When I was still at the University of Washington, I heard a lecture by Paul Yakovlev, then Professor of Neuropathology at Harvard. Now that I lived nearby, only an hour's drive from Boston, I boldly telephoned Professor Yakovlev with an unusual request. I had read Yakovlev's papers on brain control of movement. They seemed original and imaginative, but I was not sure I understood them fully, so I phoned to ask him if I might visit and have a tutorial with him on his ideas about the nature of brain control of movement. He agreed. After a splendid, 2-hour lesson, I asked if I could give him a present in return for his teaching. He asked what I had in mind. I had in mind to give him a set of slides for his collection of comparative brain material. He sniffed at my offer of a monkey brain but accepted my suggestion that I give him a set of seal brain sections. He praised the beauty of the cell stains but sniffed at the fiber stains. He said “I will put in collection and label Glickstein contribution.”

Corticopontine Projection

We had identified several parallel independent cortical targets of the lateral geniculate in cats. The projection from the geniculate to V2, area 18, is as dense as the projection to Vl. Lesions of Vl do not abolish the photic evoked response to flash on V2. Vl and V2 are in parallel not in series. Why? We speculated that one of the two areas might be involved in the processing of visual form, the other movement. Because cells in V2 are particularly sensitive to moving targets, this area might play a role in movement detection, possibly regulating the cat's own movements—either locomotion or independent use of the limbs. If this were so, a logical target for fibers that arise from cells in V2 would be the cerebellum. Projections from the cerebral cortex to the cerebellum relay in the pontine nuclei, so we set out to study the differential projection of Vl and V2 to the pons. We made lesions in area Vl or V2 and plotted the resultant degeneration in the pontine nuclei. We found a heavy projection from V2 to the pons. In our initial studies we failed to see a projection from Vl. (Glickstein et al., 1972). As Per Brodal later pointed out, there is also a corticopontine projection from Vl but much weaker than that from V2.

Some years later with Janet Cohen, Bryan Dixon, Alan Gibson, Mark Hollins, Ide La Bossiere, and Ric Robinson (Glickstein et al., 1980), I studied the pontine projection from striate and prestriate visual areas in monkeys using degeneration and orthograde tracing techniques and, later, with Jack May and Barbara Mercier using retrograde tracing (Glickstein et al., 1985). There are great differences in the extent of corticopontine projections among the monkey cortical visual areas. Cells in the dorsolateral area 17, the primary visual cortex, and cells in the inferotemporal areas did not appear to send fibers to the pons. The massive visual projection arises from dorsal extrastriate areas, beginning in area MT (V5 of Zeki) and including MST and the LIP and the adjacent visual areas in the parietal lobe. Jack May and I summarized the differences in the projections from extrastriate areas (Glickstein and May, 1982). We suggested that the medial, parietal-centered areas probably serve in the visual control of movement, and the temporal areas serve in the analysis of color and form. In the same year, Leslie Ungerleider and Mort Mishkin (1982) proposed a similar dichotomy among extrastriate visual areas, suggesting that the ventral areas are involved in identifying objects and the dorsal areas in registering their location. Some years later, Mel Goodale and David Milner proposed a distinction rather more similar to the one that Jack May and I had suggested (1992).

Oxford 1970–1971

Around 1970, my marriage began to break up. In order to help get over the attendant depression, I decided to work abroad for a year. I had written to David Whitteridge when he was Professor of Physiology in Edinburgh some years earlier. In 1970, he was now Professor of Physiology at Oxford. Why Whitteridge? I became aware of Whitteridge's scientific work from a footnote in the 1960 Freiburg symposium on Physiology and Psychophysics of Vision (Jung and Kornhuber, 1962). Doty had questioned the evidence for accurate spatial mapping of the visual fields on the primary visual cortex of cats. Whitteridge disagreed. In a footnote in the proceedings, Doty wrote that Professor Whitteridge had invited him to stop in Edinburgh on his way back to the United States, “ ... where we put the question to two cats. I must say that Professor Whitteridge had the better of the argument.” Oxford seemed as if it would be a good place to work. It was. Whitteridge wrote, agreeing that I might visit him on my way home from a meeting that I had attended in Slovakia. I arrived in England and stayed with John Sundsten, an old friend from Seattle who was on sabbatical leave working in Bristol. I phoned Professor Whitteridge to arrange my visit. He said “I am absolutely up to my eyebrows in examinations, and I must go to St. Andrew's on Tuesday; I can give you only one hour.” I suggested that he was obviously much too busy, so we might make it another time. He replied; “No, No, No, you must come.” John Sundsten and I drove across southern England in a fierce rain storm to Oxford where I was ushered in to the presence of the professor. Whitteridge began, “What do you want?” I replied that I had come to see his lab. He said “I haven't got a lab” whereupon I got up to go. Realizing that he had gone a bit too far he said, “What have you been doing?” We began to discuss the eye, and he showed me some beautiful pictures of the retina that had been published nearly 100 years earlier by Lindsay Johnson. Whitteridge had recently arranged to have several republished. Two hours into the visit he said, “Actually, I have got a lab. Let's go and have a look at it.” And then “Will you need money?” I reassured him that I had an NIH fellowship. After that peculiar beginning, we went from being good colleagues to closest friends. I miss him still. When I am near Oxford, my first thought is often to visit David—alas no longer possible.

I determined that I would start to work right away when I arrived in Oxford. So I packed and shipped two trunkfuls of lab equipment weeks before I left the States. My aim was to start working within a day or two of my arrival. I came with two possible plans for research. One was to record the receptive field of single cells in V2 before and after I had removed area Vl. The other possibility was to see if I could record visually driven cells in the pontine nuclei.

The first try was a disaster. Whitteridge suggested that I work with a medical student on the first problem. We studied the receptive fields of cells in V2 cells after I had made a lesion in Vl. The relationship between the student and me did not work. Eager for a discovery, as we recorded from cells in area V2, he said that he thought that the surround mechanism of the cells was now absent or weak. I did not agree. When he wrote that alleged observation in our lab book, I pointed out that a year from now he would believe what he had written, so I would write “I didn't see this” and sign it. Clearly not a recipe for a fruitful collaboration. The alleged dependence of V2 on an input from Vl came back to haunt me a year later when I spoke informally to some of Steve Chorover's graduate students at MIT after I returned to the States. I began my talk by saying, “It's not clear what the influence ofVl is on the receptive fields of cells in V2.” “Oh yes it is! Vl provides the surround mechanism for the receptive fields of cells in V2.” “Fascinating,” I said, “Whose lab is that from?” “Whitteridge's lab,” they chorused. I pointed out that they might be telling me about my own research. The conclusion had been put forward in a talk the student gave at Cambridge and further simplified when it was discussed by another colleague from Cambridge visiting MIT. I still do not know the answer to the question of whether the input from Vl influences the response of cells in V2 of the cat.

That collaboration did not work. Professor Whitteridge knocked on another door, that of John Stein, recently appointed medical tutor at Magdalen College, and said, “You two might have something to discuss.” We did. We still do. It was a happy collaboration. One or two days a week we would prepare a recording experiment all day, and record unit activity in the pons all night. In the morning, we would go around to John's house for breakfast. At first we turned up nothing; no visually driven cells. We modified our procedure. John had previously studied the larynx and knew how to remove it in an acute anesthetized animal in a terminal experiment. We worked with a supine preparation in which the larynx had been removed. We drilled through the bones overlying the brainstem and put a bit of graph paper next to the basilar artery for informal coordinates. During the first months of our collaboration, nothing worked. I encouraged John to give it up. He always pushed for one more go. One night, around midnight, we drove a cell visually. That was good enough news. Better yet, Professor Whitteridge was still in his office, so we could fetch him. David waved one of his wands with a black rectangle at the end, and he too drove our cell. Fantastic night. At the time we recorded results from experiments on long strips of positive photographic 35-mm film in a Grass camera. In order to dry the film we hung it from a wire on the top floor of the physiology building. The next morning, everyone could see that we had a visually driven cell.

I was introduced to the Physiological Society that year. Rather a solemn vote followed each oral presentation: “Is it the wish of the society that this abstract be published?” The audience votes as a committee of the whole. When John Stein and I reported our findings of visual cells in the pontine nuclei in a region that receives its input from the visual cortex, the audience approved its publication. However, one of the older members stipulated that, instead of the single word “Results,” “Provided he will say, the combined anatomical and physiological results …”

In addition to David Whitteridge and John Stein, there were a number of other colleagues who went out of their way to be friendly to me during my year at Oxford. One of those people was Austin, now Abbie Hughes. Austin and his wife invited me to their house for dinner and took me sightseeing to Marlborough and Stonehenge on a weekend. Two of the most active people working in the physiology department were Guy Goodwin and Ian McCloskey. Guy was a graduate student with Peter Matthews; Ian was a fellow of Pembroke College. At the time, it was holy writ that muscle spindles act only in a servo-circuit. We are unaware of their output. Guy and Ian did a number of exquisitely simple experiments to challenge that conclusion. We are indeed aware of the output of spindles. They vibrated a flexor muscle on the upper arm. Subjects (including me) reported that they felt that their arm was extending at the elbow, as if the muscle had been stretched. They did several control experiments to validate their conclusion and proceeded to replicate and show the shortcomings of earlier studies that had allegedly provided proof that we are unaware of the output of spindles. Peter Matthews was Guy's lab sponsor. Peter is an outstanding scientist and scholar. Skeptical of the conclusions at first, he was finally persuaded by the evidence. One of the best lectures that I ever attended was one given by Peter at a meeting at Oxford. Without using slides, he demonstrated the key experiments on a semihostile witness. Giles Brindley had been one of the principle exponents of the silent spindle, but he would not lie. If he felt a limb move, he reported that he felt it move. It was a magnificent session. Evidence counts.

Oxford teaches its undergraduates very well. All of the undergraduates had a tutor responsible for their education. All had tutorial sessions each week in which the focus was not on what the tutor said or wrote but what the student had written. I took the Oxford style of tutorial teaching with me back to Brown and taught with tutorials as best I could manage when I returned.

Back at Brown

I came back to Brown with enthusiasm and an eagerness to get back to work. Within a week or two of my return, Alan Gibson turned up, recommended to me by Mike Gazzaniga, who had been his Ph.D. supervisor. About the same time, Jim Baker arrived as a graduate student, recommended by Mark Berkley. One such student or post doc would have been a gift. Two were wonderful. Alan and Jim were both highly intelligent and technically gifted. I have never met a more effective lab person than Alan or as bright a new graduate student as Jim Baker. My research at the time was adequately funded, and it allowed for a one-twelfth time appointment so that John Stein could spend summers in the lab. Our plan was to record and characterize the receptive fields of pontine visual cells. John and I had found them at Oxford. We knew they were there, but we knew very little about their response properties. Our aim was to learn the nature of the visual information that is sent to the cerebellum. With Alan Gibson and Jim Baker, we set about recording from a large number of visual pontine cells. One fortunate fact was that Jim Mcllwain was a nextdoor neighbor in the physiology department. Jim Mcllwain had produced an accurate map of the representation of the visual field on the surface of the superior colliculus of cats. Our preparations were set up for recording of visual receptive fields. We would first establish the locus of the blind spot and other retinal details on a back projection screen. The visual cells in the pons are about 25 mm below the surface of the cerebral cortex. Even a slight error can lead to missing them in the pontine nuclei. It was Alan's insight that we stop the electrode at the surface of the colliculus and record the position in the visual field of the responding neurons. Thus, we had a way station about halfway down to the pons where we could confirm the trajectory of an electrode. If we were in the wrong place, we withdrew the electrode and used Mcllwain's map to correct the stereotaxic placement. We always found visual pontine cells by the second penetration. Over time we were able to record and characterize the receptive fields of several hundred pontine visual cells. At first, we tried to drive pontine visual cells with stationary or moving bars and edges. They would fire but grudgingly. The insight came when one of us walked in front of the preparation and the cell from which we were recording fired at a very high rate. We found that the editorial page of the Providence Journal also was an effective stimulus. Most pontine visual cells respond best to large, textured fields, at a preferred speed, moving in a preferred direction (Baker et al., 1976).

In addition to a cortical visual input, visual information is also relayed to the cerebellum by way of the superior colliculus. George Mower, another gifted graduate student, joined the lab in the following year. With George, we studied the target of collicular originating axons in the pontine nuclei and the response properties of pontine visual cells that are activated from the colliculus (Mower et al., 1980).

Pontine visual receptive fields differ from those of cells in the cerebral cortex. One problem that we addressed was the nature of the receptive field of cortical cells that provide an input to the pontine nuclei. The group at Penn had pioneered this approach, studying the properties of neurons in area 17 of cats that project to the superior colliculus. The technique was demanding and slow: electrically stimulating axon terminals in the colliculus and recording from antidromically activated cells in the cortex. One of the difficulties with the procedure is that you may not activate an antidromically driven cell on every penetration. Alan Gibson's technical skills gave us the results we looked for in a reasonably short time. Alan devised a four-electrode fork that we advanced through the cortex. The apparatus cycled, recording from each of the four electrodes in turn as we stimulated the pons. Our yield of antidromically activated cells increased almost fourfold. We recorded the receptive field properties of a number of cells in area 18 and the lateral suprasylvian areas whose axons project to the pons. Deep in lamina V, these cells have receptive fields that are entirely different from those that had been reported for cells in more superficial laminae (Gibson et al., 1978).

Joan Baizer, another typically bright graduate student, came to Brown from an undergraduate degree at Bryn Mawr. Joan joined me in studying the effects of cerebellar lesions on prism adaptation. If a laterally displacing prism is placed in front of the eyes, monkeys and people mispoint at first. After a few misses, they become accurate. When the prism is removed, they mispoint in the opposite direction. Charles Harris had argued convincingly that adaptation to a laterally displacing prism is not visual but probably involves recalibration of the position of a limb. The anatomical and physiological properties of the visual input to the cerebellum suggested that it would be a logical locus for such recalibration. Joan's monkeys viewed an array of lights through one eye and reached out rapidly to close a switch under the light. A laterally displacing prism was then placed in front of the eye. In the animal with a large unilateral lesion of the cerebellar hemisphere, prism adaptation was abolished on the side of the lesion (Baizer et al., 1999). The experiments had been done when Joan was a graduate student at Brown. At the time the results were puzzling, because there seemed to be no obvious reason why some cerebellar lesions affected prism adaptation while others did not. Later, when I studied the visual input to the cerebellum, the explanation seemed clear. It seemed most likely that the cerebellar region in which the lesion was effective in abolishing the adaptation is coextensive with the major target of visual information that is relayed via the pons from the cerebral cortex.

We tested these same animals in other tasks. Barbara Brown was an undergraduate at Brown. She observed the same monkeys in a device similar to one that had been devised by Kuypers and his students for studying finger use. In the animal with the largest cerebellar lesion, the animal was unable to appose index finger and thumb. The entire hand was used as a scoop in picking up a raisin from the wells.

Joan Baizer and Barbara Brown joined me in teaching my undergraduate course. Labeled “Mind and Brain” it was historically based, with all of the assignments were to the original literature. We divided the class into three, and each of us tutored one third of the class about a third of the time. Thus, I could teach each student individually or in pairs for about one third of the time during the term.

On one of my visits to Oxford, I met Lydia Sinclair. She joined me in Providence in 1974. Lydia had been training as a solicitor. In the early part of 1975 she went back to complete her articled clerk requirements to qualify as a solicitor. I joined Lydia for the spring term in 1975. Geoff Raisman and Pauline Field had moved to a Medical Research Council Lab at Mill Hill in the north of London, and Geoff kindly gave me a desk where I began to write a textbook, sharing my office with the laboratory pet, a rainbow boa constrictor.

The work continued in my lab while I was away. When I returned, I had two more excellent graduate students, Farrel (Ric) Robinson and Jack May. Ric began the task of sorting out the differential projection from cortex and colliculus to the cerebellum of cats in order to identify the cerebellar targets of visually active pontine cells. He would label a visual region of cerebral cortex with a radioactive tracer and later inject a retrograde tracer into one or another region of the cerebellar cortex. He could thus identify those retrogradely labeled pontine cells that receive a visual input. One of the major cerebellar targets of visual information is the paraflocculus (Robinson et al., 1984).

The visual information to the cerebellum in monkeys arises from the dorsal stream; the extrastriate visual areas that include the angular gyrus of the parietal lobe. Jack May, Susan Buchbinder, another Brown undergraduate, and I studied the effects of lesions of these cortical areas and compared the effects to those caused by equivalent-sized lesions in inferotemporal cortex. There is a complete dissociation in the effects of lesions. As others had discovered, temporal lobe lesions produce severe deficits in visual discrimination learning. They are without effect on skilled use of the wrist and fingers under visual guidance. The parietal lobe lesions produced the reverse effect; a severe deficit in visuomotor control without impairing visual discrimination learning (Glickstein et al., 1997).

The Offer from MRC; Leave of Absence

Training as a solicitor in England is different from that of an American lawyer. Graduates of a university in any subject can become qualified solicitors by passing a series of difficult law exams and apprenticing—in Lydia's case for 2 years—as an articled clerk. In the spring of 1980, I was offered a position with a Medical Research Council Group on the Neural Mechanisms of Behaviour, based at University College London, headed by Ian Steele-Russell. Lydia and I moved to England to try it out. My salary with the MRC was about half of the one that I had earned at Brown, and housing cost more in London than it did in Providence. But the advantages were great. Our research budget in the lab was negotiated on a 5-year basis—no grant applications. Loosely attached to University College, I had the advantages of an academic position, with fewer responsibilities. I liked the first year, so I asked Brown University to extend my leave of absence for another year. I still liked it. Lydia was close to becoming a fully qualified solicitor, so we decided to stay. I asked Russ Church, then Chairman of the Psychology Department at Brown, “How do you resign?” He replied, “A single sentence will do; two if you wish to soften the blow.”

In England, I was once again fortunate in the people that worked with me. Barbara Mercier had moved to a town near London from Oxford, where she had been employed as a lab technician. Skilled and intelligent, I hired her as a histology technician, and she went on to do independent work with me. Graduate degree programs are different in England from those in America. In America, there are usually taught courses, with exams to pass as well as a thesis to write. In England, Ph.D.s are usually research degrees. Students are given lab facilities and are expected to turn up a thesis in 3 years. In order to be allowed to register for an advanced degree, students usually need to have a first or upper second class honors degree in a related subject. Barbara had technical qualifications but did not have an undergraduate degree. She was allowed to work for a Ph.D. after she passed written and oral exams to confirm that she had an equivalent knowledge of neuroscience as someone with a degree in the subject. Barbara did a beautiful study of the differential projection from the rat barrel fields to the pontine nuclei and the basal ganglia (Mercier et al., 1990). Corticopontine cells that arise from the barrel fields are all located in lamina Vb. Cells projecting to the basal ganglia are located in lamina Va. We suspected but did not prove that there is a thin sublamina at the border of Va and Vb whose cells bifurcate to project to both targets.

A few years after I arrived, the Medical Research Council decided to discontinue our unit. There were several options open to the Council for dealing with its employees when a unit closes. One possibility would be to transfer them to another unit. But that was a nonstarter, because ours was the only one specializing in brain and behavior. The other option was for me to negotiate an academic position, and the MRC would continue to pay my salary until I retired. Chris Yeo, my colleague in the Neural Mechanisms of Behaviour Unit, and I both asked if we could stay on at University College. The chairman of Anatomy, Geoff Burnstock, and the provost of the college, Sir James Lighthill, agreed. There was a typical complexity in my actually being appointed. The University of London is a semifictitious organization that nominally includes nearly all the institutions of higher learning in the London area. University College is the oldest of these and it is, in fact, fiercely independent, but at the time, all senior appointments had to be approved by a university-wide committee of academics. The appointment procedure went through several silly steps. When the form was first sent to Senate House, where the committees meet, the word came back that I could not be appointed Professor of Neuroscience because I was not a recognized teacher in the University of London. The next proposal was that I be appointed a recognized teacher. This was bounced because I was at the time a visiting professor, and there was a statute against appointing visiting professors as recognized teachers. The College changed my status within UCL to that of Senior Fellow. Now, at last, I was a recognized teacher. But when the proposal to appoint me to a professorship was sent, it too was rejected because there were no funds to support such a chair, “What if he were to be hit by a bus?” There was, however, a consolation; “You might choose to convey upon him the title of Professor of Neuroscience.” This was done. The whole procedure took only a couple of years.

When the MRC closed the unit, Barbara Mercier chose to accept the redundancy payment offered by the Council and find a job closer to her home in Kent, avoiding a long daily commute. Chris Yeo and I had MRC grant support, and I had a position vacant for a technician. Ines Hans applied. Ines had a degree in veterinary medicine from Zagreb. She was married to a British citizen and had come to live in London. Initially, Ines had a job in a veterinary practice. She applied for a position with me to try new things. Ines worked with me for some 12 years, initially as a technician. An intelligent and highly skilled lab person, Ines was accepted as a graduate student at UCL. Together with Dutch colleagues and John Stein, we studied ponto-cerebellar pathways in monkeys (Glickstein et al., 1994). For her doctoral thesis, Ines studied behavioral and anatomical organization of the rat barrel fields. One of the problems we studied was the organization of cortico-pontine fibers within the cerebral peduncles. We found a precise arrangement of the fibers within the peduncle at the level of the midbrain. Fibers from the temporal and occipital lobes travel in the dorsolateral portion of the peduncles. Frontal lobe fibers travel in the ventromedial portion of the peduncles. Somatosensory fibers travel in the middle (Glickstein et al., 1992). With Charles Legg, who spent a sabbatical year in my lab, and Elisabetta Vaudano, who spent a year with me while completing her doctoral degree in Torino, we studied the distribution of cortico-pontine cells in the rat (Legg et al., 1989; Vaudano et al., 1991). In monkeys, only about half of the cerebral cortex sends a major input to the pontine nuclei. There is only minimal input from occipital, inferotemporal, and part of prefrontal cortex. In rats, all of the cerebral cortex projects to the pons. Like monkeys, however, the heaviest cortico-pontine projections arise from the motor areas of the cortex.

One of my duties at University College had been to organize an undergraduate degree program in neuroscience. In British universities, undergraduate courses are typically more specialized than they are in America. The usual degree course is only for 3 rather than 4 years, and there is seldom any requirement for distribution. But neuroscience is of its essence multidisciplinary, and I was asked by my chairman in the anatomy department to try to organize an undergraduate course covering the broad field of neuroscience. The course was jointly offered by five departments including zoology, physiology, pharmacology, and psychology as well as anatomy. In Britain, admission to an undergraduate course is like graduate admissions in the States. Each course admits its own students rather than a blanket admission to the university. Our first intake for the B.Sc. Neuroscience course was seven students: five from Britain and two from Greece. Another tradition in British universities is that students often stay on to do graduate work in the same university in which they did their undergraduate course. Ned Jenkinson was one of the seven of our first undergraduates. He asked to stay on and work for a Ph.D. in my lab. I was happy to agree.

Chris Yeo and Rabbit NMR

In addition to Ian Steele-Russell, the other senior researcher in the lab was Chris Yeo. Chris had a Ph.D. degree from Queen Mary University, where he had studied interocular transfer of conditioning in fish. He had come to the MRC unit before me, interested in mammalian learning. About the time I arrived in the unit, Dick Thompson reported the effects of cerebellectomy on conditioned nictitating membrane in the rabbit. A previously conditioned response was abolished after cerebellar lesions. Chris Yeo, Merv Hardiman, and I began to study the neuronal circuitry involved. We made small lesions in one or another cerebellar nuclei. We found a zone in the lateral anterior interpositus and adjacent medial dentate nucleus, in which lesions prevented acquisition of the conditioned nictitating membrane response (Yeo et al., 1985a). Chris went on to identify the associated hemispheric lobule VI as the focal area (Yeo et al., 1985b), and the effects of olivary lesions (Yeo et al., 1986). The pattern of retrograde degeneration in the inferior olivary following HVI lesions was consistent with a circuit through the same region of the cerebellar nuclei (Yeo et al., 1985c). Since that time Chris has gone on to analyze further the critical circuitry and the effects of temporary blocking of structures in that circuit.

Barrel Field to Cerebellum in the Rat

With Barbara Mercier, I had studied the projections of the barrel field layer V neurons to the pontine nuclei in rats. Ned Jenkinson, who was one of the first University College neuroscience students, joined me as a graduate student. Ned trained rats to run down an alley in the dark, observing them through a night vision scope. Rats will jump a gap of 16 cm in the dark, a distance at which they can just reach the platform on the other side of the gap with their whiskers. If they cannot feel the distant platform, they refuse to jump. If they are trained in the light, so that they see the distant platform, they will attempt a much longer jump. Ned and I made small unilateral lesions in the cerebral peduncles of rats that had been trained in the dark as well as in the light. The lesion interrupted the input to the pons, hence to the cerebellum from one or another area of the cerebral cortex. If we cut the middle portion of the peduncles, blocking the connection from barrel field, and shaved the whiskers on the side with intact connection to the pons, rats behaved as if they had lost both sets of whiskers. They would refuse to jump, even though they could reach the distant platform with the surviving whiskers. If we spared the whiskers with intact connection to the pons, the rats continued to jump. In all cases, rats would jump much greater distances in the light (Jenkinson and Glickstein, 2000).

Jan Voogd and History

When I first came to live in London, one of the people I most wanted to meet and talk with was Jan Voogd, who was then living and working in Leiden. Jan had made one of the major discoveries about the structure of the cerebellum and its connections. He found that the cerebellar cortex is divided into long, parasagittal stripes that constitute a fundamental unit of the cerebellum. The stripes are parasagittally oriented in the vermis and bend outward in the hemispheres, always at 90 degrees to the course of the cerebellar folia. Jan Voogd has since become a good friend as well as colleague. We share an interest in the comparative anatomy of the cerebellum. We have collaborated in anatomical as well as historical studies. We wrote on the contributions of the Dutch anatomist, Lodewijk Bolk, to our understanding of the comparative anatomy of the cerebellum (Glickstein and Voogd, 1995).

Inouye; Manfred Fahle

The Japanese ophthalmologist, Tatsuji Inouye, was a physician attached to the Japanese army during the 1904-1905 Russo-Japanese war. His clinical responsibility was to assess the degree of visual damage to soldiers caused by gunshot injury. Inouye took the opportunity to study in detail the visual field deficits caused by gunshot wounds of the occipital lobe. The work was published in German in 1909. I had earlier written about Inouye's work with David Whitteridge (Glickstein and Whitteridge, 1987). I published a translation of the entire monograph with Manfried Fahle some years later (Inouye, 1909, translated by Glickstein and Fahle, Brain, 2000).

Visiting Parma

In 1983 Giacomo Rizzolatti invited me to come to Parma as Professore a contratto. I gladly accepted. The visit began an enthusiasm for Italy, which I still maintain. Some of the most fun I had when I was working in Parma was to study with Giacomo the life of Francesco Gennari, the first person to identify the nonhomogeneous structure of the human cerebral cortex. From the library in Parma, Rizzolatti and I had a copy of Gennari's monograph. From a local history book, I found that Gennari had come from Mattaleto, a tiny village about 25 kilometers from Parma. I phoned the priest at Mattaleto, who gave me access to the church archives, stretching back to the 16th century. The priest was very helpful, but he found it hard to believe that anyone of any importance could have come from his tiny village. In the church archives I found a record of Gennari's birth as well as the marriage record of his parents. Giacomo Rizzolati and I published a short article about Gennari in TINS (Glickstein and Rizzolatti, 1984), and I incorporated some of our findings into an article in Scientific American on the discovery of the visual cortex (Glickstein, 1988).

I have been a visitor to several other labs in northern Italy. In Verona, with Giovanni Berlucchi, and Torino, with Piergiorgio Strata. I love the language, the people, and the food. It was, however, a severe setback to my self-confidence when my teacher in an Italian class at University College, Laura, refused to let me get by with an infinitive whenever a verb was needed independent of its tense.

Weizmann Institute

Yadin Dudai invited me to visit the Weizmann institute in Rehovot, Israel. There I met Shabtai Barash, who soon became a colleague and friend. Shabtai had a long-standing collaboration with Peter Thier in Tübingen, which began when they both were post docs in Richard Andersen's lab at MIT. Shabtai had been studying saccadic adaptation. If a person or monkey looks at a fixation target and shifts to look at a new target as soon as it appears, they are highly accurate. If the target is shifted as soon as the eyes begin to move, the saccade is inaccurate. Within a single session, the amplitude of the saccade changes. If, for example, a target comes on at 15 degrees to the right along the horizontal meridian but then is shifted to 20 degrees when the eyes begin to move, monkeys and people compensate by increasing the amplitude of the saccade over time. In collaboration with Peter Thier, Shabtai and I made lesions in the oculomotor vermis of two monkeys that had been trained in the saccadic adaptation task. Despite extensive postoperative training, there was no recovery of the ability of the monkey to adapt to the altered position of the target (Barash et al., 1999).

A Few Conclusions

My research on cortico-cerebellar circuits makes me skeptical about the current emphasis in systems neuroscience on cortico-cortical circuits. Cells in each layer of cortex have powerful differences in their properties. The cortex is often best understood in terms of its subcortical connections.

My early academic history makes me sympathetic to people that experience a bad patch in their studies. I was lucky in the fact that I had sisters and that there were institutions that helped me recover. Some are less fortunate.

Despite the great variability in how they do it, all of the universities, public and private, American and foreign, at their best share in certain underlying principles. The solution to problems and disagreements is based on evidence. They are, and should remain, institutions where teachers are free to pursue their studies, and students are free to explore. I love the international character of scholarship, and science in particular. Knowledge is without boundaries, and friendships can be formed among the most distant of colleagues.

Selected Bibliography

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Attardi D, Sperry R. Preferential selection of central pathways by regenerating optic fibers. Exp Neurol 1963;7:46–64.

Baizer JS, Kralj-Hans I, Glickstein M. Cerebellar lesions and prism adaptation in macaque monkeys. J Neurophysiol 1999;81:1960–1965.

Baker J, Gibson A, Glickstein M, Stein J. Visual cells in the pontine nuclei of the cat. J Physiol 1976:255:415–433.

Bremer F. Physiologie et pathologie du Corps Calleux. Arch Suisses Neurol Psychiatr 1956;78:31–87.

Barash S, Melikyan A, Sivakov A, Zhang M, Glickstein M, Thier P. Saccadic dysmetria and adaptation after lesions of the cerebellar cortex. J Neurosci 1999;19:1031–1039.

Berkley M, Wolf E, Glickstein M. Photic evoked potentials in the cat: Evidence for a direct geniculate input to visual IL Exp Neurol 1967;19:188–198.

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Doty RW, Glickstein M, Calvin WR. Lamination of the lateral geniculate nucleus in the squirrel monkey, Saimiri Sciureus. J Comp Neurol 1966;127:335–340.

Gibson A, Baker J, Mower G, Glickstein M. Corticopontine visual cells in area 18 of the cat. J Neuraphysiol 1978;41:484–495.

Glickstein M, et al. Temporal heart-rate patterns in anxious patients. Arch Neural Psychiatry 1957;78:101–106.

Glickstein M. A note on Wittenborn's factor analysis of Rorschach scoring categories. J Consult Psycho! 1959;23:69–75.

Glickstein M. Laminar structure of the dorsal lateral geniculate nucleus in the tree shrew (Tupaia glis). J Comp Neurol 1967;131:93–102.

Glickstein M. The discovery of the visual cortex. Sci Am 1988;256:118–127.

Glickstein M, Arora HA, Sperry RW Delayed-response performance following optic tract section, unilateral frontal lesion, and commissurotomy. J Comp Physiol Psycho! 1963;56:11–18.

Glickstein M, Cohen JL, Dixon B, Gibson A, Hollins M, LaBossiere E, Robinson F. Corticopontine visual projections in macaque monkeys. J Comp Neurol 1980;190:209–229.

Glickstein M, Gerrits N, Kralj-Hans I, Mercier B, Stein J, Voogd J. Visual ponto-cerebellar projections in the macaque. J Comp Neural 1994;349;51–72.

Glickstein M, King RA, Miller J, Berkley M. Cortical projections from the dorsal lateral geniculate nucleus of cats. J Comp Neural 1967;130:55–76.

Glickstein M, Kralj-Hans I, Legg C, Mercier B, Ramna-Rayan M, Vaudano E. The organisation of fibres within the rat basis pedunculi. Neurasci Lett 1992;135:75–77.

Glickstein M, May JG. Visual control of movement: The visual input to the pons and cerebellum. In Neff WD, ed. Progress in sensory physiology, vol. 7. Academic Press, 1982.

Glickstein M, May J, Buchbinder S. Visual control of the arm, the wrist, and the fingers; Pathways through the brain. Neuropsychologia 1997;36:981–1001.

Glickstein M, May J, Mercier B. Corticopontine projection in the macaque: The distribution of labelled cortical cells after large injections of horseradish peroxidase in the pontine nuclei. J Comp Neurol 1985;235:343–359.

Glickstein M, Milldot M.Retinoscopy and eye size. Science1970;168:605–606.

Glickstein M, Miller J, Smith OA Jr. Lateral geniculate nucleus and cerebral cortex: Evidence for a crossroad pathway. Science 1964;145:159–161.

Glickstein M, Rizzolatti G. Francesco Gennari and the structure of the cerebral cortex Trends Neurosci 1984;7:464–467.

Glickstein M, Secrist J. Interhemispheric transfer of reversal learning set. In Cerebral interhemispheric relations international colloquium held in Smolenice, June 1969. Bratislava, Czechoslovakia: Publishing House of Slovak Academy of Sciences, 1972;380–387.

Glickstein M, Sperry PW. Intermanual somesthetic transfer in split-brain rhesus monkeys. J Comp Physiol Psychol 1960;53:322–327.

Glickstein M, Stein J, King R. Visual input to the pontine nuclei. Science 1972;178:1110–1111.

Glickstein M, Voogd J. Lodewijk Bolk and the comparative anatomy of the cerebellum. Trends Neurosci 1995;18:206–210.

Glickstein M, Whitteridge D. D. Tatsuji Inouye and the mapping of the visual fields in the human cerebral cortex. Trends Neurosci 1987;9:310–313.

Goodale M, Milner D. Separate visual pathways for perception and action. Trends Neurosci 1962;15:20–25.

Jenkinson E, Glickstein M. Whiskers, barrels, and cortical efferent pathways in gap-crossing by rats. J Neurophysiol 2000;84:1781–1789.

Jung R, Kornhuber, eds. Neurophysiologie und Psychophysik des Visuellen Systems. Springer, Berlin, 1961.

Legg C, Mercier B, Glickstein M. Corticopontine projection in the rat: The distribution of labelled cortical cells after large injections of horseradish peroxidase in the pontine nuclei. J Comp Neurol 1989;286:427–441.

Luschei E, Johnson A, Glickstein M. Response of neurons in the motor cortex during performance of a simple repetitive arm movement. Nature 1968;217:190–191.

Luschei E, Saslow C, Glickstein M. Muscle potentials in reaction time. Exp Neurol 1967;18:429–442.

Mercier B, Legg C, Glickstein M. Basal ganglia and cerebellum receive different somatosensory information in rats. Proc Natl Acad Sci US A 1990; 87: 4388–4392.

Miller J, Glickstein M. Reaction time to cortical stimulation. Science 1964; 146: 1594–1596.

Miller JM, Glickstein M. Neural circuits involved in visuomotor reaction time in monkeys. J Neurophysiol 1967;30:399–414.

Miller JM, Glickstein M, Stebbins WC. Reduction of response latency in monkeys by a procedure of differential reinforcement. Psychonomic Sci 1966;5:177–178.

Mower G, Gibson A, Glickstein M. Tectopontine pathway in the cat: Laminar distribution of cells of origin and visual properties of target cells in dorsolateral pontine nucleus. J Neurophysiol 1979;42:1–15.

Mower G, Gibson A, Robinson F, Stein J, Glickstein M. Visual pontocerebellar projections in the cat. J Neurophysiol 1980;43:355–365.

Otsuka R, Hassler R. Über Aufbau und Gliederung der corticalen Sehsphäre bei der Katze. Archiv Psychiatrie Nervenkrankheiten 1962;203:212–234.

Robinson FR, Cohen JL, May JG, Sestokas A, Glickstein M. Cerebellar targets of visual pontine cells in the cat. J Comp Neurol 1984;223:471–482.

Ungerleider L, Mishkin M. Two cortical visual systems. In Ingle, et al, eds. Analysis of visual behavior. Cambridge, MA: MIT, 1982.

Vaudano E, Legg C, Glickstein M. Afferent and efferent connections of temporal association cortex in the rat. Eur J Neurosci 1991;3:317–330.

Walker AE. The primate thalamus. Chicago: University of Chicago Press, 1938.

Walls G.The problem of visual direction. Am J Optom1951;28:173–212.

Wittenborn JR. Factor analysis of Rorschach scoring categories. J Consult Psychol 1950;14:469–472.

Yeo C, Hardiman M, Glickstein M. Classical conditioning of the nictitating membrane response of the rabbit. I. Lesions of the cerebellar nuclei. Exp Brain Res 1985a;60:87–98.

Yeo C, Hardiman M, Glickstein M. Classical conditioning of the nictitating membrane response of the rabbit. II. Lesions of the cerebellar cortex. Exp Brain Res 1985b;60:99–113.

Yeo C, Hardiman M, Glickstein M. Classical conditioning of the nictitating membrane response of the rabbit. III. Connections of cerebellar lobule HVI. Exp Brain Res 1985c;60:114–126.

Yeo C, Hardiman M, Glickstein M. Classical conditioning of the nictitating membrane response of the rabbit. IV Lesions of the inferior olive. Exp Brain Res 1986;63:81–92.

Translations

Cajal SRY. The structure of the retina. Translated by Thorpe AS, Glickstein M. Springfield, IL: Charles C. Thomas, 1972.

Inouye T (with Manfried Fahle). Visual disturbances following gunshot wounds of the cortico visual areas. Brain Suppl 2000;123.

Carlton C. Hunt

BORN:

Waterbury, Connecticut

August 11, 1918

EDUCATION:

Columbia University, B.S. (1939)

Cornell University Medical College, M.D. (1942)

APPOINTMENTS:

National Research Council Fellow, Johns Hopkins School of Medicine (1946)

Associate, Rockefeller Institute (1952)

Professor, Albert Einstein School of Medicine (1955)

Head, Department of Physiology, University of Utah (1957)

Head, Department of Physiology, Yale University School of Medicine (1964)

Head, Department of Physiology, Washington University School of Medicine (1968)

Visiting Professor, Laboratory of Neurophysiology, College de France (1983)

Professor Emeritus, University of North Carolina School of Medicine (1995)

Adjunct Investigator, Neural Mechanisms Section, National Institute of Neurological Disorders and Stroke (2001)

HONORS AND AWARDS (SELECTED)

Distinguished Alumni Award, Cornell University Medical College (1996)

Distinguished Service Award, Association of Chairmen of Physiology (1997)

Carlton Hunt began his scientific career in close collaboration with Stephen Kuffler at the Wilmer Eye Institute. He became a leading expert on the muscle spindle,

a sense organ that detects changes in muscle length and movement. Working with Kuffler, he showed how the central nervous system regulates the intricate behavior of these sense organs. In later work, he elucidated the spindle's role in sensing the position of limbs in space. A gifted administrator, he also built three excellent departments of physiology at three different universities, all prior to the emergence of neuroscience as an interdisciplinary activity.

Carlton C. Hunt

At the age of 87, I can now look back over more than 50 years since beginning my career as a neuroscientist. Indeed, I entered the field well before it was called “neuroscience.” Although several medical and scientific disciplines bore the preface “neuro” in my student days (such as neurology, neuroanatomy, and neurophysiology), the idea of a field encompassing all the complex aspects of the nervous system had yet to evolve.

Chance and timing played major roles in my career. They led to my collaboration with an inspiring mentor who shaped the entire course of my professional life. In 1947, I received a fellowship in neurology from the National Research Council to go to Johns Hopkins. Modeled on the Welch Fellowship in internal medicine, this award provided support for 3 years. My original intention was to do research with A.M. Harvey, who then headed the Department of Medicine. However, Harvey suggested that I spend my first year working with Stephen Kuffler.

Harvey had met him in Sydney during the war when Steve was working with Jack Eccles at the Kanematsu Institute of Pathology. After the 1938 German invasion of Austria, Steve had escaped to England and then moved on to Australia. A recent medical school graduate, he then had no research experience and found laboratory work difficult. Several members of Eccles' group, including Eccles himself, worried that Steve might not succeed in science. Then in 1939, Bernard Katz, a fellow refugee, joined the research group. When Katz found that Steve was, as he put it, “somewhat bewildered” by the complicated terminology and interpretation of electric tracings, he taught Steve what he needed to know for experimental work. An apt pupil, Steve soon mastered the skills necessary to do first-rate research. As Katz later recalled: “Once he had started on his single nerve-muscle fiber preparation, Eccles and I felt he had clearly outrun us.”

At the end of the war, Steve left Australia for America where he first worked in Chicago with Ralph Gerard before coming to Johns Hopkins. Although only 5 years older than I, Steve was already an experienced and skillful investigator. His laboratory was located in the basement of the Wilmer Eye Institute. We met, had a good talk, and agreed to collaborate. Thus began 4 wonderful years of experimental work during which Steve introduced me to the challenge and joy of research. Despite differences in our backgrounds, we developed an extraordinarily productive, harmonious, and close relationship. Writing papers together was a collaborative effort. We read our respective drafts back and forth to each other until a consensus was reached. Steve had small hands and remarkable dexterity. His dissections were elegant and swift. He had a light touch in every sense of the word. Steve asked penetrating questions and gave advice that was never heavy handed. In addition, he had a rare talent for designing the experiments most likely to provide clear answers to difficult question.

Steve taught me how to think about biological problems, and there was much laughter between us. A complex person with a subtle sense of humor and an aversion to pomposity, Steve became a lifelong friend. As his scientific reputation grew, he often joked about the distinguished institutions with which he was associated. When Steve was elected a non-resident fellow at the Salk Institute, I asked him what he did during his visits there. His answer came without hesitation: “I sit and salk.” I have always been grateful to Mac Harvey for giving me the chance to work with the person who inspired my entire research career.

Early Years

Nothing in my background or upbringing suggested that I would become a scientist. My parents divorced when I was only a few years old. My younger sister died of diphtheria at the age of 3. Her premature death and my mother's profound grief left a deep impression on me. I grew up as the only child of a working mother who was devoted to me. My father appeared only on annual visits. His family's wealth, which was largely dissipated before I was born, had come from investments in the Erie Canal. As a result, several generations of my paternal ancestors had found it unnecessary to work.

Having a mother with a full-time job, no siblings, and an absent father meant that my childhood was rather isolated. But friends and school work kept me occupied, and I learned to be independent at an early age. My faithful companion was a beautiful German shepherd dog who followed me when I rode to school on my bicycle and waited for me at the school's front door until classes were dismissed. Friendship with a local physician proved important to my future. When I was still just a young boy, Dr. Wheaton took me with him on house calls and gave me access to his medical library. These experiences stimulated my interest in medicine.

Education and Training

I graduated from high school in 1935 at the age of 16 during the depths of the Depression. At the time, my mother's financial resources were limited, and my father was unwilling to pay for my further education. When I discussed my hopes for college with my father, his reply was unusual for a Yale graduate: “I don't know why you'd want to do that; it never did me much good.” Although he was later proud of my accomplishments, my father certainly never pressured me to go into medicine or academe.

Despite my youth, Columbia University offered me a scholarship. To minimize living expenses, my mother and I moved from New Jersey to New York City. A program called “professional options” allowed me to apply to medical school after only 3 years in college. Continuing to live at home was an economic necessity. On graduating, I applied to Cornell University Medical College and the College of Physicians and Surgeons at Columbia. Although my grades were undistinguished, I was immediately accepted at Cornell whereas Columbia insisted that I complete a fourth year of college. Impatient to begin my medical studies, I chose Cornell.

My paternal grandfather (whose own formal education had ended with expulsion from a private secondary school for adolescent misbehavior) agreed to pay the then relatively modest tuition. Cornell University Medical College turned out to be a marvelous place for me. The teaching was excellent. As a result, I became a serious and successful student. Although grades were registered, unless our marks fell below an acceptable level we never knew what they were. There was little overt competition among classmates. Preclinical subjects dominated the first 2 years of study. Basic science fascinated me, and I found the physiology course taught by Joseph Hinsey especially interesting. A forceful and engaging person, he had done important work on the muscle spindle, a sense organ that would later become my major research interest.

Laboratory experiments were an integral part of the physiology course. They were by no means easy or trivial and often lasted well into the evenings. To this day, I can still recall many of them. Although I had been a mediocre student at Columbia, my grades at Cornell were good enough for me to win election to AOA, the medical honor society.

Clinical Training

Although I remained interested in basic science, clinical work became my primary commitment. Internal medicine was especially appealing to me. When I graduated from medical school in June of 1942, I decided to seek an internship in that specialty. David Barr, the head of medicine at Cornell, invited me to join his housestaff. He was an inspiring teacher and clinician, and I enjoyed my first year of training. Interns and residents had a great deal of responsibility for patient care on the wards of The New York Hospital. We worked long, hard hours and did all the laboratory tests ourselves.

Although this experience was satisfying in some ways, from a therapeutic perspective it was frustrating. We could seldom treat life-threatening illnesses effectively. Nonetheless, there were superb clinicians among the faculty who made accurate diagnoses with the limited tools and simple tests at their disposal.

Army Service 1942–1946

Six months after Pearl Harbor, I received my medical degree and became an intern in internal medicine at The New York Hospital. When this internship year ended, David Barr urged me to continue my residency. But I felt the need to participate in the war and so decided to enlist in the army. I joined the 56th General Hospital whose staff was comprised of young doctors from Johns Hopkins and Cornell—some of whom I had known from medical school.

Our group was shipped to Britain as a general hospital. Although there was only one psychiatrist on the staff, the unit was abruptly designated a psychiatric facility. We were all assigned to treat soldiers whose mental illnesses had made them unfit for military service. Our job was to diagnose their psychiatric disorders and to keep these patients hospitalized until the necessary arrangements had been made to ship them home. Despite their serious mental problems, patients were sometimes expected to line up for inspections and stand at attention by the foot of their beds. Making them comply was not an easy task. This bizarre procedure made me wonder who was crazier—the patients or our commanding officers.

Our next assignment was to run a general hospital near Bristol. This period of useful work ended in May of 1944 when we were sent to a town near Liverpool just before the invasion of Normandy. Weeks of enforced idleness—broken by recurrent marching exercises—followed. After landing on Omaha Beach 2 weeks after D-Day, we moved inland and set up a tent hospital in pastures among the few surviving cows. In addition to American soldiers, our patients included German prisoners and French civilians. My work was to triage patients so that they would receive appropriate care as soon as possible. During this time, I became a patient myself due to a disease often fatal then: meningococcal septicemia. Early one morning, I awoke with severe chills and a high fever. Fortunately, I responded to sulfadiazine treatment and made a prompt recovery.

Three months later, we were transferred to Liege, Belgium, to staff a busy general hospital. After VE Day, our unit moved to Rouen in Normandy where we awaited transfer to the Pacific theater. Luckily for us, hostilities ended with the atomic bombings of Hiroshima and Nagasaki. Horrible though these events were, I welcomed the end of the war. Army life, with its mixture of frantic activity and excruciating boredom, taught me the value of being able to control my own time. I was very grateful to return to civilian life.

Starting Out in Research 1949–1952

On returning to my residency at The New York Hospital after the war, I felt severed from my academic roots and decided to seek more experience in the basic sciences. After finishing a year as assistant resident, my friend and medical school classmate Walter Riker helped me get a fellowship in the pharmacology department. Although I enjoyed this experience, I was still attracted to clinical medicine. After seeing a patient with partial muscle paralysis, I became interested in diseases affecting neuromuscular transmission such as myasthenia gravis. At this point, I decided to apply for the National Research Council fellowship that would lead to my collaboration with Steve Kuffler.

Our work together began, with three of us in his basement laboratory: me, Steve, and Bob Bosler, a skilled technician who vastly improved our primitive electronic equipment. At the outset, our setup was barely adequate, and we often borrowed a 35-mm camera from Mac Harvey to photograph our oscilloscope screen. We used an old, continuous-feed camera that jammed often enough to lose data from long and successful experiments. Steve and I investigated the function of small-diameter ventral (gamma) root axons. There had been suggestions, starting with Langley, that they might provide the motor innervation to muscle spindles. In accordance with this idea, O'Leary, Heinbecker, and Bishop had found that the stimulation of gamma axons, when added to the stimulation of larger motor neurons, produced no significant increase in muscle tension.

Fig. 1. C. C. Hunt and S. W. Kuffler at Johns Hopkins.

Leksell had discovered that stimulating these fibers after most of the larger ventral root axons had been blocked caused an increased firing of what were presumably sensory axons in nerves to muscle. This observation supported the idea that they supplied motor innervation to spindles. In contrast to this mammalian innervation, Laporte, Ransmeier, and Kuffler had shown that small motor neurons in frog innervated tonic extrafusal fibers.

Steve suggested we study the function of mammalian small diameter ventral root fibers by subdividing filaments in ventral roots until we had isolated single small-diameter gamma axons. We developed a preparation using cat in which single sensory axons from muscle were also isolated in subdivided dorsal root filaments. This was not very difficult. We found that stimulation of the small ventral root axons produced no detectable tension in the muscle but increased the afferent discharge in nerves to muscle.

I suggested we try isolating single sensory axons from spindles in dorsal root filaments innervated by our isolated gamma axons. Although Steve was a bit skeptical about my idea, the preparation proved to be relatively easy. We were on our way. Using this technique, we then analyzed the motor responses of muscle spindles to their efferent innervation in detail. It turned out that about 30% of the ventral root outflow in cat was fusimotor and concerned with regulation of muscle spindles, rather than with generation of muscle tension.

Fusimotor stimulation facilitated the response of spindle afferents to muscle stretch. Up to six gamma motor axons could be isolated onto a single spindle and stimulated without producing any significant muscle tension. The fusimotor axons, in turn, showed reflex motor responses very different from those produced in motor axons to skeletal muscles. This finding opened the way to a number of studies on the motor innervation of spindles. The double single fiber technique we had developed was widely used.

Muscle spindles are the principal sense organs for detecting changes in muscle length. We learned that the small gamma fusimotor axons regulate that sense organ exclusively. They provide feedback to the control of muscle tension and also impart information about muscle length to the nervous system. This research turned out to be of great importance to the understanding of mammalian spinal cord physiology. Many years later, I was delighted to learn that these studies were among Steve's favorite experiments.

After 3 years, Steve began studying ganglion cells in the cat retina and left the spindle studies to me. This pattern was typical of Steve's approach to research. He would open a new area with the collaboration of a younger colleague and then, after several years, he would open another field of inquiry—leaving the problem he had first explored to his collaborator. Steve was a brilliant and generous scientific explorer who was happy to let others answer the questions he was the first to ask. Through his unique research style, he had a profound impact on neurobiology, not only through his own work but also through the research of the many scientists he trained, inspired, and influenced. In my time with him, Steve liberated me from my clinical interests and made me a seasoned researcher.

During my fourth and last year in Kuffler's laboratory, two lively young researchers arrived who would later win the 1981 Nobel Prize: David Hubel and Torsten Wiesel. To begin with, they shared space with me and Steve. Writing in Volume 1 of this series, Hubel noted

Steve's main influence on Torsten and me was by example. He did an experiment every day, and he did virtually everything himself—dissections, recording, and writing the papers.

In their joint memoir, Brain and Visual Perception, each discussed Steve's effect on their collaboration. Hubel commented

what guided and sustained us was the attitude of Steve Kuffler ... (who) played a role that was crucial for both Torsten and me, in terms both of its day to day importance and the fact that it was sustained over some forty years.

Wiesel wrote of his wish to provide young scientists with “the opportunity that Steve Kuffler so generously gave David and me, the freedom to explore, the freedom to fail, the freedom to follow where the experiments lead you.”

When I spoke at Steve's memorial service in 1980, I mentioned the Latin phrase used by Dutch historian Johan Huizinga to describe the basic human instinct for play “Homo ludens.” Steve brought this element to research, which always made collaborating with him both intellectually rewarding and great fun. As Bernard Katz wrote in his Royal Society memoir of Steve: “(he) had the great good fortune to find endless excitement in his life's work"—an excitement that Steve transmitted to many others.

The Rockefeller Institute 1952–1955

In 1955, I felt it was time to strike out on my own. A meeting with Herbert Gasser and David Lloyd at the Rockefeller Institute led to my being offered a position there. Lloyd was an important figure in spinal cord physiology. His work provided the essential bridge between Sherrington's largely behavioral studies on spinal reflexes and subsequent research by Eccles and others using intracellular recording.

Fig. 2. H. S. Gasser at the Rockefeller Institute.

Herbert Gasser had won the 1944 Nobel Prize in Physiology or Medicine with Joseph Erlanger for their studies of nerve function. He was a remarkable man of rare modesty and high integrity. Typical of his character was his comment about winning the prize: “Dismay rather than elation was my immediate reaction.” So alien was self-promotion to Gasser that when he was nominated in 1938, he refused Erlanger's request to provide copies of his papers to the Nobel Committee. His rationale was uncompromising.

It must be well known in Stockholm that nomination for the Nobel prize coming to hand with full information must be made with the cooperation of the nominee. One is thus forced into the position of appearing, at least in some measure, to nominate oneself … my considered opinion about becoming a party to the proposal impels me into not consenting to do so.

Gasser had first encountered Joseph Erlanger as his professor of physiology at the University of Wisconsin. In his autobiographical memoir, he recalled: “the subject matter Erlanger presented differed so widely from what was anticipated that it amounted to a revelation.” Wisconsin then offered only 2 years of medical school. Gasser believed that Johns Hopkins School of Medicine, with its scholarly focus, was the ideal place to finish his medical education. For financial and personal reasons, his father wanted him to stay in the middle west. However, as Gasser wrote of himself, “(his) determination was unshakeable.” He eventually managed to gain his father's support and graduated from Johns Hopkins in 1915.

Two years later, Erlanger offered Gasser a position in the Department of Physiology at the Washington University School of Medicine. The crucial technical breakthrough for their research came in 1920 with the development of the cathode ray tube sufficiently sensitive to record nerve potentials. Writing some 40 years later, he recalled, “The most difficult step in opening up a new field had been taken. Ever afterward, Gasser never had any doubt about the direction he would follow.”

Although he already saw himself primarily as a physiologist, in 1921 Gasser agreed to become head of the Department of Pharmacology. A close colleague and collaborator, Dr. Helen Graham, vividly described him in those years:

To Dr. Gasser, an integral aspect of research is discussion and, in those days, when he had the right partner, discussion never seemed to weary him … his indifference to time and his ability to make colleagues ignore it not infrequently prolonged the Monday afternoon seminars.

In 1931, Gasser accepted a position as head of the Department of Physiology at Cornell University Medical College. Four years later, he agreed—with some reluctance—to become the second director of the Rockefeller Institute. Gasser received assurances that an experienced staff would allow him time for research. He was told that the director's most important function was “the maintenance of complete freedom to the investigators. In favor of this essential goal he had strong convictions.” The strength of this conviction would mark his 18-year tenure as Director. Gasser's scientific interests influenced the Institute's research focus. For the first time, the structure and function of the nervous system became an important subject of study there.

By the time I arrived at the Institute in 1952, Gasser had been the director for 17 years and was just a year away from retirement. Despite his administrative duties, he had continued laboratory work. I found that Gasser's incisive intellect was combined with an unusual openness to new ideas. As George Corner noted:

Investigators who went to him for counsel always left impressed by the intellectual vigor and scientific knowledge he brought to their problems, no matter what their field of science.

Gasser attributed his method of choosing research subjects to Dr. J.J. Abel (his professor of pharmacology at Johns Hopkins) who told him: “there are two times for working on a problem; before anyone has thought of it and after everyone else has left it.” His colleague David Lloyd remarked: “As a result, Gasser was always the innovator or the finalist.”

He became my ideal of a leader with complete integrity. As Gasser's friend and colleague Joseph Hinsey wrote, “Integrity was a passion with him and he was impatient with sham and pretense.” At first meeting, he seemed rather reserved and austere. But as I came to know him, his warmth and graciousness emerged. On becoming Director of the Institute, Gasser had been given the use of an elegant apartment on the upper East Side. He enjoyed entertaining visitors there or in good restaurants. Deciding where to go for dinner involved his carefully perusing an extensive collection of restaurant guides.

A unique feature of the Institute at that time was an elegant faculty dining room. It was a high-ceilinged rectangular space with large windows overlooking the East River. Jean Lous David's splendid double portrait of the chemist Lavoisier and his wife presided over one end of the room. Tables set with white cloths and napkins accommodated 8 to 12 people. Uniformed waitresses served the meals. Members of the Institute tended to congregate in luncheon groups with a common research interest. But some, including me, preferred to move around to various tables and become acquainted with researchers in other fields. I can still recall listening to lively discussions with Maclyn McCarthy and Peyton Rous.

Central to Gasser's directorship was a belief that scientists should have absolute freedom in choosing their research subjects. One of his major concerns was that accepting government grants might compromise this freedom. As a matter of principle, he refused federal funds to reimburse the awardees for their laboratory expenses. Gasser's comments at the time reflected his commitment to intellectual freedom:

The product of the Rockefeller Institute is new knowledge. It cannot be forecast and it cannot be achieved through administrative direction. All that can be done is to create optimal conditions for its production … this means fostering individuals and allowing them freedom … grants are made in the interest of defined projects … Projects, by definition, are not consonant with free inquiry.

On his retirement as director in 1953, Gasser returned to the laboratory on a full-time basis. Concerned that his experimental approach might be out of date, Gasser turned to new techniques such as electron microscopy. This allowed him to accurately measure the size of unmyelinated axons. During these years, he made important discoveries about how nerve impulses were conducted. Gasser found that the speed of conduction speed was directly proportional to the size of the axon coming from the sense organ in both myelinated and unmyelinated sensory fibers. Writing, as usual, in the third person, Gasser gave a detailed account of how he chose what to study in retirement:

between the cessation and resumption of (his) experimental activity, the outlook in neurophysiology had greatly changed. A brilliant new school of nerve physiologists had grown up with its attention focused on single fibers … Belatedly to gain proficiency in the new techniques … had no attraction.

At the interruption of the experiments on the differentiation of nerve fibers there was much left unfinished and much calling for reassessment … Here was left a sector … where he could enter without encountering much competition, one for which he had the due insight and training, and one to which he had long been dedicated.

He started along the old line without the aid of a research associate. Thus his freedom to pick up … the loose ends left from the past was unrestricted by any obligation to the welfare of an assistant.

Since our laboratories were close together, I frequently visited him to compare our data. Gasser occasionally came down to talk with me. His keen observations and critical intelligence made these informal encounters extremely worthwhile. During my time at the Institute, I studied the diameters of sensory axons in muscle spindles and Golgi tendon organs. I also worked on spinal cord physiology using the cellular approaches David Lloyd had developed.

Archie Mcintyre came to our laboratory from New Zealand. He collaborated with Lloyd and me on muscle spindle and spinal cord studies. An exceptionally able investigator, Archie later became an internationally respected authority on sensory receptors. His insight into scientific problems and grasp of new research techniques later made him a major influence on the development of neurophysiology in New Zealand and Australia. Archie loved experimental work and, like me, enjoyed Herbert Gasser's visits to our laboratory. Gasser once casually mentioned the fact that there was little known about the properties of the cutaneous sense organs innervated by peripheral nerves. As a result, Archie and I performed a series of experiments to explore this question and wrote three papers on the subject.

A letter Herbert Gasser wrote to me in 1960, just a year before he suffered a devastating stroke, reveals his ongoing interest in our research. His comments were those of an interested and supportive colleague, rather than those of a world famous expert.

I've been considering your and Archie's very impressive papers. They have a bearing on ideas I am now entertaining in an attempt to straighten out the size-velocity tangle… . At the moment, the velocities indicated in the composition of whole nerve potentials seem to be as full of deceptions as mincemeat is full of raisins … I would love to know where the top velocity comes in your estimation …

The use of a cooking metaphor to describe a complex scientific problem was typical of Gasser's unpretentious practicality.

In his introduction to the second edition of Erlanger and Gasser's book Electrical Signs of Nervous Activity, David Lloyd wrote

The milestones of the past and those of the present are markers of progress, and a milestone passed is nonetheless of enduring value to those who would follow the path of learning.

When his career was drawing to a close and mine was beginning, Herbert Gasser gave me a sense of where the path of learning might take me.

The Albert Einstein College of Medicine 1955–1957

In 1955, Henry Lawson invited me to take a position in the Department of Physiology at the newly founded Albert Einstein School of Medicine. After spending the previous years at well-established institutions, I thought this job would be an exciting adventure. The school opened its doors just after my arrival. When classes began, many buildings were still unfinished. As winter approached, we had to wear coats in the unheated lecture rooms. To demonstrate intracellular potentials for the students, we used micropipettes fabricated in another building and carried to the classrooms.

Without ever having been an associate professor, I received an appointment as a full professor and was invited to join the Executive Faculty. Among its outstanding members were Irving London in medicine, A.I. Gilman (father of A.G. Gilman) in pharmacology, and Ernst and Bertha Sharrer in anatomy. A.S. Paintal came from New Delhi to collaborate with me. We studied the reflex activity of gamma fibers to muscle nerves and called them fusimotor axons. The term was generally adopted, and the nomenclature remains far better known than our research on this topic.

The University of Utah, 1957–1964

In 1957, I received an offer to head the Department of Physiology at the University of Utah. I had never given much thought to taking such a job. When I asked Herbert Gasser's advice, he said: “You know, Cuy, you are really pulling the cart in that position.”

Although the medical school's facilities were poor, and state support inadequate, I found this position attractive. There was a strong faculty, including Max Wintrobe in medicine, Louis Goodman in pharmacology, Emil Smith in biochemistry, and Bill Carnes in pathology. The western environment, with its clear air and beautiful mountains, seemed healthy and refreshing after the decade I had spent in Baltimore and New York. A chance to recruit able scientists and to create an ambiance conducive to new directions in physiology was appealing. I agreed to take the job.

Soon, the easy availability of federal funds made the minimal level of state support less of a problem, and the department began to thrive. The group I recruited was highly productive. As Bob Martin wrote of that period

The scientific activity in the physiology department at Utah between 1958 and 1965 was amazing. In the beginning, Cuy Hunt, Ed Perl, Carlos Eyzaguirre, and myself formed the core of the neurophysiology group. Charles Edwards and George Eisenman later joined the faculty as well. The list of visiting scientists and postdoctoral fellows included Preet Gill, Motoy Kuno, Alberto Mallart, Archie Mcintyre, Autar Paintal, Guillermo Pilar, Akira and Noriko Takeuchi, and Koji Uchizoni. During that period we contributed more than forty papers to J. Physiology, the journal of choice for cellular physiology.

Ed Perl did pioneering studies on nociception. Martin and Pilar worked on the ciliary ganglion, which developed into a major field of inquiry. Lynn Landmesser came as a postdoctoral fellow and worked with Pilar. Dick Wylie joined me to study reptilian spindles. One memorable symposium I organized brought a galaxy of neuronal types to a mountain lodge for an informal scientific meeting combined with excellent skiing.

Our physiology course was unusual. Each faculty member taught the material he or she found of particular interest. In order to demonstrate photoreceptor responses, we had limulus shipped from Wood's Hole. This personal style of teaching physiology introduced students to the excitement of laboratory research.

Despite my administrative responsibilities, I continued to work in the laboratory. I analyzed the effects of axotomy on frog sympathetic ganglia using electron microscopy to study changes in structure and electrophysiology to study changes in function. The department's atmosphere was stimulating, and Bernard Katz's periodic visits from London were memorable.

In 1962, I decided to take a sabbatical and work in Bernard Katz's laboratory at University College. Most of the fellows there were Americans, and we worked in pairs. My partner was Phil Nelson who was then visiting from the National Institute of Health (NIH). He and I were given a small lab and a research problem that Katz supervised during our stay. Every weekday morning, he made rounds and reviewed our progress. Birks, Katz, and Miledi had described the changes in amphibian neuromuscular junction after presynaptic denervation. We studied the changes in structure and function of frog sympathetic ganglion cells that resulted from cutting their presynaptic nerve fibers. Phil and I then compared these findings with those that occurred in a nerve-nerve synapse. This sojourn gave me a brief but welcome respite from administrative responsibilities.

The Yale School of Medicine 1964–1967

When I returned to Salt Lake City after my sabbatical year, I wanted to make a fresh start. In 1964, I received an offer from the Yale School of Medicine to head its Department of Physiology. The Search Committee seemed eager to hire a person capable of creating a first-rate department, and the position was an open-ended appointment. A tradition of excellence had never taken root in this department, and some of its tenured professors were of distinctly dubious quality.

I was determined to recruit new and promising faculty members. However, the complications involved in effecting this transformation were not immediately apparent to me. Chief among them were academic politics and the medical school's position as a stepchild of the university. It had always been far less prominent and considerably less well endowed than Yale's undergraduate college. These factors were to make my task far more difficult.

My first appointment was a superb administrative associate, Harriet Batchelder. She was a seasoned veteran, a wise woman who knew Yale well. Politically savvy, deeply loyal, and highly organized, she quickly became essential to the smooth functioning of the department. The first and most important faculty member I recruited was Joe Hoffman. I thought general physiology, membrane transport, and cellular neurophysiology would make good intellectual combination. Joe was a leader in the field of membrane transport. He also had excellent judgment about science and scientists. Although it took me some time to persuade him to leave the NIH for Yale, I finally succeeded in doing so. He was a great asset to the department during my time at Yale and remains so to this day.

The medical school's administrative rules required that only department faculty members of equivalent or higher rank could vote on new appointments. With Joe's arrival, five full professors of physiology had voting rights. As a result, when I proposed new appointments, we were often faced with three negative votes to our two positive ones. Nevertheless, within 2 years of my arrival, Joe and I had managed to recruit a number of excellent people. These included Bob Martin, John Nicholls, Knox Chandler, Peter Curran, Carolyn and Clifford Slayman, and Dennis Baylor (then a postdoctoral fellow in another Yale department).

Along with running the department, I continued my laboratory work. At Gerhard Geibisch's suggestion, I invited Peter Heistracher to come from Vienna and collaborate with me. We studied contractile activation and deactivation of muscle fibers using short extrafusal fibers in snake skin. He and I also did preliminary studies on cat tail muscles that proved to be important to my later research.

Bill Betz, who was then a medical student at Washington University, wanted to do research in the department, so I invited him to come. As a result of this interval, Bill completed a doctorate in physiology and eventually became head of the physiology department at the University of Colorado. Another young scientist, Tony Ridge, came from Bristol to work in my lab and would later return to collaborate with me at Washington University.

Although my effort to upgrade the department looked successful to the outside world, reactions within the department were considerably less enthusiastic. My standards and administrative style were very different from those of my predecessors. A number of long entrenched professors felt threatened by the influx of new faculty members. And though I had been appointed chairman to upgrade the department, certain senior faculty members felt I was pursuing that goal far too aggressively.

The school of medicine was a highly complex institution with many overlapping areas of responsibility. For instance, a university-wide committee oversaw appointments and promotions within the medical school. The most dramatic dispute during my tenure as chairman involved the promotion of a longtime faculty member with strong Yale social connections and a highly controversial research focus. Jose Delgado had come to the department from Spain in 1950 at John Fulton's invitation. For some years, he had been implanting brain stimulators to modify behavior in animals and, more ethically questionable, in mental patients.

Delgado's most famous experiment took place in Cordova, Spain. He implanted a brain stimulator in a bull, brought the animal into an arena, and waved a cape in its direction. When the bull charged, he pushed a button, thereby activating the stimulator to stop its forward motion. In 1965, under the headline “Matador with a Radio Stops Charging Bull,” The New York Times reported this sensational feat in detail. Two photos of the event—one showing the bull charging, the other picturing the animal stopped in its tracks—were published in a number of journals. However, a keen observer noted that shadows in the two photographs indicated a time lapse of hours rather than seconds between the two events.

I was reluctant to promote Delgado to the rank of full professor for several reasons. I had doubts about his judgment and qualifications for the position. A third, and more serious, reservation was the dubious ethical goal of his work. Delgado wanted to use brain stimulators as a means to control human behavior in a broader social context. He stated “Functions traditionally related to the psyche, such as friendliness, pleasure or verbal expression, can be induced, modified, and inhibited by direct stimulation to the brain.” Delgado also asserted that he had been able to “play” monkeys and cats “like little electronic toys.” Some years later, he wrote a book whose title made his ambition clear: Physical Control of the Mind: Toward a Psychocivilized Society.

After several prominent scientists I contacted had sent negative evaluations of his work, the Promotions Committee decided the wrong people had been asked for advice. They obtained more positive letters from behavioral scientists. I threatened to resign if Delgado were promoted over my objections. In the end, a rather unusual compromise was reached. He was transferred to, and promoted in, the Department of Psychiatry.

In 1966, I was asked to chair an Ad Hoc Committee on Departmental Reorganization. After extended deliberations, some members suggested that anatomy, microbiology, and physiology be merged into a single administrative entity. Although this proposal was eventually rejected, it made me feel quite uneasy about my future as a department head at Yale. In addition, Dean Vernon Lippard, who had recruited me, retired. In his first speech to the faculty, Dr. Lippard's successor stated that, under his leadership, the Yale School of Medicine would not become a center for what he called “subhuman biology.”

I suspected that such a negative view of basic science might bode ill for the future. The introduction of rotating chairmanships in the preclinical departments also hastened my departure. My strengths were to recruit promising faculty members and to foster an ambiance to a productive and collegial group—tasks that could only be accomplished in the long term. Being rotated out of a position at which I excelled did not appeal to me.

So, after leading a revolution that lasted just 3 years, I accepted an offer to head the Physiology Department at the Washington University School of Medicine. Some Yale faculty members were openly incredulous that I was willing to leave an Ivy League school for a position at what they considered an obscure midwestern institution.

The Washington University School of Medicine 1967–1983

Over the years, I had known a number of excellent professors from the Washington University School of Medicine including Herbert Gasser, George Bishop, Jim O'Leary, Henry Schwartz, and Bill Landau. In 1967, it was an institution with a great scientific tradition and a refreshing lack of pretension. In contrast to Yale, the Washington University School of Medicine was more prominent and better funded than the undergraduate college. An Executive Faculty, composed of permanent department heads, governed the school and elected the dean on an annual basis.

The Department of Physiology, where Erlanger and Gasser did their pioneering studies on nerve, had a dwindling faculty and antiquated facilities. However, by the time I came, plans for the McDonnell Basic Sciences Building had been finalized. The new space it provided would be ample for incoming faculty members. Unlike Yale, there were far fewer vested interests to contend with in upgrading the department. And although St. Louis was a much larger city than New Haven, the social atmosphere there was far more informal and friendly.

The dean, Ken King, was a most unusual person. A highly intelligent man with a dry sense of humor, keen powers of observation, and quiet integrity, he enjoyed the trust and respect of the Executive Faculty. We all had great confidence in his judgment. As a result, he was reelected Dean annually for over 20 years.

After my experience at Yale, I found the attitudes of my fellow members of the Executive Faculty quite amazing. They actually made me feel at home in practical ways. For example, Oliver Lowry, the head of pharmacology, suggested that since the Department of Physiology was in such dire need of renovation and expansion, I should be given a larger portion of institutional funds. This was a great help both in building new space and in renovating laboratories that had long been in a dilapidated state.

On my arrival in 1967, the “spirit of the school” as Carl Cori had once called it, was still exceptional. Department heads were concerned about issues beyond their own immediate spheres of influence. They cared about the medical school's general welfare. At that time, the Executive Faculty was in the midst of a generational change. Several other new department heads came at about the same time I did. Roy Vagelos had already succeeded Carl Cori in biochemistry, and just before my arrival, Max Cowan was appointed to be the head of anatomy. Max and I became close colleagues and good friends. We shared mutual interests in science as well as common goals in building our respective departments. So, we decided to collaborate by organizing joint seminars and choosing faculty members from both our departments to serve on search committees. In the essay, that Max wrote for Volume 4 of this series, he made mention of our collegial relationship, crediting me for removing “all the usual barriers that so commonly divide academic departments.” I would only add that this was a mutual effort.

As had been the case at Yale, choosing the right administrative associate proved crucial to my success as a new department head. I hired a young woman, Jackie Baker, who was highly competent and absolutely trustworthy. I knew that with her help the department would run smoothly. My first academic appointment was Mordy Blaustein. A graduate of Washington University Medical School, his familiarity with the institution was a real asset to me. Mordy contributed in important ways to the department's growth. He gave me astute advice about scientific developments and the outstanding people in various fields. Despite Washington University's unfashionable midwestern location, the department steadily grew and improved. As excellent new faculty members arrived, persuading other people to move became easier. In addition to Mordy, my recruits included Paul De Weer, Luis Reuss and Elsa Bello-Reuss, Dale Purves, Nigel Daw, Josh Sanes, and Jeff Lichtman. When federal funds were not available, Ken King provided me with funds from the Dean's Office to purchase new equipment for incoming faculty.

The varied interests among new faculty members broadened the department's range of research. Mordy Blaustein worked on synaptosomes and later on Na+ca² exchange, Paul De Weer did research on the sodium/potassium pump, Luis Reuss studied epithelial transport, Elsa Bello-Reuss worked on renal tubules, Nigel Daw focused on vision, Dale Purves did research on neurons in the sympathetic chain, Josh Sanes studied molecules in basal lamina that determined sites of neuromuscular innervation, and Jeff Lichtman (who received his Ph.D. from our department) worked in cellular neurophysiology.

Roy Costantin was an outstanding addition to our group. He had received his M.D. from Columbia and then worked with Richard Adrian in the physiology laboratory at Cambridge before joining the faculty at his alma mater. Roy had done excellent research on muscle and was clearly a scientist of great promise. I offered him an appointment that he quickly accepted.

A short time later, Roy called me and suggested that because he had just received a diagnosis of malignant melanoma, I might want to reconsider hiring him. I assured Roy that this made no difference in my desire to have him join the department. Within a short time, he gained his colleagues' affection and admiration. Before the disease recurred, Roy did superb work in both teaching and research. His papers remain classics in the field. Roy's untimely death was a tragedy for his family and a great loss to many friends and colleagues.

Some months later, we organized a symposium in his memory. Roy's chief interest was basic problems of muscle physiology. Scientists from both sides of the Atlantic, many of whom had collaborated with him, were invited to attend. Richard Adrian and Andrew Huxley came from England for the occasion. Rather than simply being a memorial service, this gathering was also a working scientific meeting. References to Roy and his contributions to the field were woven naturally into each speaker's talk. The bitterness of losing him far too soon was tempered by a sense of Roy's ongoing influence and the enduring affection of his friends.

One veteran faculty member joined our group. Albert Roos arrived at the medical school in 1947 to work in the division of anesthesiology for the legendary head of surgery, Dr. Evarts Graham. Although he had long held a joint appointment in anesthesiology and physiology, Albert's laboratory was located across the street from our department, near the Department of Surgery in Barnes Hospital. I found Albert extremely bright and very engaging. One day in 1970, I met him in the elevator and invited him to join the physiology department on a full-time basis. He agreed to do so.

This move turned out to be an excellent idea both for him and for us. Albert savored his new environment and flourished among my new recruits. In turn, we were stimulated by his vibrant presence. His younger colleagues' cellular approach to physiology influenced Albert's research. Although Albert was over 50 at the time he joined the department, he opened an entirely new area of research. Within a few years, he became the leading authority on intracellular pH. Albert's outgoing personality and enjoyment of vigorous discussion enhanced the department's collegial atmosphere.

Another senior appointment was John Heuser, who came to Washington University from the University of California School of Medicine in San Francisco. His delicate laboratory equipment had to be moved from the west coast with extreme care. Ken King provided the funds necessary to pay the substantial expenses for having this done.

Several professors who were in place on my arrival remained in the department. Len Banaszak and Scott Matthews did excellent work in x-ray crystallography. Charlie Molnar and Russ Pffeiffer continued their studies on the cochlea. Charlie, who had helped develop the LINC computer, also headed the Computer Systems Laboratory.

In addition to administration, I managed to keep my own research going. Yas Fukami came with me from Yale, and we worked, sometimes together and at other times separately, on muscle receptors. I was fortunate to have Sherman Beacham, who was an outstanding medical student while I was at Utah, work in my lab for several years. Later, Bob Wilkinson joined me. We had a highly productive and enjoyable collaboration studying isolated muscle spindles. Trained as a physicist at Rice, Bob brought quantitative skills and knowledge to our research. In the mid-1970s, I spent three summers working in Stockholm with David Ottoson. During these visits, we made considerable progress in developing an isolated mammalian spindle preparation.

By the late 1970s, both Roy Vagelos and Max Cowan had begun to consider leaving the medical school for other positions. Strenuous efforts were made to change their minds. Chief among them was the establishment of a University Division of Biology and Biomedical Sciences. Roy served as its first director, and Max then succeeded him. The purpose of this innovation was to keep Roy and Max at the university a few years longer and also to unite the medical school's basic science departments with related departments on the undergraduate campus. Despite this effort, Roy and Max both left the medical school soon thereafter.

A Sabbatical in Paris

By 1980, I was ready to take a 6-month sabbatical in Paris to work with an old friend and colleague, Yves Laporte. Yves and I had met in the early 1950s when he was doing research at the Rockefeller Institute.

Thirty years later, Yves had become head of the Physiology Laboratory at the College de France and was elected administrator of this august institution. Several of his laboratory colleagues were then studying muscle spindles: Francoise Emonet-Denand, Julien Petit, and Lena Jami. In contrast to my isolated preparations, they used whole animals for their research. Laporte's team was highly skilled in this approach, and the results of their experiments were very interesting. By working with them, I hoped to gather information that could be useful in my isolated receptor studies. And I had always wanted to live in Paris.

My old medical school professor of physiology, Joseph Hinsey, heard about my sabbatical plans and suggested that I get in touch with his friend Dr. William Dock who lived in Paris. His father, George Dock, had served both as the head of medicine and dean at the Washington University School of Medicine. Bill began his career as a pathologist and later became an eminent cardiologist.

He possessed a remarkable grasp of medical history combined with a love for and knowledge of Paris. Although in his 80s, Bill was a indefatigable walker and a superb guide. His stories about medicine were fascinating, his narrative style was delightful, and his sense of humor was irreverent. One of Bill's favorite phrases was “a death to make your mouth water” which he applied to those fortunate enough to die quickly and without suffering. But his basic approach to living in Paris as a widowed octogenarian was “joie de vivre.” Spending time in his company taught me a good deal about how to age gracefully.

Return to Washington University 1981–1983

By the early 1980s, the medical school had changed considerably. The faculty and physical plant had grown substantially, as had the budget. Most important to me, the Executive Faculty was no longer a small, cohesive group with a common concern for the school's welfare. It had become a large group of disparate individuals whose interests centered on their own departmental agendas. Whereas the dean had formerly controlled most institutional funds, clinical departments had by then begun to accumulate large amounts of money. When some department heads took positions I considered self-serving or when they ignored obvious conflicts of interest, I reacted negatively. My refusal to support some of their decisions led certain colleagues to see me as uncooperative and overly conservative.

In 1983, the National Academy published a survey of Research Doctorate Programs in Biological Sciences, the first such assessment under-taken since the 1960s. Physiology was the only department at Washington University to be ranked among the top ten in the country. Yale's Department of Physiology, which had retained many of my recruits, was also in this group. To my surprise and delight, Carl Cori sent me a handwritten poem to mark this occasion:

Chancellors, deans, colleagues and students Washingtonienses Examine important message in Science with critical lenses.

In a contest wide, in Academia's lofty towers,

Rate programs for graduates, no flowers!

Rate giving Ph.D. degrees in Physiologia

To be honest, this is not the casa mia.

The answer came 2000 strong

The verdict was as clear as a gong.

Top rated at Washington U. is Physiologia.

Where are the Hunts—Madonna mia.

They now have a banner with which to picket,

But instead to Paris they bought a ticket.

Hurray for the Hunts.

Ironically, these findings were published just as the new Division of Biological Sciences was in the process of absorbing our graduate program.

In September of that year, when I was due to retire, members of the department organized an excellent symposium in my honor. Although being celebrated at an occasion like this is rather like going to one's own funeral, the organizers made it a happy and memorable day for me. The theme was “Biophysical Approaches to Physiology.” Nine of the eleven speakers had been members of my previous departments and were by then full professors or department heads: Carlos Eyzaguire, Arthur M. Brown, Knox Chandler, Joe Hoffman, Bob Martin, Mordy Blaustein, Motoy Kuno, Guillermo Pilar, and Edward Perl. In addition, Yves Laporte came from Paris and David Barker from England. It was an elegant and interesting occasion that gave me the pleasure of seeing many old friends and colleagues.

Retirement from Administration and Four Years in Paris 1983–1987

As my 65th birthday approached, then the age for mandatory retirement from administrative positions at Washington University, I felt it would be less awkward to be elsewhere during the search for my successor. I had headed the physiology department for 16 years (1967–1983). During that time my young recruits became able senior faculty. An important aspect of my administrative style had been to serve as a buffer between my faculty members and medical school politics. Retiring as department head substantially diminished my influence on the Executive Faculty. There seemed little point to my retaining a lame-duck position.

In 1983, with support from the Fondation de France, I took an extended leave to work again in Yves Laporte's laboratory at the College de France. On my departure, Nigel Daw became acting head. A national search for my successor resulted in an internal appointment: Philip Stahl, a cell biologist who turned the department in that direction. There was no interest in sustaining the strength I had established in neuroscience.

Three leading faculty members, Dale Purves, Josh Sanes, and Jeff Lichtman, moved to the Department of Anatomy and Neurobiology, then headed by Gerry Fischbach. Gradually, other senior faculty accepted positions as department heads elsewhere: Mordy Blaustein at the University of Maryland, Paul De Weer at the University of Pennsylvania, Dale Purves at Duke, and Luis Reuss at the University of Texas Medical Branch at Galveston.

A Second Return to Washington University 1987–1994

Four years in Paris gave me ample time to work with Yves Laporte's research group. During those years, we published a number of papers on muscle spindles. Despite my love of Paris, by 1987 returning to the United States seemed a good idea. My son had entered college, and my daughter was born in June of that year. Perhaps becoming a father again at the age of 69 impaired my ability to slip gracefully into retirement.

Mordy Blaustein kindly offered me space in his department. But because I still had so many friends and colleagues at Washington University, it seemed easier to return there. I planned to reestablish my laboratory for further study of fusimotor effects on muscle spindles. However, after a 4-year absence, obtaining space in my former department proved far more difficult than I had anticipated. Because I had spent so many years renovating and arranging space for other people, I found this situation both awkward and ironic.

Luckily, Bill Landau, who then headed neurology, offered me space in his department. Michael Chua joined my laboratory there. He had received his Ph.D. from the Australian National University and had been a postdoctoral fellow with Bill Betz at the University of Colorado. Mike brought many quantitative skills to our work. As a result, the isolated spindle research received a real boost. We used a number of fluorescent dyes to stain components within the spindle, particularly the sensory terminals. Using confocal microscopes enabled us to obtain beautifully clear images. These images could then be used to make three dimensional reconstructions.

Moving to the neurology department proved only a temporary solution to my space problem. After Bill Landau retired as head in 1991, it became obvious that I would have to seek space and a position at another institution—not easy to do in one's 70s. Although a number of my former associates at Yale were willing to provide me with some lab space there, that failed to materialize. Fortunately, Ed Perl, my former colleague at the University of Utah, offered me a position in the Department of Physiology at the University of North Carolina. The chairman, Stan Froehner, was amenable to this idea. I moved there in 1995 and continued my research on spindles with Michael Chua.

The following year, I received an award of distinction from my alma mater, Cornell University Medical College, for “notable achievement as a physician, scientist, educator, and administrator.” In 1997, the Association of Chairmen of Departments of Physiology gave me its Distinguished Service Award “for outstanding service and dedication to the discipline of physiology.” At that time, the organization's president was Paul De Weer, who had been one of my young recruits at Washington University. It was a particular pleasure for me to receive this honor from him. In a generous tribute, Paul noted that over 20 of my associates had become department heads, a number he called “unique in the annals of physiology.”

Six years later, in the fall of 2003, I was asked to speak on the occasion of Mordy Blaustein's retirement as head of physiology at the University of Maryland. He had been my first recruit to the Department of Physiology at Washington University. Hearing tributes to Mordy's 25 years of service made me realize how fortunate I had been to hire him early in his career. I also realized that when my once promising young recruits began to retire, it was a sure sign of age—both theirs and mine.

A Retrospective View

Looking back over a long career, I feel fortunate to have started out in neuroscience when it was a small and friendly enterprise—and at a time when the field was undergoing an exciting intellectual transformation. The relatively few neuroscientists then were likely to know each other and to have some familiarity with one another's work. The Society for Neuroscience, founded in 1969, now lists some 35,000 members. The range of research interests—indicated by the number of new journals—has also grown enormously. Although both these changes are signs of progress, I am glad to have started out when neuroscientists were a more cohesive group, funding was generous, and there was less pressure to tailor research for a particular agenda.

Timing was certainly a critical element in my career. For an aspiring young scientist, the chance to collaborate with Steve Kuffler was a remarkable piece of luck. And although I did not collaborate with Herbert Gasser, my contact with him proved invaluable. These two outstanding scientists, Gasser born in 1883 and Kuffler in 1914, represented consecutive generations of excellence in neuroscience. To have known them both early in my career was a privilege and an inspiration.

The availability of NIH funds during the years I was a chairman enabled me to build three fine departments. Was all this department-building in three different academic settings really worthwhile? Despite the occasional difficulties I encountered, I would say yes. To a large extent, I enjoyed the challenge of building new departments in very different places. The fact that I was able to do so more than once was a source of great satisfaction.

Although the quality of teaching concerned me, I was not known as an exciting lecturer. One medical student said: “Dr. Hunt gave the lectures in cardiovascular physiology, but his heart wasn't in it.” My most significant accomplishments were to recruit talented scientists and to create environments that encouraged their research. Watching them flourish was a great pleasure.

Although individual achievement was important, the atmosphere in my three departments was always collegial. Faculty members had a genuine interest in each other's research topics and enjoyed sharing ideas about them. Enduring friendships developed as a result. Several of my former colleagues have told me “the best years” of their lives were those spent in one of my departments. I take their comments as a high compliment.

Given current fiscal constraints, it would be difficult, if not impossible, to build three departments of similar quality today. A common recruiting style these days is to hire established “stars.” This is far more expensive and certainly less rewarding than it is to nurture the development of promising young scientists.

With the current stringency of government funding, grant applicants must predict the research results to be obtained and also demonstrate that the proposed experiments are likely to yield them. The effect of these requirements on scientists has been exactly what Herbert Gasser feared: a loss of the intellectual freedom to follow the path of discovery wherever it might lead. I was fortunate to begin my career when one could choose a research topic at will, on its own merits, and without concern about fitting it into a predetermined scientific agenda.

When he was director of the Medical Research Council, Peter Medawar wrote: “I construe my function … as mainly to create the kind of environment conducive to the advancement of learning … this is all a director … can do.” His views remind me of Herbert Gasser's remarks while he was director of the Rockefeller Institute: “New knowledge cannot be forecast and cannot be achieved through administrative direction. All that can be done is to create the optimal conditions for its production.” Like them, my constant goal as an administrator was to create the best possible environment for the advancement of learning. During some 25 years as a department head, I hope to have done so.

Acknowledgment

My wife, Marion, provided invaluable assistance in revising and editing successive drafts of this essay. Her persistent questions about the early years of my career (which antedated our marriage) helped evoke memories of the people who inspired, helped, and encouraged me.

Selected Bibliography

Chase MW, Hunt CC. Herbert Spencer Gasser, 1888–1963, a biographical memoir. Biogr Mem Natl Acad Sci 1995;67:1–33.

Cori C. The call of science. Annu Rev Biochem 1969;38:1–20.

Corner G. A history of the Rockefeller Institute, 1901–1953. Rockefeller Institute Press, 1964.

Erlanger J, Gasser HS. Electrical signs of nervous activity. University of Pennsylvania Press, 1968.

Fukami Y, Hunt CC. The structure of snake muscle spindles. J Physiol 1970;33:9–27.

Gasser HS. Comparison of the structure, as revealed with the electron microscope, and the physiology of the unmyelinated fibers in the skin nerves and in the olfactory nerves. Exp Cell Res 1958;5:3–l7.

Heistracher P, Hunt CC. The relation of membrane changes to contraction in twitch muscle fibers. J Physiol 1969;201:589–611.

Heistracher P, Hunt CC. Contractive depriming in snake twitch muscle fibers. J Physiol 1969;201:613–626.

Herbert Spencer Gasser, 1883–1963. Exp Neurol 1964;Suppl 1.

Hubel O, Weisel T. The brain and visual perception. Oxford University Press, 2005.

Hunt CC. The reflex activity of mammalian small nerve fibers. J Physiol 1951;114:456–459.

Hunt CC. Monosynaptic reflex response of spinal motoneurons to graded afferent stimulation. J Gen Physiol 1955;38:813–852.

Hunt CC. Mammalian muscle spindles: Peripheral mechanisms. Physiol Rev 1990;70:643–663.

Hunt CC, Kuffler SW. Stretch receptor discharges during muscle contraction. J Physiol 1951;113:298–315.

Hunt CC, Kuffler SW. Further study of efferent small nerve fibers to mammalian muscle spindles: multiple spindle innervation and activation during contraction. J Physiol 1951;113:283–297.

Hunt CC, Mcintyre AK. Properties of cutaneous touch receptors in cat. J Physiol 1960;153:88–98.

Hunt CC, Ottoson D. Impulse activity and receptor potential of primary and secondary endings of isolated mammalian muscle spindles. J Physiol 1975;52:255–281.

Hunt CC, Wilkinson RS. An analysis of receptor potential and tension of isolated cat muscle spindles in response to simulated stretch. J Physiol 1980;302:241–262.

Hunt CC, Wilkinson RS, Fukami Y. Ionic basis of the receptor potential in primary endings of mammalian muscle spindles. J Gen Physiol 1978;302:683–698.

Katz BK. Stephen William Kuffler, 1913–1980. Biogr Mem Fellows R Soc 1982;28:225–269.

Kuffler SW, Hunt CC, Quilliam JP. Function of medullated small nerve fibers in mammalian ventral roots: Effect muscle spindle innervation. J Neurophysiol 1951;14:29–54.

Kuffler SW, Laporte V, Ransmeier RE. The function of the frog's small nerve muscle system. J Neurophysiol 1947;20:395–408.

Langley IN. The nerve fibre constitution of peripheral nerves and of nerve roots. J Physiol 1922;56:382–396.

Leksell L. The action potential and excitatory effects of the small ventral root fibres to skeletal muscle. Acta Physiol Scand 1945;73:1–84.

MacMahon U. Steve: Remembrances of Stephen W. Kuffler. Sinauer, 1990.

Martin AR. Autobiography in collected works of A.R. Martin. Privately printed, 1995.

Medawar P. The threat and the glory: Reflections on science and scientists. Oxford University Press, 1991.

O'Leary J, Heinbecker P, Bishop GH. Analysis of function of a nerve to muscle. Am J Physiol 1935;110:636–658.

Porter R, Proske U, Mark RF. Archibald Keverall Mcintyre, 1913–2002. Hist Rec Aust Sci 2004;15:77–94.

Lynn T. Landmesser

BORN:

Santa Ana, California

November 30, 1943

EDUCATION:

University of California Los Angeles, B.A. (Zoology, 1965)

University of California Los Angeles, Ph.D. (Zoology, 1969)

APPOINTMENTS:

Postdoctoral Fellow, University of Utah (1969)

Yale University (1972)

University of Connecticut (1983)

Case Western Reserve University (1993)

Chair, Department of Neurosciences, Case Western Reserve University (1999)

HONORS AND AWARDS (SELECTED)

President, Society for Developmental Biology (1988–1989)

Arturo Rosenblueth Distinguished Professor, Center for Advanced Studies, IPN Mexico (1987)

Wiersma Visiting Professor of Neuroscience, California Institute of Technology (1989)

Secretary, Society for Neuroscience (1992–1994)

American Academy of Arts and Sciences (1993)

Arline H. and Curtis F. Garvin Professor of Medicine (2001)

National Academy of Sciences, U.S.A. (2001)

Lynn Landmesser utilized the embryonic chick spinal cord to provide the first evidence for early specification of motoneuron subtypes and their selective pathfinding. Her laboratory also demonstrated motoneuron pool-specific spontaneous bursting patterns and characterized the circuits that drive the earliest rhythmic activity and defined its role in motor circuit formation. She has also elucidated the roles of NCAM and polysialic acid in neuromuscular development, synaptic maturation, and transmission.

Lynn T. Landmesser

But for the Second World War, I would have grown up around East Orange, New Jersey, where the families of my father Charles Landmesser and my mother Eleanor Cerveny Landmesser had settled after their parents had emigrated from Germany/Ireland and Czechoslovakia, respectively, a generation before. My father, who fought in the Pacific during the war, was stationed at Camp Pendleton Marine Base in California and thus in 1943 I came to be born in Santa Ana and spent the first year of my life in Laguna Beach, often literally on the beach as my parents rented a house only a stone's throw from the Pacific Ocean. Loving the physical beauty of California and the possibility for change, my parents decided to settle there when the war ended. With no offense intended toward New Jersey, I will always be grateful for this chance of fate that allowed me to grow up in California, for I am certain that this shaped in important ways my decision to become a biological scientist. First, by exploring, as a child, the diverse environments of California, often on camping vacations, I became fascinated by the diversity of life and the adaptation of individual species to their environments. This later motivated me toward trying to understand how the behavior of such species, which was in the end the product of their nervous systems, could be so exquisitely tailored to their individual environments. Second, the State of California, with incredible foresight, had decided to create a first-class university system that was the equal of the Ivy League but which was available to all its citizens, regardless of their means.

I have always felt that had I grown up on the East Coast, my family being of modest means, I was likely not to have attended college. I probably would have done something interesting and creative with my life, but I am almost certain that I would not have become a neuroscientist. In looking back over my life, still not believing that I am at that stage to be doing so, I was struck by how the path that I eventually followed was shaped by so many chance occurrences. I suppose all lives are shaped by such chances, but I hope that by conveying these reminiscences I can reassure those that are striving toward or even just beginning to dream about a career in science that the same place can be reached by many different paths and that there is not one true correct route that must be followed.

Early Years

My father's interest in nature and the environment had a huge impact on my decision to become a biological scientist. Although my mother was always very supportive, camping vacations were something she bravely endured for the sake of the family. Whether we were exploring tide pools near Torrey Pines, watching the moonlight on the sands of the Anza Borrego desert, or hiking in mountain meadows near Sequoia my father helped me appreciate the extraordinary diversity of animal species and their adaptive behavior. These experiences no doubt contributed to my goal, articulated in an essay that we eighth graders at St. Patrick's elementary school in San Diego were asked to write as graduation approached, and which was decidedly atypical for a female at that time, to become a diver for Scripps Institute of Oceanography. By the time I graduated from high school at Our Lady of Peace Academy in 1961, with my sights on UCLA, I had decided on the less exciting but more employable career of a medical technologist. It seemed that this UCLA program would let me combine my interest in biology with a marketable skill as I sought employment 4 years hence. It was clear that after sacrificing to send me to college for 4 years, my family expected me to be able to support myself upon graduation.

UCLA and My Discovery of Neuroscience

I arrived at UCLA, which then had a student body of 40,000 or so, feeling both excitement and a bit of trepidation. It is often said that females do better at smaller private schools where they receive more personal attention, but for me the anonymity of such a large campus was comforting, for it allowed me the possibility to explore and make mistakes unnoticed and to make my own decisions, wise or not. It was to be my home for the next 8 years, during which I experienced and participated in the social and political upheavals that marked the 1960s. It was an exciting place both academically and socially with the civil rights movement and the opposition to the gradually escalating war in Vietnam having a lasting impact on my fellow students and me. Fortunately, the interesting and well-taught general biology course I was required to take my first semester caused me to abandon the medical technologist program for a major in biology. I postponed worrying about how I would obtain a job with a biology major until graduation. I was not interested in medicine, as most of my fellow biology majors were, and I had not yet realized that one could have a career doing science in academia. I did well academically especially enjoying physiology, but by my junior year I was beginning to be bored by simply acquiring new information in courses. Also from the beginning of my junior year I had begun to support myself by working 20 hours per week in the geology department, extracting and classifying fossils from rock samples. Although this provided me with the confidence that I could indeed support myself, financial concerns together with anguish over the social and moral problems facing our country, including racism, poverty, and the war in Vietnam, made much of the course work seem esoteric and irrelevant to real life. Returning to San Diego for the summer, I had almost decided on dropping out of UCLA for a few years. However, I had greatly enjoyed carrying out an independent research project on crab behavior at the end of an invertebrate zoology course and wrote to that professor to see if I could carry out an independent research program equivalent to several courses that UCLA offered to senior zoology majors. Because he was on sabbatical, my letter was forwarded to Theodore (Ted) Bullock, a world-renown neuroscientist. He wrote back saying that, if I really wanted to explore the biological basis of behavior as I had indicated, I should take his neuroscience course in the fall and, doing well in that, I could do the research project in the spring. Had he not responded and I had left school to work for several years, I probably would not have become a neuroscientist. Thus, I will be forever grateful to him.

Happily I did well in the neuroscience course, which, like Ted's interests, was broad ranging from comparative neuroscience to membrane biophysics, vertebrate neuroanatomy, and behavior. He did not so much teach as point out interesting enigmas and problems that encouraged us to learn on our own. My independent research project involved determining the effect of temperature changes on the bursting properties of spontaneously active cells in the buccal ganglion of Aplysia, and I fondly remember collecting Aplysia with my teaching assistant Mike Mote from boat slips at the Marina del Rey. My fascination with behavior of the organism was quickly transferred to the behavior of cells, as my intracellular recordings revealed the individually unique bursting patterns of different identified cells. Alan Grinnell, a newly hired assistant professor, who later became my Ph.D. mentor, helped me with fabricating electrodes and I quickly fell in love with neuroscience.

I applied (rather late but was still accepted) to do a master's with Ted Bullock. However, having just been recruited to the new UCSD campus and planning to be away for extended periods the following year, he thought it wise for me to have Alan Grinnell as an on-site co-mentor. Because Ted was moving with a group of more senior graduate students and postdoctoral fellows and his lab renovations were not on schedule, I had come to the conclusion by the end of that first year that I would have more personal attention and probably make better progress if I remained at UCLA with Alan as my Ph.D. mentor. I had in the meantime set my sights higher than a master's degree.

Alan, who had interests in both bat echolocation from his Ph.D. work at Harvard and in spinal cord and neuromuscular physiology as a result of postdoctoral studies at University College London, generously provided me with the intellectual freedom and support to pursue whatever I found most interesting. With tools being quite limited, progress in neuroscience those days required finding just the right experimentally tractable preparation to answer a specific question. Having toyed with several projects on cockroaches and moths, I settled on the crayfish muscle stretch receptor neuron as an excellent preparation to determine if transmitter receptors on neurons were selectively clustered at synaptic sites, as they had recently been shown to be at the neuromuscular junction. These large neurons were innervated by discrete bouton synapses on the soma and dendrites, and although lacking the antibodies and fluorescently tagged receptor antagonists we have today, it was possible to map the receptor distribution by iontophoresing transmitter locally. After several frustrating months of trying to get long-term stable recordings from the cells that this effort required, Susumu Hagiwara, a fine scientist and wonderful human being, who later became a member of my dissertation committee, informed me that such recordings were virtually impossible in the Procambarus species we had been using, and which I confess my fellow students and I used to filch from a pond at the Self Realization Fellowship complex near Sunset Boulevard. After ordering the preferred Astacus species from Oregon, I made rapid progress and was beginning to acquire data supporting receptor clustering when we were informed that due to severe flooding in Oregon no more crayfish would be available for 5—6 months.

Thus, it was again a chance of fate that caused me to turn my attention to an area that was to become my lifelong interest. Much of neuroscience research at that time was directed toward defining the connectivity of circuits and understanding membrane properties. The question of how such circuits were formed and either maintained or altered by experience during the life of an individual was largely ignored. Thanks to the incredible collections at the UCLA Biomedical Library, I was able to discover the two volume series of Cajal, published as the 1952 edition in French, which fortunately I was able to read. I was captivated by his lively and imaginative descriptions of growth cones battering their way around obstacles to reach their targets and how spinal cord circuits became assembled. Equally fascinating, and entertaining too, was his autobiography, Recollections of My Life, which proved one could begin a scientific career at the age of 40 and still excel, provided one was long-lived. However, lacking the tools at that time to probe underlying mechanisms, I decided to postpone the study of embryonic development.

Instead, long-term trophic interactions between neurons and their targets became my focus. A 1951 paper by De Castro, also in French and likely unavailable at many biomedical libraries, described some intriguing surgical cross-innervations in the cat that suggested that the central processes of sensory vagal neurons could make functional synapses with sympathetic ganglion cells in the superior cervical ganglion. Thus, inflating a balloon in the stomach caused sympathetic reflexes such as dilation of the pupil. This suggested to me a way to determine the extent to which the properties of a given synapse were autonomous to the pre- or postsynaptic element and the extent to which the properties could be altered by one partner influencing the other. I decided to transplant the frog sartorius muscle, the vertebrate synapse where many properties of transmission had been described by Bernard Katz, Ricardo Miledi, and their colleagues at University College London, by suturing its tendons to the lower jaw and sternum, where it could be innervated by preganglionic cholinergic fibers in the gastric branch of the vagus nerve. Lack of surgical expertise did not keep me from plunging ahead but luckily the frogs were tough and recovered rapidly from the surgery and functional synapses formed.

Although the presynaptic properties of this hybrid synapse remained preganglionic, these autonomic axons were unable to induce junctional folds or the deposition of AChE postsynaptically. More intriguing, they appeared to have altered the pharmacological properties of the postsynaptic ACh receptors to become more ganglionic in nature. Today one would think of perhaps alterations in nicotinic receptor subunit expression and I have occasionally toyed with the idea of repeating these experiments with the modern tools now available. However, at that time such molecular changes could only be inferred by pharmacology.

Wishing to pursue these ideas further in postdoctoral studies, I was frustrated by the lack of scientists in the United States who were studying trophic interactions with modern electrophysiological approaches. However, a strong group in Prague was doing just this and one of them, Radan Beranek, had visited our laboratory and encouraged me to visit Prague on a planned trip to Europe the following summer. Steeped in cold war propaganda, it was with considerable trepidation that my brother Anton and I visited both Hungary and Czechoslovakia in the summer of 1967. We were surprised to find the people of both countries warm and outgoing and I was captivated by the almost magical charm of Prague. My decision made, I enrolled in a Czech course at UCLA and began preparations for a move abroad. Then, in August 1968 the Russians invaded! However, I was assured by my Czech colleagues that the presence of an American postdoctoral fellow there would not cause them difficulties, and I applied for and, amazingly for a time at the height of the cold war, received a National Institute of Health (NIH) postdoctoral award to pursue these studies.

Then, several months before I was to defend my dissertation, I received word that my proposed mentor, Radan Beranek, had died unexpectedly. This threw me into complete confusion. Alan Grinnell was away for several months on an expedition to New Guinea and essentially out of contact. NIH informed me that I would be allowed to transfer my fellowship to any reasonable laboratory in the United States, and Richard Orkand, a member of my dissertation committee, put me in touch with Ed Kravitz at the neurobiology department at Harvard, who agreed to sponsor my postdoctoral studies. I am sure most readers will be incredulous, but although excited to study at what was considered the top neuroscience group in the country, my west coast prejudices made a move to Boston quite unthinkable. During our many enjoyable weekend outings to Boston during the two decades I came to spend in Connecticut, I would laugh at myself, but my feelings at that time were strong and real. The east seemed a bastion of old money and privilege, exactly what my compatriots and I, who came of age in the late 1960s had been idealistically struggling against.

Salt Lake City and My Foray into Developmental Neuroscience

As I respectfully disengaged from my commitment to go to Harvard, an alternative that made a lot of sense scientifically, if not politically, emerged. The physiology department at the University of Utah had also developed a strong presence in neuroscience under the leadership of Carleton (Cuy) Hunt. Guillermo Pilar, together with Bob Martin, had carried out, several years earlier, seminal studies on neuronal synaptic transmission in vertebrates, using the chick ciliary ganglion as a model preparation and he had expressed interest at a Western Nerve Net meeting (a predecessor of the Society for Neuroscience) in using the ciliary ganglion to study questions of specificity during regeneration and development. He enthusiastically welcomed me to join him in investigating this new area and I have never regretted this decision as it enabled me to explore a totally new discipline, uncluttered at that time by either concepts or facts and which later emerged as developmental neurobiology.

However, as many of my friends and colleagues questioned my sanity in rejecting Boston for the apparent physical and intellectual wilderness of Utah, I did have serious misgivings. These were only enhanced when Harriet Goff, a former UCLA student and housemate who generously agreed to accompany me on the drive there, and I, rather than taking the major north or south highway routes to Utah, chose to strike out across the backcountry of Nevada. There we encountered a huge eagle snacking on its prey in the middle of the road. After spending the night at a hotel in Tonopah, which could have been the set for the TV series Gunsmoke and where ancient cowhands rocked on the veranda, I nervously awaited my fate. The next day, after passing signs in barren wilderness that indicated that Salt Lake City was only 16 miles away, you cannot imaging my relief when a real city finally came into view.

The several years in Salt Lake City were ones of wonderful scientific discovery. The ciliary ganglion lived up to the expectations of Guillermo, and our ability to record extracellularly from two discrete but homogeneous populations of neurons embedded in the same ganglion, allowed us to make rapid progress. Following preganglionic nerve section in adult pigeons, we were able to demonstrate selective reinnervation of these populations by their preganglionic inputs, confirming, with electrophysiology, experiments made many years before by Langley using visual observations of sympathetic reflexes. Turning to development, and using chick embryos, we followed the formation of functional synaptic transmission between vertebrate neurons for the first time and found that it occurred much earlier than one would have anticipated from anatomical and electron microscopic (EM) evidence.

I was also challenged to record from smaller and smaller embryos, honing dissection skills that would later serve me well. More importantly we found that each population appeared to be selectively innervated from the outset, which ran counter to the dogma of the time. Although Sperry had articulated his chemospecificity hypothesis in 1963, it was largely based on regeneration experiments and only the final pattern of retino-tectal innervation had been characterized. It was not at all clear how this developed over time. Did neurons selectively grow to and recognize their targets from the outset by reading molecular cues or did the precise pattern of connections emerge following trial and error establishment of connections and a process of validation? Our results clearly pointed to the former.

We next attempted to address the importance of the target in specifying the properties of the presynaptic neuron, trying to distinguish between Sperry's hypothesis of two prespecified sets of neurons that connected via chemical markers and Paul Weiss' idea that the target imposed its identity on the innervating neurons (myotypic specification). Although the ciliary ganglion was the perfect place to test these hypotheses, my embryonic surgeries to remove the optic vesicle, the target of the ciliary ganglion, prior to innervation, were initially a complete disaster. Although I am often considered to be a developmental biologist, I spent a huge effort and many eggs in trying to duplicate the procedures of experimental embryologists such as Viktor Hambuger with little success. In the end, persistence won out and although these studies were not completed until I had established an independent laboratory at Yale, we were able to show that many features of these two populations developed independent of their target, including their selective innervation by preganglionic afferents.

We carried out these experiments with great enthusiasm, often working late into the night. Although Bob Martin and Cuy Hunt had moved on, Ed Perl and Motoy Kuno were there and our lab and Motoy's spent considerable time together. We shared a special camaraderie in part because as non-Mormons we were essentially outside the mainstream of Salt Lake City society. It was there that I first felt what it must feel like to be an excluded minority. Although everyone was polite and friendly, the nonMormon, university crowd more or less existed as a small separate town within a larger city. Being a 25-year-old unmarried woman was also viewed as unusual if not downright unnatural. Fortunately, Guillermo's Australian postdoctoral fellow Peter Vaughan and his wife Sue became my steadfast companions. While dining in my eighth floor apartment, which looked out on the lights of Salt Lake City and the lake beyond, we would pretend we were in some more cosmopolitan place like San Francisco.

Nonetheless I became totally captivated by the exquisite beauty of the mountains. Having spent much of my youth surfing and exploring the wonderful beaches of California, I had developed an almost mystical attachment to the ocean and could not envision living any distance from it. However, the mountains and high deserts of Utah ensnared me with their own unique beauty, making me a lifelong lover of the southwest. We spent many days skiing or hiking, sometimes climbing various peaks with the Wasatch Mountain Club, always beginning early in the morning so that we could scale them and get back down before the inevitable afternoon thunderstorms sent their lightning bolts our way. Toward the end of my stay in Utah my friendship with Guillermo deepened and he became my long-term partner in life as well as in science.

A West Coast Personality Encounters Yale

By 1971 Guillermo had begun to explore positions elsewhere as the physiology department began to disintegrate with Ed Perl and Motoy Kuno leaving for the University of North Carolina. I was contacted by Melvin Cohen to ask if I would be interested in considering a faculty position in the Yale biology department, as they were seeking someone working on neural development. My first inclination, after consulting a map to find the exact location of New Haven, was to say that I was not interested in a position on the east coast. However, Guillermo encouraged me to go for the experience of interviewing and presenting a formal seminar. I arrived in New Haven on a gloomy late spring day as the daffodils were just emerging. I enjoyed giving the seminar and meeting with the scientists there and was much more relaxed than if I had really been seeking this position. I was thus totally surprised and somewhat chagrined, when at the end of my visit I met with the chairman Clement Markert, a gruff but as I was later to discover straightforward and trustworthy person, who offered me the job. He said, however, in a take it or leave it manner, that I had only 2 weeks to accept or decline.

Upon returning to Utah, I vexed over this decision for the full period and only phoned Clem at 4:45 PM on the final Friday to accept the offer. I had decided that beginning my career at a top university such as Yale could not be all that bad and that I could always return to the west coast later when my academic career was under way. Little did I realize then that I would spend the next two decades in Connecticut. This decision also impacted on my personal life as Guillermo was offered a position at the University of Connecticut, Storrs about the same time. Finally, witnessing today the often long and discouraging struggle that many young scientists endure to find an appropriate position, I realize now how very fortunate I was.

The Yale biology department provided a fine environment for me to grow into an independent scientist, as I describe later. The larger institution of Yale, however, was a strange and anachronistic place for someone who had grown up with the social and intellectual fulmination of California in the 60s. Although the science departments, having recruited faculty from many large state universities, were more geographically diverse and democratic, the rest of Yale seemed both elitist and very staid. Due to the dearth of women there in 1972, I being one of only two in a departmental faculty of more than 30 and female undergraduates having been admitted only a few years earlier, I was asked to serve on numerous university committees. I must confess that some of the views articulated in these committees were quite shocking and could have been the basis of litigation had they become public.

I was also initially amazed that our undergraduate biology students received no academic credit for the large number of laboratory hours they were required to fulfill. It was only much later that I came to appreciate that much of Yale viewed experimental science not as a true intellectual endeavor but rather as something you did with your hands and thus decidedly “working class.” A critic was more admired than someone who actually created things, whether this was a new scientific discovery, a painting, or a music composition. Happily, after many years of struggle, our faculty was able to have this course rule modified. Also, unlike many nonscience departments, we never held meetings or dinners at Mory's, where women were only allowed if accompanied by a male. Finally, having puzzled for some time about the strange, windowless buildings scattered about campus that resembled mausoleums, I was at first incredulous when someone told me that these were secret societies. Skull and Bones and several presidents notwithstanding, at that time I could not conceive that such entities could exist in the 1970s.

But, returning to science, it was a thrill to set up one's own laboratory and I quickly attracted two graduate students who differed in many respects; Sheryl Scott came from a southern, upper middle class background and attended Duke University and Deborah Morris was a young black woman, who had grown up in New Orleans and whose father was a preacher. Although there was no overt racism, Yale had to be a challenging and uninviting environment for Debbie, who nevertheless managed admirably by having an ironic sense of humor that allowed her to laugh at and thus deflect various slights and condescending comments. Although they had very different personalities, they were both exceptional students who came to appreciate and respect each other.

Feeling that it was important for a student to take both full credit and responsibility for their initial work, I insisted, idealistically and perhaps naively, that my first students, who later came to include Marcia Honig, Betty Ferguson, and Michael Vogel, have at least one sole-authored publication. Sherry's work turned out to refute the proposal that reinnervation by the original nerve could functionally silence otherwise anatomically normal synapses on goldfish extraocular muscles. I focused on studies on the ciliary ganglion, still in collaboration with Guillermo, in which we defined many aspects of naturally occurring cell death, a phenomenon that was just coming to be appreciated. Debbie had yet to settle on a project, so together we began work on the chick spinal cord, an area that would occupy much of my subsequent scientific effort.

The limb innervating segments of the vertebrate spinal cord had been the subject of numerous studies by the early experimental embryologists, including Viktor Hamburger, Paul Weiss, Sam Detweiler, and George Szekely. They had used surgical manipulations of chick and amphibian embryos to address whether the identities of motor and sensory neurons were prespecified or determined by their targets and whether axons were selectively guided to their targets or whether specific connectivity later arose by a rather poorly defined phenomenon termed “functional validation.” The questions and concepts had all been articulated clearly by these pioneers, yet they lacked the experimental tools to unambiguously interpret the many interesting experiments they had carried out. At that time there were no anatomical, tract tracing methods such as the multicolored fluorescent, lipid soluble dyes of today and Jennifer and Matt LaVail had not yet invented retrograde labeling by horseradish peroxidase (HRP). Because multiple spinal nerves converged at the base of the limb in a plexus, there was no way to trace the paths of individual unmyelinated axons among the many thousands growing into the limb.

I quickly realized that this was a problem to which my skills in electrophysiology could be effectively applied. By stimulating individual spinal nerves and by recording from muscles or muscle nerves just as targets were being innervated, Debbie and I were surprised to discover that the many thousands of motor axons grew into the limb with amazing precision, at least at the segmental level. This study published in 1975 ran counter to the accepted ideas of the time, as articulated later in a 1978 paper by Horder, and which viewed axonal guidance as essentially passive. I myself had expected to detect many mistakes with the hope of then discovering the mechanisms by which they were removed. A few years later, after adapting the retrograde HRP labeling method to an in vitro spinal cord-hindlimb preparation, I was able to demonstrate the selectivity of axon outgrowth at the level of the individual motoneuron pool. I have often wondered why the idea of active axon guidance was so hard to find acceptance. I can only surmise that without the awareness of the vast array of guidance and recognition molecules that we now know exists, the problem of guiding a diverse array of axons over relatively long distances to their divergent targets seemed one of impossible complexity.

Our critics correctly noted that our results were compatible both with active axon guidance, as well as with motor axons maintaining topographic order while being passively guided to their targets. The next step then was to challenge motoneurons by surgically displacing them from their targets. This task was first accomplished by Debbie Morris, who transplanted supernumerary limbs onto chick embryos and thus caused motoneurons to grow into foreign limb regions. I still remember Debbie insisting on driving to Albany in a raging snowstorm so that she could learn from John Saunders, an early pioneer of developmental biology and pattern formation, how to accomplish this. Unfortunately his technique, which produced the well-formed digits he needed to assess anterior-posterior pattern formation, resulted in grossly malformed thighs, and was thus useless for our experiments. Upon her return she switched to Viktor Hamburger's published techniques and eventually succeeded. More informative however, were the surgical deletions and reversals of regions of the neural tube carried out by Cynthia Lance-Jones, when she joined the laboratory as my first postdoctoral fellow. These studies, which were based on a truly heroic number of very difficult embryonic surgeries carried out by Cynthia, were published in four papers in 1980–1981 and have come to be considered as classics.

We were able to demonstrate that motoneurons had their identities specified prior to axon outgrowth, that their axons underwent a dramatic reordering in the plexus region as they sorted into muscle-specific fascicles, and that they could find their targets even when entering the limb from abnormal locations. It seemed to us that these observations could only be explained by differences in the set of cell surface molecules expressed by discrete pools of motoneurons and by motor axons being able to respond actively to guidance cues within the limb. For readers who have experienced frustration with the reviews of their manuscripts, I only note in passing that when the latter two papers of this series were communicated to the Proceedings of the Royal Society by Stephen Kuffler, who had found them excellent and thorough, one of the reviewers found them to be “as a whole marginal and trivial with one portion uninteresting and the other better in concept but poorer in performance.” Initially deflated and quite upset, we persisted in more calmly rebutting the criticisms and the papers were eventually published. So my advice would be that if you truly believe you have something important to say, stay the course.

Subsequent studies by another postdoctoral fellow, Kathy Tosney, further explored such active pathfinding and allowed us to visualize the changes in growth cone morphology as axons made specific pathfinding choices. Our studies, together with those of David Bentley and Corey Goodman who were able to follow the growth cones of individual, identified grasshopper neurons and Christine Holt, who assessed early tectal projections by Xenopus retinal cells, gradually changed the mindset, and the concept of active pathfinding is today accepted without question. It has been heartening to see some of these early predictions experimentally validated by Tom Jessell, Sam Pfaff, and their colleagues, who discovered the transcription factor codes that define motoneuron identity and by the laboratories of Corey Goodman, Marc Tessier-Lavigne, and many others who discovered an abundance of guidance cues and their receptors. Yet even today we do not possess a full molecular understanding of how individual motoneuron pools are specified and pathfind to their targets. However, with the wonderful array of genetic and molecular tools now available, this seems likely to be achieved in the near future.

A second line of research, pursued throughout my subsequent career, was also begun at Yale. This sought to understand when and how spinal cord circuits become electrically active during embryonic development and to understand the role, if any, that such activity plays in circuit formation and refinement. Most functional studies of the spinal cords of higher vertebrates had up until that time been carried out in vivo in cats, as isolated cords did not survive well, presumably due to anoxia. It was thus a surprise and a delight to observe one evening as I removed the pins, which had been holding down an isolated spinal cord hindlimb preparation and which had been incubating to allow for retrograde HRP transport, that the cord produced a series of clearly patterned stepping movements of both limbs. Electromyographic (EMG) recordings proved that these were in fact highly patterned, but unfortunately there was no one else around that evening with whom to share my excitement. A short time later, Michael O'Donovan who had been doing cat spinal cord physiology as a postdoctoral fellow with Bob Burke at NIH, joined the lab to try to elucidate this locomotor-like activity of the embryonic chick spinal cord.

We were frustrated initially because only occasionally did cords exhibit such activity and Michael spent several months applying all combinations of possible neuromodulators to elicit movements, before coming to the important realization that adequate oxygenation was the key. His work then revealed that each motoneuron pool exhibited a highly stereotyped bursting pattern and that this appeared autonomous to the pool and was not altered when motoneurons were surgically forced to innervate foreign muscles. Thus, this physiological signature could be used to identify motoneuron pools following experimental manipulations. These observations also clearly refuted the myotypic specification hypothesis proposed earlier by Paul Weiss. Anne Bekoff, working with Paul Stein and Viktor Hamburger at Washington University, had even earlier shown similar patterned activity when recordings were made from muscles in ovo and thus from intact embryos.

Michael went on as an independent scientist to elegantly elucidate the spinal circuits underlying this spontaneous bursting activity, which we now appreciate is widespread throughout the developing nervous system, and due to the work of Carla Shatz and others we know that it plays a role in circuit refinement. In contrast, I for the most part used this bursting activity as a tool to investigate developmental questions. Because molecules that uniquely define each motoneuron pool have to this day not been identified, these physiological signatures are still of enormous help in identifying pools following experimental manipulations. In fact, Gartz Hanson, who has just completed his Ph.D. with me, is currently using such recordings to elucidate changes in motor axon fasciculation and pathfinding that he discovered were produced by altering the frequency of this early spontaneous activity.

Other Activities at Yale

In addition to the research I have briefly described, I immensely enjoyed mentoring graduate students and seeing them emerge as independent scientists and colleagues. Although they are sometimes frustrating, much as one's own teenage children, each is unique in their strengths and mentoring needs, and in the end most seem to find their way. We had a great group of graduate students at Yale and in addition to my own, I was privileged to have served on the dissertation committees of many others who went on to excellent scientific careers; these include John Thomas, Elliot Meyerowitz, Howard Lipshitz, Mark Tanouye, Tom Park, and my current Case colleague Peter Harte. I also had at Yale the most satisfying teaching experience of my career. Naively noting at a faculty meeting how inappropriate it was that we had no systems physiology when most of our undergraduate majors were pre-med, I was immediately asked to design such a course. Because it was not a required course I did not have to cover any fixed set of material and thus selected each year what seemed to be the most interesting physiological problems for which solutions were being found. We read and discussed primary literature and the exams required that the students apply the knowledge that they had acquired to solve problems.

It was a challenging course and not for everyone, but word travels quickly among undergraduates at Yale, and before long the students signing up were always those who valued what I was trying to achieve. I was pleased when, ending a pre-exam, evening review session that was running late, I noted that they did not have to worry about question X as it would not be on the exam. To which someone replied “who cares about the exam? We were up past midnight last night arguing about this question.” It was especially gratifying when I encountered a number of these students later, when giving seminars at universities where they were either medical or graduate students and they told me how important the course had been to them, even though many had not realized it at the time. Although formal mentoring of faculty was nonexistent, I myself benefited from excellent career advice from a number of more senior faculty members including Joe Gall, John Trinkaus, Joel Rosenbaum, and of course one of my most ardent and consistent supporters, Guillermo.

Finally, it was not all work. We had many social activities including a wine and cheese hour every Friday afternoon. The laboratory went on numerous hikes and picnics, some along very scenic parts of the Connecticut River. There were also lovely evenings watching the sunset as boats came into the Noank Harbor, while we dined on fresh lobster and clams at the outside picnic tables at Abbot's. I also enjoyed being a fellow at Branford College during the reign of John Trinkaus as master. Trink was a real rebel who enjoyed shocking the establishment and we were all amazed that the, in our view, staid Yale administration had selected him to be a live-in master. Yale students live from their sophomore to senior years in individual residential colleges. However, Trink and his French wife Madeleine provided scintillating conversation and political discourse at the monthly sherry gatherings at their quarters prior to dining in the college. When a new master replaced Trink upon his retirement, I found the atmosphere at these gatherings so stultifying that I attended only a few with the result that my fellowship was later withdrawn.

It was also at Yale that I first got to know and then become a close friend of Viktor Hamburger, who was then chair of the biology department at Washington University in St. Louis. Viktor, whose life was to span an entire century, had developed the embryological tools that I was able later to so effectively apply to problems in neuroscience. Having come of age in Germany at the end of the First World War, he was to experience the subsequent isolationism imposed on Germany and the eventual rise of the Nazis. He also personally knew Hans Spemann and Hilde Mangold of embryonic organizer fame, having been a student of Spemann and an admirer in both science and life, of Hilde, who died tragically of an accident early in her career. We got together each spring when he visited his daughter Carola, who was then a Classics Professor at Wesleyan University and married to Paul Greengard and who lived within blocks of the biology department. I fondly recall dinners at their home, when Viktor described some of these early experiences, both political and scientific, and thus helped bring history to life.

Later, when hosting a special lectureship for him at the University of Connecticut, I became concerned when he remained very nebulous about his return flight to St. Louis. As it turned out, Viktor, who was then in his mid-80s, had a lady friend flying up from Baltimore and they planned to spend the weekend in Vermont seeing the fall colors. The car rental agent at the airport was quite shocked when a very elderly Viktor ambled up with his cane to rent the car, and I spent the entire weekend waiting for a call from the Vermont police reporting a car accident. In the end, I got a gracious note from Viktor thanking me for the wonderful weekend they had spent seeing the fall leaves. I last met with Viktor when I was invited to give the annual Hamburger Lecture at Washington University in 1993 when he too was at the age of 93. Having recently had surgery to replace the hip joints that he had replaced many years before, he was unable to attend the seminar but asked to meet with me at his home. I expected to find him very infirm and frail, but quite to the contrary, he entertained me in his living room with appetizers and an aperitif. He then asked “What are you up to scientifically these days?” and as I began to recount some of our recent experiments, I could see him becoming increasingly impatient until he finally blurted out waving his hand “Oh, that's all in that paper you already published. I want to know what you are doing now.” That was so typically Viktor and I will always be immensely grateful that I got to know this wonderful scientist and gentleman. We continued to correspond and my last note from Viktor in 2000 thanked me for remembering his 100th birthday. I was also honored to participate in the Society for Neuroscience Symposium held in his honor that year, which was thoughtfully organized by Ron Oppenheim, one of Viktor's early students.

Motherhood and My Decision to Leave Yale

Contemplating motherhood for a developmental biologist has to come with some qualms as one is aware from direct experience of the high incidence of developmental mistakes that arise as we complex organisms translate our genetic code into cellular interactions and morphogenesis. However, it was wonderful news to learn that I was expecting, that the amniocentesis results looked good, and that we would have a son who would likely be born in March. Also this news coming shortly after I was awarded tenure, although it was not planned that way, removed the stress of worrying about having to seek another position. Following the birth of our son Gabriel Roman Pilar on March 9, 1979, I spent a month in the large Victorian home we had purchased in the village of Coventry, not far from the University of Connecticut and notable for being the birthplace of the revolutionary war hero Nathan Hale. This month was considerably more stressful than childbirth itself, as I tried to complete an overdue chapter for the Annual Review of Neurosciences, which Max Cowan had assured me could be late under the circumstances, while trying to entertain my mother and learn the essentials of early parenting. With the Annual Review production editor badgering me it seemed every other day, I finally completed the chapter and returned to the relative peace of work at Yale. I continued to maintain an apartment in downtown New Haven where Gabe and I spent the week, returning to Coventry to enjoy weekends hiking, swimming, or kayaking in nearby lakes and also where Guillermo and I undertook a decade-long renovation of our 1860 era home.

Organized day care was nonexistent at that time in New Haven, but I was incredibly lucky to have Gabe cared for by the family of Jahja Ling, now the music director of the San Diego Symphony, who was at that time studying for a Fine Arts degree at Yale. First his sister Martha and later his mother, who was like a real grandmother, provided Gabe with care that left me free from worries. He also became fluent in Mandarin. I know all working mothers have doubts about what they could have done better, but I have come to be fairly convinced that most of a child's personality is defined by genes and that we can tweak this only slightly. In fact Jahja's mother, realizing that good motherhood could only do so much, encouraged me to have three children despite being very busy. That way, she would say, you have a good chance that at least one will turn out well.

Our son has grown into a fine young man and he would have to say if he missed out on anything. He did spend a lot of late afternoon hours in the lab, discovering a myriad of uses for dry ice, including making bombs by enclosing it in rubber pipette bulbs and using it as a propellant for shooting Eppendorf tubes from plastic syringes. He also got a useful early and sophisticated introduction to computers from a variety of students, postdoctoral fellows, and even faculty members. However, at one point as I was rationalizing a trip to give a seminar by saying how one had to live up to the commitments that one has made, he dryly commented “Mom, there are lots and lots of neuroscientists. I'm sure they can find someone to replace you.” So much for feeling self-important! However, compensating partly for the inevitable parental absences that accompany a scientific career has to be the exposure that our children have to students and colleagues from countries and diverse cultures all over the world. Accompanying me at the age of 8 on a 3-week course I gave in Mexico City in 1987, he was totally impressed with the pyramids and with the long and rich history of Mexican art and culture, sagely noting how relatively impoverished the United States seemed in comparison.

Nevertheless, after almost 3 years of shuttling back and forth each week between Coventry and New Haven, I realized that Guillermo and I had to find positions in the same place. Also downtown New Haven was not the place to raise a child. As an adult I had adapted to its high crime rate, but I could not consider bringing up a child in an environment where all strangers had to be viewed as potential threats. Although several possibilities for relocation emerged, in the end I left Yale in 1983 to take a faculty position in the Section of Regulatory Biology that later became the Department of Physiology and Neurobiology at the University of Connecticut, Storrs, and which Guillermo chaired.

The University of Connecticut and My Introduction to Molecules

Many were surprised by my decision to leave Yale, especially after being promoted to Professor, for the relative isolation of Storrs, which was set among cow pastures in rural Connecticut. However, several colleagues from Harvard, who subsequently left that institution, later confided that this move had reassured them that if there was life for me after Yale, so too could there be life for them after Harvard. Our personal life, however, was far saner and although I missed many friends and colleagues at Yale, the neuroscientists with whom I interacted daily provided a stimulating environment. It was during my stay at Storrs that I also overcame my fear of gels and biochemistry. This was due largely to Jon Covault, a newly hired faculty member from Josh Sanes' laboratory who was practicing state of the art biochemistry applied to the nervous system. Prior to molecular biology and the development of monoclonal antibodies, the heterogeneity of the nervous system had made biochemistry extremely difficult and slow going. I had long wanted to find a molecular basis for the selective axon fasciculation and pathfinding events we had been studying, but at that time the only known cell surface molecules that seemed potential candidates were NCAM and Ll (then called NILE).

A truly catalytic event in helping me to bridge the divide between cellular interactions and molecules was the 1983 FASEB meeting in Saxton's River, Vermont. Urs Rutishauser, who had recently left Gerald Edelman's group at Rockefeller for a position at Case Western Reserve University in Cleveland, spoke of his recent work on both NCAM and on a large carbohydrate modification of NCAM, called polysialic acid or PSA, which appeared to modulate the adhesive properties of NCAM and axon fasciculation at least in culture. I spoke on axon fasciculation and sorting in the plexus region of the in vivo chick embryo, and we both saw the potential importance of bringing these two lines of research together. Later we talked with great excitement, as we sat under a waterfall in a stream that ran through town, of all sorts of potential experiments in which either NCAM function or its level of sialylation could be modified in vivo during embryonic chick development. We were brought back to earth as we emerged from the stream by the discovery that we were both covered with leeches. Thus began a long and fruitful collaboration.

The actual experiments had to be postponed for several years to await the perfection of reagents that would allow us to modify NCAM function or PSA expression in vivo. These included high-quality anti-NCAM Fab fragments from Urs' laboratory as well as an endosialidase that could specifically degrade the sialic acid residues on PSA in vivo. This exceptional tool was made by Eric Vimr and his colleagues, while studying the PSA that coats some classes of bacteria, including the meningococcal strains that cause meningitis. Eric fortunately brought this tool to the attention of Urs, and thus more broadly to the neuroscience community, by forcefully insisting on a Thanksgiving Day meeting at Urs' home while he was in Cleveland visiting relatives. Fortunately for our collaboration, Urs reluctantly relented. Equally important were antibodies that would enable us to visualize what our experimental perturbations were doing to PSA expression in the developing embryo. Unfortunately, PSA is very nonantigenic, but eventually both Tom Jessell and Jane Dodd at Harvard and Genevieve Rougon's group in France succeeded in preparing monoclonal antibodies that recognized this carbohydrate. Finally, the experiments that Urs and I planned in the stream at Saxton's River could proceed.

It is hard to convey how exciting it was at that time to be able to modify the function of NCAM or the expression of PSA in a defined way in space and time in the intact embryo by very local injections of antibodies or endosialidase and discern clear and reproducible alterations in axon fasciculation and pathfinding. This also marked my first use of immunostaining and I remember how Urs and I had to drive with the first batch of slides we had stained to the Biobehavioral Sciences Department where Enrico Mugnaini had the only fluorescent microscope around. Times have certainly changed! Although the power of Drosophila genetics was already apparent, genetic approaches to achieve in vertebrates what we desired were at that time not a viable option.

It became quickly apparent that the characteristic pattern of intramuscular nerve branching in slow and fast muscle regions could be differentially modified by altering the function of NCAM or Ll/NgCAM, or by removing PSA. These observations would not have been possible without a wholemount muscle preparation in which the entire detailed nerve branching pattern was beautifully revealed. Lisa Dahm, my first graduate student at UCONN, developed this preparation as she explored activity-dependent alterations in intramuscular nerve branching. She proposed that these were responsible for the rescue of motoneurons during the programmed cell death period, which Randy Pittman and Ron Oppenheim had previously shown followed blockade of neuromuscular activity. The monoclonal antibody, which was essential for the success of this preparation, had been made by Hideaki Tanaka, who joined me as a postdoctoral fellow just as I was leaving Yale. Rather than being disappointed, both he and his wife were immensely relieved not to be moving to New Haven, where the high crime rate that they had read about, especially in comparison to the safety of Japanese society, had caused them great concern. Even using this antibody, Lisa found that frozen cross sections could only reveal an apparent increase in axons and a more disorganized pattern of growth. It was only through visualization of the entire branching pattern that we could make specific detailed hypotheses that could later be confirmed with quantitative measurements of branching.

Polysialic acid, the expression of which is dynamically regulated during development and is also sensitive to the pattern of electrical activity, was subsequently shown to play key roles in multiple developmental events. We provided strong suggestive evidence that it was responsible for the different patterns of axon growth in fast and slow muscle regions. This idea was later confirmed at Case by my postdoctoral fellow, Vic Rafuse, when he ingeniously combined the removal of PSA with the creation of chickquail chimeras to cause “fast” quail motoneurons to innervate slow chick muscle. This experiment in turn built on Hideaki Tanaka's previous study showing that muscles in these chimeras were selectively innervated by the homologous foreign motoneuron pool. The work of another graduate student, Jicheng Tang, subsequently showed that PSA was also responsible for the dramatic defasciculation of motor axons in the plexus that Cynthia and I had described many years earlier, and that its removal resulted in motor axon pathfinding errors. Recently and more than a decade later, Gartz Hanson has identified PSA as a prime molecular candidate to explain the pathfinding errors that he discovered were caused by altering the frequency of early spontaneous activity.

Although I think we all try to carry out our experiments with great care and interpret our results conservatively, it is always reassuring to revisit a problem many years later, often with newly available tools, and to be able to both confirm the original findings and extend new concepts. It is often those older observations that suggest further decisive experiments. Thus, I am chagrined by the tendency of many young scientists today to consider anything not published in the last few years to be obsolete and who only read earlier work in abstract form if at all. I think that they are missing many biological gems that could be so effectively mined by the tools of today.

Another enjoyable activity, begun at Yale but carried out throughout my time in Storrs, was to participate in the Cold Spring Harbor summer course in developmental neurobiology that was organized by Dale Purves (later replaced by Corey Goodman) and Paul Patterson. The ferry ride from Bridgeport, Connecticut to Port Jefferson, New York was always refreshing and I loved being able to interact with a truly fantastic group of students, which included Marc Tessier-Lavigne, Susumu Tongawa then of recent Nobel Prize fame as he switched his career to neuroscience, and many others. There were of course also always a few laggards. It is hard to imagine two individuals so different in their approach to science or life as Dale and Paul, yet this dichotomy made for especially lively discussions and the exploration of diverse explanations for given findings.

I also remember some “wild” parties and wading in the Sound at night at the Banbury Campus where the course took place. We were clearly a bit too rowdy for the very formidable manager of the mansion there, a Mrs. Greene, if I remember correctly. I do remember my extreme embarrassment when, despite my protests, she insisted in carrying my luggage into the mansion where I stayed one time. One of the downsides to living in two places (my New Haven-Storrs days) is that needed items are often at the other location. Thus, finding no suitcase at my New Haven apartment, I had packed my belongings in a brown paper shopping bag, which was ceremoniously carried by her into the mansion.

In 1989, I was very fortunate to be invited to be a visiting Weirsma Professor at Cal Tech, while Guillermo was able to carry out a sabbatical with Henry Lester there. This provided the possibility to interact with a strong and diverse group of neuroscientists that included David Anderson, Paul Patterson, Mark Konishi, Mary Kennedy, and many others. I set out to utilize the state of the art monoclonal facility run there by Susan Oh, to use new immune suppression techniques to try to raise antibodies that would selectively recognize subsets of lumbar spinal motoneurons. Although not successful in this, I did raise a number of antibodies that were very useful to me in later research. I worked in Paul Patterson's laboratory, which had a fine group of more molecularly oriented students and postdoctoral fellows that included Zaven Kaprielian, James Sabry, and Tetsuo Yamamori. Interacting with them and doing biochemical fractionations, gels, and dot blots with my own hands further helped in demystifying molecular biology, as did getting to sit in on David Anderson's lab meetings.

This period also provided a wonderful opportunity for our son to become better acquainted with his grandparents, who lived in different locations in California, having separated about the time I entered high school. Many weekends were spent at the beach in Carlsbad where my mother lived and where I taught Gabe to boogie board and body surf, or at the desert near Joshua Tree National Monument, where we hiked, shot off rockets, or practiced target shooting with my dad. Although I loved the diverse activities possible in California just as I had as a child, the traffic, which made getting to these locations a nightmare, and the extreme overdevelopment that seemed to have ruined the California of my youth caused me to stop considering that I might one day return there. Learning that the modest stucco house in Pasadena that Cal Tech had graciously made available to us free of charge was valued, even at that time, at $450,000 cemented this decision. It was, however, a year of intellectual renewal that I will always treasure.

Returning to Connecticut, I began to become dissatisfied by the vision, or rather lack thereof, of the higher administrators at the University of Connecticut at Storrs. Seeing the potential of mouse genetics for future neuroscience research, I was dumfounded when the dean at that time, also a biological scientist, informed me that land grant universities such as ours could not expend the resources needed for mouse genetics and that we should content ourselves with using simpler organisms such as the slime mould Dictyostelium. Although I appreciated this organism as a fine model for many developmental and cell biological processes, its lack of a nervous system was clearly problematic for a neuroscientist.

Thus, although not actively seeking to relocate, I was ready to consider the possibility when in 1991 my colleagues invited me to give a seminar at Case Western Reserve University in Cleveland. Case had a very strong group interested in adhesion/guidance molecules and axon growth, which included Vance Lemmon, Jerry Silver, and my long-time collaborator Urs. Further, much to my surprise, I found Cleveland to be an attractive and very livable city. Thus, when Story Landis, the first chair of the recently created Neurosciences Department in the School of Medicine, indicated during my visit that a senior faculty position might be available in the next several years, a seed was sown that later changed my life in many ways. Both Story and Urs worked to come up with an attractive offer and in the summer of 1993 our son Gabe and I moved to Cleveland. Due to grant-related issues, Guillermo was unable to join us for several years.

Cleveland and My Introduction to Bioinformatics and Administration

Before leaving Connecticut, I was fortunate to be joined by two very fine postdoctoral fellows, Victor Rafuse from Canada and Esther Stoeckli from Switzerland, who greatly facilitated the move and ensured that experiments were up and running shortly after our arrival in Cleveland. As neurosciences space was still being consolidated, Hunt Willard, then Chair of Genetics, generously offered me space in the newly constructed Biomedical Research Building where Urs, who had become a member of the Genetics Department, was located. This edifice, like so many new research buildings, was designed in an open space mode, which efficiently lets administrators, who have no real understanding of the space needs of different types of science, titrate space to match grant income, as well as to more densely pack in researchers. Although my lab and Urs' had a combined critical mass adequate for scientific interactions, the space was poorly designed for either fluorescent microscopy, which was then our major technique, or electrophysiology. This necessitated that we use the few separate rooms for microscopy and carry out relatively delicate electrophysiological recordings in the, albeit wide, hallway with people slamming the adjacent cold room door or pushing by us to get down the corridor. Thus, we were all delighted to move several years later into windowless and somewhat more antiquated space in the Neurosciences Department, where we currently still reside.

From a personal perspective, our son was not eager to move to Cleveland. Having grown up in New England, his two major loves were sailing, and clearly Lake Erie did not measure up to the Atlantic, and skiing, where northeast Ohio was also found lacking. However, we purchased a house in Shaker Heights within a 10-minute drive from Case and came to appreciate the unique social culture of this region, which combines a liberal attitude more like the northeast with a genuine midwestern friendliness. I also have come to value living in a racially integrated town that has the community spirit to maintain an excellent public school system, from which our son greatly benefited. Finally, it was also deemed especially appropriate for me to emigrate from Connecticut to Cleveland, as the northern part of Ohio from the Pennsylvania border to Cleveland was originally the Western Reserve of Connecticut, from whence derives the rather strange name of my current institution.

Scientifically, the two major research themes begun earlier have continued to evolve and extend in interesting ways. First I have never been able to get away from NCAM. Following studies by Barbara Fredette, my last postdoctoral fellow at UCONN, and Vic Rafuse, which revealed that the expression of the different isoforms of NCAM was highly dynamically regulated and activity dependent during chick neuromuscular development, it did not seem that we could make much further progress in the chick system with the tools then available. However, the finding that neuromuscular development appeared to be totally normal in the NCAM null mouse generated by Harold Cremer in 1994 prompted us to obtain some of these mice to see if we might detect deficits that others had missed. I confess that I was partly motivated by people commenting that it was a pity that the very lovely observations we had made in the chick were not relevant to mammalian development. In the end, it took a team effort by Vic Rafuse, Christian Bose, and the very talented electrophysiologist Luis Polo-Parada, and the application of multiple techniques including physiology and the visualization of synaptic vesicle cycling via styryl dyes, to detect novel defects in synaptic transmission and the mobilization of synaptic vesicles. We concluded that NCAM, and specifically its 180-kDa isoform, is required for adult synapses to maintain transmission with repetitive stimulation and that, rather than acting as an adhesion molecule, this isoform with an intracellular domain appeared to be acting as a signaling or scaffolding molecule.

It was again a stroke of luck that brought a Swiss student Florian Plattner, who had just completed a master's degree in biotechnology and bioinformatics in Europe, to my lab to carry out 9 months of hands-on research. Florian helped me to appreciate, and thus begin to use, the vast wealth of data now available on the Internet. Through him, we discovered a highly conserved intracellular domain on NCAM that mediates these effects on transmission and that acts via myosin light chain kinase and myosin driven movements of synaptic vesicles. Thus, I am investigating a whole new area and one where I would not have expected to find myself 5 years ago. This is why science is both rejuvenating and so much fun.

Our studies of activity-dependent phenomena also took a new turn when a M.D./Ph.D. student Louise Milner, who had been investigating the selective fasciculation of slow and fast motor axons in spinal nerves, decided to determine if this phenomenon was activity dependent. Without my knowledge, she pharmacologically “blocked” spontaneous rhythmic activity during early stages of axon outgrowth and excitedly showed me the data suggesting that this had caused apparent motor axon pathfindng errors. This prompted us to characterize the cord circuits that drove spontaneous activity at these early times as it was not even clear that such cords were rhythmically active. Gartz Hanson then extended the characterization of these circuits to mice and showed that briefly reducing the frequency of such activity produced alterations in motor axon fasciculation, pathfinding errors, and changes in the expression of specific guidance/adhesion molecules. These findings challenge the traditional view that patterned electrical activity is only used later in development to refine circuits assembled via molecular signals. Our plan is to now use multi-photon calcium imaging of single cells to characterize the activity of cord circuits at the earliest stages, when motoneurons are still migrating and extending their axons, and to determine how such activity intersects with already elucidated molecular signaling pathways to lead to the assembly of functional cord circuits. I feel so grateful to be able to be exploring these new areas at my age.

With age and experience, however, comes the responsibility to try to use that experience to help both society and our scientific discipline. I thus have enjoyed serving on a number of advisory panels, both of government and scientific societies. However, I had always avoided purely administrative positions, and it was thus with some reluctance that I agreed to be interim chair of the Neurosciences Department when Story Landis left in 1995 to head the intramural program at NINOS. Story reassured me, who had spent most of my career in biology departments, that our departmental administrator Narlene Brown more or less ran the department, which luckily for me turned out to be true, and that other medical school chairs would provide me with needed advice. It was the highly congenial environment at Case and seeing the fine group of basic science chairs, who included Hunt Willard, Toni Scarpa, Fritz Rottman, and Mike Lamm, work effectively together for common goals that made me feel that I could cope with being a chair. The realization that my ideas, which I often found better than various administrators, could be put into practice also helped.

In 1999, I became actual Chair and for the most part have enjoyed building on the strong department that Story had assembled and extending it into new areas. We have recruited an excellent group of young faculty members and have managed to retain a cadre of senior scientists who are respected leaders in their fields. I was just beginning to become complacent, when our institution underwent a crisis of major proportions; this involved a caustic conflict between the medical school and our major affiliated hospital as well as the turnover of many administrators including the university president, the dean of the medical school, and the head of the hospital. I was asked to serve on reconciliation committees to try to fix the problems and to search for a new dean, which resulted in several years of emotional stress and having to focus my time and creative energy away from my true interests. However, as we now appear back on track, I find that I can turn my focus back to the department and lab.

New Mexico

This account would be incomplete without an acknowledgment of the importance that New Mexico and the home that we built there in the mountains several hours north of Santa Fe has had for me. Having been captivated by the beauty of the southwest during our sojourns in Utah, Guillermo and I, and later our son Gabe, vacationed there every summer, kayaking several times down the Green River in Utah. However, we came to prefer the ethnic and cultural diversity of New Mexico with its historic Hispanic villages and diverse Native American tribes. Toward the end of camping vacations we would look for land to purchase but could never find any we both liked and could afford. But once, returning from Lake Powell, we were captivated by the mountains and high meadows just south of the Colorado border near the towns of Chama and Tierra Amarilla and purchased a large tract of mixed ponderosa and juniper-pinion forest with amazing views especially from a ridge where the mountains around Abiqui, 40 miles to the south, are clearly visible. We were subsequently quite shocked later that year to learn that in 1967 Tierra Amarilla had been the site of a protest for land rights by local Hispanics, which resulted in the occupation of the county courthouse and the calling out of the state National Guard. However, over the years we have gotten to know and appreciate many of the locals and have had more adventures than I have space to recount. During this time, our son was able to spend wonderful periods free from television and other distractions while he explored nature at its finest. We also established a long-lasting relationship with a Navajo family whose children are like my own grandchildren. It is a place of great tranquility where I can escape each year from the hectic pace of academic life to recharge myself both mentally and spiritually. I envision that one day, when I have had enough, if not of science, then of the chores that accompany its practice today, that I will retreat there to pursue interests such as photography and writing for which I have never found enough time.

Concluding Remarks

I would like to thank the Society of Neuroscience for honoring me with the invitation to contribute this chapter and Larry Squire, who saw the importance of recording the history of our relatively young discipline in its practitioners' own words. I will also take a moment to apologize to the many people who made contributions or who have influenced my career and whom I did not have space to mention, as well as for any factual inaccuracies that my aging brain has introduced into this account. Having entered science when women were very scarce, I can honestly say that I have never felt out of place, thanks to the support and friendship of not only my mentors but of most of my peers, the vast majority of whom were male, during my days as a graduate student, postdoctoral fellow, faculty member, and finally chair.

Reflecting on both the past and future, the great excitement I feel in seeing neuroscience on the verge of so many important discoveries, is tempered by my concern over the recent rise of religious extremism, political intolerance, and anti-intellectualism in my country. Science too has changed, having lost some of its innocence as it becomes practiced for profit. Furthermore, the hectic pace of activities we seem to need to carry out to survive in science today leaves so little time for scholarly reflection. Finally, the rise of directed research in which large groups are assembled to address specific problems, although having a place, is likely to come at the expense of basic science and individual creativity, which to me will always be the engine that drives biological science. However, these are challenges for the next generation of neuroscientists to confront and hopefully solve.

Selected Bibliography

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Rodolfo R. Llinás

BORN:

Bogota, Colombia

December 16, 1934

EDUCATION:

Universidad Javeriana (Bogota), Colombia, M.D. (1959)

Australian National University (Canberra), Ph.D. (1965)

APPOINTMENTS:

Head, Department Neurobiology, IBMR, AMA/ERF, Chicago (1968)

Head, Division of Neurobiology, University of Iowa Medical School (1970)

Chairman, Department of Physiology and Neuroscience, New York University School of Medicine, New York (1976-)

HONORS AND AWARDS (SELECTED)

Bowditch Lecturer, American Physiological Society (1973)

Professorial Lecturer, College de France, Paris (1979)

Lang Lecturer, Marine Biological Laboratory, Woods Hole, MA (1982)

McDowall Lecturer in Physiology, King's College, London (1984)

“Doctor Honoris Causa” (Medicine), University of Salamanca (1985)

National Academy of Sciences, USA (1986)

Ulfvon Euler Lecturer, Karolinska Institutet, Stockholm (1987)

F.O. Schmitt Lecture and Award in Neuroscience, Rockefeller University, New York (1989)

UNESCO Albert Einstein Gold Medal Award in Science (1991)

Signoret Award in Cognition, Fondation Ipsen La Salpatriere, Paris, France (1994)

American Academy of Arts and Sciences (1996)

American Philosophical Society (1996)

Real Academia Nacional de Medicina, Spain (1996)

French Academy of Sciences (2002)

Catedra Santiago Grisolia, Valencia (2004)

Neuroscience Prize, University of Zurich (2004)

Rodolfo Llinás has carried out detailed and elegant studies of the electrophysiology of the vertebrate cerebellum. In mammalian neurons, he discovered dendrite calcium spikes, dendritic inhibition, electronic coupling, and subthreshold oscillations. At the squid giant synapse he demonstrated presynaptic calcium current. He studied the electrophysiology of thalamocortical networks in brain slices and related his findings to his pioneering work with humans using magnetoencephalography (MEG). He has also drawn on his physiological findings to propose possible commonalities among certain neurological and psychiatric disorders.

Rodolfo R. Llinás

Bogotá, Colombia

Basic Schooling

The study of nervous system function has been my profession, as well as my passion, in life. I was born in December 1934 in Bogota, Colombia, a city high in the Andes (8,700 feet above sea level), to a family of physicians. My grandfather, father, and one uncle were professors at the National University Medical School. Much of my interest in medicine, and particularly in nervous system function, arose from family discussions and only later was this reinforced by studies at school and at the university.

My first serious “encounter” with the brain occurred very early in my life. When I was four years old, my paternal grandfather, a widower, suggested to my parents that I should spend a year with him. Grandfather, a professor of psychiatry, had his office at home. One day while playing on the second floor, I happened to look down into the glass–covered patio that served as the usually boring waiting room for my grandfather's patients. To my amazement one of the patients started moving in a strange way. He bent over, fell onto the ground, and began making jerking movements and producing very strange sounds. When Grandfather came up to lunch I was waiting to ask what had happened to the patient, and most particularly, I wanted to know why this individual behaved so strangely. He mentioned that the patient did not want to behave that way, but rather, something had happened to his brain so that he could not stop his body from acting like that.

This event completely blew me away. I could not understand how this person would do something he did not want to do. Then this statement came from Grandfather:

“Not everything we do is under our control.”

And so I asked him, “Who is in control?”

His answer was “It is controlled by the brain.”

Further discussions on the subject convinced me that everything we did was brain-related, from talking, to hoping, to fearing, to every other event in which I was interested. And then I asked the question, “Please can you tell me how the brain works and how is it connected to me?”

Grandfather answered, “Sorry, I don't know.”

I explored such questions with many people for many years and found that it was basically considered a rather nerdy, even gross and unpopular subject for conversation.

The rest of my childhood was spent at home with my parents. Father was a loving, if strict, individual. A professor of thoracic surgery, he was willing to discuss almost anything as long as it was presented cogently. My youth was a bit complex as I was uninspired by religion, and so, while being socially accepted, there was the nagging problem of noncompliance, which bothered my peers and in particular my mother; my father, on the other hand, was willing to hear my arguments. I had the distinct suspicion that God was viewed as “a highly placed executive” who was mostly supposed to judge and do favors for people.

Education actually went ok, although I was far from a star pupil. Most scholastic subjects seemed boring and irrelevant to me. Nevertheless, my schooling was excellent, and I remember my teachers with gratitude. I was taught intellectual rigor at a leading school, the Gimnasio Modemo, where many of the teachers were European intellectuals and university professors who had reached Colombia before and during the Second World War.

At 17 I entered medical school (6 years) and decided to devote myself to the study of nervous system physiology, because that was what I had wanted to do since childhood. Before graduation I had the good fortune to visit R.W. Hess in Zurich. I had a copy of his book titled Das Zwischenhirn (difficult to read in a translation done by a German-speaking classmate), which included an interesting description of hypothalamic electrical stimulation and how it modified the behavior of animals. I went to Zurich to visit Hess's lab in 1954 during my second year in medical school and then again in 1956. Hess and his colleagues, Robert Hunsperger and Antonio Fernandez de Molina, the latter a professor of physiology at Madrid University and still a very dear friend and esteemed colleague, kindly offered me the possibility of participating in some of their experiments.

I was totally fascinated by the results: electrical stimulation could repeatedly activate complex stereotyped behavior, day after day. The behavioral pattern was related to the stimulus site. In attempting to reproduce such experiments back in Colombia, I understood that without a proper infrastructure animal research was impossible. Not even the cats cooperated! Cats in South America are not gentle like those in Switzerland; they are a lot more savvy. Interaction with the alley cats of Bogota, which were the ones provided by the university, was rather trying. So I opted for theoretical work for my doctoral thesis under the direction of Drs. Carlo Federici (a professor of physics and math at the National University) and Fernando Rosas (a professor of physiology). After 2 years of physics and math study, in parallel with the clinical years, I produced a thesis on circuit analysis of the visual system, using multivalued symbolic logic.

Boston

The Beginnings

With a medical degree in hand, I came to the United States to do neurosurgery at the prestigious Massachusetts General Hospital (MGH). It was clear to me that Boston would be a wonderful place to do research, especially since the MGH was near to both the Massachusetts Institute of Technology (MIT) and Harvard. MIT was particularly attractive as the external examiner for my thesis had been Warren McCulloch, whose work, in fact, had been the inspiration for my starting theoretical work. He had written important papers at the time concerning the possibility of modeling nerve net activity from a mathematical point of view. At MGH I was greeted by a very kind group of colleagues, from both psychiatry and neurosurgery. Frank Ervin, at the Stanley Cobb laboratory, offered me lab space and was extraordinarily supportive. There I met Teruo Okuma from Tokyo University and Janice Stevens from UCLA, and I published a paper on the effect of brainstem lesions on epilepsy.

After a short stay I moved to neurosurgery, but soon found that it was not what I had expected. Thus, my romantic view of surgeons dealing with human brains every day and having the time to understand better the function of the nervous system was replaced by a different reality. Neurosurgeons were intelligent, hardworking individuals addressing the brain as one would any other organ. They dealt with vascular problems, head trauma, and tumors and attempted to help patients in rather dire conditions. But for the most part, and rightly so, they were more interested in saving lives than in figuring out how the brain works.

Somewhat disillusioned, I decided to spend some time at MIT and I also, on several occasions, visited the newly appointed Professor of Neurobiology, Steven Kuffler, and members of his department at Harvard Medical School. At that time this very distinguished group, which included David Hubel, Torsten Wiesel, Edward Furshpan, David Potter, and Edward Kravitz, were basically interested in the visual system as well as in different aspects of synaptic transmission. At MIT I took some courses with Walter Rosenblith and had the good fortune to meet Jerry Lettvin, Humberto Maturana, and Walter Pitt, in addition to McCulloch.

Minneapolis

Dendritic Inhibition and Disfacilitation

However, my real interest had long been the electrophysiology of central neurons, from an intracellular perspective. I had read J.C. Eccles's book on motoneuronal physiology and thought that such techniques had to be mastered if one was serious about understanding central nervous system (CNS) circuits. And so after a year and a half in Boston, I went to the University of Minnesota with a National Institute of Health (NIH) grant to work in motoneuronal electrophysiology with Carlo Terzuolo. Working in Carlo's lab was an incredible experience; he was a truly gifted electrophysiologist, having just finished the first voltage clamp study in mammalian motoneurons with Araki at UCLA. He presented me with the possibility of learning intracellular recording at the level that I had hoped.

Carlo was a force of nature. On my arrival, he pointed to a room and said “That is your lab. So, you want to study motoneurons? Fine, let's do some work on the effects of cerebellar stimulation on motoneuron excitability.” He spent a day showing me the equipment, gave me the manuals concerning the instrumentation (mostly Tektronics), and proceeded to tell me that I was supposed to do five experiments a week by myself, which I did. I was basically left on my own; I would report to him once a week. I cannot overstate the importance of having had Carlo be as tough as nails concerning science and as hands-off as he was during this time.

The experience was superb; one had to know enough electronics to understand and modify the circuits used because many instruments were home grown or were directly adapted from electrical engineering (oscilloscopes and waveform and pulse generators). I heard comments such as “Rodolfo, don't even think of putting your finger on the glass cover, high-quality resistor in the capacity compensation circuit, OK? It is very expensive and we have only one!” and “Pull good electrodes. Get the animal from the cages left to right. Do laminectomies carefully. Don't damage the brain or spinal cord. Take detailed notes. Deal with the dark roombased photographic development of the intracellular CRT traces. And after the experiment put the cat in the freezer!” One felt a bit like Chaplin in Modern Times, but it was a fantastic experience nevertheless.

Woods Hole Interlude

Getting to Know You

During my stay with Carlo, I also had the good fortune to work at the Marine Biological Laboratory (MBL) at Woods Hole, Massachusetts, in the summer of 1962. I am presently writing this manuscript during my 37th summer at the MBL.

That particular summer was quite an experience for me. Harry Grundfest, a major force in electrophysiology at the time, invited Carlo, and I tagged along with him. At the MBL I had the pleasure of meeting many of my life-long colleagues: Mike Bennett, George Pappas, Hal Gainer, Kiyoshi Kusano, Clay Armstrong, John Dowling, Toshio Narahashi, and John Moore among others, as well as very distinguished senior investigators such as Alan Hodgkin, Andrew Huxley, K.C. Cole, and lchiji Tasaki. Also present at the MBL at that time was the Harvard group mentioned previously.

Carlo and I did intracellular experiments in lobster giant axon, attempting to create complex repetitive firing properties by manipulating the conductance of the extracellular space with an oil gap. It did not work. I also became acquainted with the squid giant synapse that Ted Bullock, Susumo Hagiwara, and Tasaki had introduced to neurophysiology a decade before. The “high” that followed the first MBL experience has stayed with me ever since.

Return to Minneapolis

Returning to Minneapolis, we continued our electrophysiological investigations of descending inputs to motoneurons, and the results had the immediacy one would wish for in other things in life. Proper recordings allowed incredible questions to be asked and, for once, one would see nature revealing “new findings” everyday. However, when I brought them to Carlo, he would quickly point out that the results had been published in extenso by others, and he would tell me, “Please go back to the lab.” And so, after about a year and a half of work, we determined that cerebellar and reticular inhibition were different, one being a disfacilitation (Llinás, 1964) and the other a direct inhibition that occurred at somatic and at, contrary to the current dogma, the dendritic level (Llinás and Terzuolo, 1965).

At that time motoneuron electrical activity was considered to be driven by synaptic input to the soma. The dendritic input was basically disregarded because before Wilfred Rall's important modeling work, neurons were assumed to be a single isopotential compartment where all synaptic inputs could be considered equivalent electrically. Moreover, the soma was considered to be the only location for inhibition, being close to the axon hillock, where the action potentials were generated.

Thus, dendritic inhibition represented a rather different view of neuronal integration, and one that we felt was sufficiently important to be presented at the International Physiological Conference in Amsterdam in 1962. Armed with slides, Carlo and I went to the meeting, and I presented our new findings to a very distinguished group of electrophysiologists. Sitting in the audience in a very prominent site was John C. Eccles. After the presentation he immediately got up and mentioned that it was well known that inhibition would only be effective if located near the neuronal axon. After the session he called me aside and mentioned that maybe it would be a good idea if I joined him in Australia to study this in more detail because we were clearly wrong.

Canberra, Australia

The Cerebellar Cortex Electrophysiology

The Canberra years were a very exciting and important time in my scientific career. They began with a seemingly interminable flight from Minneapolis to Canberra. There was plenty of activity on the way, however, because some of my fellow travelers were Australians happy to be going back home, and I left a very lively group of people when we arrived in Sydney. The next leg of the trip was made in a small plane going into Canberra, the somewhat secluded capital of Australia. At that time the Australian National University was located on the outskirts of Canberra and consisted of two main parts: the School of General Studies and the Institute of Advanced Studies. Professor Eccles had his world-renowned laboratory at the John Curtin School of Medical Research, an important part of the Institute of Advanced Studies.

I found the physiology department on the second floor and discovered the professor in his rather modest office working on a manuscript. Also on the same floor were the laboratories headed by Rosamond Eccles, John Hubbard, and David Curtis, all of whom had graduate and postdoctoral students. This was a very vibrant group of people indeed.

Following instructions regarding where to place my luggage, I was directed to University House, a truly magnificent building, then more akin to a four-star hotel than to the student lodgings found everywhere else in the world. Once organized, I returned to the laboratory to discuss the immediate plans with Sir John. Facing each other and becoming rapidly acquainted, he mentioned quite directly his ideas about nervous system function and asked, among other questions, whether I believed in psychokinesis. This was, of course, a bit of a shock because I did not expect that anything like that would come up, and I was not at all prepared. I explained that I knew what the word was supposed to mean, but that I frankly did not understand the mind (a functional property of the brain) being able to move objects at a distance.

Sir John mentioned that psychokinesis was part of the mechanism that he had considered for the relation between mind and brain (Eccles, 1951). I mentioned that I was not religious and considered such views somewhat contrary to my understanding of the world and its workings. That being said, there was no adverse reaction that I could see, and we simply decided that I was going to be working directly with him on the cerebellum. This work would follow a set of electrophysiological studies begun in his lab with two postdoctoral students, Per Andersen and Paul Voorhoeve. Thus, a short time after arriving and shortly after Per Andersen returned to his home in Oslo, I became acquainted with the equipment and began experiments.

At about the same time, Dr. Kazuo Sasaki arrived from Kyoto and was also assigned by Eccles to study the cerebellum. Thus, for 2 or so years, Eccles, K. Sasaki, and I worked on trying to understand the physiology of the cerebellar cortex. Prior to our work, extracellular field potential recordings and some intracellular recordings by Andersen, Eccles, and Voorhoeve had demonstrated that the basket cell terminals onto the soma of Purkinje and hippocampal neurons were inhibitory, which further fueled their view of the somatic nature of inhibition.

A few months after my arrival in Canberra, Eccles was awarded the Nobel Prize for Physiology or Medicine in conjunction with Andrew Huxley and Alan Hodgkin. This was, of course, a wonderful event for the lab and a lovely party was put together, but work otherwise proceeded without much fanfare. A few months later, Eccles went to Stockholm to receive the prize and came back for a rather larger party that included most of the faculty of the John Curtin School of Medical Research.

The relationship between Eccles and his students had been and was at that time extraordinarily cordial. We would work three times a week on experiments that started just after breakfast. We would be ready to record in the early afternoon. We would break at dinner time, then return to the lab and generally, end a recording session somewhere between 11 PM and 1 AM, at which time I would return to the University House while Sasaki and Eccles would drive to their respective homes. Other than work, lab members also visited the Eccles' home occasionally on weekends, where they had garden parties, and played tennis on his private court.

Immediately following his Nobel Prize, Professor Eccles had to spend a rather significant part of his time traveling and fulfilling the many invitations and lectures that are de rigueur after such prizes are awarded. So, for most of 1964 Sasaki and I worked in his absence but under his very watchful eye.

By the middle of 1964 we had characterized most of the cerebellar circuit in the sense of having defined the excitatory or inhibitory nature of all synaptic interactions in the cerebellar cortex. The electrophysiological characteristics of the cerebellar cortex turned out to be very beautiful. The climbing fibers, one for every Purkinje cell, elicited an absolutely huge synaptic potential that was, as expected, all-or-none, being in fact a unitary potential (produced by the activation of a single input fiber). This, of course, was unheard of, as central synaptic transmission was viewed as being produced by the summation of many afferent fibers that were activated in unison. In fact, the response was so large that only after Sasaki and I managed to reverse it was Eccles convinced that it was a synaptic potential, rather than an aberrant spike (Eccles, Llinás, and Sasaki, 1964a, 1966a).

The mossy fiber-granule cell pathway, on the other hand, turned out to be an extraordinary subtle synaptic input because the number of parallel fibers that a Purkinje cell receives is one of the largest in the brain. Thus, in human brains as many as 200,000 parallel fibers impinge on a single Purkinje cell. Cajal beautifully described the anatomy of this circuit in 1888. And indeed, as foretold by the anatomy, synaptic inputs occurred directly on the spines.

At this point the issue of dendritic inhibition came up once again. Most of the synaptic input onto Purkinje cell dendrites, other than parallel and climbing fiber afferents, were represented by synaptic input from stellate cells in the molecular layer of the cortex (Eccles, Llinás, and Sasaki, 1966a , 1966b). We had determined that a direct activation of the surface of the cerebellar cortex (a rather unphysiological stimulus but helpful in determining synaptic organization) evoked an early excitatory input generated by the parallel fiber-Purkinje cell synapse followed by disynaptic inhibitory postsynaptic potentials that were strongly dendritic as well as somatic, as, in fact, stellate cells largely outnumber basket interneurons. Thus, restricting our concept of inhibition to the soma was, scientifically, not a viable option. In addition, the results demonstrated that Golgi cells were also inhibitory and that their input was exclusively dendritic (Eccles, Llinás, and Sasaki, 1964b, 1966d), and so the question of dendritic inhibition had been addressed and confirmed. Over and above these questions the results demonstrated that all connectivities in the cerebellar cortex were inhibitory with the exception of the mossy fiber—the granular cell—parallel fiber system and the climbing fiber input.

This was, of course, a most exciting happening. It was the first region of the brain to be completely mapped from a physiological point of view. And so a set of seven papers to Journal of Physiology and Journal of Experimental Brain Research and two papers to Nature were written. This was easily one of the most productive times in my life. I had produced a thesis that afforded me a second doctorate, this time in physiology, and had become acquainted with a truly wonderful set of colleagues in Canberra.

Among the latter was Gillian Kimber, a student of philosophy who was finishing her Ph.D. on the philosophy of the mind. In fact, in addition to my being very interested in physiology many of the friends I had at that time were philosophers. And so it happened that Gillian and I, having similar views on the nature of mind, mine being physiological and hers being philosophical, became very close and decided to marry. It was a bit surprising for Professor Eccles because others of his students who had married Australian women had always married Catholics, he being himself a devout Catholic, as was his wife. Gillian, on the other hand, was a Protestant and student of J.J.C. Smart, the most outstanding materialist philosopher at that time. And so there was a deep contrast between this particular union and those of his former students and collaborators, such as Bernard Katz, Steven Kuffler, and Paul Fatt, who had all married Catholic women from the Eccles's social circle.

After close to 3 years, I finished my Ph.D. and wrote a thesis on the functioning of the cerebellar cortex. Spirits were, of course, extraordinarily high. The work was presented at the International Physiological Congress in Tokyo, and with the new results of Masao Ito, who had discovered that Purkinje cells were themselves inhibitory, the cerebellum loomed very large in neuroscience.

Return to Minneapolis

A Short Stop

I then returned to Minneapolis in 1965 to take up a position as Associate Professor of Physiology, following several pauses to present our work in Europe. The first was in Budapest, Hungary, at the kind invitation of János Szentagothai, and the second was in Goteburg, Sweden, where Lundberg, who had been studying the spinal cord input to the cerebellum, greeted the new results with genuine joy. Again, everything was coming to fruition with extraordinary speed and a great deal of excitement.

At this time we all had the feeling that having deciphered the neuronal connectivity of the cerebellar cortex, we would be in the position to understand global cerebellar function in short order. In hindsight I find it amazing that all of us, including Eccles, were so naive about the functioning of the nervous system. Indeed, 40 years later we still continue to address cerebellar function without an ultimate resolution. The fact was that shortly after my return to United States, I personally began to feel that our initial enthusiasm had pushed us to be overoptimistic. Clearly, understanding cerebellar function, without a context in which to frame our wonderful circuit, would be an impossible task. So I began to consider embarking on a comparative study of cerebellar function to see if a common denominator could be found that would put into context the electrophysiological details that we had addressed in the mammalian cerebellum. Again, from the work of Cajal it was evident that evolution had maintained, almost unchanged, the morphology of cerebellar neuronal circuits throughout vertebrates. The real issue at hand was whether the maintenance of an almost stereotyped neuronal circuit across vertebrates was actually paralleled by an equal invariance in electrophysiological detail.

At about that time a wonderful letter came from Eccles. He had decided to leave Australia and was planning to come to the United States to work at the American Medical Association in a brand new institute known as the AMNERF Biomedical Institute. He further wrote that he would be very happy if I could join him in his American venture as a colleague at the institute. Gillian and I had been married since the end of 1965 and felt that a move to Chicago could be very interesting and although we were moving out of a well-known university to a new institute, I felt that the move would be more conducive to scientific work. Indeed, there were no teaching requirements, and all the time could be devoted to research. The idea was to have two main labs, one that Eccles would direct and a smaller lab that I would have to do my own research. The downside, of course, was leaving many friends and colleagues, especially Carlo Terzuolo, who had been such a wonderful friend.

Chicago

Comparative Cerebellar Physiology, Dendritic Spikes, and the Vestibular Cerebellum

As we were preparing to go to the AMA at the end of 1966, Gillian and I had our first son, Rafael, who is now a neurologist at Johns Hopkins University School of Medicine. Early life in Chicago was interesting and slightly complicated. Eccles was in Australia getting ready to move to the United States with much of his equipment, while I was helping to set up a new, complex lab, and Gillian was setting up a new household.

Before we left for Chicago, Eccles asked me to train a colleague from Czechoslovakia. Helena Taborikova was a physician who was going to join us in Chicago as a collaborator. Helena had been trained in human electrophysiology and was not acquainted with single cell research. And so I invited her to spend some time with me in Minneapolis, and then she moved to Chicago at about the same time as my family.

The time in Chicago, 1966 to 1970, was scientifically very productive but rather complicated from a human point of view. Although I was quite used to American universities and colleagues, Eccles was not, and so problems began to appear almost immediately after his arrival. Indeed, in Australia he was accustomed to a great deal of deference and respect from all who surrounded him, as befits an extraordinarily distinguished scientist who is recognized throughout the scientific world. The rather rough and ready approach of the scientific community in the United States, as well as the relation to students and technical staff, was less deferential and more confrontational than that with which he was familiar. Setting up the labs was marred by the usual delays that occur with construction efforts in a city, and so it took longer than expected to get the labs working. Meanwhile, and totally unbeknownst to all of us in the department, Eccles had decided to divorce his wife of more than 40 years and leave his family of 9 children in Australia. He had decided to marry Helena, with whom he had become acquainted before coming to the United States. Not knowing about this relationship, I considered Helena a student who was starting physiology and so I did not pay her the attention or show her the deference I would have had I known that she was not coming as a colleague but as the future Lady Eccles.

This early misunderstanding generated innumerable repercussions and complications that resulted in unintended, unfortunate, and sometimes hilarious human relation problems. So, in short, what had begun as an extraordinarily cordial relation with Eccles grew into a very complex and Byzantine interaction in which people from the two labs were not allowed to talk to each other. All this engendered a dysfunctional social environment.

From a research point of view, however, the work on comparative cerebellar circuit function proceeded to generate beautiful results. At that time I had several colleagues who came to work directly with me or had been assigned to my lab by Eccles during our initial departmental structuring effort. The first of the colleagues was Charles Nicholson, a particle physicist and a student of Donald McKay at Keele University who had decided to do electrophysiology of the cerebellum. Dean Hillman, an electron microscopist who had worked with Dr. Fox at Wayne State University in Detroit, followed shortly.

The group was completed by the addition of John Freeman, Wolfgang Precht, and Steve Kitai, and we began to do comparative cerebellar physiology and anatomy. Eccles's lab had a wonderful group of postdoctoral fellows that included Henri Korn, Piergiorgio Strata, Luciano Provini, and Daniel Sax, in addition to Helena.

In our lab the basic idea was to define cerebellar function from an evolutionary perspective. My reasoning was that looking at the “natural history” of cerebellar phylogeny should define the context in which the cerebellar system had adapted to the ever increasing complexity of the CNS, thereby giving us a clue as to the general nature of cerebellar control. Over the next 3 years we studied every type of vertebrate cerebellum we could get our hands on. That included frogs, fish (elasmobranches and teleosts), reptiles (mostly alligators and turtles), birds (pigeons), and of course, several mammalian species.

In a second line of inquiry, I wanted to study the problem of cerebellar control on a well-defined set of movements. Wolfgang Precht, who had studied the vestibular system, joined the lab to do a comparative study of the vestibular system and its relation to postural and eye movement control. The original idea was to develop a horizontal rotating table that would allow quantitative physiological stimulation of the semicircular canals. The steps taken were to record incoming activity by addressing first the vestibular nerve and then the resulting cerebellar activity generated by the vestibular nerve input, which we knew was direct through the mossy fibers as well as indirect through the vestibular nucleus.

The straight electrophysiological study of the frog cerebellar circuits, which I had begun in Minneapolis with my first graduate student, James Bloedel, was combined with the work Precht and I were doing. The organization of the frog cerebellum at both the field potential and intracellular levels served as the basis for the system approach concerning the vestibular system. This set of studies demonstrated that, in fact, the organization of the frog cerebellum was quite similar to that of mammals, including the physiology of both the climbing and mossy afferent systems. More importantly, it showed that the protracted input from horizontal rotation activated Purkinje cells rather uniquely. Some of these cells responded with gradual tonic discharges, while others, seated next to each other, would respond with a rapid high-frequency short-lasting response (Precht, Llinás, and Clarke, 1971). This was not what one would expect from the results produced by direct parallel fiber stimulation!

Research in the other vertebrate forms basically confirmed that the cerebellar circuit is very much the same throughout evolution and that, although the connectivity of the cerebellum to the rest of the brain becomes more complicated in higher forms, the cerebellum, in principle, represents an almost universal solution from the point of view of circuit properties and dynamics.

It was during this phase of comparative cerebellar research that two very interesting findings were discovered in the lab. First, Purkinje cells turn out to be wonderful neurons in which to study integration. Indeed, a particular study in alligator Purkinje cells illustrated that dendrites were capable of generating action potentials. These massive spikes were conducted in a non-continuous fashion toward the soma. To me, the beauty of the system was that finally dendritic integration was clearly addressable,—but this time not as an appendage to the Purkinje cell soma but rather as the real integration site suggested by the complex connectivity. It was a place where excitation and inhibition could play dynamically on the geometry of neuronal structure.

In fact, it turned out to be the perfect place to understand exactly how it was that inhibition works by shunting excitatory currents. It was easy to show that dendritic inhibition could functionally inhibit dendritic activity without necessarily modifying somatic or axonal excitability. The demonstration of dendritic spikes, published in Science (Llinás et al., 1968), produced a real flurry of disagreement in the field with many people voicing objections. These included Calvin and Hellerstein (1969) and Zucker (1969), who wrote papers suggesting that our field potential analysis was defective, and the conclusions about dendritic spiking were wrong. This was actually quite interesting because it demonstrated to me that even good mathematicians can sometimes be misled by lack of direct access to experimental data. I, in fact, had written a book with Quastel and Hubbard (Hubbard, Llinás, and Quastel, 1969) on the electrophysiology of synaptic transmission in which we had treated field potentials in detail. Basically, the presence of dendritic spikes, which were recorded for the first time intradendritically by Charles Nicholson and myself, demonstrated that dendrites really spiked and were robust enough to be impaled, thus allowing the direct study of their electrophysiology (Llinás and Nicholson, 1971). Moreover, such recording could be combined with good anatomy and with mathematical modeling based on actual data (Nicholson and Llinás, 1971).

At about this time a rather unexpected event occurred. John Eccles left the AMA, and I stayed with my colleagues as director of neuroscience. Also at this time we were taking some steps out of the cerebellum and into brainstem physiology with a new colleague, Robert Baker. With Bob, we studied the electrophysiology and pharmacology of ocular motoneurons and found the first example of electrical coupling in the mammalian CNS. In short, although science was progressing nicely, Eccles' departure on less than-friendly terms left behind a rather sad wake. He had been a crucial person in my scientific career, and yet, the vicissitudes of life had made it impossible to continue my relationship with him. And so it was that we never spoke again.

About a year and a half after Eccles left, the AMA decided to terminate the Institute for Biomedical Research. This generated great distress because none of us had government research grants. George Beadle had replaced Roy Ritz as head of the Institute and had proposed to move it to the University of Chicago. This was not acceptable to the AMA, and so the decision was made that the Institute was to be closed 2 months after the initial announcement. This abrupt and unprecedented decision was challenged by the many members of the Institute and by the scientific community at large. Indeed, the lab directors decided to engage the AMA legally, and we ended settling out of court after some trying times. And so there it was, a lab of six people plus technical and clerical help looking for a place to go. We had been given all the scientific equipment and sufficient funds to survive for 1 year and to start a lab somewhere else.

In the midst of this turmoil, a most wonderful event that cheered Gillian and myself was the birth of our second son Alexander (presently an M.D./Ph.D. finishing his ophthalmology training at Stony Brook University Medical Center). A second event occurred just before the institute closed. As we were finishing our work on the comparative anatomy and physiology of the cerebellum, we hosted an international symposium on the evolution and development of the cerebellum. Most of the people working in the field came to Chicago. We had a truly spectacular meeting, and basically, most of the things that were known both from a comparative and a development perspective were reviewed and a voluminous book was published: This, in true AMA style, was beautifully produced (Llinás, 1969).

Iowa City

Calcium Spikes and Electrotonic Coupling in Vertebrate CNS

At that point, the issue was to find a place that would accept our group as it stood. We were all very much involved in cooperative research, and the thought of separation after working productively together for 5 years was very painful. In the midst of looking for a position or a place, the University of Iowa offered a home to our group. So we rented some trucks and moved, in circus style, all our equipment, books, and furniture to Iowa City where we were given proper professorial status. This then concluded our Chicago years and began our years in Iowa City at the Oakdale Campus. Having bid against the university for the construction of a new building (our bid) versus the renovation of an old building (their bid), we prevailed, and the funds we had secured from the AMA were invested in a Butler Building (still up and working 35 years later) twice the size of the renovated proposal.

Iowa City, basically a university town, was quite a contrast to Chicago, and I found it confining. So within a few weeks of arriving, three of us decided to buy a small airplane and we all learned to fly so that we could visit Chicago for theater and music whenever possible. This turned out to be quite a delight. Flying a Piper Cherokee in Middle America is very, very lovely. People are very kind and there are plenty of small airports. The mobility this affords adds immensely to life. It was convenient and easy to run to the plane and then go give a lecture anywhere within a 500-mile radius. This was as far as one could go in 5 hours on one tank of fuel, and it included Chicago, Minneapolis, and the surrounding universities. All of my colleagues thought it was a bit of a riot that I should come in my airplane, give a lecture, and fly out again. Those were wonderful, happy times indeed. Our work on comparative cerebellar physiology continued, and my first graduate student during the Iowa City years received his Ph.D. This was the indefatigable Wise Young of spinal cord fame.

Several interesting scientific events occurred during those years. Having noted that the so-called climbing fiber reflex was very robust, and with almost no latency fluctuation, I began to consider the possibility that inferior olivary neurons were electrically coupled. A set of experiments with Bob Baker had indeed demonstrated a short latency depolarization intracellularly that had no delay with respect to the antidromic field and did not show an obvious equilibrium potential. I got on the phone and called Costantino Sotelo in Paris and suggested to him that he should look for gap junctions in the inferior olive (IO). A few weeks later Costantino called back very excited. The expected gap junctions were there: great deduction works! (Sotelo, Llinás, and Baker, 1974; Llinás, Baker, and Sotelo, 1974).

As part of our drive toward defining cerebellar control, Andras Pellionisz, a young Hungarian mathematician from Szentagothai's lab, and I decided that it would be very important to develop a general model of cerebellar function. The basic issue was to reconstruct the connectivity and electrical properties of the cerebellar cortex and attempt to reconstruct a network circuit that would consider the cerebellar cortex as representing movements expressed in intrinsic coordinate systems. Later on while in New York, Andras carne up with the wonderful idea that perhaps a coordinate-independent type of vector transformation, as addressed by tensor analysis, could be a good approach to understand cerebellar circuit dynamics. Over the next 10 years we wrote papers on tensor analysis of neuronal networks. This was an original approach that promised the possibility of understanding the functional geometry of CNS activity (Pellionisz and Llinás, 1985). This work was not well received, although it provided the very useful concept of frame-independent vector transformations that is used these days in many labs.

Meanwhile, the work on Purkinje cells was progressing into what we called the “bird phase.” Somewhat surprisingly, Purkinje cell dendritic spikes, particularly in alligators and pigeons, were very prominent, and their duration was longer than expected for a rapidly inactivating sodium conductance. This made me wonder whether such dendritic spikes could be supported by anything other than a sodium current—the then accepted dogma concerning the action potential properties of neurons. Well, tetrodotoxin did the trick: Direct activation of Purkinje cell dendrites could not be modified by this sodium channel blocker, but the fast spike in the soma was gone. In short, Rainer Hess, a young student from Germany, and I found that Purkinje cells were capable of generating calcium-dependent spikes (Llinás and Hess, 1976). We published this work in PNAS, and once again all kinds of problems arose concerning these novel findings. Indeed, one of the sad side issues concerning this finding was that a colleague and friend of mine, Rafael Lorente de Nó, whom I admired immensely, decided not to speak to me again. During a presentation of this work at UCLA, he got up from the first row and asked in front of a large audience, “Do you really believe that those are calcium spikes? Well, you are wrong.” He stomped out of the hall in front of Susumo Hagiwara (Hagi), who had invited me to lecture and had found calcium spikes in invertebrate neurons. We were all stunned and open-mouthed. Later on, Lorente de Nó wrote me a strong letter saying that, “You have either lost your mind or your honesty.” By now it was becoming clear that new findings always seem to come with a high price.

Woods Hole from Chicago and Iowa City

Presynaptic Voltage Clamp

In a parallel life, I had been doing research at the MBL in the summer months through both the Chicago and the Iowa City years. There my interests were focused on a totally different area—the physiology and biophysics of synaptic transmission in squid. Synaptic transmission can be studied directly in the squid simply because the very large (giant) size of the synapse allows intracellular recordings from both the pre- and postsynaptic terminals. Using this approach, in 1965 we had discovered that synaptic transmission can occur in the absence of action potentials (Bloedel et al., 1966). Two other laboratories, that of Kiyoshi Kusano at the National Institute of Health (NIH) in Bethesda and Bernard Katz and Ricardo Miledi at University College London, were doing similar experiments in Woods Hole and Plymouth Labs, respectively. Quite independently we all found that indeed the secretory event resulting in a postsynaptic response does not require action potentials but only presynaptic depolarization. This was, of course, very intriguing because it clearly distinguished the electrophysiological properties of the action potential from those of its ultimate function—the release of transmitter. In 1967 Katz and Miledi demonstrated that in the presence of potassium blockers the calcium current could produce regenerative responses. This and other findings had made it clear that calcium could, in fact, generate action potentials if a sufficient calcium channel density was attained at the plasmalemma.

At about the same time as we were describing calcium spikes in central neurons, my work at the MBL with a graduate student, Kerry Walton, was centered on trying to voltage clamp the presynaptic terminal to determine directly the relation between calcium current and transmitter release. Charles Nicholson, John Blinks, and I had demonstrated calcium entry into the presynaptic terminals some years before using the photon emission protein aquorin, and Charles and I had demonstrated that the suppression potential was really at Eca₊₊ (Llinás and Nicholson, 1975). And so we knew that sufficient calcium flow could be observed if we could successfully clamp the preterminal axon. The voltage clamp experiments turned out satisfactorily. Walton and I observed a calcium current that did not inactivate and that reached equilibrium potential at the expected value given the calcium driving force. Moreover, the equilibrium potential had the same value as the suppression potential that Katz and Miledi had demonstrated some years before. In collaboration with a dear friend, Izchak Steinberg from the Weizmann Institute in Israel, we published the results together with a mathematical treatment of calcium current (Llinás, Steinberg, and Walton, 1976) using a variation of the famous Hodgkin Huxley equations. A more detailed paper followed in the Biophysical Journal (Llinás, Steinberg, and Walton, 1981a, 1981b), published after enormous effort and unsavory reviews. However, the findings were original and robust and have weathered well the ravages of time.

As these sets of studies were developing an invitation came from New York asking whether I would accept the chairmanship of the Department of Physiology and Biophysics at the New York University School of Medicine. This was a very attractive offer. Both Gillian and I had been city folk and living in Iowa City, although it was wonderful from certain points of view, could not hold us. And so in 1976, exactly 5½ years after reaching Iowa City, the whole group moved en masse to New York.

New York

Still at It

New York University School of Medicine was of course an extraordinary place. Very bright and unexpectedly friendly colleagues in every aspect of medicine populated the Medical Center. And the school had an excellent history in basic science research. A previous department chairman, Homer Smith, had been one of the luminaries of American Physiology. His immediate neighbors in the Department of Pharmacology were Severo Ochoa, a Nobel Prize winner in Physiology or Medicine concerning Molecular Biology, and Otto Levi, who also had a Nobel Prize in Physiology or Medicine for his discovery of acetylcholine as a myocardial modulator. Also present had been Eric Kandel, a colleague and friend from the MGH years who had moved with his group to Columbia University prior to our arrival. This was indeed the beginning of a very special episode in my scientific life. I remember David Sabatini, the chairman of Cell Biology, taking me for a long walk in the city, singing the praises of NYU in his incomparable manner. Very influential in my coming to New York were encouraging words by Dominic Purpura, a dear friend of many years, and at that time already the Dean at the Albert Einstein School of Medicine.

I have now been chairman of that department for close to 30 years (my longest time in a single place) and have seen neuroscience flourish at a level that would have seemed miraculous in 1976. I have also cherished my relationships with the students. I love to teach, as did my ancestors in another time and place.

Coming to New York was, of course, an exciting experience. The medical school was well organized, and we took to the two courses that we had to deliver like fish to water. Fortunately for us, the equipment that we had acquired from the AMA had been bequeathed to our group, and so we came to New York fully equipped. This included not only equipment for our machine shop, all our electronic equipment including an electron microscope, but also benches, etc. We also came with a program project grant from NIH, which we had attained in Iowa and which continues to be with us after 35 years. This grant has been the source of funding for most of the neuroscience research that we have done over the years.

Calcium Conductance in Purkinje cells, the P Type Channel

The move to NYU paralleled a shift in our approach to the electrophysiology of the cerebellum from an emphasis on in vivo work to one using in vitro preparations. This was begun with Mutsuyuki Sugimori ("Sugi"), one of the brightest persons I have ever met and my closest colleague over the last 30 years. The set of experiments we did from this time on concerned the ionic mechanisms at the single cell level relating to the so-called intrinsic properties of neurons. Sugi and I published a detailed study on the electrophysiological properties of the soma and dendrites of Purkinje cells in vitro (Llinás and Sugimori, 1980a, 1980b). The results clinched the calcium nature of dendritic spikes very nicely, as well as the noncontinuous nature of spike conduction in dendrites. In addition, the results demonstrated a new type of sodium current that we named “non-inactivating” or “persistent,” which was independently described by Wayne Crill at University of Washington in Seattle.

Further, studies on Purkinje cells in vitro using single channel recordings performed with a postdoctoral fellow, Maria Usowicz (Usowicz et al., 1992) from University College London, demonstrated that the channels were non-inactivating and had a distinct single channel conductance. Because they were discovered in Purkinje cells, we named them P channels. This P channel turned out to be an alpha one subunit channel whose open time is modulated by the delta subunit at a molecular level. The P channels were then described morphologically using an antibody generated by injection of a P channel protein into rabbits and indeed, demonstrated that the channel is present in the dendrites and up to the level of the spines in Purkinje cells.

We had found that funnel web spider poison blocks P channels and used that venom in one of its forms (a polyamine), isolated by Bruce Cherksey, as a synthetic blocker. We found that in its presence Purkinje cells lost their calcium electroresponsiveness (Llinás et al., 1992) (except for the T channel conductance that occurs when Purkinje cells are injured), as did the squid giant synapse under presynaptic voltage clamp. Two more recent steps have allowed us to pinpoint the physiology and distribution of the P channels. With David Tank and John Connors at Bell Labs, Sugi and I defined intradendritic calcium spikes, using calcium dependent dye imaging (Tank et al., 1988), and with Winfried Denk (Denk, Sugimori, and Llinás, 1995), one of the developers of two photon microscopy, we also defined, at the Bell Labs, the electrophysiological properties of single spines. These sets of experiments went on to characterize the repetitive firing properties of Purkinje cells, with our own version of the two photon system developed by Sugi (Sugimori and Llinás, 1990).

The Inferior Olive: T type Calcium Channels and Multiple Electrode Recording

This set of studies was followed in short order by a set of in vitro studies in the IO carried out with a then postdoctoral fellow, Yosi Yarom, from the Hebrew University in Jerusalem (today one of the pillars of Israeli neuroscience). Using a brainstem slice preparation, we discovered that IO neurons were not just strange looking, they also behaved most unconventionally. Thus, they demonstrated a new type of calcium conductance that generated calcium-dependent spikes when the membrane potential was negative to rest! This calcium conductance showed voltage-dependent inactivation at potentials positive to −65 mV (Llinás and Yarom, 1981). We named these events “low threshold spikes.” Today we now know that this calcium conductance is supported by at least two different types of T type calcium channels.

We also discovered that near resting level these neurons were capable of self-paced subthreshold oscillations (Llinás and Yarom, 1986). This intrinsic electrical property turned out to have a frequency of 8 to 10 Hz in vivo and 1 to 10 Hz in vitro, depending on the slice section through the IO, the temperature, and other tissue variables. As always, flack followed. In giving a lecture on subthreshold oscillations at Penn, my friend Brian Salzberg asked in a jocular tone, “Hey, Rodolfo, are you sure that is not 60 cycles?” Indeed, having something as weird as beautifully regular membrane potential oscillations continuously going on and not being either action potentials or synaptic transmission was pretty peculiar and difficult to stomach at the time. Since then, fortunately, many examples of subthreshold oscillations have been found in other neurons.

As this work was in progress, basically defining the electrophysiology of the elements in the IO and Purkinje cells, I began a related set of multiple electrode in vivo experiments that were designed to address the functional significance of the olivocerebellar system in a more physiological setting. The fact that IO neurons fired very slowly, were electrically coupled, and demonstrated subthreshold oscillatory activity indicated to me that the system operated in parallel, that is with IO activity probably organized in a time coherent manner, most probably as a pacemaker of sorts. Moreover, if this was the case, the only way to understand its organization would be to record from many Purkinje cells simultaneously and determine if synchronous complex spike activity could be detected.

These experiments used up to 90 individual electrodes that recorded from an equal number of individual Purkinje cells recorded extracellularly. The work in anesthetized rats was initiated with Jim Bower, who at that time was a post doc in my lab, continued with Kasuo Sasaki (Sasaki, Bower, and Llinás, 1989) (not related to the Sasaki of Canberra times), Masaji Fukuda, and Tomoya Yamamoto, and published years after the work was finished (Fukuda, Yamamoto, and Llinás, 2001). As it turned out, the electrophysiological properties of Purkinje cell complex spike activity related directly to the properties of the IO coherent electrical properties. We found that the neurons in the IO, being electrically coupled, generated well organized, and temporally coherent complex spike activity in Purkinje cells. The activation occurred in well-defined Purkinje activity bands oriented in a rostro-caudal direction over the cerebellar cortex. This work was continued and very much enhanced by Izumi Sugihara, Eric Lang, then a graduate student, and John Welsh. I will get to that work in a more contextual vein momentarily.

Contextualizing Olivo-cerebellar System Function

The ultimate significance of the olivocerebellar system, although murky, does appear a little clearer when put together with the electrophysiology and the neurology of the cerebellar system. Indeed, Holmes working at Queens Square London during the First World War, had described a set of patients with cerebellar lesions that, in addition to ataxia, demonstrated a disappearance of the so-called physiological tremor described by Sherrington as having an approximate 10-Hz frequency. It became evident to me that this 10-Hz physiological tremor was probably generated at the IO and could provide the “time binding” properties (i.e., the ability to engage motoneuronal networks simultaneously along the neuraxis) that characterize active motricity.

In agreement with this conclusion was a pharmacological study using harmaline, an alkaloid known to enhance physiological tremor in animals and man. It is known as “yage” by the Amazonian Indians, who use it as a ritualistic hallucinogen. We knew from early experiments (Llinás and Volkind, 1973) that this drug enhanced climbing fiber activation of Purkinje cell activity that correlated well with the enhanced tremor. When applied in vitro to brain slices including the IO, harmaline increased the amplitude of T currents that support oscillations in these cells (Llinás and Yarom, 1986). This increased activity, in theory, would enhance physiological tremor. Harmaline tremor is coherent in time and indicates that under these conditions the IO acts as a single oscillator. A second important finding was that specific pharmacological lesions of the IO prevented harmaline tremor. Having understood something about the property of electrical coupling and the organization of the olivocerebellar system, the question arose: How could a coupled IO be modulated such that it would not behave as a single oscillator? I had proposed in 1974 the possibility that inhibitory terminals that contact the IO glomerulus could work to momentarily decouple neurons of the IO by shunting trans-dendritic currents (Llinás, 1974). A similar inhibitory base decoupling had been described by Spira and Bennett (1972) in Navanax, probably subserved by a different mechanism because invertebrate neurons have no dendrites.

That such a mechanism is in fact present at the olive was demonstrated in collaboration with Eric Lang. He showed that damage to the cerebellar nuclei produced an immediate coherence of olivary neurons, resulting in coactivation of complex spikes throughout the cerebellar cortex (Lang, Sugihara, and Llinás, 1996). Years before, Nelson and Mugnaini (1989) had discovered that a proportion of the cerebellar nuclei cells actually returned to the IO and that such neurons were GABAergic, and Sotelo et al. (1986) had found that the GABA terminals were part of the IO glomerulus, where we had initially described the location of the gap junctions. Indeed, these three findings had demonstrated that the cerebellum does control the coupling at the IO, and so it can dynamically specify the distribution of coherence at the IO. This was very satisfactory.

This timing view, of course, is in total disagreement with the very popular view that the climbing fiber system had as its ultimate function the modification of parallel fiber Purkinje cell synapses and so serves as the biological basis for motor memory. Once again, as on past occasions, our finding became a source of heated discussions and disagreements. For the timing hypothesis to be correct, the olivocerebellar system had to produce coherent activation of Purkinje cells regardless of their location in the cerebellar cortex. Because the cerebellar cortex is folded, the issue of timing as produced by the conduction time of the climbing fiber action potentials became a critical issue. I remember considering the possibility that the conduction velocity for climbing fibers could be tweaked such that the input to the Purkinje cells would be isochronous regardless of position in the cerebellar cortex. In fact, experiments by Sugihara, Lang, and myself had shown that the conduction time for Purkinje cell activation was roughly 4 milliseconds plus or minus half a millisecond for any region of the cerebellar cortex (Sugihara, Lang, and Llinás, 1993). Indeed, it turned out, as expected, that the conduction velocity of the climbing fibers was indeed related to the length of the pathway between the IO and Purkinje cells. This isochronicity of the olivocerebellar system has been observed in reptile cerebella as well (Ariel, 2005).

Such research was further elaborated in our lab with John Welsh, who came to NYU as a post doc to do behavioral work with the goal of correlating volitional movements with multiple recorded Purkinje cell activity in nonanesthetized rats! The paradigm called for correlating the timing of complex spike activation to tongue movements, which actually worked very nicely (Welsh et al., 1995). Furthermore, our colleague Chris DeZeeuw and his team in the Netherlands had demonstrated that fully half of the cerebellar nuclear cells are GABAergic and that they return to the IO. This indicates the functional importance of this connectivity, given that the half of the total cerebellar output is used to regulate the electrical coupling in the IO. Also with Chris, we found that climbing fiber synchrony actually occurred bilaterally in the cerebellum (DeZeeuw et al., 1996; Leznik, Makarenko, and Llinás, 2002).

An aspect that was missing related to the actual direct demonstration of the existence of clusters of coupled neurons in the IO. This was shown by a graduate student, Elena Leznik, and myself using voltage dependent dye imaging (Leznik, Makarenko, and Llinás, 2002), and their absence was demonstrated with electrical coupling block (Leznik and Llinás, 2005). Of course, the issue remains whether this olivo-cerebellar arrangement can actually control motor coordination. A couple of significant findings were discovered by Vladimir Makarenko. The first was the demonstration that the oscillations in the 10 neuron are chaotic (Makarenko and Llinás, 1998), with an intriguing phase reset property. That is a robust oscillation that is also nimble, as opposed to the rather dull periodic oscillator. That work proceeded with two colleagues from Russia, Victor Kasantsev and Vladimir Nekorkin, with the development of microchips that simulated IO neurons and the construction of motor controllers (Kazantsev et al., 2003). In short then, one message that arises from this research is that motricity is really a discontinuous function of time (Llinás, 1991). And it makes sense; discontinuous control is simpler and more economical from a computational perspective than continuous control.

At present we have been studying cerebellar long term depression (LTD) and motor learning. We have found that the T-588 neuroprotective drug developed by Toyama Pharmaceuticals can block LTD produced by the temporal coherent activation of climbing and parallel fiber activity on the Purkinje cells. This LTD has been considered to be the mechanism responsible for cerebellar learning. T-588 was found to prevent LTD by acting on the necrotic pathway leading to cell death. And so the possibility arose that LTD was not a learning mechanism, but rather a cell protection mechanism. Indeed, its oral or parenchymal administration to rodents had no effect on either motor or eye blink conditioning but blocked LTD quite completely. So at present there is strong evidence that LTD may, in fact, not be related to learning of motor behavior.

Woods Hole from New York

The Molecular Aspects of Synaptic Release and the Calcium Concentration Microdomain

Concerning research at the MBL after moving to New York, the trip certainly became less laborious than our trips from Iowa City. Over the years the squid giant synapse has continued to afford good experimental food for thought concerning synaptic release. That being the case, Sugi and I have continued to go to the MBL from New York for the last 30 years.

After the voltage clamp experiments, I had decided to study synaptic latency and described with my student, Sandy Simon, and Sugi a method to voltage clamp the preterminal with a spike wave form profile (rather than a step function pulse) and determine the actual characteristics of the calcium current that causes synaptic release following an action potential (Llinás, Sugimori, and Simon, 1982). That worked well and gave us the first direct demonstration of the real calcium current time course and amplitude following a spike potential. Sandy and I also published a biophysics paper concerning the possible distribution and size of the intracellular calcium concentration profiles at the active zone responsible for transmitter release. The concentration turned out to be rather large (in the hundreds of µM), given the high concentration of this ion in sea water (Simon and Llinás, 1985). Of course, I remember discussing with one of my colleagues in Woods Hole that it was interesting but it would never could be experimentally demonstrated, given the small size of the event. Well, as it happened, we thought of a way using a special low affinity aequorin (a protein that emits light in the presence of calcium) kindly provided to us by Dr. Shimomura at the MBL. The paper demonstrating the existence of such calcium concentration microdomains by using a single photon imaging system was published by Sugi and I in collaboration with Bob Silver (Llinás, Sugimori, and Silver, 1992).

From a molecular perspective our interest in the release problem led Sugi, John Gruner, Jen Wei Lin, and me to work in collaboration with Paul Greengard and his student Teresa McGuinness (Lin et al., 1990; Llinás et al., 1991) on synapsin I, a protein discovered in Paul's lab. This study demonstrated that synapsin I holds synaptic vesicles next to the active zone, and when phosphorylated, it untethers the vesicles and makes them accessible for release.

A second set of studies addressed the calcium-sensing protein synaptotagmin that had been characterized by Thomas Sudhof as the calcium sensor for synaptic transmission. With antibodies against this protein made for us by our colleagues Katsuhiko Mikoshiba and Mitsunori Fukuda, we (Sugi and I) showed that it too blocked synaptic release by preventing vesicular fusion. Indeed, the ultrastructure implemented by our friend and colleague Jorge Moreira demonstrated that the vesicles were kept in the active zone, because in the absence of this calcium sensor release does not take place (Mikoshiba et al., 1995; Sugimori et al., 1998). Other aspects of molecular control of synaptic release were done with such friends as Scott Brady and his colleagues Jordi Marsal, Chi Kun Tong, Herman Moreno, Bernardo Rudy, and Joseph Schlessinger.

This molecular approach has been one of the most rewarding aspects of my work in synaptic transmission and one that I hope to continue for years to come.

Meanwhile in New York

This was a very active time in the lab with many postdoctoral fellows and students from Europe and Japan as well as the United States. In addition to the central setup that Sugi and I used, we had two laboratories with a total of four electrophysiological setups. Work proceeded basically along two lines. One was a study of variations in intrinsic properties in in vitro brain slices in the 1980s in which Pepe Lopez-Barneo, Serge Charpak, Chris Leonard, Tony Grace, Denis Pare, Kerry Delaney, Susan Greenfield, Emilio Geijo-Barrientos, and Atushi Nambu worked over that decade. The second line of research focused on the development of isolated in vitro brainstem and whole brain preparations, originally in the early 1980s with Yosi Yarom, and in the middle 1980s with Brian MacVicar, Marco deCurtis, and Michel Muhlethaler. Some of this work was summarized in a review paper I wrote in 1988 concerning intrinsic electrical properties of central neurons (Llinás, 1988).

Neurolab

In a departure from everyday problems on Earth's surface and following a meeting with two friends, Wally Wolfe and Frank Sulzman, the thought came to mind that given that we had all worked on the vestibular system, it would be interesting to propose to NASA a shuttle flight be devoted to the study of all aspects of the nervous system in microgravity. Accordingly, a proposal was sent and NASA responded with the Neurolab, a mission that generated much information about neuroscience in many life forms ranging from fish to humans. Our own involvement was headed by Kerry Walton, with Dean Hillman and myself as co-investigators. We studied the effect of microgravity on spinal cord function. Among the people involved in the overall project was Alain Berthoz, a dear friend with whom I had collaborated over the years and who had a genuine interest in coordinate systems from the time of Pellionisz. The work headed by Walton defined a critical period for motor development for the first time (Walton et al., 1992). We also studied the development of cortical and hypothalamic circuits in collaboration with Javier DeFelipe from the Cajal Institute.

All in all, Neurolab was an interesting experience. We organized meetings at the MBL, and the different groups were assembled. As often happens with research, much was accomplished by some of the projects, whereas others accomplished much less. However, we all learned about team work at a level we had not experienced before. Projects had to be carefully designed at an exasperatingly minute level (e.g., define the animal's cage weight and building material) 1 or 2 years in advance. However, this also provided for a new and truly frustrating experience. Once you had written up your plan you could change nothing, even if newer, better techniques became available. That aspect, for scientists who are accustomed to optimizing techniques “on the fly,” was a nightmare.

The Thalamocortical System, Cognition, and Dysrhythmia

As the work on the cerebellum proceeded, I began another line of research in the early 1980s concerning the electrophysiology of thalamic neurons, known to be the major entry into the cerebral cortex. For reasons concerning the rhythmicity, I intuitively expected thalamic neurons to have electrical properties that were in some way similar to those of inferior olivary neurons. Delightfully enough, low threshold spikes were observed in vitro on the first intracellular recording. Indeed, when thalamic neurons were artificially hyperpolarized, a T channel current was deactivated and allowed the cell to oscillate at low frequency near 3 to 4 Hz. The work was published in a set of papers with Hendrik Jansen, a postdoctoral fellow from Denmark (Jahnsen and Llinás, 1984a, 1984b). These have turned out to be a rather significant set of findings. Also to my delight, Mircea Steriade and colleagues from University of Laval in Quebec came out simultaneously with similar findings in the cat in vivo (Deschenes, Roy, and Steriade, 1982). Although they could not determine the ionic mechanisms, the electrophysiological characteristics they found were exactly the same we had seen in vitro.

Mircea has continued with his research in this area, and we have been friends and at times serious critics of each other's work for over two decades. Although for the most part we agree, he is critical of my intellectual attachment to gamma band activity in relation to consciousness. Another very important colleague in this field is Ted Jones, a superb anatomist/physiologist and a dear friend and colleague, with whom Mircea and I have written books and organized scientific meetings and symposia.

Thoughts About Cognition

A second aspect of interest to me concerning the electrical properties of thalamic neurons was the fact that they all behaved similarly. That was initially unexpected because thalamic neurons provide the main afferent input to all areas of the cerebral cortex, and so one would expect differences pertaining to different cortical properties. The immediate consequence of this homogeneity was the possibility of having a unifying common mechanism that would address cortical activity globally as well as specifically. Thus, modifying membrane potential across the thalamic nuclei would necessarily result in a huge functional event at the cortical level. It became evident then that activation of the T channel conductance in the thalamus, if prevalent, should produce a low frequency activation of the cortex, which had been known to engender sleep. So T channels became a major key into brain function at the thalamic level. Moreover, because T channels in the IO could be considered as engendering the muscular rhythmicity that allows movement to be coordinated, T channels in the thalamus could be viewed as regulating the two huge functional events in the brain—that of being awake and that of being asleep.

Because the thalamus addresses the cortex in a rather powerful way and because the cortex returns to the thalamus an even larger number of synaptic contacts, the thalamocortical pathway is perhaps one of the most important systems operating in the brain. The fact that this neuronal coherence is capable of being modulated rather rapidly explains, in principle, the ability we have to fall asleep very quickly, as one sees during boring lectures, and our ability to wake up quickly, as when one's neighbor puts his elbow into you and mentions, “You're snoring.” So one important issue is that one can fall asleep or wake up very fast. The second is that when one falls asleep all of the systems fall asleep simultaneously, and similarly, when one wakes up, all aspects of one's sensory perception wake up at the same time.

So at this point in my career, the essence of nervous system function appeared to be defined as a set of embedded structures starting with the ionic channels with defined but simple properties that give neurons specific intrinsic electrical properties (Llinás, 1988). The next step would be the harnessing of significant “quorum sensing” states by the weaving of specialized neuronal circuits that would allow neuronal activity to coexist in time in order to produce cognition and motricity. This must occur, as in the case of cerebellar networks, as the product of evolution where complexity is attained by building on circuits sculpted by natural selection. In particular, when considering “higher nervous functions” the thalamus viewed as the hub in brain function appeared a beautiful structure from which to build. It became evident that the anatomical separation of midline thalamic structures—the mediodorsal, centrolateral (intralaminar), and centromedial—from the phylogenetically newer dorsal thalamus was central in global brain function. The beauty of the arrangement becomes clear when one realizes that the phylogenetically old medial group projects directly to the apex of cortical pyramidal cells and that this cortical arrangement characterizes the cortical circuits in reptiles in which the dorsal thalamus is absent. This is in contrast to the six-layered cortex of vertebrates in which the appearance of the dorsal thalamus is accompanied by the appearance of layers two, three, and four, the newcomers to the cerebral mantle.

The interaction between these two systems, known also as the specific system for the dorsal thalamus and the nonspecific system for the medial thalamus, became an important issue in my thinking. Indeed, it has been known from early neurology that damage of the dorsal thalamic nuclei, for instance of the lateral geniculate nucleus, produces visual problems similar to those encountered by damage of the visual cortex itself. Similar damage in the other thalamic relay nuclei, such as the ventral lateral nucleus and the medial geniculate nucleus, produced damage to the sense of touch and hearing, respectively. So, damage of the thalamocortical system was known to remove aspects of cognition without necessarily altering the overall cognitive state.

Contrary to the rather specialized nature of cognitive loss due to dorsal thalamic damage, medial thalamic lesions result in total disappearance of consciousness (akinetic mutism) if a lesion occurs bilaterally or hemineglect if it occurs in only one side. In the latter case patients would see only half the world and not know about the existence of the other half. For example, clock faces would only go from 12 to 6 o'clock and people's faces would have a right or a left side only. This was known to happen not only with the perceived but also with the imagined world. So for instance, the film director Federico Fellini, a hemineglect patient, when asked to describe his view of a place from memory, would describe the scene differently depending on his imagined location, with one side always missing from his description. Thus, hemineglect encompasses both a perceptual and a cognitive problem as well as anosognosia.

Gamma Band and Cognition

From another perspective, attempting to define what aspect of brain function supports cognition became, to me, a plausible question to ask when considering what other properties thalamic neurons support. It was clear from our work and that of others that high-frequency activity in both the cortex and thalamus seemed to correlate well with cognitive events. The original discovery that gamma band activity (brain rhythms at 30 to 50 Hz) was related to cognition was described at the field potential level in behaving cats by Arlette Rougeul-Buser (Rougeul-Buser et al., 1983). Suddenly, electrophysiology took off with gamma band activity being recorded at the single cell level in the visual cortex by Wolf Singer and Charles Gray (Gray and Singer, 1989) and in our lab at the intracellular level as a subthreshold oscillation both at a cortical (Llinás and Grace, 1989; Llinás, Grace, and Yarom, 1991) and thalamic neuronal level. Thus, in thalamic neurons, Christine Pedroarena and I showed that dendritic P channels are most probably responsible for this subthreshold oscillation at gamma band frequency (Pedroarena and Llinás, 1997). This has recently been modeled mathematically by Paul Rhodes and myself (Rhodes and Llinás, 2005).

The significant issue here was that the thalamocortical system, given its loop connectivity, could easily go into recurrent gamma band oscillation. This was aided by the intrinsic properties of both thalamic and cortical neurons as well as the tendency for synaptic facilitation, as demonstrated in a second set of experiments with Pedroarena (Pedroarena and Llinás, 2001).

The question, then, was whether gamma band oscillation had a functional significance and if so, how such significance could be determined. I felt that if we could measure from a substantially large number of neurons, then perhaps the significance of this oscillatory property would become apparent. In a set of in vitro experiments using voltage dependent dye imaging, implemented initially in collaboration with Diego Contreras, the activation of the cortex with different rhythmic electrical white matter stimuli gave us a clear result. Indeed, the results indicated that the geometry of thalamocortical activity is determined by the frequency of the thalamocortical oscillations (Contreras and Llinás, 2001). Thus, low frequency stimulation produced coherent activation of a large portion of the cortex, whereas high frequencies produced punctate activity. These experiments were repeated in a thalamocortical slice with Francisco Urbano and Leznik. Those results demonstrated that, in addition to functional geometry, coactivation of specific and nonspecific thalamic systems produced supralinear summation as expected if the two systems were temporally coincident (Llinás, Leznik, and Urbano, 2002).

This geometry of activation, I believe, is fundamental in defining sleep/wake cycles as well as the dream state and the moment-to-moment internal representation of our perceived world. I also feel that in order to support the ongoing perceptual state that characterizes wakefulness, the system would have to be sufficiently agile to the point of constructing such images at better than 30 different “frames” a second (the picture presentation rate of movies and TV).

The next step in this analysis was that of defining and trying to understand cognitive binding. That is, the ability we have to bind cognitive sensory bits that arrive separately into our brain and are anatomically distant from each other in brain space. Thus, for instance, the perception of a small bird in one's hand requires the brain to assemble the bird's color, form, weight, sound (if it is making one), and smell into a single percept, a “mental object,” as my friend Jean Pierre Changeux has so eloquently named it (Changeux, 1983).

So now the question is: How can we experience this “object” as one single perceptual entity when different parts of the percept are represented in different parts of the brain? This is a fundamental issue that is still generating great debate. Singer and Gray (1995) and Francis Crick and Chris Koch (1995) represent the cortical view of binding, which assumes that coherence in time, at cortical level exclusively, is the probable mechanism. A second view, which we have pushed, holds that cognitive binding must indeed operate as a time binding functional entity but as a recurrent thalamocortical loop, as indicated by the experiments described later. A similar view on theoretical grounds, is held by Gerald Edelman and Giulio Tononi (Edelman, 1989; Edelman and Tononi, 2000) and Francisco Varela (Varela et al., 2001). In our case however, we define the issue of binding as related to temporal coincidence in involving the specific and nonspecific thalamocortical loops (Llinás, 1987; Llinás and Paré, 1991) based on direct experimental evidence to be reviewed later. Accordingly, through synchronous activation, the thalamocortical system binds in time not the activation of muscles as in the case of movement but rather binds the components of the percept into a single event. A corollary to this view impacts not only normal physiology of the brain but the variations of physiology conventionally known as pathology.

Enter Magnetoencephalography

Although research into the thalamocortical system was proceeding at the single cell and at the multicellular level in vitro using voltage dependent dye imaging, I was desperately wanting to determine whether events similar to those recorded in our animal experiments could be confirmed or excluded in human brain function. We needed a noninvasive technique with enough temporospatial resolution to test the hypothesis that arose from the in vitro and in vivo electrophysiological research.

And so in the mid 1980s, we began research using magnetoencephalography (MEG). An NYU School of Medicine lab was given to us in Bellevue Hospital, where we installed the first multichannel commercially generated system in the United States. It was produced by a company originally called SHE, then Biomagnetic Inc. (BTI), and now 4D. MEG was initially developed at MIT by David Cohen and then at NYU by Sam Williamson and Lloyd Kaufman. I started recording human MEG signals with a few superconductive coils in one Dewar, then graduated to a set of two Dewars, one on top of the head and the other one at its bottom, in a yaws type arrangement we jokingly referred to as “the nut cracker.” We finally graduated to the present system with 148 recording coils that cover the whole cranial surface. The virtue of MEG consists in recording the magnetic rather than the electrical signature of neuronal activity. The technology is more expensive and complex than electroencephalography (EEG), but it has the important advantage that, as beautifully demonstrated by Yoshio Okada, the fields recorded are not modified in any way by the intervening brain tissue, the cranium, or the scalp, making the recordings very close to what can be attained using electrocorticography. Having been convinced that the device was capable of generating meaningful information about brain activity, we began to analyze the coherent activity of the brain generated by spontaneous events. Fourier transform analysis of spontaneous brain rhythms described the normal rhythms seen by EEG recordings and, to our delight, much of the electrophysiology that we had seen in vitro and in vivo using field potential recordings.

It seemed, therefore, that this MEG approach was a possible link between research at the circuit level in laboratory animals and at the macroscopic level in humans. Several bright graduate students and post docs began to rotate through the lab. And so after a few years of perfecting techniques and computer programs to localize and image the recorded data, Urs Ribary, Andy Ioannides, myself, and a set of students began experimenting with this new recording methodology. Together we produced a paper that addressed the issue of the recurrent nature of gamma hand activity (Ribary et al., 1991). It related directly to the recording of the thalamic loop activity at gamma hand frequency. This paper was followed by MEG recording of gamma band activity during dreaming, which I believe demonstrates that dreaming and wakefulness are related states (Llinás and Ribary, 1993), and a correlation study indicating that temporal binding is congruent with coherent gamma band activity (Joliot, Ribary, and Llinás, 1994) and more generally, to global cognition (Llinás et al., 1998). At the experimental level more directly, Mircea Steriade and colleagues had demonstrated with simultaneous thalamic and cortical recordings in cat that a real recurrent loop at gamma band is operant (Steriade et al., 1996).

Beyond cognition, MEG has served as a good approach to brain neuroscience and has generated a group of Ph.D.s in the field. Among the students during the early 1990s Fred Lado, studying somatosensory responses, and Josh Cappell, studying fictive language, were the first to obtain their combined M.D./Ph.D. degrees in MEG. Josh Schulman and Rey Ramirez followed with Ph.D.s in this field. The latter did much more development at the mathematical level and implemented good localization techniques. Rey also studied vision, while Schulman studied patients with psychiatric disorders and central pain, and Kevin Sauve, a Ph.D. in philosophy, is presently finishing his second doctorate in temporal binding of somatosensory aspects of cognition.

To make a very long story short, MEG results continued to provide a good correlation between cognition and the electrical activity of the brain, suggesting, indeed, that different cognitive events can be related to specific electrical events at brain level. We felt that a good way to test such a hypothesis further was to consider pathological conditions in which brain electrical activity could be related to the neurological characteristics of several conditions. So we began a study in patients with Parkinson's disease, having theorized in an early paper that the frequency of Parkinson's tremor could be similar to the frequency obtained in thalamic cells in vitro when the cells were hyperpolarized. The connection was the well-known fact that damage to the substantia nigra nucleus is the basic etiology of Parkinson's disease. This is produced by a depletion of dopamine input to the basal ganglia resulting in pallidal disinhibition that releases inhibitory background synaptic inhibition on the motor thalamus. This being the case, it was proposed that this membrane hyperpolarization would activate the thalamic T channel system and trigger low-frequency oscillation, i.e., a “disconnection” syndrome produced by excess inhibition. This low-frequency oscillation could then have two effects: make the motor system behave as though it was asleep—also known as paralysis agitans—and also, generate tremor, these being the two known symptoms of Parkinson's. The results demonstrated very clear thalamocortical oscillatory activity and a paper was published with Jens Volkmann (Volkmann et al., 1996), a postdoctoral student who was finishing his neurological training. This work is continuing in more detail and utilizing more sophisticated analysis routines with graduate student, Kimberly Moran.

I had the good fortune at that time to meet Daniel Jeanmonod, a professor of neurosurgery and neurology at Zurich State University who, based very much on our original papers on thalamic electrophysiology, had been thinking of the so-called low threshold oscillation of the thalamus as generating Parkinson's disease. Daniel, from a neurosurgical neurological point of view, and I, from a physiological point of view, had arrived at very similar conclusions. Namely, that both the negative symptoms, e.g., the inability to generate movement, and the positive symptoms, e.g., presence of tremor, of Parkinson's disease were the products of low frequency oscillation of the thalamus.

Based on commonality of thought and instant friendship, we decided to collaborate and proceeded to put our heads together concerning the origin of Parkinson's disease. An obvious question that had been troubling us both was what would happen if similar disconnection syndromes were to occur in other nonmotor thalamic nuclei. So putting together MEG and human neuron recordings Daniel had made during surgery, we produced a hypothesis that suggested that many neurological and psychiatric diseases had a similar neuronal origin. The difference between the diseases was the localization of these abnormalities in different groups in the thalamus or in different parts of the cortex that could also result in a low frequency thalamocortical activity. This general concept was named thalamocortical dysrhythmia (TCD). We thought TCD included petit mal epilepsy, which in fact had been previously shown to be due to T channel activation of thalamic neurons, Parkinson's disease, irreversible depression, phantom limb pain, tinnitus, obsessive-compulsive disorders, and some aspects of schizophrenia. All of these, according to our hypothesis, were produced by disconnection of the thalamus allowing a low frequency thalamocortical attractor to be generated that would have sufficient resiliency to be maintained for long periods. A paper was written on this subject (Llinás et al., 1999) that was coauthored by two physics math colleagues, Eugene Kroneberg, a real rocket physicist from St. Petersburg, Russia, and Partha Mitra, a well-known and respected theoretical neuroscientist.

This hypothesis is still very much under discussion. The success of deep brain stimulation and stereotaxic micro lesions in many of these diseases strongly suggests that, indeed, they are all disconnection properties that generate abnormal brain rhythms and well-defined pathologies. A very constructive aspect of all this is a unification of psychiatry and neurology under neuroscience with the possibility of studying common mechanisms capable of producing the abnormal conditions relating to these two fields of knowledge.

The advantage of a unified view such as this (despite its obvious simplification) is the possibility of addressing many of these ailments pharmacologically because they ultimately relate to disconnection syndromes or channelopathies. The possibilities for the future are bright indeed. New pharmacological compounds may be developed using rational drug development, which take into account the small differences that channels may have at different levels in the CNS. The other avenues that become extraordinarily important are the attempts to generate particular disease models by knocking out specific types of channels in given nuclei. So, at present we find ourselves beginning collaborations with colleagues such as Soonwoo Shin in Korea, who has developed a thalamic knock-out mouse where either T or P channels are impacted. These, to our delight, demonstrate similar types of neurological conditions, as expected in thalamocortical dysrhythmia both from a behavioral and an electrophysiological phenotype.

All in all, my scientific life has been a set of experiments done with different animals with a variety of techniques, but all based on the assumption that brain function is ultimately understandable. Indeed, the scientific method is sufficiently powerful to provide the answers in our struggle to understand the properties of the brain. From afar this set of studies may seem a kaleidoscope of unrelated experiments and ideas. In reality the many aspects of my work have been orchestrated by a deep sense that we can understand the nature of brain activity, or more fundamentally, the nature of what we are (Llinás, 2001). The brain is, basically, more capable than it is complex. Deep in the recesses of my being, I have always felt that our nature is no more mysterious than the rest of the physical world. The biggest impediment to our true understanding seems to lie with us; by wanting to be angels we deny our nature. I remember writing, some years back, that we may ultimately prove to be simpler than our intellect feared or our vanity hoped.

Selected Bibliography

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Bloedel JR, Gage PW, Llinás R, Quastel DMJ. Transmitter release at the squid giant synapse in the presence of tetrodotoxin. Nature 1966;212:49–50.

Calvin WH, Hellerstein D. Dendritic spikes vs cable properties. Science 1969;163:96–97, and response by Llinás et al. in the same article.

Changeux JP. L 'homme neuronal. Paris: Hacherte, 1983.

Contreras D, Llinás R. Voltage-sensitive dye imaging of neocortical spatiotemporal dynamics to afferent activation frequencies. J Neurosci 2001;21:9403–9413.

Eccles JC. Hypotheses relating to the brain-mind problem. Nature 1951;168:53–55.

Crick F, Koch C. Cortical areas in visual awareness. Nature 1995;377:294–295.

Denk W, Sugimori M, Llinás R. Two types of calcium response limited to single spines in cerebellar Purkinje cells. Proc Natl Acad Sci 1995;92:8279–8282.

Deschenes M, Roy JP, Steriade M. Thalamic bursting mechanism: an inward slow current revealed by membrane hyperpolarization. Brain Res 1982;239:289–293.

DeZeeuw CI, Lang EJ, Sugihara I, Ruigrok TJH, Eisenman LM, Mugnaini E, Llinás R. Morphological correlates of bilateral synchrony in the rat cerebellar cortex. J Neurosci 1996;16:3412–3426.

Eccles JC, Llinás R, Sasaki K. Excitation of cerebellar Purkinje cells by the climbing fibers. Nature 1964a;203:245–246.

Eccles JC, Llinás R, Sasaki K. Golgi cell inhibition in the cerebellar cortex. Nature 1964b;204:1265–1266.

Eccles JC, Llinás R, Sasaki K. The excitatory synaptic action of climbing fibres on the Purkinje cells of the cerebellum. J Physiol 1966a;182:268–296.

Eccles JC, Llinás R, Sasaki K. The inhibitory interneurones within the cerebellar cortex. Exp Brain Res 1966b;1:1–16.

Eccles JC, Llinás R, Sasaki K. Parallel fibre stimulation and responses induced thereby in the Purkinje cells of the cerebellum. Exp Brain Res 1966c;l:17–39.

Eccles JC, Llinás R, Sasaki K. The mossy fibre-granule cell relay of the cerebellum and its inhibitory control by Golgi cells. Exp Brain Res 1966d;l:82–101.

Edelman GM. Neural darwinism. New York: Basic Books, 1989.

Edelman GM, Tononi G. A universe of consciousness. How matter become imagination. New York: Basic Books, 2000.

Fukuda M, Yamamoto T, Llinás R. The isochronic band hypothesis and the climbing fiber regulation of motricity. An experimental study. Eur J Neurosci 2001;13:315–326.

Gray CM, Singer W Stimulus-specific neuronal oscillations in orientation columns of cat visual cortex. Proc Natl Acad Sci 1989;86:1698–1702.

Hubbard JI, Llinás R, Quastel DMJ. (By invitation of the British Physiological Society) Electrophysiological analysis of synaptic transmission. London: Edward Arnold Publishers; Baltimore: Williams & Wilkins, 1969.

Jahnsen H, Llinás R. Electrophysiological properties of guinea pig thalamic neurones: An in vitro study. J Physiol 1984a;349:205–226.

Jahnsen H, Llinás R. Ionic basis for the electroresponsiveness and oscillatory properties of guinea pig thalamic neurones in vitro. J Physiol 1984b;349:227–247.

Joliot M, Ribary U, Llinás R. Neuromagnetic coherent oscillatory activity in the vicinity of 40-Hz coexists with cognitive temporal binding in the human brain. Proc Natl Acad Sci 1994;91:11784–11751.

Kazantsev VB, Nekorkin VI, Makarenko VI, Llinás R. Olivocerebellar cluster-based universal control system. Proc Natl Acad Sci 2003;100:13064–13068.

Lang EJ, Sugihara I, Llinás R. GABA-ergic modulation of complex spike activity by the cerebellar nucleo-olivary pathway in rat. J Neurophysiol 1996;76:255–275.

Leznik E, Llinás R. Role of gap junctions in synchronized neuronal oscillations in the inferior olive. J Neurophysiol 2005;94:2447–2456.

Leznik E, Makarenko V, Llinás R. Electrotonically mediated oscillatory patterns in neuronal ensembles: An in vitro voltage-dependent dye imaging study in the inferior olive. J Neurosci 2002;22:2804–2815.

Lin Jw, Sugimori M, Llinás R, Mc Guinness T, Greengard P. Effects of synapsin I and calcium/calmodulin-dependent protein kinase II on spontaneous neuro-transmitter release in the squid giant synapse. Proc Natl Acad Sci 1990;87:8257–8261.

Llinás R. Mechanisms of supraspinal actions upon spinal cord activities. Differences between reticular and cerebellar inhibitory actions upon extensor motoneurons. J Neurophysiol l964;27:1117–1126.

Llinás R, ed. Neurobiology of cerebellar evolution and development. Chicago: AMA, 1969.

Llinás R. 18th Bowditch Lecture: Motor aspects of cerebellar control. Physiologist 1974;17:19–46.

Llinás R. 'Mindness' as a functional state of the brain. In Blakemore C, Greenfield SA, eds. Mind waves. Oxford: Blackwell, 1987;339–358.

Llinás R. The intrinsic electrophysiological properties of mammalian neurons: A new insight into CNS function. Science 1988;242:1654–1664.

Llinás R. The noncontinuous nature of movement execution. In Humphrey DR, Freund HJ, eds. Motor control: Concepts and issues. John Wiley & Sons Ltd., Dahlem Konferenzen, 1991;223–242.

Llinás R. I of the Vortex. From neurons to self MIT Press, 2001.

Llinás R, Baker R, Sotelo C. Electrotonic coupling between neurons in the cat inferior olive. J Neurophysiol 1974;37:560–571.

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Llinás R, Grace AA, Yarom Y.In vitro neurons in mammalian cortical layer 4 exhibit intrinsic oscillatory activity in the 10 to 50 Hz frequency range. Proc Natl Acad Sci 1991;88:897–901.

Llinás R, Gruner J, Sugimori M, Mc Guinness T, Greengard P. Regulation by synapsin I and Ca2+/calmodulin-dependent protein kinase II of transmitter release in the squid giant synapse. J Physiol 1991;436:257–282.

Llinás R, Hess R. Tetrodotoxin-resistant dendritic spikes in avian Purkinje cells. Proc Natl Acad Sci 1976;73:2520–2523.

Llinás R, Leznik E, Urbano F. Temporal binding via cortical coincidence detection of specific and non-specific thalamocortical inputs: A voltage dependent dye imaging study in mouse brain slices. Proc Natl Acad Sci 2002;99:449–454.

Llinás R, Nicholson C. Electrophysiological properties of dendrites and somata in alligator Purkinje cells. J Neurophysiol 1971;34:532–551.

Llinás R, Nicholson C. Calcium role in depolarization-release coupling: An aequorin study in squid giant synapse. Proc Natl Acad Sci US A 1975;72:187–190.

Llinás R, Nicholson C, Freeman JA, Hillman DE. Dendritic spikes and their inhibition in alligator Purkinje cells. Science 1968;160:1132–1135.

Llinás R, Pare D. Of dreaming and wakefulness. Neuroscience 1991;44:521–535.

Llinás R, Ribary D. Coherent 40-Hz oscillation characterizes dream state in humans. Proc Natl Acad Sci 1993;90:2078–2081.

Llinás R, Ribary U, Contreras D, Pedroarena C. The neuronal basis for consciousness. Phil Trans R Soc Land B 1998;353:1841–1849.

Llinás R, Ribary U, Jeanmonod D, Kronberg E, Mitra PP. Thalamo-cortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci 1999;96:15222–15227.

Llinás R, Steinberg IZ, Walton K. Presynaptic calcium currents and their relation to synaptic transmission: A voltage clamp study in squid giant synapse and a theoretical model for the calcium gate. Proc Natl Acad Sci 1976;73:2918–2922.

Llinás R, Steinberg IZ, Walton K. Presynaptic calcium currents in squid giant synapse. Biophys J 1981a;33:289–322.

Llinás R, Steinberg IZ, Walton K. Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse. Biophys J 1981b;33:323–352.

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Llinás R, Sugimori M. Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices. J Physiol 1980b;305:197–213.

Llinás R, Sugimori M, Hillman D, Cherksey B. Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system. TINS 1992;15:351–355.

Llinás R, Sugimori M, Silver RB. Microdomains of high calcium concentration in a presynaptic terminal. Science 1992;256:677–679.

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Llinás R, Terzuolo CA Mechanisms of supraspinal actions upon spinal cord activities. Reticular inhibitory mechanisms upon flexor motoneurons. J Neurophysiol 1965;28:413–422.

Llinás R, Volkind RA. The olivo-cerebellar system: Functional properties as revealed by harmaline-induced tremor. Exp Brain Res 1973;18:69–87.

Llinás R, Yarom Y. Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro. J Physiol 1981;315:569–584.

Llinás R, Yarom Y. Oscillatory properties of guinea-pig inferior olivary neurons and their pharmacological modulation: An in vitro study. J Physiol 1986;376: 163–182.

Makarenko V, Llinás R. Experimentally determined chaotic phase synchronization in a neuronal system. Proc Natl Acad Sci 1998;95:15747–15752.

Mikoshiba K, Fukuda M, Moreira JE, Lewis FMT, Sugimori M, Niinobe M, Llinás R. Role of the (;2A domain of synaptotagmin in transmitter release as determined by specific antibody injection into the squid giant synapse preterminal. Proc Natl Acad Sci 1995;92:10703–10707.

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Nicholson C, Llinás R. Field potentials in the alligator cerebellum and theory of their relationship to Purkinje cell dendritic spikes. J Neurophysiol 1971; 34:509–531.

Pedroarena C, Llinás R. Dendritic calcium conductances generate high frequency oscillation in thalamocortical neurons. Proc Natl Acad Sci 1997;94:724–728.

Pedroarena CM, Llinás R. Interaction of synaptic and intrinsic electroresponsiveness determine corticothalamic activation dynamics. Thalamus Related Systems 2001;1:3–14.

Pellionisz A, Llinás R. Tensor network theory of the metaorganization of functional geometries in the central nervous system. Neuroscience 1985;16:245–273.

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Rhodes PA, Llinás R. A model for thalamocortical relay cells. J Physiol 2005;656:765–781.

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Alan Peters

BORN:

Nottingham, England

December 6, 1929

EDUCATION:

Bristol University, B.Sc. (1951)

Bristol University, Ph.D. (1954)

APPOINTMENTS:

University of Edinburgh (1958)

Harvard University (1963)

Boston University (1966)

HONORS AND AWARDS (SELECTED)

Symington Prize in Anatomy, Anatomical Society of

Great Britain and Ireland (1962)

President, American Association of Anatomy Chairmen (1976)

Krieg Cortical Discoverer Award, Cajal Club (1990)

President, American Association of Anatomists (1992)

Henry Gray Award, American Association of Anatomists (1998)

Sanford L. Palay Award (2004)

Alan Peters is one of the foremost anatomists of the mammalian nervous system. He was one of the first to determine the structure of myelin sheaths in the central nervous system and used light and electron microscopy to characterize the ultrastructure of neuroglia and neurons, as well as the microcircuitry and organization of neurons in cerebral cortex and the organization of thalamocortical projections. With S.L. Palay and H. deF. Webster, he co-authored three editions of the definitive text on the fine structure of the nervous system, and with E.G. Jones he created the authoritative series The Cerebral Cortex, which appeared in 14 volumes, 1984–1999. More recently, he has studied the anatomy of normal aging in the primate brain.

Alan Peters

When I received the invitation to contribute an autobiographical chapter to this volume I felt flattered; then I began to think what I might put into the chapter. Memories of events and people that I had not thought about for years came flooding into my mind, and I hope that most of the memories turn out to be accurate, so that I do not offend anyone I have omitted. Then in preparation for putting the chapter together I read some of the contributions to previous volumes. Most of the contributors cited their involvements with numerous collaborators, and I began to realize that although I know many people in science, basically I have been most content to either work alone or with one or two graduate students or postdoctoral fellows. I have never wanted to have a large laboratory with numerous collaborators. But I have been lucky in that I have collaborated with some very knowledgeable and pleasant people, and I have been especially lucky in having a series of excellent, bright and hard-working research assistants. Over the years they have made it possible for me to carry out a productive research program, despite the administrative duties I had as Chairman of a Department of Anatomy for 32 years. These research assistants, Charmian Proskauer, Julian Saldanha, Lauren Kimerer, Dan Kara, Kathy Harriman, Karen Josephson, and especially Claire Folger (Sethares), have made such major contributions to my research that I have always felt that their efforts should be recognized by including their names in the list of authors on articles.

If I omit someone that I have worked with, please forgive me. It is not that I do not appreciate the work we did together but only that there is no space to describe every research project in which I have been involved. The only way I can give a lucid account of my interests over the past 40 years is to confine myself to the major research themes I have followed.

Early Years

I was born in Nottingham, England, in 1929. My parents lived in a rented, semidetached house, but within a year of my arrival they moved into a row house in what was termed a working class district. The reason for the move was that my father, who was employed at a tobacco factory, was only on part-time work because of the depression, and the rent for the new house was more affordable. In those days, of course, it was not customary for a wife to work, so there was only my father's income to support the family. Nottingham was basically an industrial town, and most of the neighbors worked in the lace trade, at Players tobacco factory, in the local coal mine, or at a factory that made bicycles. Nevertheless, it was a friendly neighborhood and not a bad place to grow up. Because the houses were so close to each other, the neighbors looked after one another and socialized; everyone knew everyone else's business, where the children were, and when anyone was ill. My mother and father often talked about moving into a larger house, but somehow they never got around to doing it. The house was nearby where my father worked, and my mother so liked the area that she lived in that house until she died at the age of 95.

When I was 4 years old I started my education at a nearby nursery school, and a year later I transferred to the local junior school, which was about half a mile away from home. I stayed there for the next 6 years, until the age of 10, when I took the entrance examination for the local grammar school. The system of public schooling in England in those days was such that all children up to age 10 went to one of the local junior schools, and then at the age of 10 or 11 the better students took the entrance examination for one of the grammar schools, which were the prime source of university applicants. In Nottingham there were three grammar schools for boys. If a student passed the entrance examination, he transferred to a grammar school where students stayed until at least the age of 16, and some stayed until the age of 18 if they were to go to university. Students who did not take or pass the grammar school entrance examination transferred at the age of 11 to the local middle school, and then advanced to senior school, where they stayed until the age of 15. Luckily, I passed the entrance examination and was given a place at High Pavement Grammar School.

The year I took the entrance examination for grammar school was an unusual one, because on September 3, 1939, the Second World War was declared. As a consequence, I remember that in my last year at junior school we attended school in shifts and had some classes in the local church hall, because the school had been taken over by the Home Guard and Civil Defence units. In addition, some of the teachers had been called to serve in the armed forces. Consequently, there was neither enough space nor teachers available to teach all of the pupils simultaneously.

Despite the beginning of the war, people went about their business very much as usual, and so in September 1940, I entered High Pavement Grammar School. It is interesting in retrospect to recall that the entering class of about 120 pupils was divided into four classes depending on their performance on the entrance examination. How they assessed abilities other than performance on that examination I have no idea, but nevertheless the brightest pupils were assigned to a “Classics” form in which the emphasis was on Greek, Latin, geography, history, and general subjects. The second group was assigned to an “A form,” which was for pupils who were mathematically oriented, and for them the emphasis was on mathematics, physics, chemistry, German, and Latin. The third group, the one to which I was assigned, was the “B form.” We were considered not bright enough to understand advanced mathematics and physics, so our emphasis was on biology, chemistry, French (because it was less complicated than German), geology, and Latin. The fourth group was the “General” form, and their curriculum covered a wider range of topics, with emphasis on general science, geography, history, woodwork, and metal work.

On Monday through Friday, the school day lasted from 9 AM until 4:30 PM, and we had at least an hour of homework each evening. One afternoon per week and Saturday mornings, we played the sport appropriate for the season: rugby or cross-country running in winter and cricket or rowing in summer. Because I had a strabismus, I did not “have an eye” for a cricket ball, and I elected to row in the summer.

In retrospect it is clear that the education I received at grammar school was an excellent one, and being assigned a biology class was the first step in defining what I would do in my later life.

Although the education was excellent, it was somewhat disrupted by the war, because almost every night we were awoken by the air raid sirens and had to take shelter in the reinforced cellar under the house. It was not that many bombs were dropped on Nottingham, but the German airplanes followed the river Trent to fly to other locations, and as they passed over Nottingham, antiaircraft guns bombarded them. The result was that a great deal of shrapnel for the antiaircraft gun shells dropped from the sky, and unless one had a steel helmet it was dangerous to be outside. In addition, there was a general shortage of food, and most of the able-bodied men, as well as a number of women, were called up into one of the branches of the armed forces. One of those called up was my father, who was recruited into the Air Force, leaving my mother and I to fend for ourselves for the last couple of years of the war.

Otherwise, I progressed uneventfully through the first 5 years of grammar school, and in 1945 I sat the School Certificate Examination. This was a national examination given to pupils in the fifth form of grammar school, and the results of this examination largely determined how you would spend the rest of your life. Most pupils left school after taking the examination, but about 20% of them were selected to go on to enter the sixth form for a further 2 years of education to prepare for entry into university at the age of 18. I did sufficiently well in the School Certificate Examination to be selected to enter the sixth form, and I continued in the biology stream. That entailed a concentration in science and we took classes in chemistry, physics, zoology, and botany. Because there were only about 10 of us in the class, we received a great deal of individual attention, and in addition to lectures we were guided to carry out experiments in well-equipped laboratories. We also had a large amount of free time in which we were expected to work by ourselves. But other responsibilities also came with being in the sixth form. Most of the sixth formers were made prefects, and essentially it was the prefects who oversaw the discipline in the school, because they took care of classes in the teacher's absence and could impose detentions on students who were misbehaving.

At the end of the 2 years in the sixth form I took the Higher School Certificate Examination, which was essentially the entrance examination for university. I recall that I obtained two honors and two passes in the four subjects that I submitted for the examination. This was good enough to gain entry into a university but not good enough to obtain a scholarship. This meant that if I were to go to university my parents would need to help pay for my education, which they could not afford to do. Because my parents knew nothing about higher education, both of them having left school at the age of 14, this obviously presented a dilemma. Mr. Crossland, who was Assistant Head Master at High Pavement School, offered a solution. Mr. Crossland was much feared by us boys, because he was in charge of the discipline in the school, and being taken before him was one of the things to very much avoid. However, under his tough exterior he was a very caring man, and after the results of the examination came out he asked me what I intended doing in the future. I told him that I would like to go to university but that my parents could not afford to support me. After a conference with Mr. Crossland, my parents were persuaded to let me stay on in the sixth form for 1 more year, after which I would take the Higher School Certificate Examination one more time to try to qualify for a state scholarship that would pay my tuition at university and a stipend. So I stayed on at school for 1 more year, and on taking the examination at the end of that year I gained honors in all of the four subjects tested and was awarded a state scholarship to Bristol University to read zoology. This was the university I had chosen because of the good reputation of its zoology department.

However, during this third year in the sixth form it was also recommended that I take the Open Cambridge University Entrance Examination to try for a place at Cambridge University. As a result of that examination I was awarded a scholarship to study medicine at Downing College, because my real ambition at that time was to become a medical doctor. However, when I went for the interview at Downing College, I was told that they could offer me a place, but I would not be able to activate it for at least 2 years, because they were giving entry preference to those who either had been called up into the armed forces at the end of the war or had completed 2 years National Service, which all males had to do at that time. Being stubborn and seeing my goal of going to university fading into the distance, I decided to give up the idea of medicine and to postpone doing my 2 years National Service until I had finished university. Consequently, I went to Bristol University to read zoology, a decision that I have never had cause to regret, even though I never really became a card-carrying zoologist.

University

I started at Bristol University in September of 1948, and again because preference was being given to those who had been in the Armed Forces, I could not get accommodation in one of the halls of residence of the university. Instead, I was allocated lodging with a family. To save train fare, my father managed to get me a ride to Bristol on one of the lorries that transported goods from the tobacco factory where he worked to one in Bristol. Thus, I was delivered to my lodgings. I have forgotten the name of the family with whom I lodged for a couple of years, but the household consisted of a mother and her adult daughter, and quite soon after my arrival they told me that they belonged to a temperance society, which meant that they did not approve of drinking and the problems it caused. In any case, at that time I did not have money enough to spend much on drink and so it did not bother me. I suppose that I must have been a rather annoying lodger, but they were very kind to me: My room was comfortable and the breakfast and dinners they provided were good.

Each morning I would either walk or get a bus to the university, where I took courses in my two major subjects, chemistry and zoology. Usually there were two lectures each morning and every afternoon, except Wednesdays when there were laboratory classes.

On Wednesday afternoons, Saturday afternoons, and Sunday mornings I went out to the University Boat Club, which was located several miles away on the road to Bath. Rowing was not one of the major sports at Bristol University, so the membership of the Boat Club was not very large. Because I had spent some 5 years rowing while at school, I was soon given a place in the first eight. I continued to row for the entire time I was at Bristol, and in addition to getting my University Colors, I became Captain of Boats. Rowing was a very pleasant way to spend my spare time, but early on I was given a wake-up call, because I had spent so much time rowing in my first year that I almost did not pass the end of term examination.

At the end of the second year at university, during which I learned all about the classification of animals and some ecology, I was selected to enter the honors class in zoology, and at the same time I moved to lodgings on the other side of town. There were only nine of us in the honors class, and being such a small group we received a great deal of personal attention from the faculty, especially in terms of the laboratory portion of the course. I do not think that any of the faculty had worldwide reputations, but they were very good teachers. Among the best was Jack Kitchen who was a protozoologist interested in contractile vacuoles, and one of the highlights of the year was a course of lectures offered by the ethologist Kondrad Lorenz, who was visiting and gave a month-long course in animal behavior and imprinting. Among the students in the honors class were a few with whom I retained contact after graduation. One was Mike Mortimer who went off to Rhodesia after graduation to take up fish farming and then, after one of the more troubling times in Africa, came back to the United Kingdom as a forest ranger. Unfortunately Mike died at quite a young age. Another member of the class was Clive Edwards who after graduation joined the Ministry of Agriculture, went off to Purdue University to complete his Ph.D., and after retiring from the civil service in Britain came to America as Chairman of the Department of Entomology at Ohio State University in Columbus, Ohio, where he is one of the world's experts on soil ecology and earthworms. He and I shared an apartment during my three graduate years at Bristol.

At the end of the honors year I was awarded an upper second class honors degree, the only first class honors degree being given that year, and Professor John E. Harris F.R.S., who was the head of the zoology department, invited me to stay on to pursue a Ph.D., which would take another 3 years. I accepted his offer, and he put me on to a graduate support grant he had available. Because I had a strong background in chemistry, he suggested that a good project, and one that interested him, would be to investigate the mechanism of staining nervous tissue with reduced methylene blue and with silver salts. At that time, these were two of the main methods for the general staining of nervous tissue, but no one understood how these staining methods worked and how they could be controlled. Prof. Harris wanted to use the methods to stain the nervous systems of developing fishes, which was one of the research topics that interested him. But as far as I knew he never actually used the methods himself.

Graduate Study

When I started my graduate studies in 1951, I was allocated a laboratory in a small concrete building where all of the graduate students in the zoology department were housed. Following the traditions of the day, I was very much left to my own devices, conferring with my advisor, Prof. Harris, only about once every 3 months when I informed him what I had been doing, and he made suggestions about how I might proceed. Because there were six graduate students in the building, the atmosphere was congenial, and we frequently conferred with each other about our research, and in retrospect this was the main way that we expanded our education. Among the graduate students at that time was John Treherne, who was an entomologist and was later to play an indirect but important role in deciding my future. John was 1 year ahead of me, and after completing his Ph.D. he went into the army and later went to Cambridge University as an entomological physiologist. He eventually became president of Downing College. Another graduate student was Lionel Carter, who was a biochemist; after graduation he went to work for Imperial Chemical Industries in Brixham, Devon, where he was in charge of their anti-fouling marine division and could indulge in his passion for sailing.

As I indicated previously, my first research project was concerned with the mechanism and conditions for the vital staining of nervous tissue with reduced methylene blue. The methylene blue was reduced so that it became colorless, and after tissue or whole fish embryos were put into the solution under anaerobic conditions the tissue or embryo could be removed and the preparation oxygenated. The nervous tissue, which had taken up the dye, eventually oxidized and became intensely blue, so that the nervous system could be examined (Harris and Peters, 1953). At that time I knew almost nothing about the nervous system, other than the rather superficial survey course I had during undergraduate studies, but looking at the stained cells and their processes I was fascinated by the complexity of it all.

After completing that study, I went on to examine the mechanism of silver staining of nervous tissue. The reason for carrying out these studies was because silver staining was one of the few routine methods available for examining the nervous system in tissue sections. These studies resulted in my first individual paper, which showed that the specificity of silver staining is largely due to binding of silver salts with hisitidine groups on proteins. The article was published in Nature (Peters, 1953), and as I completed my thesis, a series of other articles on the mechanism of silver staining followed (Peters 1955, a–d).

The last of the articles in this series (Peters, 1955d) was an electron microscopic study of the disposition of silver in stained nervous tissue. I had read about the emerging field of electron microscopy, and this seemed an interesting way to determine where the silver particles are located in nerve cells and their processes. I was lucky to obtain the help of a Professor Hewer from the pathology department, who had had a Cambridge rocking microtome for light microscopy adapted and geared to cut sections as thin as 0.1 microns. I also obtained help from Dr. Tony Lee in the veterinary school. After tissue sections had been silver stained, they were embedded in methyl methacrylate, and my first thin sections were made using thin, steel razor blades that had been sharpened by rubbing them on the inside of a wet drinking glass, a technique we had used during the war to extend the lives of razor blades. But as I was doing this study, it came to our attention that Harrison Latta had published an article on how to make glass knives, which made thin sectioning much easier. However, obtaining thin sections was only the first of the challenges: The second was getting the Phillips electron microscope in the physics department to remain stable long enough to get pictures of the thin sections on its 35-mm roll of film. The results were by no means spectacular, but they did show the metallic particles of silver formed during staining to be aggregated along the fibrous components within the cytoplasm of the nerve fibers, not in the interspaces between the neurofibrils and not in the myelin sheaths.

In the autumn of 1954, I submitted my thesis for examination, and because my external examiner was out of the country, it was not until the beginning of 1955 that I heard I had been awarded a Ph.D. degree. I had no idea about what I would do with the degree in zoology. However, I did assure my fiancée, Verona, that she would not be marrying a zoo keeper, but naively I had not given my future a great deal of thought. I knew that at the beginning of 1955 I would be called up into the army to do my 2 years of compulsory National Service, and I more or less decided to defer making any decisions about my future until the end of that time.

Military Service

I need to say something about my military service, because effectively it was during this time that my professional scientific future became decided.

I was called up to serve in the Royal Army Signal Corps, presumably being posted to that unit because of my scientific background. I entered the army in January 1955, and, after completing my basic training, I was selected to go to Officer Training School at Eaton Hall in Chester. I spent 6 months there learning drill, military law and tactics, and physical education, which seemed to largely consist of running for miles with full packs. This latter experience convinced me never to take up jogging for pleasure.

At the end of the training I was commissioned as a 2nd lieutenant in the Royal Army Medical Corps (RAMC). The reason for that posting was as follows. John Treherne, who was a fellow graduate student at Bristol and who graduated a year ahead of me, was in the Medical Corps and was completing his service at a place called Porton, which was an army research station. His commanding officer at Porton had asked John if he knew of anyone who could replace him when he completed his 2 years of National Service. John recommended me as his successor, and this was the reason for my commission into the RAMC. After being commissioned, I was posted to the RAMC Depot, where it was intended that I should stay for a month or so until John Treherne was demobilized, when I would be posted to Porton as his replacement.

However, our well-laid plans went awry. We had not anticipated the regulations that governed postings from the RAMC Depot. The rule, strictly adhered to, was that officers were posted out of the depot in the same sequence in which they arrived, and while I was at the depot, a vacancy occurred for an adjutant at a field ambulance in Germany. Because I was the next officer in line for a posting, I was sent to Germany to take the position. As an aside the next officer in line after me was someone with a bachelor's degree in biology and no research experience, and he got the posting to Porton. However, in retrospect, things worked out very well, because I gained a great deal of experience and confidence as a result of my experiences in the army in Germany.

I was allowed 10 days embarkation leave before departing for Germany, and so I called my fiancée with this news. We had already decided to get married some time in the future, and we concluded that it would be best if we got married before I left for Germany. In the space of a week, my wife to be, Verona, in her typical unflustered fashion, managed to get everything set for the wedding, including getting the wedding license and arranging for the reception. So we got married and had a honeymoon, after which I departed for Germany, leaving her behind. I had known my wife since I was in my teens, and I had always thought that she was unattainable. But when I was home for a week during my graduate student years, I had phoned her to ask if she would come to the Nottingham Goose Fair with me. To my surprise and delight she agreed to accompany me to the fair, which had its origin in medieval times, and that was the beginning of our courtship and eventual marriage. We have now been married for almost 50 years, for which I consider myself very fortunate.

As adjutant to a field ambulance, I was more or less in charge of the management and discipline of the unit, which included making sure that the soldiers did not get into too much trouble. Essentially, I was the only trained officer in the unit. All of the other officers had medical degrees and were concerned with medical and not military problems. We had a very sociable life, and one of the perks was that the officer's mess had been previously occupied by the German army, who had laid down a good stock of wines in the cellars, so that on mess nights we were able to sample good wines and brandy.

When I departed for Germany, there seemed to be little chance of my wife and I being together until I finished my military service at the end of 1956, but being an adjutant to a field ambulance, I had to be thoroughly familiar with a book called Queen's Regulations, which govern all aspects of military life. I found that in Queen's Regulations it was stated that National Service RAMC officers were allowed to have their wives with them. In reality, this referred to officers with medical degrees, who were either 1st lieutenants or captains. When the regulations were written there were no 2nd lieutenants in the RAMC, and in fact there were only about six of us when I was in the army. However, regulations being regulations, my colonel agreed that the regulations should be followed, and my wife gave up her job and was able to join me for the last 8 months of my military service.

At the end of 1956, as my demobilization from the army became closer, I began to think seriously about my future, but being in Germany made it difficult to make contact with people who might offer me a job. However, one day one of the medical officers, who was reading the British Medical Journal and looking for a job for himself, saw that postdoctoral fellowships in basic science were being offered by Edinburgh University. In my graduate student days, I had been in contact with Prof. George Romanes, who was the professor of anatomy at Edinburgh, and so I knew that he had some interest in silver staining. Consequently I wrote to Prof. Romanes and asked him if I could come to work with him as a postdoctoral fellow. To my delight and relief, he offered me a postdoctoral fellowship, and we agreed that I should start working with him at the beginning of 1957, after I had been demobilized. So in January 1957 Rona and I caught the train to Edinburgh, arriving on a rather typical winter's day with gray skies and the gray stone of Edinburgh welcoming us.

Edinburgh

My first impressions of the Department of Anatomy at Edinburgh University were rather mixed. I found that it was basically a teaching department and that the faculty largely consisted of retired doctors and others with medical degrees who did not like working with patients. However, there were some exceptions and among them were George Romanes and Alan Muir, who I will say more about later. The general lack of interest in research is perhaps best illustrated by the fact that when I asked the chief technician for some glassware to resume my silver staining studies he went into the basement to find some for me. The only trouble was that the glassware was graduated in drachms and ounces, and glassware graduated in metric units had to be ordered for me. I was also struck by the fact that the professor, George Romanes, was the only one who had the authority to order anything, so every request for supplies or equipment had to go through him. He also oversaw the allocation of typists and of technical staff, each of whom had their own territories and would generally do nothing until requested to do so by either him or by the chief technician. However, I soon got used to the system, which was typical of departments of anatomy in Britain at that time, and it did not really interfere with my research.

I might add that George Romanes, who was a generous man with a very wide background and knowledge of anatomy, had largely given up research by the time I arrived in Edinburgh. In addition to running the department, George Romanes gave the bulk of the anatomy lectures, which were presented in an old-fashioned, tiered lecture theatre where dissections, including the public dissection of the body snatcher Burke, used to be carried out. Much of the rest of George Romanes' time was spent in rewriting the series of textbooks on anatomy that had been initially written by the Cunninghams, who were among the first professors of anatomy at Edinburgh. But despite these commitments, George Romanes was very supportive, and because my laboratory was next to his office, most days we met to discuss my research as we puffed away on our pipes.

During this first year, I continued working on silver staining of nervous tissue and developed methods of staining that used silver proteinates, similar to the Protargol silver proteinate that was used in Bodian's silver stain (Peters, 1959). I also became very interested in physical developers as a means of intensifying the silver stains and undertook the staining of a series of rat embryos in which I intended to study the development of the spinal cord. However, as I began to learn more about the nervous system and become more interested in what was being stained by silver, I began to realize that silver stains are not all that useful for studying the central nervous system. Virtually all nerve cells and their processes are stained by silver, but only short lengths of any of the processes are visible in any one section. Consequently, processes of neurons cannot be followed for any distance, making connections between neurons almost impossible to determine. Another difficulty is that only the largest of the axonal boutons are stained by silver. I suppose that I had been too obsessed with the mechanism of the staining process and, at that time, had such a poor knowledge of the nervous system that it took me several years to realize the real inadequacies of silver staining.

A Faculty Member

After I had been a postdoctoral fellow for a year, George Romanes offered me a lectureship in anatomy, and I took the job. Apart from doing research, my responsibility was to help teach the dissection and histology laboratories on the nervous system. This meant learning the material, because my background in zoology had not covered any nervous system in detail. I also set about learning some general histology, but I could not become enthused by gross anatomy, which I have never learned.

At about the same time that I became a faculty member, Alan Muir in the department acquired an electron microscope, one of the new AEI 6As. Alan had been to America on sabbatical leave and had spent the year with Ed Dempsey in St. Louis, learning techniques of electron microscopy, techniques that he now offered to teach me. However, in 1958 the techniques for making thin sections were still somewhat primitive. The tissue had to be embedded in methyl methacrylate, which became warm as it polymerized, often causing the tissue to explode and fragment. Also, at that time, we had early model, MT-1, Porter-Blum ultramicrotomes that heated up when a light was turned on, causing the plastic embedded blocks of tissue to expand. This meant that the thickness of the thin sections was not very consistent. In addition, to make glass knives, we had to score sheets of glass and break it with pliers. Finding the best glass was always a challenge, and the consensus was that old and brittle glass made the best knives. Consequently, it was with great glee that Alan Muir and I heard that Glasgow was scrapping its old tramcars to replace them with trolley cars. We knew that the windows of the old tramcars were made of plate glass, so Alan and I borrowed a truck and went over to Glasgow to get the plate glass from the breaker's yard. We brought it back and stored it in the basement of the anatomy department. That pile of glass kept us with knives for the remainder of the time I was in Edinburgh.

Among other things, Alan Muir was interested in peripheral nerves, and so the first project that we undertook together was on the development of nerve sheaths in phrenic nerves of rats (Peters and Muir, 1959). The instigation for the study was that some years previously, in 1954, Betty Geren had shown the myelin sheaths of peripheral nerves to have a “jelly roll” structure with the membranes of the Schwann cells being wrapped around the axons in a spiral fashion. It had also been shown that in mature animals several unmyelinated axons occupied the same Schwann cell, whereas Arthur Hess (1956) had shown that in developing sciatic nerves single, unmyelinated axons occupied Schwann cells, and such unmyelinated axons became less common as development proceeded and myelinated nerve fibers appeared. Our study was undertaken to examine the mechanism whereby the axons of developing nerves become partitioned by Schwann cells to achieve the mature state. In effect we found that early in development Schwann cells surround bundles of small axons and that as more Schwann cells are generated the axons gradually become segregated. Axons invested individually by Schwann cells become myelinated, whereas others, which share the same Schwann cell, remain unmyelinated. The diagram we produced to illustrate these developmental changes is often reproduced in modified form, even though the source tends to be neglected.

Later, Alan Muir and I went on to examine the membrane junctions at the terminal bars between endothelial cells (Muir and Peters, 1962).

Central Myelin Sheaths

At about the same time that Alan Muir and I were examining developing peripheral nerves, Mike Gaze, who was a lecturer in the Department of Physiology, asked me to do some silver staining of the optic nerves of Xenopus tadpoles, in which he was studying visual system development. I was amazed at the transparency of these tadpoles, in which the optic nerves were readily visible. So I decided to prepare some of the optic nerves for electron microscopy. At that time no one had managed to interpret the structure of the myelin sheaths in the central nervous system, although the “jelly roll” form of the myelin sheaths on peripheral nerves had been worked out a few years earlier as a result of the studies of Betty Geren (1954) and David Robertson (1957). However, it was assumed by Sarah Luse (1956) and by De Robertis et al. (1958) that the structure of central myelin, and the mechanism of its formation, were different from peripheral myelin.

I began by examining myelin sheaths in the optic nerves of Xenopus tadpoles that had been fixed by immersion in osmium acid, but the fixation was not good. Optic nerves that had been fixed by immersion in potassium permanganate proved to be much better, because permanganate preserves membranes. John Luft had introduced potassium permanganate as an alternative to osmium tetroxide in 1956, and although it preserves membranes, it has the disadvantage that it does not preserve other organelles, such as ribosomes and neurofilaments. But by examining optic nerves fixed with permanganate, I was able to show that central myelin also has a spiraled structure, and the difference from peripheral nerve sheaths is that the cytoplasm on the outer turn of the sheath is confined to a small external tongue process that is a ridge of cytoplasm connecting to the parent oligodendrocyte (Fig. 1). Interpretation of the structure of central myelin sheaths had also been confounded by the absence of a basal lamina around the myelin sheaths, which allows adjacent sheaths to come into contact with each other and produce an intraperiod line (Peters, 1960a).

Fig. 1. Diagrams to show the structure of peripheral myelin (1A) and central myelin (1B). The cytoplasm of the axon, the Schwann cell, and the myelin forming glial cell are stippled. On both, the cytoplasm (C₁) lies internal to the first turn of the spiral, which begins at the internal mesaxon (M₁). The intraperiod line (I) arises within the internal mesaxon, which is formed by apposition between the external surfaces of the myelin-forming cell membrane. The major dense line (D) results from contact between the cytoplasmic surfaces of the same membrane. Both lines continue in a spiral and alternate throughout the thickness of the myelin sheath. In peripheral nerves, a continuous layer of cytoplasm (C₀) surrounds the myelin spiral, which terminates at the external mesaxon (M₀). In the central nervous system, the outer cytoplasm is confined to a tongue process so that the major dense line in the outermost line of the sheath, expect in the region covered by the tongue. (Reproduced from the Journal of Cell Biology 1960;7:121-126, by copyright permission of The Rockefeller University Press).

While I was preparing the paper on the structure of central myelin sheaths for publication, Colin Wendell-Smith, who is now in Tasmania, was spending some time in the laboratory learning the techniques of electron microscopy, and he and I talked about how I could prepare a diagram showing the spiraling of myelin lamellae. The problem was how to draw a spiral. After much debate we solved the problem by hammering a 6-inch nail into a board and tying a pen to the nail with a piece of string. Winding the string onto the nail allowed a very nice spiral to be drawn with the pen. It needs to be added that in the same issue of the Journal of Biophysical and Biochemical Cytology (vol 7, 1960) in which my results were published was an article by Maturana (1960), describing the structure of central myelin sheaths in the optic nerves of various anurans. Fortunately, our findings were in complete agreement.

Interpreting the structure of central myelin sheaths gave my career a significant boost. I later extended these studies to the optic nerves of rats and was able to show that the formation of central myelin is basically similar to that of peripheral myelin (Peters, 1960b). I was also able to demonstrate that there is a radial component in central myelin (1961,1964a), a component that was later shown to be due to narrow, tight junctions between myelin lamellae. Largely on the basis of these studies, in 1962, the Anatomical Society of Great Britain and Ireland awarded me the Symington Memorial Prize in Anatomy. Subsequently I was able to demonstrate the connections between oligodendrocytes and central myelin sheaths (Peters, 1964b), as well as the form of the nodes of Ranvier in the central nervous system (Peters, 1966).

At that time, there were few electron microscopists in Britain looking at nervous tissue, but on trips to meetings of the Anatomical Society, I was able to hold discussions with George Gray, who was at University College in London and had described two types of synapses in cerebral cortex (Gray, 1959), and with David Robertson, who had been recruited by J.Z. Young to University College in London. David had a state of the art electron microscope laboratory that was the envy of us all, and he was working on peripheral nerves and his unit membrane theory.

Comparative Anatomy of Nerve Sheaths

Having a background in zoology, I decided that it would be interesting to look at the peripheral nerve sheaths in lower vertebrates, namely Amphioxus and Myxine, by electron microscopy. As expected, I found that no myelin was present in Amphioxus and that the structure of the dorsal roots was such that small axons are aggregated into bundles and larger axons are segregated from the smaller ones. In fact, the nerves have features intermediate between those of developing nerves and of mature unmyelinated nerve fibers in mammals (Peters, 1963a).

The next step was to examine the fine structure of the peripheral nerves of Myxine, in which Nansen, the Norwegian polar explorer, had recognized in 1886 that the peripheral nerves were also unmyelinated. Because hagfish were not readily available in Britain, but were abundant in Norway, I wrote to Professor Jan Jansen at the Department of Anatomy in Oslo to ask if I could come to collect some Myxine. He readily agreed, and in 1962 I had the pleasure of spending 2 weeks in Oslo, where I was very impressed by the high standard of research going on in the department. At that time, Alf Brodal, Per Andersen, Ted Blackstad, and Jan Jansen Jr. were in the department so that it had a galaxy of scientific talent. Each of these people, as well as myself and others, made contributions to a book called The Biology of Myxine, which was dedicated to Prof. Jan Jansen and published in 1963. Electron microscopy showed that each axon in the peripheral nerves is surrounded by its own individual Schwann cell sheath (Peters, 1963b).

Boston 1963–1964

In 1960, I had met Sanford Palay at an international meeting in Delft, Holland, and we met again at the Anatomical Association meeting in London in 1961. Several months later, Sandy Palay came to Edinburgh to visit me, and we discussed the possibility of my spending a year in Boston. It was a possibility that I very much relished because Sandy Palay was in the forefront of neurocytology, and he had recently developed a method of perfusing brains with solutions of osmic acid (Palay et al., 1962). This produced a quality of fine structural preservation superior to that routinely obtained by immersing excised pieces of tissue in buffered solutions of osmic acid. Also, at that time, it was almost imperative for British anatomists to get their “BA,” or “Been to America.”

So I applied for a Carnegie Trust travel fellowship, which I was awarded, and in 1963 I took my wife and two daughters we had at that time on a transatlantic liner to Montreal, from where we embarked to Boston. There I spent a year at Harvard Medical School, where I was given the position of Visiting Lecturer in Anatomy.

Sandy and I discussed what we should do during my year's sabbatical. We concluded that it would be interesting to look at the lateral geniculate nucleus of the cat, because at that time little was known about the synaptology in the thalamus, and Torsten Wiesel and David Hubel in the physiology department at Harvard had some interesting data on the responses of neurons in the lateral geniculate body to visual stimulation. It was hoped that it would be possible to produce anatomical and physiological correlations that would be enlightening.

Although Sandy Palay and his colleagues had been perfusing rats' brains with buffered osmic acid, they had never tried to perfuse the brain of anything as large as a cat. We calculated that it would take about a liter of 1% osmic acid to perfuse the brain of a cat, and as can be imagined, with that amount of osmic acid, the fumes given off during perfusion were strong, even though we were using a perfusion table with a down draft. The fumes became even stronger when we opened the skull to expose the coal black and brittle brain so that the lateral geniculate body could be removed for electron microscopic processing. We perfused two or three cats using this technique, and the osmic-acid fumes usually managed to fix my corneas and olfactory epithelium so that I had misted vision and could not smell anything for several days after each perfusion. Nevertheless we obtained some well-fixed tissue, and eventually Sandy Palay and I published a paper on the structure and synaptology of the lateral geniculate nucleus of the cat (Peters and Palay, 1966). We recognized the existence of what we called a synaptic glomerulus, which consisted of neuronal processes surrounded by astrocytic sheaths, and in the glomerulus we found that the axon from the retina, the central axon, forms asymmetric synapses with two other kinds of processes. One of these processes was obviously a dendrite, and the second kind of process, which also synapsed with the dendrite, contained synaptic vesicles. At that time, it was not known that dendrites can be presynaptic, so we assumed the second vesicle-containing process was an axon. It was not until several years later that Ted Famiglietti, who was then a graduate student in my laboratory, did a more thorough investigation to show that the second type of vesicle-containing processes, the one postsynaptic to the central axon of the glomerulus, and presynaptic to the other dendrite, is itself a dendrite. Consequently, the thalamic glomerulus contains dendro-dendritic synapses (Famiglietti and Peters, 1972).

In the 1960s the anatomy department at Harvard was arguably the foremost department for cell biology in the country. The head of the department was Don Fawcett, and he had recruited a galaxy of talent, which included such people as Sandy Palay, Betty Hay, Jean-Paul Revel, Sus Ito, and Dick Coggeshall. All of these faculty were doing electron microscopy, and the standards they set were very high, so I learned a great deal about cytology from them. In addition, in Sandy Palay's laboratory at that time were two other visitors. One of them was Facundo Valverde from the Cajal Institute in Madrid, who was producing exquisite Golgi preparations of visual cortex, and the other was Paulo Hashimoto from Japan.

In 1964, toward the end of my time in Boston, Sandy Palay and I discussed the possibility of writing a book on the fine structure of the nervous system, which would explain what electron microscopy had contributed to our understanding of the nervous system and its components, and how electron microscopic (EM) images of the nervous system could be interpreted. However, after much discussion, we decided to postpone such an endeavor, because there were problems still to be solved and parts of the neuron that had not yet been recognized. One such part was the axon initial segment.

I was fortunate to be asked to give a number of seminars during my stay in Boston. One visit was to Los Angeles, where I met a number of people with whom I remained in contact, including Larry Kruger, Carmen Clemente, and Dan Pease. Another trip was to St. Louis, where I met Ed Dempsey, Bryce Munger, and Sarah Luse. I had not been warned that Sarah Luse thought the pale neuroglial cells, which I considered astrocytes, were oligodendrocytes, and so my descriptions of neuroglial cells caused somewhat of a stir. But at the barbeque following the talk, Sarah Luse and I amicably agreed to differ on which neuroglial cells were which.

Edinburgh 1964–1966

On returning to Edinburgh I continued to examine central myelin sheaths and started to examine the fine structure of the cerebral cortex, about which little was known at that time. I think that my choice of the cerebral cortex as an interesting part of the nervous system to study was influenced by the very insightful opening chapter on cerebral cortex largely written by Rafael Lorente de Nó in Fulton's Nervous System, in which there are interesting comments on the organization and connections of the neurons of cerebral cortex and descriptions of some of the cell types as they were known in 1938. One problem was getting good preservation of cerebral cortex, because we could not afford to use osmic acid as a perfusate and did not have the right equipment to cope with the fumes. Our problems were largely solved by perfusing brains using mixtures of formaldehyde and glutaraldehyde. Glutaraldehyde had been introduced in 1963 by Sabatini, Bensch, and Barrnett, and Russ Barrnett had told me about glutaraldehyde and its virtues during a taxi ride we took together in New York in 1964. The introduction of glutaraldehyde started the present era of greatly improved tissue preservation. Glutaraldehyde is a dialdehyde that has excellent crosslinking properties, but in the early days it was a very tedious process to produce pure glutaraldehyde from the commercially available product.

Soon after my return to Edinburgh I received a letter from James Vaughn, who was a graduate student of Dan Pease, whom I had met in California in 1964, asking me if he could come to Edinburgh as a postdoctoral fellow. I agreed, and in 1965 Jim Vaughn joined me in Edinburgh. Together we worked on the development of astrocytes in the optic nerves of rats in material fixed by perfusion with fixatives containing mixed aldehyde solutions. The use of these glutaraldehyde/formaldehyde solutions made the preservation of the material much better than that obtained earlier, and we were able to show how astrocytes form the glial limiting membrane, how they segregate the initially unmyelinated nerve fibers, and how the frequency of intermediate filaments within astrocytes increases as they mature (Vaughn and Peters, 1967).

Soon after Jim Vaughn's arrival, I received a phone call from Boston University asking me if I would agree to be considered as a candidate for the chair of anatomy at the medical school. Of course I was flattered that they would even consider offering such a position to someone as young as me, because I was only 36 at the time. To satiate my curiosity I agreed to go to Boston for an interview. Before I left, I remember telling my wife that this was a waste of time, but I thought I may as well go to Boston to meet up with old friends I had made there during my sabbatical year. After several interviews I was offered the chairmanship of the Department of Anatomy, and it became clear that they wanted someone who would generate a research program in the department, in which they were prepared to create several new positions. During a subsequent visit it was arranged for me to go to Bethesda to make a visit to Natural Institute of Health (NIH) so that I could assess the possibility of obtaining funding to set up an electron microscope unit in the department. The officials at NIH were very encouraging and told me that such funding was indeed possible and so I returned to Edinburgh wondering what I should do.

At about this same time I had begun to talk to George Romanes about being promoted to senior lecturer, but he did not seem very keen on the idea because it would mean my jumping several steps of the promotions ladder, which was rarely done. One had to progress one step at a time, regardless of merit. I think that he was also reluctant because, unlike the large majority of faculty members in departments of anatomy in Great Britain, I did not have a medical degree. There were few doctoral programs in anatomical sciences at that time, and if I recall correctly every professor of anatomy in Great Britain had a medical degree, the one exception being J.Z. Young at University College in London.

At about the same time that I received an official offer of the chair in anatomy at Boston University, I did get a letter of promotion from Edinburgh University. But weighing my prospects of a career in anatomy in Great Britain, with the lack of medical degree, against the prospect of a career in the United States, I decided to take the offer from Boston University, where I have now worked for almost 40 years.

As an aside, Alan Muir and I left the anatomy department at Edinburgh at the same time. I, who had a Ph.D., came to Boston University School of Medicine, while Alan Muir, who had a medical degree, took the chair in anatomy at the Royal Dick Veterinary School in Edinburgh. Unfortunately Alan Muir died at the age of 50 in 1974.

Boston 1966–Onward

Because the Department of Anatomy at Boston University was essentially a teaching department at that time, I had negotiated with the dean for additional positions so a research program could be developed. My first appointment was Jim Vaughn, who had agreed to come to Boston with me from Edinburgh. He arrived in Boston ahead of us because the immigration authorities were holding up my family and me until Boston University had permission to fill their position with a foreigner. But in the end everything was settled, and I remember writing an NIH grant application while we were still in Edinburgh. I wrote it as we were packing our belongings, and my wife typed it for me, producing the necessary six carbon copies. Fortunately, despite my lack of experience with grant writing, the application was funded for 5 years and supported the setting up of an electron microscope facility. That grant was funded by the National Institute of Neurological Disorders and Stroke in 1966 and was continuously funded until the year 2000, when I decided not to renew the grant so that I could spend my time studying the effects of normal aging on the brain.

One of my main problems on leaving Edinburgh was what to do with the large number of 3¼-inch square glass electron microscopic negatives that I had accumulated over the years. I decided that the solution was to select 200 of them, the ones that I knew I could not live without. Consequently, I had a wooden box made specially, and I carried this heavy chunk of glass with me as hand baggage on our trip to the States, being concerned that the plates might be damaged by the baggage handlers. However, some 5 years later, I still had not taken the lid off the box, and eventually I ended up throwing most of those negatives away.

When I took over the department in 1966, we only had some 80 medical students and some 5 faculty members who taught. But the department had some reputation for studies of the nervous system, because my predecessor was Arthur Lassek, who worked on the pyramidal tract, and prior to him was LeRoy Conel, who had produced several volumes, which are still quoted, on the development of the cerebral cortex in humans.

In 1966 it was difficult to find faculty who were qualified in anatomical sciences, and I was lucky to know that Jay Angevine at Harvard had a graduate student named Jim Hinds, who was working on histogenesis in the olfactory bulb. So I offered Jim a faculty position, even before he had completed his doctoral degree, and fortunately he accepted the position and came to join us. Jim stayed in the department for several years, doing ground-breaking work on the development and the effects of aging on the olfactory bulb. I think that it was in 1984 that Jim told me he intended to give up science and was going to Maine to work as a chartered accountant. He is still working as a charted accountant, but he and his wife spend their spare time studying lichens.

Another early recruit was Ita Kaiserman-Abramof, who was working in Sandy Palay's laboratory. Consequently, by the end of 1968 the department had a nucleus of faculty who were doing research.

From my point of view, those early years were very productive. Jim Vaughn and I continued to work on neuroglial cells and made a series of studies on the development and structure of myelin sheaths. The studies on neuroglial cells led Jim and I to write a paper on a third type of neuroglial cell in the central nervous system (Vaughn and Peters, 1969). At that time no one had recognized microglial cells in the normal nervous system, and we were somewhat unsure whether this third cell type represented microglia. But in retrospect, I think our conclusion that the cell type we were describing was a stem cell is correct, and that our third cell type is now recognized as being an oligodendroglial precursor. Later, Jim and I summarized our work on the neuroglial cells in a chapter in which we described the morphology and development of neuroglia (Vaughn and Peters, 1971). Looking back at the illustrations in that chapter, it is interesting to see how much the preservation of nervous tissue had improved between 1960 and 1970.

The other set of studies that Jim Vaughn and I carried out were those on the formation and structure of myelin sheaths. These studies culminated in Jim and I collaborating to write a chapter on the morphology of myelin (Peters and Vaughn, 1970) in a short book called Myelination, which I edited with Alan Davison (Davison and Peters, 1970). I believe this chapter is a good summary of what was known about myelin at that time. Shortly afterward, in 1970, Jim, who was now recognized as being an excellent electron microscopist, was recruited by Eugene Roberts to join the Division of Neurosciences at the City of Hope in Duarte, California, where they were working on glutamic acid decarboxylase (GAD) and γ-amino butyric acid (GABA). Jim eventually became the chair of the department and has done seminal studies focused on the development of spinal cord.

In addition to these studies, I was still working on the neurons of the cerebral cortex, and one of the first articles we published from Boston was on the features of the initial axon segment in cortical neurons. As mentioned earlier, one of the reasons Sandy Palay and I had for deciding not to write the book on fine structure of the nervous system at the end of 1964 was that we had not yet recognized the initial axon segment. I had recognized this part of the axon of neurons in the cerebral cortex while still in Edinburgh, and on getting back to Boston in 1966, I told Sandy about my observations that in the cerebral cortex this part of neurons is characterized by fascicles of microtubules and by an electron dense undercoating of the axolemma. Sandy told me that he, along with Constantino Sotelo and Paula Orkand, had now also seen this portion of the axon in the lateral vestibular nucleus and in the cerebellum, and so we agreed to pool our data. Consequently, in 1968 we published two articles describing the axon initial segment, one general article (Palay et al., 1968) and another one describing the axon initial segment and axon hillock in pyramidal cells of the cerebral cortex (Peters, Proskauer, and Kaiserman-Abramof, 1968). With the characteristics of all portions of neurons established, the way was clear for us to think about proceeding with a book on the fine structure of the nervous system, but before describing how we went about writing that book, I would like to make a few comments about Boston in the 1970s.

One of the nice things about being in Boston at that time was that there were many active groups working on the nervous system, and at Boston University one of my more interesting colleagues was Norman Geschwind, who had been appointed to the chair of neurology at the same time I took over anatomy. In addition to those working in the anatomy department at Harvard, there was the neuroscience group that was being developed by Frank Schmitt, and over at MIT was the group working with Walle Nauta. At least once a week I would go over to either Harvard or MIT to attend seminars, because in those days there was no trouble with parking, which made life easy.

One of the people I met at MIT was Lennart Heimer, who was working in Walle Nauta's group. Lennart, along with Robert Fink, had developed two methods for the selective staining of degenerating axonal boutons. These methods were essentially modifications of the Nauta method for staining degenerating axons but had the advantage that degenerating nerve fibers could be traced to their terminations. However, doubts had been expressed by a number of investigators about whether the Fink-Heimer method actually stained degenerating axonal boutons, and Lennart came to me to ask if it would be possible to do an electron microscopic study of tissue labeled by the Fink-Heimer method to really determine whether the silver was being deposited in degenerating axonal boutons. So we examined some tissue in which lesions had been placed in either hippocampus or olfactory bulb and were able to show that in material stained by the Fink-Heimer method the silver is indeed deposited in degenerating axonal boutons (Heimer and Peters, 1968). This proved the validity of the Fink-Heimer method, which for many years provided an important tool for tracing central nervous pathways.

The Fine Structure of the Nervous System

First Edition

As I have said, when I returned to Boston, Sandy Palay and I started talking once again about writing a book devoted to the fine structure of the nervous system. By that time, a number of excellent atlases showing electron micrographs of cells had appeared, the most notable ones being those of Porter and Bonneville (1963) and Fawcett (1966), but these atlases had little on the central nervous system. We felt that an atlas devoted to the nervous system would be useful, but in addition to showing electron micrographs, we concluded that the book should have some descriptive text. Because Sandy Palay and I were then involved with studying the central nervous system, we decided that it would be a good idea to recruit someone with expertise in the peripheral nervous system, and an obvious choice was Henry deF. Webster, who was in the neuropathology department at Mass achusetts General Hospital. Harry readily agreed to join us in the endeavor and in 1968 we started to select pictures and to write the text.

We had already thought about a suitable publisher for our book, and the Paul Hoeber Company seemed to be a good choice. However, in the 2 years it took us to complete the book, the Paul Hoeber Company had been bought out by Harper and Row, who seemed unprepared to receive our manuscript and plates and did not know who would do the half-tone printing. A detailed account of our problems has been given by Sandy Palay (1995), and despite our best efforts to ensure that the illustrations would be of good quality, we were very disappointed with the rather faint and lightly printed illustrations that finally emerged in the 1970 edition of the Fine Structure of the Nervous System. Nevertheless, despite little advertising, the entire run of 5000 copies had been sold by 1972. Looking back, is interesting to note that this edition listed only 550 references, practically all of the articles on neurocytology that had been published up until that time. Also there were obvious gaps in our knowledge. Microglial cells had not been characterized, almost nothing was known about the morphological correlates of inhibition, and except in the olfactory bulb, it was not recognized that dendrites could be presynaptic.

I later discovered that the Russians had published a pirated edition of our book. It appeared in 1972, and I met the translator, whose name I have forgotten, at a dinner party at Paul Yakovlev's house when he gave me a copy of his book. When I asked him if there were any royalties connected with this Russian edition, he told me that of course there were royalties and that all I had to do was to go to Moscow and collect them, although I would not be able to take the money out of Russia!

We received enough positive comments from colleagues that we began to think about a second, enlarged edition that would cover the many advances recently made in neuroscience. We approached Harper and Row and asked them if they would consider publishing a second and expanded edition of our book. They told us they were not interested in books with small-volume sales, but offered to sell the rights of the book to another publisher. Fortunately, when we signed the contract for the first edition, our attorney had insisted that one of us (A.P.) should hold the copyright. Harper and Row were very surprised to discover this fact, which allowed us to seek another publisher of our own choosing. This time we selected Saunders, who was represented by John Dusseau. He assured us that he personally would ensure good-quality reproduction of our electron micrographs: a promise he kept.

Second Edition and Cambridge

We began preparations for the second edition in 1973, when I went to Cambridge on sabbatical leave as a visiting professor in the Department of Anatomy. The reasons for going on sabbatical leave were two-fold. The official reason was so that I could spend time in the university libraries to read and begin writing for this new edition. However, another reason was that Rona and I were still not sure whether we wanted to live permanently in the United States. By this time we had added a third daughter to our family, and we thought that exposing them and ourselves to living in Britain for an extended period would enable us to make up our minds about our future. We soon realized that there is no perfect place to live and that we were happy with our lot in the United States.

It is interesting to look back on facts that influence one's decisions. The trigger in this case was that I had a money order in dollars that I wanted to exchange into pounds sterling, but the bank in Cambridge was reluctant to make the exchange because, at that time, the dollar was fluctuating against the pound. This was aggravating because we had bills to pay and things we wanted to buy. Eventually I persuaded the bank to give me some pounds, and at the end of the day, I took the bus home and decided it would be nice to buy a bottle of wine for dinner. It was 6 o'clock in the evening when I got off the bus, and as I walked over to the local wine shop, the shopkeeper pulled down the blind to indicate that he was closing. I knocked on the door, but he would not open the shop for me, and so I went home angry, without the wine, and told my wife that if that was the way people behaved here, we were going back to the States, which we did.

Through the kind offices of Gabriel Horn, I was fortunate enough to be made a Visiting Fellow at King's College and enjoyed the break from administrative duties as chairman of the department at Boston University. Professor R.J. Harrison, who was the professor of the Department of Anatomy in Cambridge, was also good enough to allow me to learn something about scanning electron microscopy while I was there, and this resulted in a publication on the ependyma and chroroid plexus in the lateral ventricles of the rat (Peters, 1974), as well as some scanning electron microscope pictures that were included in the second edition of our book. This second edition appeared in 1976, and it had 118 plates, only 30 of which had been included in the first edition of our book. This new edition had an expanded text, and the illustrations covered such new items as freeze-fracture, scanning electron microscopy, and tract tracing. This edition contained some 1700 references, three times more than in the first edition, and even they did not cover the neurocytology literature completely. By the early 1980s this edition was also out of print, and again, the success of the book led us to consider a third edition. However, as with our publishers for the first edition, Saunders decided it was not interested in small press runs. So we looked around for yet another publisher and finally decided on Oxford University Press, largely because Jeffrey House, who was the editor for Oxford, impressed us as someone we could trust and work with—an evaluation that turned out to be true.

Third Edition

We spent 2 years putting together the third edition, and to keep up momentum Sandy Palay and I met at his house every Wednesday to go over the text we had produced during the previous week and to select the plates. This time I took off to Hawaii to do some of the writing, a place that I had longed to see since growing up and reading books about the South Sea Islands. The third edition had a publishing date of 1991. The text was again expanded and the number of plates increased to 137, of which 51 were new. Oxford University Press did an excellent job of reproducing the plates, and this may be one reason why the Science Book Club selected it as one of their offers. It is interesting that even after 14 years, copies of the book are still being sold, largely because of the quality of the plates, because the text is now somewhat dated.

I like to think that this book set standards for the quality of electron micrographs of the nervous system and that it has served as a source of reference for those beginning to study the cytology of the nervous system.

A more detailed account of our tribulations with publishing our book on The Fine Structure of the Nervous System can be found in a memoir that Sandy Palay wrote for an issue of the Journal of Comparative Neurology published in 1995 in honor of my 65th birthday (Palay, 1995). This issue was put together by Jim Connor and Bob Skoff without my knowledge and contains articles by a number of former graduate students and postdoctoral fellows who had been in the Department of Anatomy at Boston University during my tenure as chairman. Of course, I was delighted to be honored in this special way and touched that these students, now colleagues, would plan this journal issue in my honor.

Sandy Palay retired from Harvard in 1990, and he spent the next 3 years continuing to edit the Journal of Comparative Neurology from his home in Concord. I would often go to his home and enjoyed our discussions of science and life in general. Unfortunately, at about the time that he gave up editing the Journal of Comparative Neurology, Sandy's health began to fail, and he died in 2002. The last venture we undertook together was a paper in 1996 on “The Morphology of Synapses” that was published in the 25th anniversary issue of Journal of Neurocytology, dedicated to “The Synapse” (Peters and Palay, 1996). This article was doubly appropriate, because it will be remembered that in 1956 Sandy Palay published the first account of the fine structure of the synapse in mammals. When he examined thin sections of the abducens nucleus, he had encountered club-like profiles that were filled with mitochondria and vesicles aggregated against the presynaptic membranes abutting the surfaces of dendrites and cell bodies. Furthermore, this presynaptic membrane was separated from that of the postsynaptic one by a thin extracellular space, thus confirming Cajal's inference that neurons do not form a syncytium (Palay, 1956).

I felt very honored and pleased when, in 2004, I was selected by the editorial board of the Journal of Comparative Neurology and by the Cajal Club to be the first recipient of the Sanford L. Palay Award for contributions on the structure of the nervous system, an award funded by John Wiley and Sons to acknowledge Sandy's contributions as editor of the Journal of Comparative Neurology.

Cerebral Cortex: The Book Series

Toward the end of the 1970s, I realized that very few comprehensive accounts of the cerebral cortex existed, and I began to think that the gap might be filled through publication of a short series of books dealing with the kinds of neurons that are present in the cerebral cortex, how they are organized, the types of neurotransmitters they use, and their physiological properties. However, I felt that I needed someone to join me in this endeavor, and I approached Edward G. Jones to see if he would be interested. At that time Ted was the chair of anatomy at Irvine, California, and fortunately, he embraced the idea enthusiastically. After we had decided that the first volume should be devoted to the various cell types in cortex, we realized that it would be sensible to recruit an advisory board who would give the series more credibility, and we were fortunate that when we approached John Eccles, Ed Evarts, Norman Geschwind, Vernon Mountcastle, Walle Nauta, Sandy Palay, and Fred Plum they all readily agreed to serve on the advisory board for the project.

Our intent originally was to produce just three or four volumes, but ultimately, the series extended to 14 volumes. Plenum Press published the first volume in 1983, and the series continued through 1999. The compilation of the series was not difficult. In consultation with the advisory board, Ted and I decided which topics were suitable for a given volume and then in turn we would take on the task of writing to potential authors. After they had agreed to write a chapter, the one responsible for that volume would harass recalcitrant authors, make any necessary corrections to the manuscripts, and send them off to the publishers. Because the series was well received, it was rare that anyone who was asked to write a chapter turned us down. As different volumes continued to be produced, we recruited others to help edit given volumes, often members of the advisory board, whose membership necessarily changed over the 15 years spanned by the series. With reluctance, Ted and I decided to terminate the series after Plenum Press, our original publishers, were bought out by Kluwer. The price that Kluwer wanted to charge for each volume was so high that we believed only few volumes would be sold. In our minds, this would necessarily reduce the availability of the books and make them less accessible to the readers we wanted to reach. The last volume in the series was meant to be one on cat primary visual cortex, which Bertram Payne and myself were to edit.

Fortunately, Kluwer/Plenum Press was not averse to releasing us from our contract, and Bert and I were able to work with Academic Press on the publication of a book called Cat Primary Visual Cortex (Payne and Peters, 2002). But even then the price was much higher than we would have wished, and the book was far from being a best seller. I think it is becoming increasingly obvious that most publishing houses no longer want to get involved with small-volume sales, even though one would think that with modern technology the cost of publishing books would have decreased.

Research Themes

As I began to write about the research I had done in Boston over the years, I realized that because of my various research interests a year-by-year account of the research I have done was not going to work. Consequently, I have decided to present the research with which I have been involved in terms of the themes I have pursued. That way, I hope that the following account has some logic and is not too disconnected.

General Studies of Cerebral Cortex

In the late 1960s there had been few studies of the characteristics of cells and their processes in cerebral cortex, and so every time one looked at a thin section of cortex with the electron microscope, something new turned up. In reality the only way to approach the problem of the identification of characteristics of the various components of the cerebral cortex was to sit down at the electron microscope for long hours and take pictures of anything that looked interesting. We would then go over the electron micrographs and use grease pencils to try to label each profile and assign it to a cell type. This approach led Ita Kaiserman-Abramof and me to discover that some of the profiles of asymmetric synapses, now known to be excitatory, on dendritic spines in cerebral cortex show the postsynaptic density at synaptic junctions to be in two parts, separated by a space. On reconstruction from serial thin sections, we found that this appearance is produced because the disc-like postsynaptic densities of such synapses are perforated (Peters and Kaiserman-Abramof, 1969).

Following up on this observation, we found that in Golgi-impregnated preparations of cerebral cortex, the dendritic spines can be described as being of three types: stubby spines, which are rather short; mushroomshaped spines, which have large bulbous heads; and thin spines, which are long (Peters and Kaiserman-Abramof, 1970). This classification of dendritic spines has stood the test of time and is still used as the basis for descriptions of changing frequency and morphology of dendritic spines in the cortices of animals that have been subjected to alterations in diets or behavioral environments, whereas increases in the frequency of perforations at axo-spinous synapses are regarded by some as one of the bases of learning.

For some reason that I am no longer certain about, Ita and I then went on to examine the Betz cells in cat motor cortex (Kaiserman-Abramof and Peters, 1972). I assume that we chose to examine these cells because at that time there were few neurons in the cerebral cortex that could be specifically identified, and the Betz cells can be readily recognized by their large size, making it possible to carry out a Golgi study of these cells in correlation with the electron microscopic analysis. It was in this study that we also developed methods for estimating the numbers of synapses on the surfaces of neuronal cell bodies in an attempt to try to provide data that would be useful to neurophysiologists examining the properties of these large neurons.

In 1971 Deborah Vaughan came to work with me as a postdoctoral fellow, and because Debbie had a great deal of experience in electron microscopy during her graduate work, we decided that it would be interesting to examine serial thin sections to reconstruct the three-dimensional shapes of dendrites and to find out how dendrites ended. Although it is not too uncommon to use serial thin sections for electron microscopy nowadays, at that time there had been only one or two studies in which serial thin sections had been used to make reconstructions. The first problem was to cut series of thin sections with the ultramicrotomes that were then available, and the second problem was how to mount the series of thin sections onto copper grids with single slots and no bars. We eventually developed a technique for doing this, and, using sections of layer 1 of cerebral cortex, which has few cell bodies and many dendrites running through it, we produced some of the first three-dimensional reconstructions of dendrites and their endings. After making the reconstructions by hand, we found that dendrites can have very long mitochondria and that both symmetric and asymmetric synapses are intermixed along the shafts of dendrites. We also discovered that although all dendritic spines appear to have an asymmetric synapse, some of them also have a symmetric one. However, we were disappointed to find that dendrites just end bluntly and that there is no specialization at their ends (Vaughan and Peters, 1973).

Quite soon after completing that study, Debbie Vaughan and I got involved with looking at the effects of aging on the central nervous system. I will have more to say about that later, but in 1974 we published one of the first studies of the effects of age on neuroglial cells, showing that all three classical types of neuroglia accumulate inclusions in their cell bodies with age (Vaughan and Peters, 1974).

Even in the 1980s, although we had looked at a variety of individual neurons in the cerebral cortex with Golgi-EM techniques that were developed in the 1970s, very little was known about the composition of the cortex in terms of the proportions of pyramidal and nonpyramidal cells present in the various layers, how they were arranged, and what criteria could be used to identify the various neuronal types in EM preparations. To get more information about the composition of the cerebral cortex, a technician that I had at that time, Dan Kara, persuaded me that we ought to undertake a marathon study of cell types in cerebral cortex. The approach was to take adjacent thin and 1-micron thick sections through rat visual cortex. We would then draw and number each cell that we saw in the 1-micron thick section, after which we would examine the adjacent thin section and take corresponding electron micrographs of each cell. We ended up by taking more than 2000 electron micrographs of cells in the various layers of rat visual cortex, but we did develop criteria for characterizing the pyramidal (Peters and Kara, 1985a) and nonpyramidal (Peters and Kara, 1985b) neurons in rat visual cortex, as well as for the first time determining how many profiles in each layer of cortex can be attributed to pyramidal or nonpyramidal cells and how many neurons there are present in this particular cortical area (Peters, Kara, and Harriman, 1985). For example, we found that there are some 120,000 neurons beneath 1 mm² of cortical surface and more than a million neurons throughout area 17 of the rat.

Golgi—Electron Microscopy

A problem with normal electron microscopy, in which individual thin sections are examined, is that one only gets a two-dimensional picture. The various profiles of neurons can only be related to each other through an analysis of serial sections. However, numerous serial thin sections are required to determine any relationships, and even with a herculean effort only portions of neurons can be reconstructed. On the other hand, successfully impregnated Golgi-stained material can show the cell bodies, dendrites, and sometimes a portion of the axons of individual neurons in three dimensions. In the 1960s this led a number of investigators such as Ted Blackstad (1970) and Bill Stell (1965) to attempt to blend these two techniques by making thin sections of Golgi-impregnated neurons, so that the synaptic relationships of impregnated neurons could be revealed.However, this approach met with limited success, because the electron-dense deposit of silver chromate produced by the Golgi method either fell out of the thin sections containing portions of the impregnated neuron, tore the section, or heated up in the electron beam, causing the surrounding embedding plastic to expand. Various attempts were made to solve this problem, but with limited success, and in 1975–1977 Alfonso Fairén from the Cajal Institute in Madrid came to the laboratory to learn electron microscopy and to try to determine if the Golgi-EM procedure could be improved.

After several unsuccessful attempts at doing Golgi-EM, I was riding home on the turnpike one evening thinking about the problem, when it occurred to me that one solution was to try to gold tone the material impregnated by the rapid Golgi method. I had used gold toning many years earlier while working on the mechanism of silver staining. In gold toning of silver-stained sections, gold is used to replace the silver deposit, and the idea was to determine if the silver-chromate deposit generated by Golgi impregnation could be replaced by gold particles. I arrived at the laboratory the next day and suggested to Alfonso that he ought to try gold toning. To our delight, Alfonso achieved a successful gold toning of Golgi-impregnated neurons on the first attempt. The Golgi-impregnated sections were immersed in gold chloride, which was reduced by oxalic acid, and the silver chromate was then removed by immersion in sodium thiosulphate. The impregnated neurons were still visible but semitransparent, and in the electron microscope the gold could be seen as small, dense particles in a neuron with intact cytology. We perfected the technique and designed a microtome chuck that could be removed from the ultramicrotome to allow the progress of sectioning to be examined under the light microscope. We published this new Golgi-EM procedure (Fairén, Peters, and Saldanha, 1977), which was used for several years by ourselves and other laboratories, to examine the synaptology and axonal connections of neurons. Pushing this new technique to its limit, Alfonso and I also worked with Edward White, who had recently joined the department to show that it was also possible to use the gold-toning technique on sections of Golgi-impregnated tissue containing degenerating thalamocortical axons terminals, which had been caused to degenerate as a result of experimental lesions. Thereby both the presynaptic and postsynaptic components of thalamocortical synapses could be identified (Peters, White, and Fairén, 1977). This new technique allowed us to examine numerous types of neurons, especially the nonpyramidal cells of cortex, about which little was known, and most importantly to determine the types and locations of synapses formed by their axon terminals.

Nonpyramidal Neurons

One of the first nonpyramidal cell types we examined using our new Golgi EM procedure was the smooth and sparsely spined stellate cell in cerebral cortex. Alfonso Fairén and I were able to show that the axons of these neurons form symmetric synapses with a variety of postsynaptic partners (Peters and Fairén, 1978). Charmian Proskauer, who was one of my excellent research technicians, and I then went on to examine some of the cortical interneurons with myelinated axons. In addition to showing that their cytology and synaptic inputs are similar to those of the stellate cells with unmyelinated axons, we were also able to show that in those neurons with myelinated axons the Golgi impregnation stops at the initial axon segment (Peters and Proskauer, 1980a). By a stroke of good luck, as Charmian and I examined our many Golgi-impregnated sections, we were fortunate to come across two impregnated cells in the same section: One cell was a pyramidal cell and the other a multipolar stellate cell with an axon that appeared, on the basis of our light microscopic examination, to form synapses with the pyramidal cell. We indeed found that the axon of the stellate cell formed nine synapses with the pyramidal cell: five synapses with the cell body, one with the apical shaft, and three with basal dendrites (Peters and Proskauer, 1980b). I believe this was the first time that synaptic connections had been positively identified between two identified neurons in cerebral cortex, and the first demonstration that an inhibitory neuron can synapse with different parts of a pyramidal cell surface.

Bipolar Cells

We next used the Golgi-EM technique to examine the bipolar cells in rat visual cortex. Martin Feldman and I were among the first ones to describe these interesting cells in our light microscopic account of the forms of non-pyramidal cells in Golgi-impregnated rat visual cortex (Feldman and Peters, 1978). Lauren Kimerer, another research assistant, and I were able to show that our Golgi-impregnated bipolar cells have axons that form asymmetric synapses with the dendritic spines of pyramidal cells and that consequently they are excitatory neurons (Peters and Kimerer, 1981). This result was puzzling, because it had been assumed that all nonpyramidal cells are inhibitory neurons, and our result was at odds with the observations made earlier by John Parnavelas and his colleagues in London (Parnavelas et al., 1977). In their EM examination of Golgi-impregnated bipolar cells in rat visual cortex, they had found the axons of bipolar cells to form symmetric synapses. The situation became even more puzzling when in 1984 Alfonso Fairén and his colleagues in Spain described a Golgi-impregnated bipolar cell in cat visual cortex that formed asymmetric synapses (Fairén et al., 1984). Bipolar cells became more prominent when it was discovered that large numbers of them label with antibodies to vasoactive intestinal polypeptide (VIP), and, to further muddy the waters, it was found that such bipolar cells have axons that form symmetric synapses, as Jim Connor, then a postdoctoral fellow in the laboratory, and I were also able to demonstrate (Connor and Peters, 1984).

A resolution to the problem emerged when Kathy Harriman, another research assistant, and I carried out further study of the bipolar cells (Peters and Harriman, 1988). We confirmed that VIP-positive bipolar cells have axons forming symmetric synapses, but examination of another 10 bipolar cells by the Golgi-EM technique showed that although eight of them formed asymmetric synapses, as we had described earlier, two of them formed symmetric synapses. So in effect there are two populations of bipolar cells. However, little attention has been paid to the excitatory bipolar cells, and their transmitters appear not to have been identified.

Chandelier Cells

One of the most interesting cells in cerebral cortex is the chandelier cell, which Peter Somogyi at Oxford University first showed to form synapses with the axon initial segments of pyramidal cells in cerebral cortex (Somogyi, 1977). Because of the location of these axo-axonal synapses, it was suspected that they were inhibitory in function. We were able to confirm this in a study we carried out with Charles Ribak, who had been my graduate student and had gone to do postdoctoral work with Jim Vaughn at the City of Hope. Using the Golgi-EM technique in combination with labeling with a GAD antibody, we were able to show that the symmetric synapses, which the axon terminals of chandelier cells form with the axon initial segments of pyramidal cells, use GABA as their neurotransmitter (Peters, Proskauer, and Ribak, 1982).

Other Golgi-EM Studies

If I recall correctly, the only other studies we carried out using the Golgi-EM technique were on cortical development and on stellate cells in cat visual cortex. The study of cortical development was carried out with Michael Miller, who came to the laboratory as a postdoctoral fellow. We were able to follow the maturation of pyramidal cells in rat cortex and show that dendrites acquire asymmetric synapses before they acquire symmetric ones. We also found that the spines of dendrites begin as low, broad protrusions, which acquire synapses and gradually become longer as they mature into the common lollipop type spines of the adult (Miller and Peters, 1981). These and other studies that Michael carried out on normal development formed the basis for his very interesting subsequent observations on the effects of alcohol on development.

Although it was not difficult to generate Golgi-impregnated pyramidal cells, to impregnate stellate cells in layer IV of monkey visual cortex was a much more serious challenge. But Richard Saint Marie, who came to the laboratory as a postdoctoral fellow, persisted and was eventually able to impregnate a few stellate cells with visible axons. Using the Golgi-EM technique, he was able to show that like pyramidal cells, only symmetric synapses occur on the cell bodies of the layer IV stellate cells and that most of the synapses received by stellate cells are on their dendritic spines. Dick was also able to show that the spiny stellate cells have axons that form asymmetric synapses and the synapses they make with dendritic spines outnumber those made with dendritic shafts by two to one. This research clearly showed that spiny stellate cells and pyramidal cells have many features in common, and basically they differ only in the distribution of their dendritic trees (Saint-Marie and Peters, 1985).

The era of EM studies of Golgi-impregnated neurons essentially came to an end with the development of the technique of intracellular filling by neurophysiologists. This technique allows the physiological properties of neurons to be evaluated before they are filled to study their morphology, and early on some of the most insightful descriptions of cortical cells were those given by Kevan Martin and David Whitteridge, who at that time were at Oxford (see Martin, 1988). Interestingly, intracellular filling showed the axonal plexuses of cortical neurons to be much more wide-spread and complex than Golgi impregnations had revealed. As a consequence, we now know much more about the projections of cortical neurons and where their axons synapse. However, even now, although we have extensive information about axonal terminations, as far as the cerebral cortex is concerned, there is a dearth of information about the origins of the synaptic inputs that specific types of cortical neurons receive. However, it can be estimated that a pyramidal cell in cortex probably receives input from as many as 1000 other pyramidal cells and as many as 75 inhibitory neurons (Peters, 2002). Such complex interactions between cortical neurons are difficult for me to comprehend.

Thalamic Inputs to Cerebral Cortex

One of my long-term interests has been the nature of the thalamic input to cerebral cortex. This interest began with a study that Charles Ribak, now a professor at Irvine, California, did as a graduate student in my laboratory. He carried out an autoradiographic study of the projections from the lateral geniculate nucleus, which in the rat had received little attention at that time, even though a number of studies had been carried out on the geniculate input to cat and monkey visual cortex. Chuck showed that there is a major peak of labeling in layer IV of rat visual cortex, with minor peaks in layers I and VI, and some extension of the labeling into areas 18 and 18a. He was also able to demonstrate very extensive projections from the ventral geniculate nucleus to the brainstem (Ribak and Peters, 1975). Soon after completing this study, Chuck left to do a postdoctoral fellowship with Jim Vaughn at the City of Hope, where they had developed an antibody to GAD, and, as I mentioned earlier, Chuck and I later collaborated on showing that the input from the chandelier cells to the axon-initial segments of pyramidal cells in cortex is inhibitory.

The autoradiographic study sparked our interest in trying to determine which types of cortical neurons are postsynaptic to the thalamic axon terminals. Consequently, using the only appropriate method available at that time, Martin Feldman and I made lesions in the lateral geniculate nucleus of the rat, and after a suitable time had elapsed, we carried out a series of EM studies to determine where the thalamic terminals, now degenerating, form their synapses. We found the axon terminals form asymmetric synapses, most of which are with dendritic spines, although a small percentage of thalamic terminals synapse with dendritic shafts and with neuronal perikarya (Peters and Feldman, 1976). By reconstructing the postsynaptic dendrites using serial thin sections, we were able to show that the latter two postsynaptic sites belong to nonpyramidal cells (Peters et al., 1976), and when we subsequently reconstructed the dendrites that receive thalamic inputs on their spines, it became apparent that various kinds of neurons with spinous dendrites can receive thalamic afferents (Peters and Feldman, 1977). This led us to postulate that the geniculate afferents to layer IV and lower layer III of visual cortex terminate on any neuronal entity capable of forming asymmetric synapses. This postulate was strengthened by the results we obtained using our newly developed Golgi-EM gold toning technique to examine Golgi-impregnated neurons in the visual cortices of rats whose lateral geniculate nuclei had been lesioned (Peters et al., 1979).

Consequently, we came to the conclusion that the thalamic afferents to cortex do not synapse with specific types of neurons but synapse with any neuronal component in layer IV and lower layer III capable of forming asymmetric synapses. More information about this postulate can be found in the book Cortical Circuits, written by Ed White (1989), who found similar results in his combined degeneration–Golgi-EM studies on the thalamic projections to the barrel field of the mouse. Ed wrote this very useful book after leaving Boston University to take the chair of anatomy position at Ben Gurion University of the Negev at Beer Sheva, Israel. After he left, I acquired Ed White's electron microscope, and I am still using it. However, I have used only once the 70-mm camera that Ed had installed to take the numerous electron micrographs of serial thin sections he generated to produce the balsa wood models of dendrites that hung from the ceiling of his laboratory and were constructed to examine the thalamic input to mouse barrel field.

Essentially, these studies on the thalamic input to cerebral cortex had come to an end by the 1980s, but my interest was revived as a result of conversations I had with Bertram Payne. These conversations led us to analyze what we know about the geniculate input to cat primary visual cortex. Bert had a life-long interest in cat visual cortex and was interested in the results that Engin Yilmaz, who was a postdoctoral fellow from Turkey, had recently obtained on the organization of neurons in cat visual cortex. Engin and I had shown that the neurons in this cortex are organized into modules that are centered on pyramidal cells. On average, these pyramidal modules are 56 microns in diameter (Peters and Yilmaz, 1993), and Bert Payne and I began to consider how many geniculate afferents each module might receive. We soon realized a great deal of quantitative data had been published on these geniculocortical afferents, so we set about to correlate and analyze this data (Peters and Payne, 1993). The analysis turned out to be very interesting. I will not give the results in detail, but it emerged that there is an enormous convergence of thalamic input onto individual pyramidal cell modules, and that individual spiny stellate cells in layer IV each receive 100–125 synapses from the geniculocortical afferents. This accounts for only about 5% of the total excitatory inputs these cells receive. Correlated with this conclusion are two other interesting facts. One is that Rodney Douglas and Kevan Martin (1991) had previously calculated that at least 100 active synapses are necessary to generate an output discharge from spiny stellate cells. The other is that most of the earlier studies using degeneration had shown that 3 to 4 days after making lesions of the lateral geniculate body only about 5% of the terminals in visual cortex degenerate. Because the thalamus dominates the functioning of the cortex, it was generally thought that this number must be far too low. It was thought that the small percentage must be due to the fact that all of the thalamic axon terminals do not degenerate simultaneously, so that at any one time only a small percentage of them show signs of degeneration. This explanation was generally accepted even though the peak of degeneration is at about 3 to 4 days postlesion, and most of the terminals have disappeared by 5 days.

Subsequently, Bert Payne and I, along with Julian Budd from the University of Sussex, also analyzed the published data on the geniculocortical input to layer IVC of monkey striate cortex (Peters, Payne, and Budd, 1994). The data showed that the input to a given layer IVG neuron is derived from about 24 overlapping axonal plexuses and that only 1.3–1.9% of the excitatory input to layer IV cells is provided by the magnocellular layers of the lateral geniculate nucleus (LGN), and 3.7–8.7% from the parvicellular layers. Again, there is the question about whether these low values are correct. They seem to be consistent with most findings, although Ed White and his colleagues have reported that in the barrel field of the mouse cortex as many as 20% of the asymmetric synapses are from the thalamus.

Other Work Carried Out with Bertram Payne

I looked forward to the many discussions that Bert and I had about the structure and functioning of cerebral cortex, because he had a very good analytical mind and a tremendous background knowledge of visual cortex and its connections. However, despite much talk, we only really worked together on two experimental projects. One project we did together was on the transcallosal projections from cat visual cortex (Peters, Payne, and Josephson, 1990). A graduate student in my laboratory, Candice Hughes, had recently shown that after injection of horseradish peroxidase (HRP) into the 17/18a border in rat cerebral cortex, some of the neurons labeled in the contralateral cortex were nonpyramidal cells (Hughes and Peters, 1990), and Bert wondered if some nonpyramidal cells in cat visual cortex had similar callosal projections, because it had been shown that in cat, callosal projections can either excite or inhibit neurons in the opposite hemisphere. Consequently, we did a similar experiment in cats, making injections of HRP at the area 17/18 border. As in the rat, we did find labeled, callosally projecting nonpyramidal cells in the cat and concluded that as many as 10–32% of the nonpyramidal cell population at the area 17/18 border may have callosal projections. We sought to pursue this result by planning further experiments, which we presented in a grant application. Unfortunately, the reviewers knew that only pyramidal cells have axons that project across the corpus callosum, so we were not able to continue these studies, although others have since confirmed that some nonpyramidal cells do project callosally.

The other experimental project Bert and I undertook was on the distribution of cytochrome oxidase patches and Meynert cells in monkey visual cortex (Payne and Peters, 1989). We were able to show that the Meynert cells predominantly lie beneath the spaces between the cytochrome oxidase patches in layer II/III. On the basis of the functional connections of neurons in area 17, we suggested that this arrangement indicates that the Meynert cells are involved in the detection of movement in the visual field.

The last combined endeavor that Bert and I undertook was to edit a book on cat primary visual cortex (Payne and Peters, 2002), which was supposed to be one of the books in the cerebral cortex series. Bert and I wrote an extensive introductory chapter for the book, making the case that primary visual cortex in the cat consists of both area 17 and area 18. Bert did most of the writing for the chapter, and I think that both the chapter and the book are useful references, but, unfortunately, the book did not sell many copies because the publishers made the price of the volume prohibitive.

Unfortunately, shortly after the book on cat visual cortex was published, Bert became ill and died prematurely in May of 2004, at a time when his work on the reorganization of cortex after lesioning was reaching its peak.

Pyramidal Cell Modules

Another long-term interest of mine has been in the organization of pyramidal cells in cerebral cortex into modules. I had been searching for some columnar organization in the cerebral cortex since reading the early account of the cortical neurons and their connections by Lorente de Nó (1938), who suggested that cortical neurons are interconnected to form vertical columns. This concept was reinforced by Vernon Mountcastle's (1957) demonstration that in cat S1 cortex, neurons are organized into microcolumns, such that if an electrode is passed vertically through the cortex, successive neurons along the path are excited by the same stimulus to the body surface.

After searching for some vertical organization in cerebral cortex, in 1972 Terry Walsh, who had recently joined the department as a faculty member, and I noticed that in semithick tangential sections through layer 4 in area 3 of plastic embedded rat cerebral cortex, the ascending apical dendrites of layer 5 pyramidal cells are arranged into groups, or clusters, spaced about 50 microns apart, and that as these apical dendrites ascend through layer 3, the apical dendrites of the layer 3 pyramidal cells are added to the clusters (Peters and Walsh, 1972). We suggested that the clusters of apical dendrites are the centers of modules of pyramidal cells and that these modules might be the morphological equivalents of the microcolumns that Vernon Mountcastle (1957) had proposed to be the basic functional neuronal units of cerebral cortex. Independently, and almost simultaneously, Fleischhauer and colleagues had found similar clustering of apical dendrites in the rabbit and cat (Fleischhauer et al., 1972), and so it appeared likely that organization of pyramidal cells into modules might be a common feature of neocortex.

To investigate how these pyramidal cell modules might form, Martin Feldman and I undertook a study of the development of rat cerebral cortex using both Golgi-impregnated material and electron microscopy. We found that in tangential sections the radial glial cells of the developing cortex are surrounded by clusters of apical processes belonging to migrating neurons, and we concluded that the pyramidal cell modules in the mature brain are derived from the neuroblasts that migrate along individual radial glial fibers (Peters and Feldman, 1973). This is in line with the results of the studies made by Pasco Rakic on the migration of neuroblasts along radial glial fibers in monkey cerebral cortex (e.g., Rakic, 1990) and would imply that the radial glial fibers should be at the center, or form the axis of, the pyramidal cell module. However, over the years, the mechanism of how the pyramidal cell modules are formed has continued to nag at me. Because the cortex is formed inside out, the layer 5 pyramids are formed before the layer 3 pyramids, and if these neurons use the same radial glial fibers to migrate through the cortex, it would seem that migrating and ascending processes of the layer 3 pyramidal cells would push the processes of the layer 5 neurons away from the radial glial fibers so they could have access to them. Consequently, in the pyramidal-cell modules of the mature cortex, the apical dendrites of the layer 3 pyramids would be in the middle of a cluster, and those of the layer 5 pyramids would be on the outside of a cluster. But the reverse is true (Peters and Kara, 1987), and in a later study of development using tangential sections through the developing cortex of rats, I was able to show that the profiles of the radial glial fibers are not at the centers but at the peripheries of the clusters. I presented this proposition at a symposium held in Edinburgh in 1991 to mark the retirement of Mike Gaze, who first introduced me to Xenopus tadpoles and to their optic nerves (Peters, 1993).

Marty Feldman and I continued our studies on the organization of pyramidal cells by showing that dendritic clusters are present in the cortices of rats, cats, monkeys, and humans, suggesting that they are a general feature of mammalian neocortex (Feldman and Peters, 1974). We also looked ardently for structures resembling “barrels” in cortices other than rat and mouse somatosensory cortex, but after we had hallucinated many times, we had to conclude that barrels are not a common feature of neocortex.

In the early studies, the only way to examine how pyramidal cells are organized into modules was through reconstruction using serial, 1-or 2-micron thick sections of plastic embedded tissue, as we had done in rat visual cortex (Peters and Kara, 1987). This is obviously a very tedious process and did not encourage us to extend our studies of pyramidal cell modules into the cortices of other animals. However, toward the end of 1980, a number of investigators had shown that antibodies to microtubule associated protein 2 (MAP2) label the cell bodies and dendrites of neurons. Ken Kosik in the Department of Neurology at Harvard Medical School was kind enough to supply us with antibody to MAP2, and so Claire Folger, and I set about to examine the organization of pyramidal cells in primary visual cortex of the monkey (Peters and Sethares, 1991). This antibody clearly shows the cell bodies of neurons and the clustering of the apical dendrites of the pyramidal cells in monkey visual cortex, so that we were able to generate a three-dimensional model of the pyramidal-cell modules in this cortex, for which Claire used her artistic talents to produce a nice diagram. These also showed that the apical dendrites of the pyramidal cells of layer 6A do not contribute to the clusters but form bundles that ascend only as far as layer 4C. The other feature of this cortex that became obvious through use of the MAP2 antibody is that the cell bodies of the neurons of layer 4A are arranged into cones, which fit into the pockets, or holes, in the honeycomb pattern of cytochrome oxidase staining in layer 4A. I will not give more details, because they can be found in the publication (Peters and Sethares, 1992). We were very pleased by the results we obtained with the MAP2 antibody, and this encouraged us to examine the pyramidal-cell modules in cat visual cortex (Peters and Yilmaz, 1993), the mouse barrel field (White and Peters, 1993), and in area 18 of rhesus monkey cortex (Peters et al., 1997). It became evident that although there are variations in the patterns, the organization of the pyramidal cells into modules is a common feature of the neocortices of a variety of mammals (Peters, 1997).

I was able to present what was known about the organization of neurons in cerebral cortex into modules as part of a symposium that I arranged at the 106th meeting of the American Association of Anatomists (AAA) in San Diego when I was President of the organization in 1993. I was fortunate enough to persuade Vivian Casagrande, Ted Jones, and Francis Crick to make presentations at the symposium, which was well-received by the members of the association and led to a long discussion that went on well beyond the time allotted to it. Unfortunately, the presentations made at that symposium were never published. The symposium was toward the end of my term as president of the AAA, and for me the symposium was one of the highlights of my tenure. But looking back at that year, it seemed that I was kept quite busy because there were many decisions to make. However, there seemed to be little time to complete anything satisfactorily, and my frustration with that situation led me to propose that the term of president of the AAA should be for 2 years and not 1 year. But to achieve this, it was necessary to rewrite the constitution of the AAA. Luckily, there was little opposition to the changes I proposed, and, in retrospect, there is no doubt in my mind that changing the constitution was my most significant accomplishment during my tenure as president of the AAA.

Getting back to cerebral cortex—another question that arose as we investigated the cortex is whether any of the nonpyramidal cells contribute to the modular pattern of organization. By using various stains and antibodies to label different types of nonpyramidal cells, it became evident that in monkey primary visual cortex, at least, the only nonpyramidal cells that repeat regularly are the double-bouquet cells, whose axons are aptly described as resembling horse tails. Antibodies to calbindin show these cells and their horse-tailed axons rather nicely, and so we were able to show that there is one horse-tailed axon per module (Peters and Sethares, 1997). However, the role that these double-bouquet cells play is still not clear, and it can only be supposed that they provide some form of vertical inhibition. It is interesting that these double-bouquet cells rarely appear in Golgi preparations and little was known about their morphology until antibodies became available.

If one looks at myelin-stained sections of most cortical areas, especially those of the primary visual cortex, well-defined, vertical bundles of myelinated nerve fibers can be seen passing through the cortex, and, in tangential sections, it is evident that, like the clusters of apical dendrites of pyramidal cells, these vertical bundles of nerve fibers are arranged in a regularly spaced pattern. Moreover the center-to-center spacing of the vertical bundles of myelinated axons is similar to that of the clusters of apical dendrites that define the axes of the modules, and the obvious question to ask is: How are they related? It turns out, of course, that many of the nerve fibers in the vertical bundles arise from the pyramidal cells and, consequently, we proposed that each pyramidal cell module has its own output bundle of nerve fibers (Peters and Sethares, 1996). The basic concept that we proposed is that each pyramidal cell module has a unique set of inputs and response properties, which are slightly different from those of the modules surrounding it. This being so, nerve fibers originating in that module carry a unique set of efferent information, which is passed on to other cortical areas.

Unfortunately, although it is generally recognized that there are pyramidal cell modules in cerebral cortex, the level of interest in these morphological modules is relatively low. I hope that more neuroscientists will eventually pay attention to them, because I believe that they are the fundamental functional units of cerebral cortex and that the pyramidal cell modules are synonymous with the microcolumns defined by Vernon Mountcastle.

Studies on Normal Aging

In 1972 I became involved in studies of changes that the normal brain undergoes as it ages, and in recent years these studies have been the focus of my research effort. I initially became involved in this research through my contact with Marott Sinex, who at that time was the chairman of the Department of Biochemistry at Boston University.

Marott had been very influential in setting up the National Institute on Aging, and he had been encouraged by the new institute to submit a program project grant to them, which he did. The outcome was that this was the first program project funded by the institute. At that time there were few scientists interested in the effects of normal aging, and so the program lacked focus. For example, it covered such topics as the effects of aging on the olfactory and auditory systems and cerebral cortex, effects on connective tissue, and the effects of age on chromatin and RNA. Then in 1979, when Marott stepped aside, I became the Principal Investigator and decided to focus the program more on the effects of aging on the nervous system. At that time we were using rats, and it became increasingly apparent that under laboratory conditions rats became grossly overweight and died at a younger age than normal. Also there are few tests that can be done to assess the effects of age on the cognitive status of rats, and so it seemed to us that rats did not provide the best model for normal aging.

Serendipitously, at about the time we were becoming concerned with the value of the rat model for normal aging, I met an old acquaintance, Dr. Johannes Tigges, at a scientific meeting and discovered that Yerkes Regional Primate Research Center at Emory University had a number of aging rhesus monkeys. The primate center was willing to cooperate with us, and so in 1984 we changed our animal model of aging to the rhesus monkey, which closely resembles the human and is capable of responding to a variety of behavioral tests that can be used to establish cognitive status. Moreover, although rhesus monkeys can develop senile plaques in their brains, they do not acquire neurofibrillary tangles and do not get Alzheimer's disease, making them an excellent model for normal aging studies. In the realm of human aging, much of the emphasis is on Alzheimer's disease, which is certainly devastating for both the patient and their families, but it should be borne in mind that the majority of humans age normally, and yet we know almost nothing about what changes are taking place in their brains. For me, this is what makes the study of the effects of normal aging on the primate brain so exciting, because almost every study of normal primate brain aging enters virgin territory. It is one of the few fields of neuroscience research where one can still make fundamental and new discoveries. The effects of aging on the brain are so intriguing that for the past several years, essentially since I resigned from the chair of anatomy in 1998, I have devoted most of my time to this area of research and hope that I can continue to do so for several more years.

When we began our studies of the effects of aging on the brains of rhesus monkeys, very little was known about their longevity and so the first task was to determine the life span. This was done by examining the animal records kept at Yerkes, and it turned out that the maximum life span is about 35 years (Tigges et al., 1988), so that each monkey year is equivalent to about 3 human years.

With this change in species, Drs. Douglas Rosene and Mark Moss, who had worked with monkeys previously, undertook the behavioral testing to assess the cognitive status of the monkeys we were using, and Tom Kemper, who has a profound knowledge of neuropathology, also joined the program so that we could relate our findings on the monkey to what happens in the aging human brain. In these initial studies of normal aging in rhesus monkeys I, along with Johannes Tigges, started to examine cerebral cortex; Dr. Deborah Vaughan began to study the spinal cord; and Drs. Marty Feldman and Mike Harrison focused on the auditory system.

When this program started, it was assumed that normal cognitive decline was due to a loss of cortical neurons. Hence, the expression “He, or she, is losing his/her neurons” when someone is forgetful, but as we learned more about the effects of aging on the monkey cortex, it became apparent that there is not a significant overall loss of cortical neurons with age, and I think that the concept that cognitive decline is not due to extensive neuronal loss from cerebral cortex is now generally accepted (Peters et al., 1998; Peters and Rosene, 2003). However, it must be stated that few cortical areas other than motor cortex (Tigges, Herndon, and Peters, 1990), primary visual cortex (Vincent, Peters, and Tigges, 1989; Peters and Sethares, 1993), and area 46 of prefrontal cortex (Peters et al., 1994) of primates have been thoroughly examined, and so some surprises might yet be in store as other cortical areas are scrutinized.

Morphologically, the cells that show the greatest effects of aging are the neuroglial cells, and if one wants to determine whether a given section of cortex is from an old monkey, it is best to look at the neuroglial cells and not the neurons, because, with age, neuroglial cells become filled with inclusions (Peters et al., 1991). The origins of most of phagocytosed material in the astrocytes and the microglial cells is not yet known, but it is evident that some of the material is derived from myelin sheaths, which break down during aging and even degenerate, especially if the axon degenerates.

Our first indication of myelin degeneration was when Marty Feldman and I encountered large, round, fluid-filled profiles in gray and white matter of old monkeys. It turned out that these profiles were due to ballooning of some myelin sheaths (Feldman and Peters, 1998), and as we looked more closely at nerve fibers in the electron microscope, it became evident that other aging myelin sheaths accumulate dense cytoplasm in pockets between their lamellae (Peters et al., 2000; Peters, 2002c). However, despite these degenerative changes, myelin continues to be produced with age, so that there is an increase in the numbers of myelin sheaths that have redundant myelin, producing sheaths that are much too large for the enclosed axon, as well as an overall increase in the thickness of myelin sheaths, which is partly due to an increase in the frequency of unusually thick myelin sheaths (Peters et al., 2001). But the situation becomes even more complicated, because looking at electron micrographs of myelinated nerve fibers in areas 17 and 46, Claire Folger and I noticed that there is an increase in the frequency of profiles of paranodes with age (Peters and Sethares, 2003). This occurs even though there is not a significant increase in the lengths of paranodes, which occur at the two ends of lengths of myelin and are the sites where the myelin lamellae terminate adjacent to the nodes of Ranvier. We concluded that the increase in the frequency of paranodes could only occur if the numbers of internodal lengths of myelin increase with age. This would happen if there were remyelination taking place, such that some of the original internodal lengths of myelin degenerate to be replaced by shorter lengths of myelin. We then went on to look for evidence of remyelination in old monkeys and found some short internodal lengths of myelin and inappropriate thin myelin sheaths, both of which are considered to be the hallmarks of remyelination.

Interestingly, this apparent increase in the number of myelin internodes is correlated with an increase in the number of oligodendroglial cells in cerebral cortex (Peters and Sethares, 2004), and the question is: Where do these new oligodendroglial cells come from? Others, for example, Dr. Joel Levine at Stony Brook, have proposed that these new oligodendroglial cells arise from oligodendroglial cell progenitors in the brain and that these progenitors label with an NG2 chondroitin proteoglycan antibody (e.g., Levine et al., 2001). Joel Levine was kind enough to supply us with some of this antibody, and when we examined the labeled cells in the electron microscope, it turned out that they had some features in common with astrocytes. In fact these cells had been described several years ago by Reyners et al. (1982), who called them β astrocytes. However, it turns out that these cells are not astrocytes but a fourth type of neuroglial cell that has been largely overlooked by electron microscopists because of their similarity to astrocytes (Peters, 2004). How wonderful after all of these years of looking at thin sections to encounter a cell that has been overlooked.

We now know that the galaxy of myelin changes that occur in the cortex are also present in white matter. Moreover, Julie Sandell and I have found that not only is myelin disrupted but that there is also a significant loss of nerve fibers with age from white matter. We have shown such a loss of nerve fibers from the optic nerve (Sandell and Peters, 2001), anterior commissure, (Sandell and Peters, 2003), and the corpus callosum. As is well known, the nerve fibers in the anterior commissure and the corpus callosum belong to neurons in cerebral cortex, and yet there is no significant overall loss of these neurons. This leads to the conclusion that some of the cortical neurons lose their long projecting axonal branches, although their cell bodies and dendrites remain intact. Their profuse local axonal plexuses are probably sustaining these neurons. This may not be too surprising, because the local plexuses have more axon terminals than the projection branches, because some 95% of the axon terminals forming synapses in the cortex originate from these local axonal plexuses (Peters, 2002b).

So what effects do these age changes in nerve fibers have on the aging brain? The proposition is that loss of nerve fibers from white matter leads to decrease in connectivity between parts of the brain, resulting in what clinicians refer to as a disconnection syndrome. Concomitantly, degenerative changes in myelin, as well as the increase in the frequency of internodal lengths of myelin brought about by remyelination, lead to a decrease in the speed of conduction along nerve fibers, which in turn results in alterations in the timing in neuronal circuits. The consequence of this may be the phenomenon experienced by almost every old person, the inability to instantly remember names. However, old people do not forget; it just takes longer to recall, which may be because the timing in a neuronal circuit must be just right, to mimic the timing when the memory was consolidated.

Finis

This seems like an appropriate theme upon which to end this account. It has been good to recall events in my scientific life, some events that I had not thought about for years, with memories gradually coming back to me as I have undertaken the writing. I am sure that there are events that I have not been able to recall, but hopefully, nothing of great import. I have certainly enjoyed my scientific life, and as I have often said to students, we are very fortunate that we are paid to do what we enjoy mostscientific research. In my case I have also been very fortunate in other ways, especially in my marriage of almost 50 years to my wife Verona. She has provided a very stable and loving environment for myself and our three daughters, has always supported me in my career moves, taken care of the social side of our lives, and has always been uncomplainingly willing to move from place to place as my career progressed.

Selected Bibliography

Cipolloni PB, Peters A. The termination of callosal fibers in the auditory cortex of the rat. A combined Golgi-electron microscope and degeneration study. J Neurocytol 1983;12:713–726.

Connor JR, Peters A. Vasoactive intestinal polypeptide-immunoreactive neurons in rat visual cortex. Neuroscience 1984;12:1027–1044.

Fairén A, Peters A, Saldanha J. A new procedure for examining Golgi impregnated neurons by light and electron microscopy. J Neurocytol 1977;6:311–377.

Famiglietti EV, Peters A. The synaptic glomerulus and the intrinsic neuron in the dorsal lateral geniculate nucleus of the cat. J Comp Neurol 1972;144:285–334.

Feldman M, Peters A. A study of barrels and pyramidal dendritic clusters in the cerebral cortex. Brain Res 1974;77:55–76.

Feldman ML, Peters A. The forms of non-pyramidal neurons in the visual cortex of the rat. J Comp Neurol 1978;179:761–794.

Feldman ML, Peters A. Ballooning of myelin sheaths in normally aged macaques. J Neurocytol 1998;27:605–614.

Harris JE, Peters A. Experiments on vital staining with methylene blue. Q J Micr Sci 1953;94:113–124.

Heimer L, Peters A. An electron microscope study of a silver stain for degenerating boutons. Brain Res 1968;8:337–346.

Hughes CM, Peters A. Morphological evidence for callosally projecting nonpyramidal neurons in rat visual cortex. Anat Embryol 1990;182:591–603.

Hughes CM, Peters A. Types of callosally projecting nonpyramidal neurons in rat visual cortex identified by lysosomal HRP retrograde labeling. Anat Embryol 1992;186:183–193.

Kaiserman-Abramof IR, Peters A. Some aspects of the morphology of Betz cells in the cerebral cortex of the cat. Brain Res 1972;43:527–546.

Miller M, Peters A. Maturation of rat visual cortex: II A combined Golgi-electron microscopic study of pyramidal neurons. J Comp Neurol 1981;203:555–573.

Muir AR, Peters A. Quintuple-layered membrane junctions at terminal bars between endothelial cells. J Cell Biol 1962;12:443–448.

Palay SL, Sotelo C, Peters A, Orkand PM. The axon hillock and the initial segment. J Cell Biol 1968;38:193–201.

Payne BR, Peters A. Cytochrome oxidase patches and Meynert cells in monkey visual cortex. Neuroscience 1989;28:353–363.

Payne BR, Peters A. The concept of cat primary visual cortex. In Payne BR, Peters A, eds. The cat primary visual cortex. San Diego: Academic Press, 2002;1–130.

Peters A. Silver impregnation of nerve fibres. Nature 1953;171:613.

Peters A. A general purpose method of silver staining. Q J Micr Sci 1955;96: 323–328.

Peters A. Experiments on mechanism of silver staining.

a. I. Impregnation. Q J Micr Sci 1955;96:84–102.

b. II. Development. Q J Micr Sci 1955;96:103–155.

c. III. Quantitative studies. Q J Micr Sci 1955;96:301–315.

d. IV Electron microscope studies. Q J Micr Sci 1955;96:317–322.

Peters A. Experimental studies on staining of nervous tissue with silver proteinates. J Anat Lond 1958;93:177–194.

Peters A. The structure of myelin sheaths in the central nervous system of Xenopus Laevis (Daudin). J Biophys Biochem Cytol 1960a;7:121–126.

Peters A. The formation and structure of myelin sheaths in the central nervous system. J Biophys Biochem Cytol 1960b;8:431–446.

Peters A. A radial component of central myelin sheaths. J Biophys Biochem Cytol 1961;11:733–735.

Peters A. The structure of the dorsal root nerves of Amphioxus. An E.M. study. J Comp Neurol 1963a;121:287–304.

Peters A. The peripheral nervous system. In Brodal A, Range R, eds. Biology of myxine. Oslo: Universitetsforlaget, 1963b;92–123.

Peters A. Further observation on the structure of myelin sheaths in the central nervous system. J Cell Biol 1964a;20:281–296.

Peters A. Observations on the connexions between myelin sheaths and glial cells in the optic nerves of young rats. J Anat London 1964b;98:125–134.

Peters A. The node of Ranvier in the central nervous system. Q J Exp Physiol 1966;51:229–236.

Peters A. The surface fine structure of the choroid plexus and ependymal lining of the rat lateral ventricle. J Neurocytol 1974;3:99–108.

Peters A. Pyramidal cell modules in rat visual cortex: Their structure and development. In Sharma SC, Faweett JW, eds. Formation and regeneration of nerve connections, Boston: Birkhauser Inc., 1993;102–120.

Peters A. Pyramidal cell modules in cerebral cortex. In Delfino A, Motta PM, eds. Recent advances in microscopy of cells, tissues and organs. Rome: Antonio Delfino Editore 1997;187–192.

Peters A. Structural changes in the normally aging cortex of primates. In Changing views of Cajal's neuron. Progr Brain Res 136, 2002a;455–466.

Peters A. Examining neocortical circuits: some background and facts. J Neurocytol 2002b;31:183–193.

Peters A. The effects of normal aging on myelin and nerve fibers: A review. J Neurocytol 2002c;31:581–193.

Peters A. A fourth type of neuroglial cell in the adult central nervous system. J. Neurocytol 2004;33:345–357.

Peters A, Cifuentes JM, Sethares C. The organization of pyramidal cells in area 18 of the rhesus monkey. Cerebral Cortex 1997;7:405–421.

Peters A, Fairén A. Smooth and sparsely-spined stellate cells in the visual cortex of the rat: A study using a combined Golgi-electron microscope technique. J Comp Neurol 1978;181:129–172.

Peters A, Feldman M. The cortical plate and molecular layer of the late rat fetus. Z Anat Entwickl-Gesch 1973;141:3–37.

Peters A, Feldman ML. The projection of the lateral geniculate nucleus to area 17 of the rat cerebral cortex. I. General description. J Neurocytol 1976;5:63–84.

Peters A, Feldman ML. The projection of the lateral geniculate nucleus to area 17 of the rat cerebral cortex. IV. Terminations upon spiny dendrites. J Neurocytol 1977;6:669–689.

Peters A, Feldman ML, Saldanha J. The projection of the lateral geniculate nucleus to area 17 of the rat cerebral cortex. II. Terminations upon neuronal perikarya and dendritic shafts. J Neurocytol 1976;5:85–107.

Peters A, Feldman ML, Vaughan DW. The effect of aging on the neuronal population within area 17 of adult rat cerebral cortex. Neurobiol Aging 1983;4:273–282.

Peters A, Harriman KM. Enigmatic bipolar cell of rat visual cortex. J Comp Neurol 1988;267:409–432.

Peters A, Josephson K, Vincent SL. Effects of aging on the neuroglial cells and pericytes within area 17 of the rhesus monkey. Anat Rec 1991;229:384–398.

Peters A, Kaiserman-Abramof IR. The small pyramidal neuron of the rat cerebral cortex. The synapses upon dendritic spines. Z Zellforsch 1968;100:487–506.

Peters A, Kaiserman-Abramof IR. The small pyramidal neuron of the rat cerebral cortex. The perikaryon, dendrites and spines. Am J Anat 1970;127:321–356.

Peters A, Kara DA, Harriman KM. The neuronal composition of area 17 of rat visual cortex. III. Numerical considerations. J Comp Neurol 1985;238:263–274.

Peters A, Kara DA. The neuronal composition of area 17 of rat visual cortex. I. The pyramidal cells. J Comp Neurol 1985;234:218–241.

Peters A, Kara DA. The neuronal composition of area 17 of rat visual cortex. II. The pyramidal cells. J Comp Neurol 1985;234:242–263.

Peters A, Kara DA. The neuronal composition of area 17 of rat visual cortex. IV. The organization of pyramidal cells. J Comp Neurol 1987;260:573–590.

Peters A, Kimerer L. Bipolar neurons in rat visual cortex: A combined Golgielectron microscopic study. J Neurocytol 1981;10:921–946.

Peters A, Leahu D, Moss MB, McNally KJ. The effects of aging on area 46 of the frontal cortex of the rhesus monkey. Cerebr Cortex 1994;6:621–635.

Peters A, Miller M, Kimerer LM. Cholecystokinin-like immunoreactive neurons in rat cerebral cortex. Neuroscience 1983;8:431–448.

Peters A, Morrison JH, Rosene DL, Hyman BT. Are neurons lost from the primate cerebral cortex during normal aging? Cerebr Cortex 1998;8:295–300.

Peters A, Moss MB, Sethares C. Effects of aging on myelinated nerve fibers in monkey primary visual cortex. J Comp Neurol 2000;419:364–376.

Peters A, Muir AR. The relationship between axons and Schwann cells during development of peripheral nerves in the rat. Q J Exp Physiol 1958;44:117–130.

Peters A, Palay SL. The morphology of laminae A and A1 of the dorsal nucleus of the lateral geniculate body of the cat. J Anat 1966;100:451–486.

Peters A, Palay SL. The morphology of synapses. J. Neurocytol 1996;25:687–700.

Peters A, Palay SL, Webster H deFThe fine structure of the nervous system. Neurons and their supporting cells, 3rd ed. Oxford University Press 1991.

Peters A, Payne BR. Numerical relationships between geniculocortical afferents and pyramidal cell modulus in cat primary visual cortex. Cerebral Cortex 1993;3: 69–78.

Peters A, Payne BP, Budd J. A numerical analysis of the geniculocortical input to striate cortex in the monkey. Cerebral Cortex 1994;4:215–229.

Peters A, Payne BR, Josephson K. Transcallosal non-pyramidal cell projections from visual cortex in the cat. J Comp Neurol 1990;302:124–142.

Peters A, Proskauer CC. Smooth or sparsely spined cells with myelinated axons in rat visula cortex. Neuroscience 1980a;5:2079–2092.

Peters A, Proskauer CC. Synaptic relationships between a multipolar stellate cell and a pyramidal neuron in the rat visual cortex. A combined Golgi-electron microscope study. J Neurocytol 1980b;9:163–183.

Peters A, Proskauer CC, Feldman ML, Kimerer L. The projection of the lateral geniculate nucleus to area 17 of the rat cerebral cortex. V. Degenerating axon terminals synapsing with Golgi impregnated neurons. J Neurocytol 1979;8: 331–357.

Peters A, Proskauer CC, Kaiserman-Abramof IR. The small pyramidal neuron of the rat cerebral cortex. The axon hillock and initial segment J Cell Biol 1968;39:604–619.

Peters A, Proskauer CC, Ribak CE. Chandelier cells in rat visual cortex. J Comp Neurol 1982;206:397–416.

Peters A, Rosene DL. In aging, is it gray or white? J Comp Neurol 2003;462: 139–143.

Peters A, Saldanha J. The projection of the lateral geniculate nucleus to area 17 of the rat cerebral cortex. III. Layer VI. Brain Res 1976;105:533–537.

Peters A, Sethares C. Organization of pyramidal neurons in area 17 of monkey visual cortex. J Comp Neurol 1991;306:1–23.

Peters A, Sethares C. Layer IVA of rhesus monkey primary visual cortex. Cerebral Cortex 1992;1:445–462.

Peters A, Sethares C. Aging and the Meynert cells in rhesus monkey primary visual cortex. Anat Rec 1993;236:721–729.

Peters A, Sethares C. Myelinated axons and the pyramidal cell modules in monkey primary visual cortex. J Comp Neurol 1996;365:232–255.

Peters A, Sethares C. The organization of double bouquet cells in monkey striate cortex. J. Neurocytol 1997;26:779–797.

Peters A, Sethares C. Aging and myelinated nerve fibers in prefrontal cortex and corpus callosum of the monkey. J Comp Neurol 2002;442:277–291.

Peters A, Sethares C. Is there remyelination during aging of the primate central nervous system? J Comp Neurol 2003;460:238–254.

Peters A, Sethares C. Oligodendrocytes, their progenitors and other neuroglial cells in the aging primate cerebral cortex. cerebral cortex 2004;14:995–1007.

Peters A, Sethares C, Killiany RJ. The effect of age on the thickness of myelin sheaths in monkey primary visual cortex. J Comp Neurol 2001;435:241–248.

Peters A, Vaughan DW. The central nervous system. In Johnson JE, ed. Aging and cell structure, New York: Plenum 1981;1–34.

Peters A, Vaughn JE. Morphology and development of the myelin sheath. In Peters A, Davison AN, Thomas cc, eds. Myelination. New York: 1970;3–79.

Peters A, Walsh MT. A study of the organization of apical dendrites in the somatic sensory cortex of the rat. J Comp Neurol 1972;144:253–268.

Peters A, White EL, Fairén A. Synapses between identified neuronal elements. An electron microscopic demonstration of degenerating axon terminals synapsing with Golgi impregnated neurons. Neurosci Lett 1977;6:171–175.

Peters A, Yilmaz E. Neuronal organization in area 17 of cat visual cortex. Cerebr Cortex 1993;3:49–68.

Ribak CE, Peters A. An autoradiographic study of the projections from the lateral geniculate body of the rat. Brain Res 1975;92:341–368.

Saint-Marie RL, Peters A. The morphology and synaptic connections of spiny stellate neurons in monkey visual cortex (area 17). A Golgi-electron microscopic study. J Comp Neurol 1985;233:213–235.

Sandell JH, Peters A. Effects of age on nerve fibers in the rhesus monkey optic nerve. J Comp Neurol 2001;429:541–553.

Sandell JH, Peters A. Disrupted myelin and axon loss in the anterior commissure of the aged rhesus monkey. J Comp Neurol 2003;466:14–30.

Tigges J, Gordon TP, McClure HM, Hall EC, Peters A. Survival rate and lifespan of rhesus monkeys at the Yerkes Regional Primate Research Center. Am J Primatol 988;15:263–273.

Tigges J, Herndon JG, Peters A. Neuronal population of area 4 during the life-span of the rhesus monkey. Neurobiol Aging 1990;11:201–208.

Tigges J, Herndon JG, Peters A. Axon terminals on Betz cell somata of area 4 in rhesus monkey throughout adulthood. Anat Rec 1992;232:305–315.

Vaughan DW, Peters A. A three dimensional study of layer 1 of the rat parietal cortex. J Comp Neurol 1973;149:355–370.

Vaughan DW, Peters A. Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: An electron microscope study. J Neurocytol 1974;3: 405–429.

Vaughn JE, Peters A. Electron microscopy of the early postnatal development of fibrous astrocytes. Am J Anat 1967;121:131–152.

Vaughn JE, Peters A A third neuroglial cell type. An electron microscopic study. J Comp Neurol 1968;133:269–288.

Vaughn JE, Peters A The morphology and development of neuroglial cells. In Pease DC, ed. Cellular aspects of neural growth and differentiation. University of California Press, 1971;103–134.

Vincent SL, Peters A, Tigges J. Effects of aging on the neurons within area 17 of rhesus monkey cerebral cortex. Anat Rec 1989;223:329–341.

White EL, Peters A. Cortical modules in the posteromedial barrel subfield (Sm I) of the mouse. J Comp Neurol 1993;334:86–96.

Additional Publications

Blackstad TW. Electron microscopy of Golgi preparations. In Nauta WJ, Ebbesson SOE, eds. Contemporary research methods in neuroanatomy. New York: Springer Verlag, 1970;186–216.

Davison AN, Peters A. Myelination. Springfield, C.C. Thomas, 1970.

De Robertis E, Gerschenfeld HM, Wald FJ. Cellular mechanism of myelination in the central nervous system. Biophys Biochem Cytol 1958;4:651–656.

Douglas RJ, Martin KAC. Opening the grey box. Trends Neurosci 1991;14:286–293.

Fairén A, De Felipe J, Regidor J. Nonpyramidal neurons. General account. In Peters A, Jones EG, eds. Cerebral cortex, vol. 1. New York: Plenum Press 1984;201–253.

Fawcett DWThe cell: Its organelles and inclusions. Philadelphia: Saunders, 1966.

Fleischhauer K, Petschel H, Wittkowski WVertical bundles of dendrites in the neocortex. Z Anat Entwickl-Gesch 1972;136:213–223.

Geren BB. The formation from the Schwann cell surface of myelin in peripheral nerves of chick embryos. Exp Cell Res 1959;7:558–562.

Gray EG. Axo-somatic and axo-dendritic synapses of the cerebral cortex. An electron microscope study. J Anat 1959;93:420–433.

Hess A. The fine structure and morphological organization on non-myelinated nerve fibers. Proc Roy Soc B 1956;144:496–506.

Levine JM, Reynolds R, Fawcett JW. The oligodendrocyte precursor cell in health and disease. Trends Neurosci 2001;24:39–47.

Lorente de N6 R. Cerebral cortex: Architecture, intracortical connections, motor projections. In Fulton JF, ed. Physiology of the nervous system. London: Oxford University Press, 1938;274–301.

Luft JH. Permanganate: A new fixative for electron microscopy. J Biophys Biochem Cytol 1956;2:799–802.

Luse SA. The formation of myelin in the central nervous system of mice and rats, as studied with the electron microscope. J Biophys Biochem Cytol 1956;2:777–784.

Martin KAC. From single cells to simple circuits in the cerebral cortex. Q J Exp Physiol 1988;73:637–702.

Maturana HR. The fine structure of the optic nerve of Anurans—an electron microscope study. J Biophys Biochem Cytol 1960;7:107–120.

Mountcastle VB. Modality and topographic properties of single neurons in cat's somatic sensory cortex. J Neurophysiol 1957;20:408–434.

Palay SL. Synapses in the central nervous system. J. Biophys Biochem Cytol 1956;2(Suppl):193–202.

Palay SL. A memoir in appreciation of Alan Peters on his sixty-fifth birthday. J Comp Neurol 1995;355:2–5.

Palay SL, McGee-Russell SM, Gordon S, Grillo MA. Fixation of neural tissues for electron microscopy by perfusion with solutions of osmium tetroxide. J Cell Biol 1962;12:385–410.

Parnavelas JG, Sullivan K, Lieberman AR, Webster KE. Neurons and their synaptic organization in the visual cortex of the rat. Electron microscopy of Golgi preparations. Cell Tissue Res 1977;183:499–517.

Payne BR, Peters A, eds. The cat primary visual cortex. San Diego: Academic Press, 2002.

Porter KR, Bonneville M. An introduction to the fine structure of cells and tissues. Philadedelphia: Lea and Febiger, 1963.

Rakic P. Principles of neural cell migration. Experientia 1990; 46:882–891.

Reyners H, Gianfelici de Reyners E, Maisin JR. The beta astrocyte: A newly recognized radiosensitive glial cell type in the cerebral cortex. J Neurocytol 1982;11:967–983.

Robertson JD. New observations on the ultrastructure of the membranes of frog peripheral nerve fibers. J Biophys Biochem Cytol 1957;3:1043–1047.

Sabatini DD, Bensch K, Barrnett RJ. Cytochemistry and electron microscopy: The preservation of cellular ultrastructure and enzymatic activity by aldehyde fixation. J Cell Biol 1963;17:19–58.

Somogyi P. A specific axo-axonal neurons in the visual cortex of the rat. Brain Res 1977;136:345–350.

Stell WK. Correlations of retinal cytoarchitecture and ultrastructure in Golgi preparations. Anat Rec 1965;153:389–397.

White EL. Cortical circuits. Synaptic organization of the cerebral cortex. Boston: Birkhauser, 1989.

Martin Raff

BORN:

Montreal, Canada

January 15, 1938

EDUCATION:

McGill University, B.Sc. (1959)

McGill University, M.D.C.M. (1963)

APPOINTMENTS:

Royal Victoria Hospital, Montreal (1963–1965)

Massachusetts General Hospital (1965–1968)

Postdoctoral Fellow in Immunology, National Institute for Medical Research, Mill Hill, London (1968–1971)

MRC Developmental Neurobiology Program, Biology Department, University College London (UCL) (1971–2002)

Professor of Biology, Biology Department, UCL (1979–2002)

Scientist, MRC Lab for Molecular Cell Biology, UCL (2002–)

Emeritus Professor of Biology, Biology Department and MRC Lab for Molecular Cell Biology, UCL (2002–)

HONORS AND AWARDS (SELECTED)

Fellow, Royal Society of London (1985)

Academia Europaea (1988)

Feldberg Prize (1989)

President, British Society of Cell Biology (1991–1995)

British Academy of Medical Sciences (1998)

Foreign Honorary Member, American Academy of Arts and Sciences (1999)

Dunham Lectures, Harvard University (2001)

United Kingdom-Canada Rutherford Lectures (2002)

Hamdan Prize for Apoptosis in Disease and Health (2002)

Foreign Associate, National Academy of Sciences, USA (2003)

Honorary Fellow, University College London (2004)

Kuffler Lectures, UCSD, 2004

Honorary Doctorate, McGill University (2005)

Martin Raff began his scientific career as an immunologist and then brought his interest in the problem of cell identity to developmental neurobiology. He charted the origins of glia and used Schwann cells, precursors of oligodendrocytes, and retinal cells to make major contributions to understanding the regulation of cell size and number, the control of cellular differentiation and maturation, and the role of extrinsic and intrinsic mechanisms in the generation of cell diversity.

Martin Raff

I retired in September 2002 after 34 years as a scientist. I was almost 65, the standard retirement age in Europe. Although I consider my time as a scientist to have been a joy and a privilege, I had been planning my retirement and looking forward to it for more than 10 years. This was mainly because of Michael Heidelberger, an eminent immunochemist whom I had never met. When I was 51, I learned that Heidelberger had a National Institutes of Health (NIH) grant at the age of 101. I quickly calculated that, if I followed in Heidelberger's footsteps, I was not yet even a third of the way through my career. This revelation was so depressing that I promised myself I would stop at 65, which immediately cheered me up.

I am now 67, and retirement has been everything I had hoped it would be. Thanks to my kind colleagues, I have remained a member of the Medical Research Council (MRC) Laboratory for Molecular Cell Biology (LMCB) and an emeritus professor in the Biology Department at University College London (UCL). I do many of the things I did before retirement, but the pressure is off. I no longer run a laboratory or write papers or grants, which means that I can decline to referee papers and grants without guilt—a wonderful liberation. I am still connected to science, because I sit on many scientific advisory boards and am still a coauthor of the cell biology textbook Molecular Biology of the Cell.

Now seems a good time to look back at my research career, before I forget most of it.

Growing Up

Born and educated in Montreal, I got off to an unpromising start in school by failing kindergarten. I kept running away and returning home at recess, which suggested to both the authorities and my parents that I was not ready for school. I started again the following year, and it was relatively smooth sailing from then on.

My father was a physician and my mother a full-time housewife. My brother is my only sibling; because he is exactly 2 years older, we shared birthdays. My childhood was generally happy and unremarkable, but I did have a number of peculiarities that were much more troubling to others than to me. I frequently stole small things from friends or family members, and I lied more often than most children. I hated losing and, as a result, had many temper tantrums. When I was 8, for example, I had a tantrum after losing a foot race. Surprisingly, they allowed me to race again three times against the winner, and this was followed by three more tantrums as I lost each time. I was also unusually fearful and could not stay alone in our house until I was in my teens. My parents, brother, and friends accepted my peculiarities with remarkable calm and good humor, and I gradually grew out of them. Looking back on this period, at what a pain in the behind I must have been, I find it inexplicable that those around me seemed not to notice and treated me with unremitting kindness.

Until my early 20s, sports dominated my life. Football, basketball, ice hockey, skiing, tennis, and sailing occupied much of the time that I was not in class. It was a great advantage having a park a few hundred yards away with a football field, two baseball diamonds, tennis courts, a ski hill, and a hockey rink. It was also advantageous having an older brother with whom I could play sports. He also stimulated me to read books and listen to music, because my parents had little interest in either.

I did well in school, and although I took all of the math and science courses available, I was not a budding scientist. I took courses in physics, chemistry, algebra, trigonometry, and intermediate algebra, but there were no biology courses available: We were taught how to brush our teeth but that was all the biology taught during my 12 years in school. It was only many years later that I realized how strange that was. What was the education board thinking? I would still not know where my heart is located if I had not eventually studied medicine.

Another oddity about growing up in Montreal in those days was that, although the city was about 70% French, I rarely saw a French Canadian. Where were they? I still wonder. We learned French from a young age, but never from a French Canadian. Soon after I left Montreal, at the age of 26, the French reclaimed their city, and it is now the great French Canadian city it should have been all along.

I spent the most enjoyable time of my youth at a coed summer camp in northern Ontario called Wabi-Kon. I spent 2 months there every summer from age 7 to 21—first as a camper, then counselor, then swimming instructor, and finally as a sailing instructor. The camp was on an island on beautiful Lake Temagami. There were no cars on the island and no electricity in the cabins. The camp focused on water sports and canoe tripping, and it had a wonderful spirit, encouraging free choice and discouraging competition. It was as close to utopia as I have experienced. I still have friends from those days, and I returned often with my children to camp on one of the many islands on the lake. Even today, I try to spend a few days on the lake every few years.

McGill Years

When studying for my B.Sc. at McGill University, I generally enjoyed the humanities more than the sciences and math. In the science courses, I spent many tedious afternoons in laboratories. Had I begun with an interest in becoming a scientist, these labs would have killed it. It was only when I started doing real science years later that I appreciated how far removed these lab classes are from experimental science: Trying to reproduce a result that the professor wants is not the same as trying to find out something new about how the world works. For me, these lab classes were more than unhelpful; they were also actively destructive, because they made me think that science was difficult and boring and that I was no good at it. I suspect that they are still deterring many students from pursuing a career in science.

I stayed on to study medicine at McGill, more out of sloth than a passion to treat disease. Many of my friends were doing it, and I found it attractive to have another 4 years without having to worry about what I would do with my life. Although I often accompanied my father on house calls (largely to ride the automatic elevators while he saw his patient), his life as a family physician was not especially appealing to me, mostly because he seemed to work too hard.

Despite my less than noble motives for studying medicine, I greatly enjoyed my 4 years in medical school, partly because it was my first real exposure to biology. We spent an excessive amount of time studying anatomy, however, so that my brain is still cluttered with detailed and useless anatomical facts that, unlike more useful information, I cannot seem to forget. There was an enormous amount of rote learning, but our teachers were excellent, and they prepared us well for practicing medicine. Medical school is probably not an optimal preparation for being a scientist. It trains you to look backward and compare the patient at hand with similar patients seen previously, whereas a scientist tries to see things in new ways, in order to make discoveries. This would rarely be a good way to treat a patient.

After medical school, I did a rotating internship and a year of residency in medicine at the Royal Victoria Hospital, one of the McGill teaching hospitals. I started my internship on the cardiorespiratory ward, which was an exciting and often terrifying experience. I had never seen anyone die before, and many of the patients on our ward died within the first week of my starting. In those days, hospitalized patients did not just die; they suffered a cardiac arrest, and if they were successfully resuscitated, they were transferred to the cardiorespiratory ward, where they frequently had more cardiac arrests and usually died. Moreover, the house officers on duty on the cardiorespiratory service were called to help resuscitate patients who had a cardiac arrest anywhere in the hospital, and so we rarely had an uninterrupted meal or night's sleep. I learned a great amount of medicine fast, however.

I delivered a number of babies during my rotation in obstetrics, and so I was well prepared when I had to deliver my own daughter, Kim, years later. She emerged unexpectedly fast at 4 AM, when there were no doctors or nurses around on the obstetrics floor at University College Hospital in London, which was right across the street from where I worked.

When it came time to choose a medical specialty to pursue after my year as a medical resident, I drew up a table listing the advantages of the various possibilities, giving a value out of ten for interest, life style, earning potential, and so on. This proved invaluable, because the specialties that came up with the highest scores made my heart sink, until I juggled the numbers so that neurology came first, making it clear to me that neurology was what I really wanted to do. Paul Rosman, an old friend, encouraged me to apply to the neurology program at the Massachusetts General Hospital (MGH) in Boston where he was at the time. I applied, shaved my beard before going for an interview, and was accepted.

Neurology at the MGH

I greatly enjoyed my 3 years as a neurology resident at the MGH. I was strongly influenced by Raymond Adams, C. Miller Fisher, and E.P. Richardson, who were outstanding practitioners and teachers. I especially liked the second year of the program, which we spent in neuropathology. There were no night calls, and we had ample time to read, think, and talk. At weekly “brain cutting” meetings run by E.P., we were given a brief medical history of a patient who had died recently and were asked, in turn, to discuss what neurological disease we thought the patient had. The answer would usually be revealed when E.P. took the brain out of a pot and sliced it. This could be extremely embarrassing, as when we all failed to diagnose a classic case of poliomyelitis that had been sneakily pulled from the archives. None of us had ever seen a case of polio, but it was nonetheless humiliating to not have even mentioned it as a possibility.

On Tuesday evenings, we examined the histological slides of the nervous system and other organs of a deceased patient. Without being given any history at all, we were asked, in turn, to discuss what neurological disease we thought that the patient had. One evening, we examined slides of Einstein's brain; we all thought we were looking at the brain of a young person, because there were no hints of the usual signs of aging despite his 76 years.

During the neuropathology year, we each removed the brain (and, in some cases, the spinal cord, nerves, and muscle) from about 50 patients who had died, whether or not they had a neurological disease. Before starting, we read the patient's medical records to see if there was anything of neurological relevance. On one occasion, I noticed that the patient, who had died of a pulmonary embolus, had had a neurological illness 6 weeks before. He was diabetic and had awakened one morning with weakness and loss of sensation in a random pattern in one leg, consistent with a diagnosis of diabetic mononeuropathy multiplex. Virgilio Sangalang, a senior fellow in neuropathology, and I suspected from the history that he may have had ischemic strokes (infarcts) in scattered nerves of his affected leg, and so we took as many nerves as we could and processed them for histology. We found just what we expected (Raff, Sangalang, and Asbury, 1968). This pathology in diabetic mononeuropathy multiplex had not been described before, although there was one report of an ischemic lesion in a cranial nerve of a diabetic patient who had had an acute episode of ophthalmoplegia. It remains a mystery how, in our case, infarcts occurred specifically in multiple nerves almost simultaneously, although it presumably reflected an underlying diabetic angiopathy.

Twenty-five years after leaving the MGH, I was invited back for several days as the Raymond Adams Visiting Professor in Clinical Neurology. Although I had not seen a patient since leaving, it was a thrill to make rounds on the neurology ward and observe that Adams and Fisher, now in their mid-80s, were as sharp as ever and indistinguishable from how I remembered them.

Exodus from America

During my time in Boston, the Vietnam War continued to escalate, and the war and the military draft dominated American politics. In the middle of my second year of residency, a lawyer friend in Washington, DC informed me that there was likely to be a change in the draft law that would make immigrant physicians eligible for the draft until the age of 35, instead of 26 as it had been until then. The change would affect me, because I was in Boston as a landed immigrant with a green card. Checking to see whether there could be a possibility of joining the National Guard, the Reserves, or the Public Health Service, I learned that these options were closed to immigrants. I quickly obtained clearance from my local draft board and the Internal Revenue Department, and my family and I flew back to Montreal and returned to Boston the next day, exchanging our green cards for exchange visitor visas at the American Immigration desk at the airport.

We were able to switch visas, because the change in the draft law was still several weeks away. The new visa, however, meant that I had to leave the United States at the end of my training, which was just over a year away. Until I changed visas, I had been planning to stay in the United States after my residency, possibly to do neuro-ophthalmology with David Cogan at the Massachusetts Eye and Ear. Now I needed a new plan. I asked my friend Barry Arnason, a neurologist and neuroimmunologist at the MGH, if he had any suggestions. At a similar stage in his career, he had done experimental immunology with Guy Voisin at l'Hôpital St. Louis in Paris. He suggested that I do the same and offered to arrange it. I agreed, and a few hours later it was all arranged.

Within weeks, however, a physicist friend in Boston sent an article to me entitled “Immunology at Mill Hill” that had just been published in Science. It described the immunological research being done at the National Institute for Medical Research (NIMR) in Mill Hill, London. Although I could not understand most of it, it seemed clear that the NIMR would be an exciting place to do immunology. Besides, I had loved London when I visited years earlier, and I was worried about learning French and immunology at the same time in Paris; my poor French was especially embarrassing considering that I grew up in Montreal. Barry warned me that it would be difficult to obtain a place at the NIMR, and so I decided to write to the immunologist whose work I could understand least from the article—Avrion (Av) Mitchison. This turned out to be an immense stroke of luck, and it changed the entire course of my life.

Mitchison accepted me, and the American National Multiple Sclerosis Society awarded me a postdoctoral fellowship to work with him. My fellowship application was based on a basic immunology project, written by Mitchison, that I did not understand and never actually carried out. I am greatly indebted to the American National Multiple Sclerosis Society for funding a Canadian to work in the United Kingdom on a project with no obvious connection to multiple sclerosis (MS). I am also grateful to the society for supporting several postdocs to work with me in later years, when our research, by pure chance, was somewhat more relevant to MS.

Immunology at the NIMR

I arrived in London in the autumn of 1968. I was 30 years old. I was not planning to become a scientist; I was planning to spend 2 years doing experimental immunology before returning to the United States as an academic neurologist in a teaching hospital. I knew almost no immunology and even less about experimental science. I did not even know that there was more than one strain of mouse. It did not take me long, however, to realize that, by sheer good luck, I had chosen the right person and right place. Av was an ideal mentor, and the NIMR was the perfect environment to learn science in general and immunology in particular. It was overflowing with outstanding immunologists. Besides Av, there were Ita Askonas, Brigid Balfour, David Dresser, John Humphrey, Peter Medawar (who was the Director of the NIMR), Mike Parkhouse, Roger Taylor, Alan Williamson, and Henry Wortis, as well as those on sabbatical, including Alistair Cunningham, John Owen, Klaus Rajewsky, Eli Sercarz, and Byron Waksman, and various American postdocs, including Harvey Cantor and Paul Plotz.

This was an exciting time in immunology. It was becoming clear that there are two functionally distinct classes of lymphocytes–thymus–derived T cells and bone-marrow-derived B cells. Because the two classes of cells look the same and occur together in the peripheral lymphoid organs such as the spleen and lymph nodes, there was an urgent need for methods to distinguish and separate them from each other. Av had recently heard the Boston immunologist Arnold Reif describe an alloantigen called theta (later called Thy-1) that was present on the surface of mouse thymus lymphocytes. As thymus lymphocytes give rise to T cells, Av thought that Thy-1 might also be present on T cells but not B cells, in which case it could serve as a useful T-cell marker.

Using an antibody- and complement-mediated cytotoxicity assay that I learned from my lab-mate Marion Ruskowicz, I first showed that Thy-1 is present on peripheral lymphocytes as well as on thymus lymphocytes. I then examined lymphocytes from mice that Sandra Nehlsen (a Ph.D. student of Medawar who worked across the hall from me) had been chronically treating with anti-lymphocyte serum to deplete T cells. I found that the spleen and lymph nodes of these mice contained normal numbers of Thy-1-negative lymphocytes but very few Thy-1-positive lymphocytes, strongly suggesting that Thy-1 is present on T but not B cells as Av had suspected (Raff, 1969). I then used the antibodies to analyze a system that Av had developed to study the collaboration between lymphocytes from mice immunized with a carrier protein A and lymphocytes from mice immunized with a hapten coupled to carrier protein B; when both lymphocyte populations were transferred into irradiated mice and immunized with the hapten coupled to carrier protein A, the mice produced large amounts of antihapten antibodies. Before transferring the cells, I treated one or other population with anti-Thy-1 antibodies and complement to kill the T cells and showed that the carrier-A-primed cells were T cells and the hapten-primed cells, which produced the antibodies, were not (Raff, 1970a).

When it came time to publish these findings, Av would not put his name on the papers, even though the projects were his idea and he had begun to produce the anti-Thy-1 antibodies for the project before I had arrived in London. This exceptional act of generosity had an enormous influence on my career. Thy-1 rapidly became a standard marker for mouse T cells, and the two papers gave me immediate international recognition after only 2 years in science. This was not special treatment: I was to see it repeated over and over again with subsequent generations of Mitchison students and postdocs. Av always did his own experiments, and many of his contributions have been landmarks in immunology, but, because he let his students and postdocs publish on their own, his contributions to science are far greater than is documented in the literature. Similarly, it would be difficult to deduce our connections to Av from the literature. Had I known then what I know now, I would have insisted that his name be on those two papers.

In a series of very fruitful collaborations with John Owen, who was on sabbatical from Oxford, we used the anti-Thy-1 antibodies to study the distribution, development, and functions of T cells (Owen and Raff, 1970; Raff and Owen, 1971). In addition, to directly visualize Thy-1 on lymphocytes, I turned to fluorescence microscopy, using fluorescent anti immunoglobulin (Ig) antibodies to detect the bound anti-Thy-1 antibodies on living T cells. Despite the primitive fluorescence microscopes of the time, the method worked well, but the experiments turned up an unexpected result: In control experiments, in which I omitted the anti-Thy-1 antibodies, the fluorescent anti-Ig antibodies on their own labeled a substantial proportion of peripheral lymphocytes. Roger Taylor, working across the hall, had independently obtained similar results using radioactive anti-Ig antibodies, and we published these findings together (Raff, Sternberg, and Taylor, 1970) as one of the first direct demonstrations of Ig molecules on the surface of lymphocytes, which immunologists had postulated would serve as receptors for antigens.

The finding of Ig on some lymphocytes but not on others raised the question of which class of lymphocyte expressed the Ig. To find out, I examined lymphocytes from mice depleted of T cells, either by chronic treatment with anti-lymphocyte serum or by thymectomy, irradiation, and bone marrow transplantation. I found that all the Ig-positive cells were B cells (Raff, 1970b), which began a prolonged and frustrating search by many laboratories for the antigen receptors on T cells. After many false leads, the antigen receptors on T cells were identified as Ig-like proteins years later. Surface Ig, however, rapidly became a standard marker for B cells in all vertebrates. Later, when we moved to UCL, for example, John Owen and I collaborated with Max Cooper, who was on sabbatical from Birmingham, Alabama, and used anti-Ig antibodies and tissue explant cultures to show directly that B cells develop in the fetal liver and adult bone marrow (Owen, Cooper, and Raff, 1974), rather than in the gut as had been suggested by others (including Max), and that B cells arise from pre-B cells, which have already begun to make IgM heavy chains (Raff et al., 1976).

Cell Biology at the NIMR

When I visualized Ig on the surface of B cells with fluorescent antibodies, a remarkable feature of the staining was that it was located at one pole of the cell, forming a fluorescent “cap” (Raff, 1970b). Göran Möller at the Karolinska Institute in Stockholm saw the same distribution almost 10 years earlier (Möller, 1961). To determine what was special about the pole of the cell where the Ig was located, I collaborated with Stefanello de Petris, an Italian scientist working at the NIMR. Nello was an expert in using ferritincoupled antibodies to localize antigens in cells in an electron microscope. For reasons known only to him, he labeled lymphocytes with ferritincoupled anti-Ig antibodies at two temperatures: 4°C and room temperature. The results were spectacular: At 4°C, the Ig was seen in small patches all over the B cell, whereas at room temperature, it was all in a cap at one pole (dePetris and Raff, 1972, 1973). The implications were clear: The Ig is apparently normally distributed over the entire B cell surface, and the binding of the anti-Ig antibodies induces the capped distribution, but only at the higher temperature. The finding that cell-surface Ig molecules can move in the plane of the membrane was among the earliest lines of evidence that cell membranes are two-dimensional fluids, rather than two-dimensional deformable solids, a realization that dramatically changed the way one thought about membrane structure and function.

The next few months were the most exciting of my career. Nello and I returned to immunofluorescence experiments. We quickly showed that it is the cross-linking of the surface Ig molecules by the bivalent anti-Ig antibodies that induces the Ig to cluster into patches on the B cell surface, because monovalent Fab fragments of the anti-Ig antibodies did not induce Ig patches. At room temperature, an actin-dependent process actively moves the patches to one pole of the cell. We also found that antibody binding induces the endocytosis of the surface Ig, rapidly clearing the Ig from the cell surface, providing an explanation for the phenomenon of antibody-induced antigenic modulation, previously described by Ted Boyse and Lloyd Old at the Sloan Kettering Institute in New York. A similar mechanism is now known to be responsible for the down-regulation of many types of cell-surface receptors following the binding of their extracellular signal molecules.

At this point, we discovered that our former colleague Roger Taylor, who had since moved to Bristol University, and his post doc Philip Duffus had similar findings, and we published our fluorescence observations together (Taylor et al., 1971). We tossed a coin to determine the order of authors, and, embarrassingly, I was devastated when Nello and I lost the toss. Needless to say, the results of the toss had no obvious effects on any of our careers.

Our observations on ligand-induced patching, capping, and endocytosis were undoubtedly the most important discoveries with which I have been associated. They have had implications for so much of cell biology, including membrane structure, turnover, and function, as well as for cell signaling and vesicular traffic. New implications continue to be revealed; only quite recently, for example, it was discovered that synaptic plasticity often depends on similar redistributions of neurotransmitter receptors on the postsynaptic side of synapses. These experiments with Nello transformed me from an immunologist to a cell biologist, although, initially at least, I had still considered myself to be a clinical neurologist rather than a scientist. The transition to a scientist occurred in a single night.

In 1970, Av accepted the Jodrell Chair in the Zoology Department at UCL, a chair that his mentor Peter Medawar had occupied some years earlier. One evening, Av mentioned that, if I would consider staying in science and in the UK, he would be happy to have me join him at UCL when he moved there in 1971. That night I decided to do it, which was the best and most important decision of my life.

Looking back on my NIMR days, I am impressed at how different things were then compared to today for most people starting a career in the biological sciences. So little was known then that almost every experiment resulted in an interesting discovery. Unlike now, it was relatively easy to publish papers in good journals: I published 11 first-author papers in my first 3 years, 5 of them in Nature. (Interestingly, the one that became a Citation Classic [Raff, 1970b] was published in Immunology, a relatively low impact journal.) My rapid start had little to do with me; I was in the right place at the right time, with a brilliant mentor and outstanding colleagues. Even with luck, however, it would be hard to get off to such a rapid start today, and it is sobering to realize that those few years as a novice were to be the most productive of my career.

The Move to UCL and the Hunt for Neural Cell Markers

As my MS postdoctoral fellowship was about to run out, I had to decide how to fund my salary and research at UCL. Av suggested that we write a joint application to the MRC for a 5-year program grant. We proposed to use the antibody strategy, which had proved so useful in studying cells of the immune system, to study cells of the mammalian nervous system. Given that neither Av nor I had any track record in neurobiology, it is remarkable that the MRC funded the grant in full, including my salary. Over the next 31 years, I renewed the grant five times, so that the MRC provided my salary and research support until I retired in 2002. Although I did not have a tenured position, this was a wonderful arrangement because it allowed me to do full-time research in a university, with few teaching or administrative responsibilities. For the first 20 years or so, our group was physically embedded in Av's Tumor Immunology Unit, which was generously funded by the Imperial Cancer Research Fund (ICRF, now Cancer Research UK) until Av left UCL for Berlin. Although we were not financially part of the unit, the ICRF services were invaluable to us. Moreover, during this entire period, I had the wonderful privilege of sharing an office with Av, who was a protective patron, inspiring role model, and generous friend.

The research plan was to raise antibodies against cells of the nervous system and use them to distinguish and separate the different cell types so that we could study their development and interactions, mainly in a culture dish. This was before the monoclonal antibody revolution, and there were many formidable problems to overcome. Because neural cells are fixed in complex arrangements in the nervous system, they are much more difficult to isolate than are lymphocytes. Moreover, we would need relatively pure populations of cells for raising and testing antibodies, and so we might be defeated by the very problem we wanted to solve. To overcome this catch-22, we decided to start with cells from neural tumors; as each tumor initially arises from a single cell, its cells should be relatively homogeneous. We took advantage of the discovery by Hermann Druckrey and his colleagues at the University of Freiburg that one can induce tumors of the peripheral nervous system (PNS) and central nervous system (CNS) in a high proportion of rats by injecting either newborns or their pregnant mothers with the chemical carcinogen ethylnitrosourea (ENU) (Ivankovic, Druckrey, and Preussmann, 1966).

Kay Fields, an American phage molecular biologist who had just finished a post doc in Geneva, took on the project of inducing the tumors, isolating cell lines from them, and raising antibodies against the lines (Fields et al., 1975). After absorbing the antisera with normal non-neural tissues and different neural tumor cell lines, we hoped to obtain antibodies that distinguished one neural cell type from another. Of the various antisera that Kay produced, one specifically labeled the surface of Schwann cells in cultures of newborn rat sciatic nerve cells (Brockes, Fields, and Raff, 1977). She called the antigen rat neural antigen 1 (Ran-1), which others showed years later was the low affinity NGF receptor protein, p75. This was the lab's first useful neural cell marker. It had taken 5 years to show that the immunological approach could work with cells of the nervous system.

These 5 years were difficult. I knew little neurobiology and found it hard to learn more. I remained immersed in immunology and cell biology, and it was a struggle to switch my interests. My scientific friends were immunologists; I was invited to talk mainly at immunology and cell biology meetings; and the young scientists that applied to work with me wanted to do immunology or cell biology. During this time, I continued to collaborate with Nello de Petris (who had also moved with Av to UCL) on ligand-induced redistribution of cell-surface molecules and its implications. A Ph.D. student who joined us from Scotland, Durward Lawson, used electron microscopy to study the cell biology of histamine secretion by rat mast cells; he showed, for example, that a stimulant attached to a solid bead caused exocytosis exclusively at the site of contact with the bead, indicating that the response could be localized and need not involve the cell as a whole as had been thought (Lawson, Fewtrell, and Raff, 1978).

I am not sure that I could have made the transition from immunology and cell biology to developmental neurobiology without Jeremy Brockes. He joined the laboratory as a post doc from the neurobiology department at Harvard Medical School, then the mecca of neurobiology, and he played a crucial part in both our first neurobiological success and my conversion to neurobiology. He initially collaborated with Kay to show that Ran-1 could be used as a Schwann cell marker. My first graduate student, Peter Stern, had shown earlier that Thy-1 was present on rat and mouse fibroblasts (Stern, 1973). Jeremy and Kay showed that anti-Ran-1 and anti-Thy-1 antibodies labeled nonoverlapping populations of cells in cultures of newborn rat sciatic nerve cells; whereas anti-Ran-1 antibodies labeled the Schwann cells, anti-Thy-1 antibodies labeled most of the non-Schwann cells (Brockes, Fields, and Raff, 1977). These findings allowed Jeremy to devise a strategy for purifying Schwann cells that depended on killing the contaminating non-Schwann cells with anti-Thy-1 antibodies and complement (Brockes, Fields, and Raff, 1979).

Schwann Cells

Jeremy and I went on to study some of the properties of purified rat Schwann cells. We found, for example, that either an increase in intracellular cyclic AMP (Raff, Hornby-Smith, and Brockes, 1978) or an extract of bovine pituitary glands (Raff et al., 1978a) stimulated the cells to proliferate, apparently by distinct mechanisms. These findings enabled us to produce large numbers of cultured Schwann cells (Brockes, Fields, and Raff, 1979). When Jeremy left to take up his first independent position at Cal Tech, he and his Ph.D. student Greg Lemke purified the Schwann cell mitogen in the pituitary extract (Lemke and Brockes, 1984). They called it glial growth factor (GGF), which was the first member of the Neuregulin family of extracellular signal proteins.

Rhona Mirsky, who initially came on sabbatical from Dartmouth Medical School and later returned permanently to UCL, showed that Schwann cells, unlike oligodendrocytes, require signals from axons to maintain their normal expression of myelin proteins and glycolipids (Mirsky et al., 1980). It was around this time that Rhona began a long-term collaboration with Kristjan Jessen, a post doc originally from Iceland, that continues to this day. The Mirsky-Jessen Group in the Anatomy and Developmental Biology Department at UCL rapidly became one of the world's leading laboratories studying Schwann cell development and biology.

Anne Mudge, an Australian post doc from Harvard Medical School, used purified populations of Schwann cells and embryonic sensory neurons (from dorsal root ganglia) to demonstrate that Schwann cells have a dramatic influence on the development of the neurons, inducing them to undergo their normal morphological transformation from an immature bipolar form to a mature pseudo-unipolar form (Mudge, 1984). After Rhona left our MRC Program, Mudge took her place and has remained a close, but independent, colleague ever since.

Many years after our initial studies on Schwann cells, my last graduate student, Ian Conlon, returned to these cells to address a fundamental, but understudied, problem in cell biology—how cell growth (enlargement) and cell-cycle progression are coordinated to ensure that proliferating cells maintain an appropriate size. He showed that GGF stimulates Schwann cells to progress through the cell cycle but does not stimulate them to grow, whereas insulin-like growth factor 1 (IGF-1) on its own does the opposite (Conlon et al., 2001). Using these two signal proteins, he provided evidence that the size of proliferating Schwann cells at division does not depend on a cell-size checkpoint as we had suspected; instead, their size at division depends on how fast the cells are growing and how fast they are going through the cell cycle, and these rates depend on the concentrations of extracellular signals that control cell growth, cell-cycle progression, or both (Conlon and Raff, 2003).

Our initial studies on Ran-1 and Schwann cells provided a much-needed proof of principle that we could use antibodies to identify and purify a neural cell type. Our goal, however, was to use this approach to study cells of the CNS, which was much more challenging.

Optic Nerve as a Model System

To begin to define markers for CNS cells, we turned to cultures of newborn rat optic nerve cells. The advantage of these cultures is that they do not contain neurons, and so they are not much more complex in terms of cell types than cultures of sciatic nerve. Fortunately, Amico Bignami and Larry Eng and their colleagues had already identified glial fibrillary acidic protein (GFAP), an intermediate filament protein expressed by astrocytes but not by oligodendrocytes, microglial cells, or neurons (Bignami et al., 1972). We obtained anti-GFAP antibodies from Bignami and found that they labeled two morphological types of astrocytes, which we later called type-1 and type-2 astrocytes; the former had a fibroblast-like morphology and the latter a process-bearing morphology (Raff et al., 1983). Other cells in the culture had multiple branching processes and were GFAP-negative, and we assumed that they were oligodendrocytes. I then tested a number of lectins and antibodies, hoping that some would label these putative oligodendrocytes. I found one that did: Antibodies against a major myelin glycolipid—galactocerebroside (GC)—labeled these cells and no others in optic nerve cell cultures (Raff et al., 1978b).

By this time, George Kohler and Cesar Milstein had developed the monoclonal antibody technology that dramatically increased the power of the antibody approach. Perry Bartlett, an Australian post doc from Johns Hopkins University, made our first monoclonal antibody by immunizing mice with cultured brain astrocytes. He called the cell-surface antigen that the antibody recognized Ran-2 (Bartlett et al., 1980), which we showed later was expressed on type-1 but not type-2 astrocytes in optic nerve cell cultures. Becky Pruss, a post doc from UCLA, made our second monoclonal antibody. She made it against GFAP, but it turned out to react with all intermediate filament proteins, including those from squid and a marine worm, providing the first evidence that all of these proteins were homologous, which was very surprising at the time (Pruss et al., 1981). Mike Klymkowsky, a post doc from UCSF, microinjected the antibody into 3T3 cells and showed that it caused the intermediate filaments to collapse around the nucleus. This had no effect, however, on cell shape, motility, or division, indicating that intermediate filaments are not required for these cell activities, which was also a great surprise at the time (Klymkowsky, 1981). Becky also made a rabbit anti-GFAP antiserum that we used for the next 30 years to identify astrocytes.

We obtained a monoclonal antibody made by Marshall Nirenberg and his colleagues at the NIH called A2B5, which we also used for 30 years to help identify and purify another cell type—the oligodendrocyte precursor cell—that became my main interest until I retired. A2B5 recognizes certain gangliosides and was initially thought to label neurons specifically (Eisenbarth, Walsh, and Nirenberg, 1979). We found, however, that it also labeled the surface of oligodendrocyte precursor cells and type-2 (but not type-1) astrocytes in optic nerve cultures (Raff, Miller, and Noble, 1983). The precursor cells and type-2 astrocytes could also be labeled on their surface by tetanus toxin, which Rhona Mirsky and her Ph.D. student Linda Wendon had shown previously bound to the surface of cultured PNS and CNS neurons (Mirsky et al., 1978).

We therefore had increasing evidence that type-1 and type-2 astrocytes are molecularly and morphologically distinct, which made us think that they may derive from different cell lineages. A fortuitous finding enabled us to show that both type-2 astrocytes and oligodendrocytes develop in culture from a common progenitor cell. Our colleague Jim Cohen had begun using a serum-free culture medium for his cultures of cerebellar cells that was based on a medium originally described by Jane Bottenstein and Gordon Sato. He suggested that I try it on my optic nerve cell cultures, which we normally maintained in 10% fetal calf serum (FCS). Remarkably, whereas cultures with 10% FCS contained many type-2 astrocytes and very few oligodendrocytes, those in serum-free medium contained the opposite. I suspected that this result might reflect the different survival requirements of type-2 astrocytes and oligodendrocytes. But when I showed the cultures to my 15-year-old son, Adam, he suggested an alternative possibility: Maybe the FCS induces cells destined to become oligodendrocytes to become type-2 astrocytes instead. He was absolutely right, and it was relatively simple to demonstrate it (Raff, Miller, and Noble, 1983). I like to think that I would have eventually arrived at this crucially important conclusion myself, but who knows?

Together with two post docs, Mark Noble from Stanford and Bob Miller from UCL, I went on to show that type-1 astrocytes develop from one type of precursor cell, whereas both oligodendrocytes and type-2 astrocytes develop from a common, A2B5-positive precursor, which we therefore initially called an O-2A progenitor cell (Raff, Abney, and Miller, 1984). Largely from the work of Bob Skoff at Wayne State University (Skoff, 1990) and our collaboration with a close UCL colleague Barbara Fulton (Fulton, Burne, and Raff, 1991), it gradually became clear, however, that type-2 astrocytes are probably not present in the normal optic nerve (or possibly elsewhere in the CNS), and so we began to refer to the oligodendrocyte precursors as OPCs. Rochelle Small, a post doc from Yale, collaborated with Mark Noble and his colleagues to show that OPCs migrate into the developing rat optic nerve some time before birth (Small, Riddle, and Noble, 1987), suggesting that the neuroepithelial cells that form the optic stalk give rise only to type-1 astrocytes, whereas OPCs are immigrants from the brain.

Laura Lillien, a post doc from the University of Wisconsin in Madison, and Simon Hughes, a post doc from Cambridge University, identified signals (other than FCS) that could induce OPCs to become type-2 astrocytes in culture. Simon found that extracts of developing optic nerve could induce OPCs transiently to express GFAP (Hughes and Raff, 1987) and, together with Laura and Michael Sendtner in Munich, showed that the active protein was ciliary neurotrophic factor (CNTF) (Hughes et al., 1988; Lillien et al., 1988). Laura went on to demonstrate that CNTF plus extracellular-matrix-associated molecules made by optic nerve cells induce OPCs to become stable type-2 astrocytes in culture (Lillien, Sendtner, and Raff, 1990). Some years later, John Kessler and colleagues showed that bone morphogenic proteins (BMPs) on their own induce cultured OPCs to become stable type-2 astrocytes (Mabie et al., 1997). BMPs are produced in the developing CNS, so why do type-2 astrocytes apparently not develop there? Toru Kondo, a post doc from Japan, later showed that optic nerve glial cells, including OPCs themselves, produce BMP antagonists such as Noggin, which greatly decrease the sensitivity of OPCs to the type-2-astrocyte-inducing activity of BMPs; he also showed that BMPs in FCS are responsible for inducing OPCs to become type-2 astrocytes (Kondo and Raff, 2004a).

An Intrinsic Timer in OPCs

Remarkably little is known about how the timing of developmental processes is controlled. Erika Abney, a Mexican immunologist and a friend from my immunology days, joined our group in the late 1970s, and it was her initial findings that first aroused my interest in the developmental timing problem. Using GFAP to identify astrocytes, GC to identify oligodendrocytes, and the presence of beating cilia to identify the ependymal cells that line the ventricles in the CNS, she determined when the first cells of each type appear in the developing rat brain. Analyzing cell suspensions from embryonic day eleven (E11) through to birth at around E21, she found that the first astrocytes appear at E15–16, the first ependymal cells at E17–18, and the first oligodendrocytes at the time of birth. Amazingly, when she isolated cells from E10 brain and cultured them in 10% FCS, the times of first appearance of these three cell types were the same as if the cells had been left in the developing brain. Moreover, when cultures were prepared from E13 brain, all these cell types appeared 3 days earlier, just as in vivo (Abney, Bartlett, and Raff, 1981). Even today, I find these results remarkable, because the main morphogenic cues in the developing brain are missing in these cultures: there is no anterior and posterior, ventral and dorsal, medial and lateral, or inside and outside. The findings suggested that some timing mechanisms apparently operate normally in dissociatedcell cultures, and they made me think that we might be able to understand their molecular basis. I did not think, however, that we could study them in brain cell cultures, which, in principle, could contain hundreds of different cell types. We therefore returned to optic nerve cell cultures.

We focused on the timing of oligodendrocyte development. What is it that determines when an OPC stops dividing and differentiates into an oligodendrocyte? Like oligodendrocytes, most cell types in mammals develop from dividing precursor cells that stop dividing after a limited number of cell divisions and terminally differentiate. In no case do we know why the precursor cells stop and differentiate when they do.

As in the brain, we found that the first OPCs in the developing rat optic nerve stop dividing and differentiate into GC-positive oligodendrocytes around the day of birth. Moreover, as long as there are sufficient numbers of type-1 astrocytes present, the timing is remarkably similar in cultures of embryonic optic nerve cells (Raff, Abney, and Fok-Seang, 1985). Mark Noble, who had started his own laboratory at the Institute of Neurology in London, showed that type-1 astrocytes produce a mitogen for OPCs, which is required to prevent OPCs from prematurely differentiating (Noble and Murray, 1984). Both he and our UCL colleague Bill Richardson independently showed that the mitogen is platelet-derived growth factor (PDGF) (Richardson et al., 1988; Noble et al., 1988). Together, our three laboratories showed that PDGF can bypass the need for large numbers of type-1 astrocytes and allow normal timing of oligodendrocyte development in sparse embryonic optic nerve cell cultures (Raff et al., 1988).

Sally Temple, a Ph.D. student from Cambridge University, demonstrated that OPCs have a cell-intrinsic mechanism that helps determine when they stop dividing and differentiate into oligodendrocytes (Temple and Raff, 1986). She placed an individual OPC onto a monolayer of type-1 astrocytes in a microwell and found that the cell proliferates and that the progeny cells stop dividing and differentiate at about the same time. She then showed that if the two daughter cells of an OPC are placed on astrocyte monolayers in separate microwells, they tend to divide the same number of times before they differentiate, establishing that an intrinsic counting or timing mechanism is built into each OPC. We spent much of the next 15 years trying to determine how the intrinsic mechanism operates. This seemed a worthwhile effort, because we suspected that similar mechanisms probably operate in many types of precursor cells.

An important advance in understanding the intrinsic mechanism came from Ben Barres (who was Barbara Barres at the time). He joined us as a post doc from Harvard Medical School, where, as a Ph.D. student, he did important work on the physiology of glial cells. He made two critical contributions to the analysis of the intrinsic counting or timing mechanism in OPCs. First, he developed a sequential immunopanning method to purify OPCs from neonatal rat optic nerves (Barres et al., 1992). He used Perry Bartlett's monoclonal anti-Ran-2 antibody to eliminate astrocytes, a monoclonal anti-GC antibody (made by Barbara Ranscht in Tiibingen) to eliminate oligodendrocytes, and the A2B5 antibody to select positively for OPCs. His purification procedure revolutionized our ability to study these cells. Second, he showed that the intrinsic mechanism depends on thyroid hormone as well as on PDGF (Barres, Lazar, and Raff, 1994). Without PDGF, the cells prematurely stop dividing and differentiate. In the presence of PDGF but without thyroid hormone, most OPCs fail to stop dividing or differentiate; if thyroid hormone is added after the time when most OPCs would have differentiated had the hormone been present all along, the cells quickly stop dividing and differentiate. These findings suggested that the cells can count divisions or measure time in the absence of the hormone but that the hormone is required for the cells to withdraw from the cell cycle and differentiate when the intrinsic mechanism indicates it is time. Nathalie Billon, a post doc from France, and Yasu Tokomoto, a post doc from Japan, later collaborated with Björn Vennström at the Karolinska Institute to show that α1 thyroid hormone receptors mediate this effect of the hormone on OPCs (Billon et al., 2002). Yasu also showed that one or more members of the p53 family of proteins are required for thyroid hormone to trigger OPC differentiation (Tokumoto, Tang, and Raff, 2001), and Nathalie, in collaboration with Gerry Melino and his colleagues in Rome, provided evidence that p53 and p73 are the relevant family members (Billon et al., 2004); it remains to be discovered how these proteins function in OPC differentiation.

Fen-Biao Gao, a post doc from Duke University, used the Barres method to purify OPCs from embryonic rat optic nerve and showed that, in serum-free cultures containing PDGF and thyroid hormone, the purified cells stop dividing and differentiate on the same schedule as they do in vivo (Gao, Apperly, and Raff, 1998). He also showed that young OPCs proliferate for longer than older ones, suggesting that the reason OPCs from the same age optic nerve go through a variable number of divisions before they differentiate is because they vary in their stage of maturation (Gao and Raff, 1997). Most importantly, he provided strong evidence that the intrinsic mechanism that helps control how long OPCs proliferate before they differentiate does not depend on counting cell divisions but instead measures time in some other way (Gao, Durand, and Raff, 1997). But what is the other way?

Ian Hart, a training neurologist doing a Ph.D., had earlier collaborated with Bill Richardson to show that the intrinsic mechanism probably does not depend on changes in either the number of PDGF receptors on the OPC cell surface or the signaling pathways that the receptors activate. He showed that OPCs that have stopped dividing and begun to differentiate still retain large numbers of PDGF receptors (Hart et al., 1989a), which can still be stimulated by PDGF both to increase intracellular Ca²+ (Hart et al., 1989b) and to activate the transcription of immediate-early genes in the nucleus of these differentiating cells (Hart, Richardson, and Raff, 1992).

The first clue about the molecular nature of the intrinsic timer came from Béa Durand, a post doc from Strasbourg. She showed that the amount of the cyclin-dependent protein kinase inhibitor p27Kip1 progressively increases in the nucleus of purified OPCs as they proliferate in the presence of PDGF and the absence of thyroid hormone (Durand, Gao, and Raff, 1997). The amount of the protein reaches a plateau at the time when most of the cells would have stopped dividing if thyroid hormone had been present; without the hormone, the cells continue to proliferate, despite the high levels of p27Kip1. Béa then collaborated with Jim Roberts in Seattle to show that, in cultures containing PDGF and thyroid hormone, mouse OPCs that are deficient in p27Kip1 divide for a day or two longer than wild-type OPCs before they differentiate, suggesting that p27Kip1 is one component of the timer (Durand et al., 1998). Jim Apperly, a Ph.D. student, showed that over-expression of p27Kip1 accelerates the timer, providing further support for a role of p27Kip1 in the timing process (Tokumoto et al., 2002). As most of the organs in p27KiP1-deficient mice contain more cells than normal, it seems likely that p27KiP1-dependent timers operate in many types of precursor cells. Yasu Tokumoto went on to show that p27Kip1 mRNA levels remain constant as the protein increases in proliferating OPCs, suggesting that the increase in the protein over time depends on post-transcriptional mechanisms that remain to be identified (Tokumoto et al., 2002).

Toru Kondo showed that the inhibitor of differentiation (Id) protein Id4 is also a component of the timer, although it works in the opposite way from p27Kip1 (Kondo and Raff, 2000a). Id proteins inhibit basic helix-loop-helix gene regulatory proteins that are required for differentiation in many types of precursor cells; in this way, they promote proliferation and inhibit differentiation of the precursors. Toru found that Id4 protein decreases as purified OPCs proliferate in the presence of PDGF and the absence of thyroid hormone and that, in this case, the mRNA and protein decrease in parallel, suggesting that a transcriptional mechanism is probably responsible for the progressive decrease in Id4 protein. Over-expression of Id4 prolongs proliferation and inhibits differentiation, consistent with the idea that the normal fall in Id4 helps determine when OPCs stop dividing and differentiate.

The OPC timer, like other intracellular timers, is still poorly understood. It is clear that it is complex and depends on the progressive increase of some intracellular proteins like p27Kip1 and the progressive decrease of others like Id4. Both transcriptional and post-transcriptional controls have roles, but how these controls operate remains a mystery.

Adult OPCs

Charles ffrench-Constant, a medically trained Ph.D. student, found that there are small numbers of OPCs in cell suspensions prepared from adult rat optic nerves (ffrench-Constant and Raff, 1986). Like their neonatal counterparts, these adult OPCs are A2B5-positive and develop into type-2 astrocytes when cultured in 10% FCS and into oligodendrocytes when cultured in serum-free conditions, although they differentiate more slowly than do neonatal OPCs. Mark Noble and his colleagues independently found these cells and characterized them in more detail; most important, they showed by time-lapse recording that adult OPCs can develop from neonatal OPCs in culture (Wren, Wolswijk, and Noble, 1992).

We had great difficulty using immunocytochemistry to identify OPCs in the intact developing and adult optic nerve. Julia Burne, a technician turned Ph.D. student, in collaboration with Barbara Fulton, used a technique developed by Becky Pruss (after she had left London) to label cells, including OPCs, that have Ca²+ (and cobalt)-permeable glutamateactivated ion channels (Pruss et al., 1991). The method used the glutamate agonist quisqualate to stimulate such cells to take up cobalt, which could then be precipitated, enhanced with silver, and visualized by either light or electron microscopy. In this way, Julia and Barbara could specifically label OPCs in the intact rat optic nerve. They found that OPCs acquire progressively more complex cell processes as the nerve matures and that they constitute about 5% to 10% of the cells in the adult optic nerve (Fulton, Burne, and Raff, 1992). They also found that the processes of these cells end on nodes of Ranvier. Previously, Bob Miller and Barbara had injected horseradish peroxidase into individual cells in the adult optic nerve and found that some cells extend processes exclusively to nodes (Miller, Fulton, and Raff, 1989); we originally thought that these cells were type-2 astrocytes, but it is now clear that they are OPCs, as was later confirmed by Arthur Butt and his colleagues at King's College London (Butt et al., 1999).

Adult OPCs are among the most interesting cells in the mammalian CNS. They are among the few cell types that Cajal missed, although they are 5% to 10% of the cells throughout the CNS (excepting the retina), as assessed by staining with antibodies against the NG-2 proteoglycan, which Joel Levine and Bill Stallcup at the Salk Institute originally showed recognize OPCs (Levine and Stallcup, 1987). In white matter, OPCs send their processes to nodes of Ranvier, and in both white and grey matter, they receive excitatory synapses, as convincingly shown by Dwight Bergles and his colleagues at Johns Hopkins Medical School (Lin and Bergles, 2002). They proliferate in response to injury and can produce new oligodendrocytes in response to myelin damage (Levine, Reynolds, and Fawcett, 2001). Given their abundance in both white and grey matter, their complex morphology, and the low rate of oligodendrocyte turnover in the normal CNS, it seems unlikely that the normal function of adult OPCs is simply to replace lost oligodendrocytes, but their other functions remain a mystery. There is a pressing need to study the consequences of eliminating these cells in the adult CNS.

An Intrinsic Maturation Program in OPCs

Why do OPCs become progressively more complex during development? Is it because their environment changes, because they intrinsically mature over time, or both? Fen-Biao Gao showed that perinatal OPCs have an intrinsic developmental program that changes many aspects of the cell over time (Gao and Raff, 1997). He first compared the properties of purified E18 OPCs with P10 OPCs (which are 10 days older), using time-lapse video recording of individual clones in culture. He found that, in cultures containing PDGF and thyroid hormone, the embryonic OPCs have a simpler morphology, divide and migrate faster, and divide more times before differentiating than do P7 OPCs. Remarkably, when he cultured purified E18 OPCs in serum-free medium in PDGF (without thyroid hormone, to prevent their differentiation) for 10 days, he found that the embryonic cells acquire the properties of the P10 cells, indicating that developing OPCs have an intrinsic maturation program that progressively changes many properties of the cell.

Dean Tang, a Chinese post doc with a Ph.D. from Wayne State University, showed that purified P7 OPCs can proliferate in culture for more than a year in PDGF without thyroid hormone. After many months in culture, the OPCs start to express GC even though they continue to proliferate and do not express other oligodendrocyte markers (Tang, Tokumoto, and Raff, 2000). This is not a culture artefact, for Ben Barres and his colleagues at Stanford showed earlier that OPCs in the rat optic nerve start to express GC after many months in vivo (Shi, Marinovich, and Barres, 1998). It seems that the intrinsic OPC maturation program continues to change the cells for months, which is remarkable. Intracellular programs that change developing cells over time are among the most mysterious processes in development and deserve much more attention than they have received.

We were surprised to find that OPCs did not undergo replicative cell senescence and permanently stop dividing, even after more than a year of proliferation in culture. The cells remain diploid, and unlike genetically immortalized cells, they maintain p53-dependent and Rb-dependent cell-cycle checkpoint mechanisms (Tang, Tikumoto, and Raff, 2000). Dean could rapidly induce them to acquire a senescent phenotype by culturing them in FCS or by treating them with DNA-damaging drugs. At the same time, our neighbors Alison Lloyd and her colleagues had obtained very similar results with purified rat Schwann cells (Mathon et al., 2001). Together, these studies showed that, unlike human cells, some normal rodent cells can apparently proliferate indefinitely in culture: They continue to express telomerase and therefore do not undergo progressive telomere shortening and uncapping, which cause most normal human cells to stop dividing after a limited number of divisions, a process logically called replicative cell senescence. So-called replicative senescence in rodent cells, by contrast, results from “culture shock” caused by high concentrations of serum and/or oxygen or by other stresses, rather than from a telomere-dependent cell-division counting mechanism (Wright and Shay, 2000).

Conversion of OPCs to Neural Stem-Like Cells

The isolation of human embryonic stem (ES) cell lines and embryonic germ (EG) cell lines in 1998 triggered a cascade of hope, hype, and hysteria that continues to amplify to this day. A surprising observation by Toru Kondo dropped us into the middle of this stem cell storm. We had supposed that OPCs were committed to becoming oligodendrocytes (and possibly type-2 astrocytes), but Toru showed that this was not the case: They could be reprogrammed by extracellular signals to become multipotential cells that can produce both neurons and glia (Kondo and Raff, 2000b). He found that, if he treated purified OPCs with BMPs for 2 to 3 days and then with basic fibroblast growth factor (FGF-2), the OPCs convert to a phenotype that closely resembles CNS neural stem cells. They can proliferate indefinitely in FGF-2, and depending on the signal proteins in the culture medium, they are able to give rise to type-1 astrocytes and neurons, as well as to oligodendrocytes and type-2 astrocytes, just as CNS neural stem cells do. Thus, OPCs are specified to become oligodendrocytes, but they are clearly not irreversibly committed to do so.

As mentioned earlier, the BMPs induce OPCs to become type-2 astrocytes, and Toru showed that this step is required for the conversion of purified OPCs to stem-like cells. He found that the BMP treatment rapidly induces the transcription of a variety of genes that are normally expressed in neural stem cells (Kondo and Raff, 2004b). He focused on the induction of the sox-2 gene, which encodes a gene regulatory protein required for neural stem cell proliferation and normal CNS development. He identified an enhancer sequence in the sox-2 promoter that is required for the gene to be expressed in neural stem cells. He showed that both the tumorsuppressor protein Brca-1 and the chromatin-remodeling protein Brahma are recruited to the enhancer when OPCs are treated with BMPs for 2 days and that both proteins are required for the induction of sox-2. He also showed that the histone H3 associated with this enhancer is progressively modified during the conversion process (Kondo and Raff, 2004b).

There is evidence that adult OPCs can also convert in culture to neural stem-like cells that can give rise to both glia and neurons (Palmer et al., 1999). Given their abundance, their wide distribution in the CNS, and their ability to proliferate in response to injury, the endogenous OPCs in the adult CNS should be ideally suited for repairing the damaged CNS. The more one can learn about how to control their behavior the better.

A Diversion into Cell Death

Interest in cell death reached almost hysterical levels in the 1990s, although it never quite reached the intensity of the current preoccupation with stem cells. We became involved in cell death by chance in the late 1980s. There was a controversy about how OPCs differentiate into oligodendrocytes. My colleagues and I had proposed that it occurs by default when OPCs stop dividing and that it therefore does not require instructive signals in the way that type-2 astrocyte differentiation does. Arthur McMorris at the Wistar Institute, however, proposed that oligodendrocyte differentiation is induced by IGF-1 (McMorris et al., 1993). To try to resolve this controversy, Ian Hart cultured single OPCs in microwells as Sally Temple had originally done, only he omitted FCS and all signal proteins from the culture medium. To his dismay, the cells always died; if, however, he added either IGF-1 or high enough concentrations of insulin to activate the IGF-1 receptor, the cells lived and quickly differentiated into oligodendrocytes. Ben Barres and I repeated these observations with purified OPCs, and the results were the same: No matter how densely packed the cells, without appropriate signal proteins, such as IGF-1, the cells rapidly died, and they did so with the typical features of apoptosis (Barres et al., 1992). We concluded that IGF-1 is a survival signal for OPCs rather than a differentiation signal.

Around this time, I attended a Dahlem Conference in Berlin on neurodegenerative disorders. It was during this meeting that I first paid attention to evidence that apoptosis is an active process: a form of cell suicide. This had been suggested 20 years earlier by Kerr, Wyllie, and Currie (1972), but their insight had little impact until genes devoted to apoptosis and its regulation were identified in Caenorhabditis elegans (reviewed in Horvitz, 2003). I started wondering why OPCs in culture should need extracellular signals to avoid killing themselves, especially as the culture medium contains all the nutrients cells require. It was known that some developing neurons require signal proteins (neurotrophic factors) secreted by their target cells to survive, and there was strong evidence that the neurons competed for limiting amounts of these proteins. This arrangement provides a powerful way to match the number of neurons to the number of target cells they innervate. It occurred to me that the same mechanism might operate for most animal cells, which might require continuous signaling from other cells to avoid suicide; this might be the simplest strategy to ensure that animal cells only survive when and where they are needed (Raff, 1992). We spent a number of years testing this idea, and we were unable to kill it.

All of the normal cell types we tested behaved in the predicted way: When cultured alone without extracellular signals, they died by apoptosis. Yasuki Ishizaki, a post doc from Japan, showed that even lens epithelial cells (Ishizaki et al., 1993) and chondrocytes (Ishizaki, Burne, and Raff, 1994), whose normal neighbors in vivo are all cells of the same type, require extracellular signals to avoid apoptosis in culture. For these cells, the signals are autocrine factors secreted by other lens epithelial cells or chondrocytes, respectively. Miguel Weil, a post doc from Israel, Mike Jacobson, a post doc from UCSF, Harriet Coles, a Ph.D. student from Oxford, and my daughter Kim, who spent time in the lab while at university, together showed that all of the nucleated cells in various explanted mouse organs can be induced to undergo apoptosis if they are treated with a high concentration of the protein kinase inhibitor staurosporine in the presence of the protein synthesis inhibitor cycloheximide (Weil et al., 1996). These findings suggested that all nucleated mammalian cells can undergo apoptosis and that they constitutively express all the proteins required to do so.

Ben Barres studied the role and regulation of apoptosis during oligodendrocyte development in vivo. Many years earlier, Sam David, a post doc from Montreal, obtained indirect evidence that axons may promote the survival of oligodendrocytes and/or their precursors in the developing optic nerve. He found that transection of the neonatal rat optic nerve results in a dramatic decrease in both oligodendrocytes and OPCs (David et al., 1984). Ben now showed that 50% or more of the oligodendrocytes produced in the normal developing rat optic nerve die by apoptosis, apparently in a competition for limiting amounts of survival signals provided by the axons (Barres et al., 1992). He showed that transection of the rat optic nerve at the end of the first week of postnatal life causes most of the newly formed oligodendrocytes in the nerve to die by apoptosis, as expected if these cells require signals from axons to survive (Barres et al., 1993). Julia Burne then studied transgenic mice made by Jean-Claude Martinou and colleagues in Geneva that over-express the bcl-2 gene in neurons, including retinal ganglion cells (RGCs). Because Bcl-2 suppresses apoptosis, it decreases the RGC death that occurs during normal retinal development and thereby increases the number of axons in the transgenic optic nerve. She showed that, as a consequence of the increase in axons, oligodendrocyte cell death in the developing transgenic optic nerve is greatly reduced, so that the number of oligodendrocytes is increased to match the increase in axon numbers (Burne, Staple, and Raff, 1996). (Julia later showed that the increase in axons is also associated with an increase in astrocyte numbers in the nerve, but in this case it is because the axons stimulate astrocyte proliferation rather than astrocyte survival during development, LBurne and Raff, 1997].) Some years later, Pierre-Alain Fernandez, a French post doc, showed that our old friend GGF is an important axon-associated survival signal for oligodendrocytes in the developing optic nerve (Fernandez et al., 2000).

Earlier, Ben had found that axons in the developing optic nerve also stimulate OPC proliferation or survival (Barres and Raff, 1993). Thus, his work indicated that axons increase oligodendrocyte numbers by promoting both oligodendrocyte survival and the proliferation or survival of their precursors. He showed that the proliferation or survival effect on OPCs depends on electrical activity in the axons (Barres and Raff, 1993), whereas the survival effect on oligodendrocytes does not (Barres et al., 1992).

When we first started working on cell death, very little was known about the nature of the intracellular apoptotic program. In addition to showing that the death machinery is ubiquitously and constitutively expressed, our contributions to understanding the nature of the program were largely to show what is not required. Mike Jacobson showed that it does not require the presence of a nucleus (Jacobson, Burne, and Raff, 1994), which was surprising at the time, given that nuclear condensation and fragmentation are central features of apoptosis. Others had reported that the Bcl-2 protein is located in the inner mitochondrial membrane, raising the possibility that both apoptosis and its inhibition by Bcl-2 might depend on oxidative phosphorylation. Mike excluded these possibilities by showing that cells without mitochondrial DNA, which are incapable of oxidative phosphorylation, can still undergo apoptosis and that Bcl-2 can still protect them (Jacobson et al., 1993). Similarly, it had been suggested that the apoptotic program depends on the generation of reactive oxygen species and that Bcl-2 inhibits apoptosis by blocking their generation. Mike largely excluded these possibilities by showing that both apoptosis and Bcl-2 protection occur in anaerobic conditions, where reactive oxygen species are unlikely to be generated (Jacobson and Raff, 1995). The real breakthrough, however, came from Bob Horvitz and his colleagues, who showed that apoptosis depends on special proteolytic enzymes, now called caspases (Horvitz, 2003).

There are many cases in animal development where large–scale apoptosis occurs but its function is unknown. One example is the folding and fusion of epithelial sheets, as occurs in the formation of the neural tube. Miguel Weil used peptide caspase inhibitors in chick embryo cultures to show that neural tube closure depends on apoptosis (Weil, Jacobson, and Raff, 1997). He used the same approach to show that the loss of organelles during the terminal differentiation of keratinocytes depends on caspases (Weil, Raff, and Braga, 1999); Yasuki Ishizaki had shown earlier that the same is true for the loss of organelles during the terminal differentiation of lens cells (Ishizaki, Jacobson, and Raff, 1998).

Our last foray into cell death was to study the clearance of apoptotic cells by phagocytosis. Rahul Parnaik, a Ph.D. student from Cambridge University, collaborated with our UCL colleague John Scholes to show that the rate of clearance depends on whether macrophages or nonprofessional phagocytes such as fibroblasts or astrocytes do the clearing (Parnaik, Raff, and Scholes, 2000). They showed that, when a macrophage (or microglial cell) encounters apoptotic cells, it immediately engulfs them and digests them in less than an hour, whereas a nonprofessional phagocyte delays for hours before engulfing apoptotic cells and then digests them very slowly. Remarkably, if apoptotic cells are first aged in vitro, nonprofessional phagocytes ingest them immediately, suggesting that the ingestion depends on late-appearing properties of the apoptotic cell. This clever arrangement presumably enables professional phagocytes to do the clearing if they are present in adequate numbers; if they are scarce, however, nonprofessionals will ingest the apoptotic cells before the dead cells spill then intracellular contents. It is still unknown what these late changes in apoptotic cells are that are needed to signal to nonprofessional phagocytes.

The most interesting question, however, is not how apoptotic cells signal to phagocytes, but rather how live cells inhibit macrophages from eating them. A live cell is about the only thing that macrophages do not ingest, because they happily ingest plastic or glass beads, bits of wood, lipid droplets, and so on. Presumably, the putative “don't eat me” signals produced by healthy cells are lost when the cells undergo apoptosis, but such signals remain to be identified.

Axonal Degeneration

Much effort has been devoted to understanding the nature of the neuronal cell death that occurs in various neurodegenerative diseases. Does it occur by apoptosis or by some other mechanism? It is likely, however, that neuronal death in these diseases occurs too late to be clinically important, because degeneration of the axon probably disconnects a diseased neuron from its target long before the neuron dies (Raff, Witmore, and Finn, 2002). Axonal “dying back,” for example, occurs in many neurodegenerative diseases. In this process, there is a progressive degeneration of the axon over weeks or months, beginning distally and spreading toward the cell body. The selective degeneration of an axon, without the death of the parent neuron, can also occur during normal neuronal development and in response to local injury and to a variety of metabolic, toxic, and inflammatory disorders. Some forms of axonal degeneration, including Wallerian degeneration, seem to depend on an active and regulated program of self-destruction, rather than a passive “wasting away,” and in this respect resemble apoptosis. John Finn, a post doc from Johns Hopkins Medical School, and Alan Whitmore, a post doc from the Institute of Ophthalmology in London, investigated how similar the mechanisms of apoptosis and axonal degeneration actually are.

They found that the mechanisms are molecularly distinct. In contrast to apoptosis, John found that in both Wallerian degeneration and distal axonal degeneration induced by the local withdrawal of neurotrophic factors caspases are not activated and caspase inhibitors do not block the degeneration (Finn et al., 2000). Alan collaborated with Craig Thompson and his colleagues at the University of Pennsylvania to show that Wallerian degeneration occurs normally in mice that lack both Bax and Bak, two crucial pro-apoptotic proteins of the Bcl-2 family required for most forms of apoptosis (Whitmore et al., 2003).

To explain why so many different types of chronic insults to neurons can result in the same axonal “dying back” response, we proposed that neurons insulted in these ways may activate a self-destruct program in their axons, beginning peripherally, to disconnect from their target cells to conserve resources (Raff, Whitmore, and Finn, 2002). We also suggested that a similar program may be used by developing neurons to eliminate unwanted axonal branches in the axonal pruning process that occurs normally in neural development. It is still not known whether either of these hypotheses is correct, but I suspect that neurodegenerative disease research would benefit if more of it shifted its emphasis from neuronal death to axonal degeneration.

Cell Diversification in the Retina

We mainly studied the sciatic and optic nerves because they are relatively simple neural systems. From time to time, however, we dipped our toes into the more complex terrain of the retina. Charles ffrench-Constant, for example, showed that the rat retina does not contain OPCs or oligodendrocytes partly because there is a barrier where the optic nerve joins the eye that prevents OPCs from migrating from the nerve into the retina (ffrenchConstant et al., 1988). We principally used the retina, however, to address one of the big questions in developmental biology: How do cells diversify in developing animals? The question is especially challenging in the CNS, where there are probably more molecularly distinct cell types than in the other parts of the body put together. The retina is an especially attractive part of the CNS in which to approach the problem.

Takashi Watanabe, a neurosurgically trained post doc from Tokyo University, devoted himself to this project in the late 1980s. He first showed that the astrocytes in the rat retina migrate into the developing retina from the optic nerve head (Watanabe and Raff, 1988), as had been suggested by Jonathan Stone in Australia (Jonathan had earlier spent a sabbatical period with us). This finding fit well with lineage tracing experiments of others that had recently shown that multipotential retinal precursor cells can give rise to the photoreceptors, neurons, and Müller glial cells of the retina, but not to the astrocytes. These landmark lineage studies, performed independently by Turner and Cepko (1987), Holt and Harris and their colleagues (Holt et al., 1988), and Wetts and Fraser (1988), identified the central question in retinal cell diversification: How do the multipotential precursors decide what type of retinal cell to become?

Takashi began to address this question by studying the timing of rod development. Using anti-rhodopsin antibodies to unambiguously identify rods, he found that the first rods appear in small numbers in the rat retina at E20 and then increase rapidly for the next week or so. Although rhodopsin-positive rods failed to develop in dissociated-cell cultures of E15 retina, they did develop right on schedule if the E15 cells were centrifuged into a pellet that was then cultured on a floating polycarbonate filter. The pellet culture system allowed him to mix cells from different developmental ages. He labeled the DNA in proliferating E15 cells with bromodeoxyuridine (BrdU) and mixed the labeled cells with a 50-fold excess of unlabeled newborn retinal cells. The surprising finding was that the labeled E15 cells did not give rise to rods until the equivalent of E20, just as they did when cultured alone (Watanabe and Raff, 1990). Thus, the presence of the newborn cells, which were producing large numbers of rods from the start of the culture, did not affect the timing of rod development by the E15 cells, The result was unexpected because all three laboratories that had done the lineage tracing studies had concluded that retinal precursor cells remain uncommitted until around the last cell division, when extracellular signals dictate what the daughter cells become. (They came to this conclusion largely because they found two-cell clones of mixed cell type.) Takashi's results, however, suggested that retinal precursors change their intrinsic developmental potential as development progresses. On the other hand, although the presence of neonatal cells did not alter the time at which the E15 cells first gave rise to rods, they did increase the proportion of rods that the E15 cells generated, apparently by producing a short-range, rodpromoting, diffusible signal (Watanabe and Raff, 1992). We concluded from these studies that a combination of cell-cell interactions and an intrinsic developmental program in the precursor cells that changes a cell's developmental potential over time contributes to retinal cell-type diversity, a view that is widely held today (Livesey and Cepko, 2001).

Abbie Jensen, a post doc from the University of Wisconsin in Madison, and Valerie Wallace, a post doc from the University of Toronto, worked together to show that the signal protein Sonic Hedgehog is made by RGCs and stimulates retinal precursor cells to proliferate (Jensen and Wallace, 1997). Valerie went on to show that RGC-axon-derived Sonic Hedgehog also stimulates the proliferation of astrocytes in the developing optic nerve (Wallace and Raff, 1999), while Abbie developed a clonal-density culture system in which she could follow the proliferation, differentiation, and death of individual retinal precursor cells. Using this system, Abbie showed that, even when cultured in a homogeneous and constant environment where the cells cannot contact cells outside their own clone, the precursor cells vary in their proliferative capacity, cell-cycle time, and the cell types that they generate (Jensen and Raff, 1997).

At around the same time, Costas Neophytou, a Greek Ph.D. student from Cambridge University, provided an answer to a question raised by Takashi's earlier experiments: Why do rhodopsin-positive rods develop in high-density, dissociated-cell retinal cultures only if FCS is not present? He showed that Müller cells in culture secrete leukemia inhibition factor (LIF), which acts to arrest rod development at a stage just before rhodopsin is made (Neophytou et al., 1997). By stimulating Müller cell proliferation, FCS indirectly arrests rod development. Interestingly, FCS, for unknown reasons, does not stimulate Müller cell proliferation in pellet cultures, which is why rhodopsin-positive rods develop in these cultures even in the presence of FCS. Costas's findings corrected earlier findings that were interpreted to show that CNTF and LIF respecify cells fated to become rods to become bipolar cells instead (Ezzeddine et al., 1997).

We continued to work on retinal development until just before I retired. Alan Whitmore and Michel Cayouette, a post doc from Quebec, worked together to show that some retinal precursors in the newborn rat retina divide asymmetrically (Cayouette et al., 2001). They found that most precursors in the retinal neuroepithelium divide horizontally, with their mitotic spindle oriented in parallel to the plane of the epithelium, but a minority divide vertically, with their spindle oriented at right angles to the epithelium. They also found that the mNumb protein, a mammalian homologue of the Drosophila cell-fate determinant Numb, is located at the apical pole of the precursor cells, so that in vertical divisions only the apical daughter cell inherits mNumb.

Michel then used time-lapse video recording of GFP-labeled retinal precursors in explants of newborn rat retina to follow the fates of daughter cells produced by either vertical or horizontal divisions (Cayouette and Raff, 2003). He showed that the two daughters of horizontal divisions almost always become photoreceptors, whereas the two daughters of vertical divisions almost always become different—usually one becoming a rod and the other either an interneuron or a Müller cell. Thus, at this stage of retinal development, the plane of division along the apical-basal axis clearly influences cell-fate choice, and Michel provided indirect evidence that the asymmetrical segregation of mNumb in vertical divisions might be involved possibly by inhibiting Notch signaling in the apical daughter cell, as has been shown for Numb in Drosophila.

To study the relative importance of cell-intrinsic mechanisms and extracellular signals in cell-fate choice in the developing retina, Michel extended Abbie's observations by developing a serum-free and extract-free clonal-density culture system to follow the fate of individual clones of proliferating E16–17 rat retinal precursor cells. Remarkably, he found that the precursors behave similarly in these cultures and in explant cultures of E16–17 retina in 10% FCS, both in the number of times the precursors divide before differentiating and in the cell types the precursors generate (Cayouette, Barres, and Raff, 2003). These unexpected results challenged the prevailing view (mentioned earlier) of how cells diversify in the developing vertebrate retina. They suggest that positive inductive signals are unlikely to be important in determining cell-fate choices, at least from E16–17 onwards. We suspect that the precursors are variously programmed before this time and then step through their particular developmental program independently of instructive extracellular signals. Also surprisingly, Michel found that some retinal precursors in dissociated-cell culture rotate their mitotic spindle through 90 degrees just before dividing, consistent with his previous evidence that asymmetrical divisions are important for some cell-fate choices. If this model of preprogramming is correct, one needs to determine when and how retinal precursors become preprogrammed, how many preprograms there are, and how the programs operate.

Sally Temple, now at Albany Medical College, and her colleagues have provided compelling evidence for similar preprogramming of mouse cortical precursor cells (Qian et al., 2000). It remains one of the great challenges for developmental biologists to discover how intracellular programs alter the developmental potential of precursor cells over time. Encouragingly, Chris Doe at the University of Oregon is making rapid progress in analyzing the molecular mechanisms involved when Drosophila neuroblasts change their developmental potential as they undergo a stereotyped sequence of asymmetrical divisions (Grosskortenhaus et al., 2005).

Molecular Biology of the Cell

I have spent almost 30 years as a coauthor of the cell biology textbook Molecular Biology of the Cell. Jim Watson convinced me and the other authors to join the project by pointing out that whatever we do in science others will do either before or soon after, but writing this book could be a unique contribution. I think he was probably right, but he was dead wrong when he said that it would take us just two summers to write the book. Instead, it took six summers and two-to-three other meetings each year. It is now in its fourth edition, and we are currently writing the fifth. The book has consumed a large part of my life, but it has been great fun, and I learned an enormous amount from my coauthors and the many scientists who generously helped us over the years. I am not sure whether it helped my science, but it greatly broadened my interests in cell biology.

Summing Up

I have been inordinately lucky in my career. My choices to become a scientist, to start at the NIMR, and to work with Av all depended on chance rather than on careful thought. Unlike many scientists, I have received more credit than I deserved, especially during my first few years in science.

I have been especially lucky in the students, post docs, and research assistants I have had as colleagues. They have been a privilege and joy to work with, and their successes are a continuing source of pleasure and pride. Our group was relatively small, usually consisting of one or two Ph.D. students, four or five post docs, a research assistant (who doubled as lab mother), and frequently a senior scientist on sabbatical. In Table 1, I list the lab members over the years (I apologize if I have left anyone out).

Although we worked on diverse biological problems, the questions were quite consistent. How does a developing cell decide whether to survive or die, to grow or stop growing, to proliferate or stop proliferating, or to differentiate into one cell type rather than another? To what extent does the decision depend on intrinsic mechanisms, signals from other cells, or both? We tried to focus on subjects that were unfashionable at the time, such as intracellular developmental programs, developmental timing, cell survival control, animal and cell size control, and axonal degeneration.

I learned much from Av, my only mentor—too much to summarize here. One of the most useful lessons he taught me by his example was the importance and benefits of sharing—even with your competitors—ideas, reagents, and results of experiments. For a student or post doc, this is not intuitive behavior, because one's instinct is to be protective for fear of being scooped. The benefits of sharing therefore need to be taught. To my knowledge, we never suffered from sharing reagents or results long before they were ready for publication. Instead, we benefited greatly from the feedback we received and from the many reagents we obtained from other scientists.

Table 1. Past Members and Associates of the Raff Lab

I also learned from Av the value of reporting back on the scientific meetings I attended. I attended many meetings and felt guilty being away so much. The most compelling justification was that I sometimes learned things at a meeting that saved us months or years of work. Thus, whenever I turned down an invitation to a meeting, I had nightmares that I would miss something of overwhelming importance to us. Reporting back on meetings diminished my feelings of guilt, because it helped the students and post docs keep up to date. It had the added advantage that I had to take detailed notes at meetings and review them before reporting back, which helped me digest and remember what was presented.

During my immunology years, Niels Jerne had an important influence on me. He later won a Nobel Prize for his conceptual contributions to immunology. When I first met him at the Basel Institute for Immunology, which he directed, he told me that young scientists (like me) run so quickly that they see only the large objects, whereas older scientists (like him) walk slowly behind, paying attention to small objects that have much to tell us. I was not sure exactly what he meant, but I tried to slow down anyway. He also advised me to discourage my children from becoming scientists, because it would put them under excessive pressure. This seemed sensible advice, and I did not encourage my children to become scientists. I did not entirely succeed, however. My oldest son, Jordan, studied biochemistry at Bristol University and is a successful Drosophila cell biologist at the Gurdon Institute at Cambridge University. It used to be that scientists asked Jordan if he was my son; now they ask me if I am his father. His younger brother, Adam, studied computer science at Edinburgh University and is setting out in business with his wife, having invented powerful new ways to search the Web. Daughter Kim, the youngest, studied biology at Cambridge University and became an intellectual property lawyer before becoming a mother. They are all happily married and thriving. They have produced five adorable grandchildren and, luckily for me, live close by.

I have also been extremely fortunate to have the MRC support my salary and research for 31 years. We rarely did what we proposed to do in our 5-year grant applications. As far as I know, no one ever compared our original proposals with our progress reports, which meant that we had complete freedom to change directions at will, which we did frequently. Will the public and governments continue to support the kind of curiosity-driven science that we did? It would be unwise to assume so.

It would also be unwise to assume that our species has the will and collective intelligence to preserve life on Earth. After all, most people on the planet know little more about how the world works than our ancestors did thousands of years ago. How can we expect them to understand the problems that threaten the biosphere and to take appropriate action, especially if they think it is all in the hands of God?

Selected Bibliography

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Billon N, Terrinoni A, Jolicoeur C, McCarthy A, Richardson WD, Melino G, Raff M. Roles for p53 and p73 during oligodendrocyte development. Development 2004;131:1211–1220.

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Wilfrid Rall

BORN:

Los Angeles, California

August 29, 1922

EDUCATION:

Yale University, B.S. (Physics, 1943)

University of Chicago, M.S. (Biophysics, 1948)

University of New Zealand (Otago), Ph.D. (Physiology, 1953)

APPOINTMENTS:

Manhattan Project (University of Chicago, 1943–1946)

Biophysics Fellow (Chicago & Woods Hole, 1946–1948)

University of Otago Medical School (Dunedin, NZ)

Physiology Lecturer (1949–1950)

Senior Lecturer (1951–1956)

Naval Medical Research Institute, Biophysics (1956–1957)

National Institutes of Health, Office of Mathematical

Research, NIAMD (1957–1967)

National Institutes of Health, Mathematical Research Branch, NIDDK (1967–1994)

Visiting Fellow, Australian National University (1988)

Visiting Fellow, UC-Berkeley (1992)

HONORS AND AWARDS (SELECTED)

Yale University Regional Scholarship (1940–1943)

Highest Honors in Physics (with Yale B.S., 1943)

Rockefeller Foundation Travel Fellowship (1954–1955)

Central Council of IBRO (1968–1973)

NRC-NAS Committee for Brain Sciences (1968–1973)

Council of Society for Neuroscience (1970–1972)

NRC-NAS National Committee for IBRO (1972–1976)

NIH Senior Scientific Service Performance Award (1983)

Scientist Emeritus of the NIH (1994)

Wilfrid Rall pioneered biophysical modeling and computation for dendritic neurons, with a focus on functional insights, testable predictions, and reinterpretation of experiments. With research collaborators, he demonstrated the functional importance of synapses on dendrites, predicted the discovery of dendrodendritic synapses, and identified the dendritic spine as a possible locus for plasticity.

Wilfrid Rall

On several occasions, younger scientists have asked me variations of the following question: Is it really true that you have had the exciting experience of seeing your theoretical modeling predictions confirmed by neurophysiological experiments? The answer is yes, more than once, and each time was an exciting experience. Several examples are described later.

The interplay between theoretical modeling and neurophysiological experiments has led to valuable functional insights; these insights provide a basis for improved models and improved experiments. Also, such modeling sometimes corrects previous misinterpretations of experimental results. Examples will be found later.

I welcome the invitation to contribute a chapter for this volume. At age 83 (in 2005), I can offer some perspective, as a Scientist Emeritus of the National Institutes of Health (in 1994), and as one of the Founders of the Society for Neuroscience (in 1970). Also, I have recently gained an almost Olympian perspective, living in the Virginia Blue Ridge at elevation 3400 feet, about 40 miles west of Thomas Jefferson's Monticello.

Background

In retrospect, I was fortunate in my choice of parents: They had mostly good genes, and they had nurturing instincts as teachers and idealists with a love of literature, of nature, and of creative activity, such as art, music, and poetry. Both were born in Europe: my father, Udo Rall, 1894 in Heilbronn, Germany; my mother, Doris, 1896 in Zug, Switzerland. They met in California, on a mountain-top, in 1920. I was born in Los Angeles, on August 29, 1922; my brother, Waldo, was born on March 20, 1924.

My brother and I grew up feeling different from our contemporaries: We spoke German at home before we started school; instead of church on Sunday, we went hiking in celebration of nature. My parents became pacifists, in reaction to the carnage of World War I (note that “Wilfrid” is a contraction of will frieden, “wish for peace"). We read books together: for example, the original German (pre-Disney) Bambi, and also poetry and mythology. It was assumed that my brother and I would do well in school, and we did.

We attended the UCLA teacher training school for 3 years, and then public elementary school in Los Angeles. Our public secondary schooling was in Washington, DC. Our move from California was due to the Depression: My father's small business could no longer support three partners. Fortunately, a good friend provided entree to Franklin D. Roosevelt's (FDR's) “New Deal” (in 1933); my father became an expert in facilitating self-help cooperatives for the Federal Emergency Relief Administration (FERA) and for the Works Progress Administration (WPA). Later, he was invited to write a proposal for rural electric cooperatives; this contributed to the creation of the Rural Electrification Administration (REA). He served several years as a coop-education specialist in the REA. He was also active in consumer cooperatives in the DC area. At this time, my mother served for awhile on the National Board of the Women's International League for Peace and Freedom. In his retirement, my father enjoyed artistic pursuits: poetry, painting, sculpting, and experimenting with unusual enameled-copper compositions.

High School and College (1937–1943)

Western High School (located next to Georgetown University in Washington, DC) was academically oriented and encouraged students to apply for university scholarships. I kept busy with math and science courses, debating team, yearbook, and orchestra. Although a scholarship to George Washington University had already been awarded to me for being part of a champion high school debating team (in 1939, the DC-Baltimore area), it was my good fortune to win a Yale University Regional Scholarship (in 1940, SE region). This provided me with an outstanding educational opportunity.

My Yale class was 1944, but I graduated in October 1943, with highest honors in physics. Because of World War II, Yale held classes during the summers of 1942 and 1943. Many classmates were drafted or volunteered for military service, but science majors were deferred by their draft boards to continue their studies and become part of the scientific manpower pool. Within a week of graduation, I traveled to Chicago to join the Physics Division of the World War II Manhattan Project at the University of Chicago. My courses at Yale were mostly in math and science, but I did also enjoy courses in history and philosophy. I even joined the Yale Political Union (debating society), and became leader of the Labor Party. The leader of the Conservative Party was Lloyd Taft; Seth Taft was President of the Political Union (the classmates were the son and nephew, respectively, of Senator Robert Taft).

During my final two semesters at Yale, I was one of three undergraduate students admitted to the core physics course for graduate students. This course met for 90 minutes, 5 days a week, and required solving all of the problems provided by our thick textbook, Introduction to Theoretical Physics, by Professor Leigh Page (who taught the course). I now appreciate that working through all those physics problems, as well as assisting in the advanced physics lab course, provided me with an unusual opportunity to develop my physical intuition and my approach to problem solving. These helped me later when confronting problems in biophysics and neurophysiology.

Manhattan Project during World War II (1943–1946)

The Manhattan Project operated at many sites, all given deceptive names. At the University of Chicago, it was the Metallurgical Laboratory. The director was Professor Arthur H. Compton, Nobel Laureate in Physics. The Head of the Physics Division was Professor A.J. Dempster, the founder of mass spectrography and the discoverer of the U-235 isotope of uranium. Upon my arrival (October 1943), I was assigned to Professor Dempster, along with two other recently arrived young physicists.

My first task in Chicago was to assist Dr. A.E. Shaw in the design and construction of an updated mass spectrograph, based on Dempster's suggested improvements of his original design. I actually produced the engineering drawings, with Shaw looking over my shoulder. Armed with a top priority at the physics machine-shop, as well as the electronics and glassblower shops, we proceeded to assemble and test this new equipment, which had much in common with a cyclotron; it included a high-frequency spark source (that could ionize heavy metals inside a high vacuum), together with a high-voltage accelerator, a strong electromagnet, and a photographic collection system. A detailed description was later declassified for publication in the Review of Scientific Instruments (Shaw and Rall, 1947).

This equipment was needed in Hanford, Washington, where the Manhattan Project had sited its plutonium production facility, on a bend of the Columbia River (for supply of water cooling). Our equipment was disassembled and carefully packed aboard a U.S. Army truck. Four military policemen were assigned to drive this truck to Hanford. At the last minute, I was assigned to accompany this shipment. The trip was an adventure that took about a week. Upon our arrival at a vast conglomeration of temporary buildings, my presence became critical, because I insisted that the truck be taken, not to the general receiving dock, but directly to the building in which the equipment was to be reassembled.

It is relevant to note that uranium (a heavy metal element with atomic number 92) consists predominantly of atoms having atomic mass 238; only a small percentage of natural uranium is the isotope with atomic mass 235. A very special property of U-235 atoms is the following: If a neutron is captured by its atomic nucleus, this nucleus becomes unstable and it undergoes fission; that is, it splits into two smaller atoms, whose combined mass is less than the parent mass, and the missing mass appears as a tremendous release of energy (as predicted by Einstein's equation). Also released are two neutrons; these neutrons can trigger more fission of U-235, and synchronous fission of many U-235 atoms is the key to an atomic bomb.

But that is not all. The common uranium isotope, U-238, has a different special property; when it captures a slow neutron, it can become a new element with mass number 239, and atomic number 94; this is known as plutonium, P-239. And remarkably, plutonium has the same special property noted previously for U-235; it is an alternative ingredient of an atomic bomb. But plutonium does not occur in nature; it must be manufactured in a specially constructed “pile” that consists of a three-dimensional lattice of uranium cylinders supported in a graphite structure (graphite slows the neutrons, favoring capture), together with special water-cooling. When conditions are perfect, the chain reaction of fission, neutron production, and neutron capture, can be controlled to produce significant quantities of plutonium. However, a possible complication was anticipated, because some fission product isotopes have a large capacity to capture neutrons. If too many neutrons are captured by these isotopes, this can quench the chain reaction and prevent the production of plutonium. Thus, it is important to monitor the fission product isotopes that result from pile activity; hence the need for our mass spectrograph. An interesting description of the quenching problem encountered at the Hanford plutonium production piles is provided in an excellent book by Richard Rhodes (1986).

Although the U.S. Army policy was to keep young scientists ignorant of activity at different Manhattan Project sites, we knew quite a lot via the insider-grapevine; however, we were very careful not to breach security to the outside. Two Yale classmates and two high school classmates also served on the Manhattan Project. My brother worked at four different sites: St. Louis, Chicago, Oak Ridge (Tennessee), and Los Alamos (New Mexico). His draft board drafted him while he was at Los Alamos; after completing basic training, he was assigned to a special engineering detachment (SED) and returned to Los Alamos. Before Shaw and I left Hanford, physicist friends of Shaw's took time to show us around the production facilities. They also mentioned that security policy provided code names for several distinguished European physicists who consulted at this site: Enrico Fermi was Mr. Farmer, Eugene Wigner was Mr. Wagner, and Neils Bohr was Mr. Baker.

After the scientists from Los Alamos completed their successful test at Almagordo, New Mexico (July 1945) we knew that the atomic bomb was proven possible. Dr. Leo Szilard felt a heavy burden of responsibility; it was he who had persuaded Einstein to write the letter to FDR that led to the Manhattan Project; also, although few knew this, it was Szilard who held a top-secret British patent that described the design of a pile for plutonium production. The reason he and other European scientists dedicated their efforts to the Manhattan Project was their very real fear that the Nazis might succeed first in making an atomic bomb. Once Germany was defeated, Szilard felt strongly that the A-bomb should not be used on a populated Japanese city. He prepared a petition, addressed to FDR, urging that the Japanese be invited to observe a test-demonstration, on an uninhabited island, and then be given an opportunity to surrender. I signed that petition. It never reached FDR, but it did reach Secretary Stimson. Both Stimson and President Truman decided that first use of the atomic bomb was justified; many lives were saved (on both sides) by removing the need for an invasion of Japan.

Many years later, I had an opportunity to converse several times with a Japanese military historian. After I felt comfortable in talking with him, I told him that I had signed that petition, and I asked whether he thought the proposed test-demonstration might have succeeded. He said that he feared not; he said that his mother was a young schoolgirl at that time and said that she, and all of her friends, had sharpened sticks with which to defend their homeland from invasion.

Leo Szilard founded the “Council for a Livable World” because of his concern that unwise militarists might regard nuclear weapons as routine tools. He wanted to ensure that there are enough level heads in the U.S. Senate to curb unwise nuclear policy. His idea was to provide expert nuclear physics advice to all Senators and also to generate financial support to help elect enlightened Senators. This task has prospered, but much remains to be done. Szilard's legacy has recently been augmented by the establishment of a “Center for Arms Control and Non-Proliferation” in a newly renovated building on Capitol Hill, near the Senate Office Buildings. A dedicatory bronze plaque, at the entrance to this center, identifies many contributors; this list includes me, in memory of my parents.

Basic Physics Research (1946)

Before leaving the Manhattan Project, I had the opportunity to carry out some basic research, using Dempster's mass spectrograph. As fission products, the elements palladium and iridium each have two radioactive isotopes; the problem was to determine which isotope (atomic mass) belongs with which radioactive half-life. In each case, it was possible, by running a longer than usual experiment, to collect a sufficient amount of material in the spread-out mass spectrum so that these isotopes could be distinguished by radioautography: A brief photographic exposure to the mass spectrum identified the isotope with the short half-life, while a longer exposure identified also the isotope with the longer half-life. These results were declassified as an abstract (Rall, 1946). In a different experiment, I provided careful measurement of nonuniform spacing in the mass-spectrum of zirconium isotopes (Rall, 1948); this measurement was of great interest to Dr Maria Goeppert-Mayer (1963 Nobel Laureate in Physics), because it confirmed a prediction of her theoretical model of nuclear structure. Although I could have continued with Professor Dempster, to complete a Ph.D. under his supervision, I decided to switch from nuclear physics to biophysics.

Biophysics at Woods Hole and Chicago (1946–1948)

Professor K.S. Cole had been with the Manhattan Project in Chicago. In 1946, he participated in founding an Institute of Radiobiology and Biophysics and also a Biophysics Ph.D. program at the University of Chicago. My friend, A.E. Shaw, introduced me to George Marmont, who was preparing to go to Woods Hole that summer (with Cole) for research on squid giant axons. I was offered an opportunity to participate in this research. I became a Biophysics Fellow of the new institute, both for summer research at Woods Hole and for predoctoral studies at the University of Chicago.

Thus, my switch from physics to biophysics began in Woods Hole, during two summers (1946 and 1947). I learned to dissect squid giant axons, to assist with special electrode manufacture, and to assist in the earliest experiments using “current clamp” and “voltage clamp” on a “space-clamped” giant axon. Marmont had designed a sea-water chamber that provided uniform extracellular voltage along a length of the squid axon (by use of two guard rings, flanking a longer central region of the chamber); he had also designed electronics that used negative feedback to maintain a constant current across the axonal membrane, from the extracellular bath to an axial intracellular electrode (Marmont, 1949). Thus, he expected to control a uniform membrane current density, and observe membrane voltage transients. It was Cole who argued the advantages of voltage clamping; it avoids the complication of capacitative current and puts the focus on the ionic current across the membrane. We did both experiments.

Cole and Marmont argued the pros and cons with Alan Hodgkin, when he visited the University of Chicago in 1948 (see pp. 281–283 of Hodgkin, 1992). Hodgkin understood Cole's interest in the diphasic current transient observed under voltage clamp, and together with Katz and Huxley, he succeeded in distinguishing the initial inward sodium ion current from the slower outward potassium ion current (Hodgkin, Huxley, and Katz, 1949; see also pp. 288–303 of Hodgkin, 1992). This was a major breakthrough; it depended not only upon excellent biophysical experiments and mathematical modeling but also upon awareness of sodium and potassium ionic concentration differences and the importance of rapid changes in membrane permeability to sodium versus potassium ions in the generation of an action potential. This research fully deserved the Nobel Prize that it won.

The University of Chicago provided excellent interdepartmental courses to facilitate a switch from physics to biophysics and physiology. In 1946, the university had an influx of advanced students (from the GI Bill, and from World War II research labs); new courses were organized, including a 200-level survey of biology, given by senior faculty of many departments. Richard Podolsky and I both enjoyed this course as a part of Cole's biophysics predoctoral program. An advanced course in general physiology was organized by Manuel Morales, Herbert Landahl, John Hearon, and others of several departments. It is remarkable that later, Cole, Morales, Hearon, and Podolsky were all at the Naval Medical Research Institute (NMRI) when I visited there in 1954; it was Morales who had facilitated biophysics at NMRI. I audited a course in mathematical biophysics by Nicholas Rashevsky, a nuclear physics course by Enrico Fermi, and a symbolic logic course by Rudolph Carnap. I also took a geneticstatistics-probability course with Sewall Wright; this provided me with a grasp of probability theory that helped me in later modeling of motoneuron populations (Rall, 1955a; Rall and Hunt, 1956).

During my time at the University of Chicago, I put some effort into uniting several student housing co-ops. Also, I married Ava Lou Freed (in 1946); she was a co-op member and a graduate student with the interdepartmental Committee on Human Development. She completed her M.A. degree in 1948. She deserves credit for being supportive of my preference for basic biophysical research, when her father was urging me to pursue an M.D. degree.

The university provided a stimulating environment, but my wife and I began to think about a change from the Chicago climate. I had not yet chosen a Ph.D. thesis problem and had found that Cole and Marmont did not provide a harmonious research environment. I became interested in a theory of synaptic inhibition proposed by J.C. Eccles, in New Zealand. Eccles responded positively to my exploratory letter, and I decided to accept his offer of a lectureship in his physiology department. Because I had more than enough course credits for an M.S. degree at the University of Chicago, I only needed to write a suitable essay to complete the requirements. I chose to discuss “The Field of Biophysics.”

Although I explored Professor Cole's suggestion of a two-dimensional array that would focus on the intersections of subdivisions of physics in one dimension, with subdivisions of biology in the other, I found that I preferred a different approach. This was a hierarchy of systems, from subatomic systems, with integration into atomic systems, then molecular systems, then self-reproducing systems and simple unicellular organisms, then multicellular organisms, and onward to large ecological systems. Biophysics is key to many of these systems and to the integration from one level to the next. My essay explored biophysics from this point of view (Rall, 1948).

Spinal Cord Physiology in Dunedin, New Zealand (1949–1956)

Professor J.C. Eccles headed the physiology department of the Medical School at the University of Otago, in Dunedin, New Zealand. The Province of Otago was settled by Scotsmen who named Dunedin after Edinburgh; a statue of Robert Burns stands in the central octagon. The local citizens established the first university and the first medical school in New Zealand. Although now part of the University of New Zealand, they proudly retain the original name, the University of Otago.

My wife and I made a 3-week trip by sea, from Vancouver, B.C., via Hawaii and Fiji, to arrive in Auckland, New Zealand in January 1949. At Eccles' suggestion, we brought our car on the same ship, and we drove from Auckland to Wellington, where we visited friends. A ferry took us to Christchurch, in the South Island, and we drove southward to Dunedin. Americans were scarce in Dunedin, and we received a warm welcome from the Eccles family, as well as others in the department and in the community.

The physiology department had a very busy schedule, which included lectures and labs for 2 years of medical school, plus a general physiology course, as well as special courses for dental, nursing, and home science students. Nevertheless, Eccles aimed to keep up his basic research momentum with at least one experiment a week; this involved an all-day/night experiment on cat spinal cord. I gave lectures in general physiology and helped run the student lab courses, but my major responsibility was to be fully involved in the research. This included dissections, assembling the set-up, and sharing with Eccles the planning and conduct of the experiments and the subsequent analysis of the data (recorded on glass photographic plates). When the experiment went well, it continued far into the night. Fortunately, I had the needed stamina and interest to keep up with Eccles during this rigorous routine.

Both A.K. Mcintyre and L.G. Brock, who joined the department around the same time, became friends who coached me in the fine points of dissecting the spinal cord, dorsal and ventral roots, and also the muscle nerves of the cat hind limb. Two busy years of effort produced the following research papers (Brock, Eccles, and Rall, 1951; Eccles and Rall, 1950, 1951a, 1951b). We studied post-tetanic potentiation in motoneurons and the effects of graded strengths of stimulation to a number of muscle nerves in the cat hind limb. Much of this research was related to that of D.P.C. Lloyd, the author of the neurophysiology chapter in Fulton's Textbook of Physiology. I believe that Lloyd had done his degree at Oxford, with Eccles as supervisor; also Mcintyre had visited Lloyd shortly before coming to Dunedin.

At that time, most of our recording was from ventral roots; some was also done with steel electrodes inserted into the spinal cord. This was 2 years before the beginning of micropipette recording from individual motoneurons. In Dunedin, we first learned about micropipette recording from Dexter Easton, who came as a Fulbright Fellow from the University of Washington (in 1950); he was aware of the early experiments by Woodbury and Patton. Woodbury, and also Karl Frank, had learned the micropipette technique at the University of Chicago, from Gilbert Ling, who had pioneered this technique on single muscle fibers. Also, Hodgkin (1994, p. 283) acknowledges learning this technique from Ling in 1948; this technique was rapidly adopted by many, including Nastuk and Hodgkin, Fatt and Katz, and others noted by Hodgkin (1994, p. 287). Incidentally, I got to know Gilbert Ling in 1947, when he taught the physiology lab course that I took. He was very bright and very helpful. When I met him again, many years later, he seemed to have become lost on a side track.

Eccles decided promptly that he must not fall behind in the application of micropipettes to motoneurons of cat spinal cord. Brock was asked to focus on learning to make micropipettes, and Coombs was recruited from the physics department to take charge of modernizing stimulating and recording electronics. They produced early results in time for the Cold Spring Harbor Symposium on Quantitative Biology held in June 1952. Although I could have been part of this effort, I had already begun work on independent Ph.D. thesis research, described later.

Here, I note that Eccles (an Australian) moved from Dunedin to Canberra, to be the first Professor of Physiology at the Australian National University (in 1952). Archie Mcintyre (also Australian, born in Tasmania) succeeded Eccles as Professor in Dunedin; also, I became Senior Lecturer in Physiology. Several years later, Mcintyre became the first Professor of Physiology at Monash University, in Melbourne.

Monosynaptic Input-Output: Theory and Experiment (1951–1953)

Archie Mcintyre had drawn my attention to the monosynaptic input-output relation that had been demonstrated by Lloyd (1943, 1945) at the spinal segmental level. The magnitude of the almost synchronous output voltage transient (recorded in the ventral root) was plotted against the magnitude of the almost synchronous input voltage transient (recorded in the dorsal root). The resulting input-output curve rises almost linearly from zero over the first half of increasing input, but then it bends over into a level plateau, for larger values of the input measurement. A correct understanding of this plateau proved to be of critical importance.

I had become interested in developing and testing a theoretical model of this input-output relation, based on the concept of a population of motonuerons upon which the relevant synapses were randomly distributed. This leads to a probabilistic model of the population response; as the number of active synapses is increased, those motoneurons which happen to receive more of this monosynaptic input will reach threshold for discharge of an action potential. The simplest assumption to try first is that the motoneuron population fits a normal probability distribution, with respect to synaptic numbers and discharge threshold. The input-output relation implied by such a statistical model was formulated and computed (Rall, 1953b, 1955a).

We knew that only the largest afferent fibers (group Ia) in the muscle nerve make direct synapses with the motoneuron population of that nerve in the spinal cord. These afferent fibers differ from smaller diameter afferent fibers in having the lowest threshold to electrical stimulation and the highest conduction velocity. Thus, a brief shock to a muscle nerve (in the cat hind limb) produces an almost synchronous impulse volley in these (group Ia) afferents; this volley reaches the direct (monosynaptic) synapses on the motoneuron population long before slower impulses in smaller afferent fibers reach other targets, some of which can provide later, polysynaptic input to this motoneuron population. This knowledge ensures that the almost synchronous output volley, recorded in the ventral root, is truly a monosynaptic output from this motoneuron population, caused by the group Ia input volley.

However, it was important to understand that the magnitude of the input volley (recorded from the intact dorsal root) can include contributions from impulses in group Ib and perhaps some group II afferent fibers, especially with a large stimulus shock. This portion of the input record does not contribute to the monosynaptic input. It was necessary to correct for this by determining the relation between “effective monosynaptic input” and the “recorded input volley magnitude.”

This insight explains the error of previous interpretations of the input-output relation: The plateau of maximum output for input magnitudes greater than 60% had been misinterpreted as “output saturation,” implying that all of the motoneurons in that population had fired an impulse into the ventral root. My experiments demonstrated the error of this misinterpretation in two different ways: (a) they showed that the last 40% of the input measurement does not represent “effective monosynaptic input"; (b) they also showed that the observed maximum output did not represent the total discharge of the motoneuron pool (see next).

Point b was demonstrated by performing the input-output experiment at four different levels of reflex excitability, in the same preparation: (1) the maximum output at the first level was estimated as 72% of total pool discharge; then (2) the reflex output was enhanced by using brief post-tetanic potentiation, yielding a shifted input-output relation whose maximum output was estimated as 84%; then (3) added anesthetic was used to reduce reflex excitability, yielding a shifted input-output relation whose maximum output was estimated as 37% of total pool discharge; then (4) brief post-tetanic potentiation was used to produce another shifted input-output relation whose maximum output was estimated as 60% of total pool discharge (Rall, 1951, 1953b, 1955b).

Note that without the correction for ineffective input, each of these four experimental input-output relations showed a plateau. These four different levels of output plateau clearly could not all represent output saturation (total pool discharge). This further supported the importance of finding the relation between the “effective monosynaptic input” and the experimentally recorded input volley magnitude. It was very satisfying that, with this correction, these four experimental input-output relations could be fitted with a simple probabilistic model, by adjusting the value of only one model parameter, namely the one that corresponds to reflex threshold (Rall, 1953b, 1955a,b). This agreement provides a good example of where predictions of a simple theoretical model were confirmed by experiment, (especially when the experiment was sufficiently comprehensive).

I note further, that two probabilistic models (differing in the definition of the threshold condition) were tested. The simplest assumed that a motoneuron discharges when the number of simultaneously activated synapses on this motoneuron reaches or exceeds a specified threshold number; the other model assumed that a smaller number of activated synapses could succeed, provided that they were concentrated in a subregion (zone) of the motoneuron's receptive surface. I found that the experimental data could be fitted by both models. Thus, this test did not settle the question about whether the threshold region is zonal. However, it did show that the local, zonal concept of Lorente de Nó (1938) is not necessary to explain the input-output relation, as others had thought. My Ph.D. thesis was completed in 1953; my sabbatical leave began in 1954.

More complete description and discussion of this research can be found in several places: There are the original papers (Rall, 1955a, 1955b); a useful summary appeared later in a book chapter (Rall, 1990), and also as Appendix A.2 in another book (Segev, Rinzel, and Shepherd, 1995), in which Appendix A.1, by Julian Jack, is also relevant.

lsopotential Soma (1953)

In my input-output study, I gave no explicit consideration to the dendrites of the motoneurons. Lorente de Nó had put his focus on the soma and on subzones of the soma surface; in fact, he asserted that the effects of activated synapses would be cumulative only for synapses located close together, and not for synapses located far apart (Lorente de Nó 1938). Thus, I was interested in exploring questions about the rate of spread of localized membrane depolarization on the motoneuron soma surface.

I considered the mathematical physics of passive membrane depolarization on a spherical soma (Rall, 1953a, 1953b). What I discovered is that passive (electrotonic) spread of local membrane depolarization is very much more rapid over a spherical soma surface than it is along cylinders of axonal and dendritic dimensions. The mathematical solutions contain time constants for equalization of passive membrane potential over a spherical soma. By using reasonable values for resistance and capacitance, these time constants are found to be about a thousand times smaller than the (RC) time constant of the passive membrane; i.e., microseconds compared to milliseconds. Thus, I was able to conclude that “the passive electrotonic response to a focal (synaptic) current loses its spatial decrement almost completely by the time the 'synaptic potential' reaches its maximum value” (Rall, 1953b, 1955a).

The physical-intuitive explanation of this mathematical result depends upon the relatively low electrical resistance between different regions of the sphere interior. It is this low resistance that is responsible for the small equalizing time constants that correspond to rapid equalization of soma membrane potential. This low resistance contrasts with the relatively high core resistance found along the interior of a thin cylinder, which is responsible for the length constant, lambda, and for equalizing time constants found for dendrites (Rall, 1969).

Once this is understood, it becomes clear that this biophysical result does not really depend on the precise spherical shape that was assumed for the mathematics; this result should hold true for any globular shape that is free of constricted cross-sections. This insight provides the basis for the simplifying assumption that the soma membrane may be regarded as isopotential, relative to nonuniform membrane potentials in dendritic trees (Rall, 1959b).

Sabbatical Leave in London and New York (1954–1955)

As beautiful as the mountains and coastline of New Zealand really are, academics do feel isolation from the rest of the world. Consequently, the university was inclined to approve sabbatical leave after 5 years of faculty service. The local salary scale was not sufficient for travel and subsistence elsewhere, but I was fortunate to be awarded a travel fellowship from the Rockefeller Foundation, for research visits with Bernhard Katz, at University College London, and with David Lloyd, at the Rockefeller Institute for Medical Research (about to become Rockefeller University). Both Katz and Lloyd were friends of Archie Mcintyre, and both had read my Ph.D. thesis.

Our travel began with an ocean voyage from Wellington to Sydney, across the Tasman Sea; this was the roughest sea voyage in my experience; in fact, I was one of the few passengers who did not become fully seasick. We visited with friends in Sydney, and also with Coombs, Eccles, and Fatt in Canberra, before boarding an Italian ship that stopped in Sydney, Melbourne, Perth, Jakarta, Colombo, Aden, and the Suez Canal, on the way to Naples and Genoa. We got off in Naples, and then enjoyed our first visit to Italy, which included visits to Rome and Florence. Coming from New Zealand, we appreciated the ruins and the sense of history. The museums were cold (heated only by small charcoal burners in February 1954), but seeing the paintings and sculptures was a treat, anyway. Then, via rail, we made our way to Paris and to London.

It was a pleasure to meet Bernhard Katz and the active group of young investigators in his Biophysics Group, at University College London. This group included Jose del Castillo, who later came to the National Institutes of Health (NIH) and then to a chair in Puerto Rico; Liam Burke, who later moved to Australia and to a chair in Sydney; Bob Martin, who later moved to Yale and then to a chair in Salt Lake City; B.L. Ginsborg, who later moved to a chair in Glasgow; and Charles Edwards, who later was at Yale and at NIH. Paul Fatt was then in Canberra, where I had met him several weeks earlier.

I knew that Katz had originally come from Germany to London at the invitation of Professor A. V. Hill. In the preface to Katz's classic first book, Electric Excitation of Nerve, Oxford Press, in 1939, it was noted that this had originally been written as a review to be published in Ergebnisse der Physiologie, but due to Nazi policy at that time, the editors informed Katz that they could publish his review only if he would accept an Aryan coauthor. Fortunately, this persuaded Katz that it was time to leave Germany and accept Hill's offer to help him get his review published in England. Later, Katz served in the Australian Armed Forces; this included duty on a Pacific island as a spotter of Japanese aircraft. In the late 1940s, there was a research collaboration on the neuromuscular junction, by Eccles, Katz, and Kuffler, at a research institute in Sydney. Much later, when Katz held a Readership in London, Eccles offered Katz a new Chair in Biophysics at Canberra; it is my understanding that this offer prompted University College to offer him a Biophysics Chair in London.

At the time of my visit in 1954, Katz was doing experiments with Jose del Castillo on the neuromuscular junction; I played a small role by doing some theory and calculations related to their iontophoresis from micropipettes. I also had my first experience of presenting some of my research results to a meeting of the Physiological Society. Before this meeting, several of us did practice runs for Katz and Professor G.L. Brown; we all received the important advice: if you try to cram too much into your slides and words, you actually communicate less. On several occasions since, I have passed this good advice on to others.

On the day that I was to go to Cambridge for a visit with Alan Hodgkin, Katz offered to drive us there; he had just acquired his first car, from A.V. Hill. Displaying the required “Learner” plates, he drove with Bob Martin as his driving mentor. Hodgkin and Katz were old friends, and we all enjoyed lunch together. During my research visit with Hodgkin, I discussed a number of my theoretical approximations and calculations (including iontophoresis, spherical electrotonus, and my input-output thesis). He was interested and offered me encouragement that was very important to me, coming, as I did, from voluntary exile in the Antipodes. I never actually published my work on iontophoresis, but it provided a valuable interaction with colleagues at that time. We also visited physiologist friends at Oxford, including L.G. Brock and Marianne Fillenz (both had only recently come there from Dunedin), and also Charles Phillips (who learned micropipette technique from Brock). Later, Phillips wrote me when he, with Powell and Shepherd, was writing up their experimental research on the olfactory bulb. He expressed their interest in a theoretical approach to their experimental results; this was followed up when Shepherd came to NIH to work with me.

While based in London, my wife and I did visit the continent, including brief visits to relatives in Switzerland and Paris. But then it was time to sail to the United States, to visit Dave Lloyd and Cuy Hunt in New York, as well as NIH and family in Bethesda, Maryland.

The Rockefeller Institute for Medical Research was impressive. I met many distinguished scientists, including Herbert Gasser, who was in close touch with Lloyd and Hunt. Gasser had recently retired from the directorship of the institute; he was succeeded by Detlev Bronk, who then oversaw the transition into Rockefeller University. I briefly met Rafael Lorente de Nó; his laboratory was near that of Lloyd, but there did not seem to be much scientific interaction, because his interest had shifted from electrophysiology to biochemical research. I sensed that he was of the old Herr Professor tradition (with dogmatic tendencies), and there seemed little point in trying to explain to him the insights about soma and dendritic electrotonus that I had gained.

Several years later, when Lorente de Nó presented a seminar at NIH, there was a very emotional incident. During questions and discussion, Tasaki went to the blackboard to explain a point; he erased a small area that happened to include some equations from Helmholtz. Lorente exploded, “You can't do that to Helmholtz.” The audience was astonished and amused. At that time (perhaps 1960) both Lorente and Tasaki did not accept the Hodgkin-Huxley theory of nerve membrane permeability changes causing the action potential. I felt a little sad; I had admired the pioneering neuroanatomy and electrophysiology that Lorente de Nó had accomplished in earlier years (in Spain and St. Louis); I had also read his two thick monographs on electrotonus, which included a valuable mathematical-physics section by Leveret Davis Jr, with whom Lorente had studied and collaborated at Cal Tech. But I could see that Lorente, even with his demonstrated versatility, had dogmatic tendencies that made it impossible for him to accept insights from others that did not fit his own insights and prejudices.

I did one or two experiments with Dave Lloyd, but then his time was preempted by his participation on the scientific committee that advised the National Polio Foundation on the Salk vaccine research; this was then in its final stages. Here I note that an excellent neurophysiologist Birdsey Renshaw (whom I had met briefly at Woods Hole in 1947) had recently died of polio, after nursing his family; this was a tragic loss to neurophysiology.

Cuy Hunt and I performed a number of experiments that followed earlier research by Hunt, Lloyd, and Mcintyre on “firing index” distributions in a motoneuron population. We succeeded in providing a theoretical model that could account for the data in terms of excitability fluctuations imposed on a neuron population having a normal probability distribution of firing thresholds (Rall and Hunt, 1956). This provides another example of theoretical model predictions that were confirmed by targeted experiments.

Also, while living in Manhattan, I discovered a small sculpture gallery that offered classes in a studio on the second floor. Attending one evening a week, I enjoyed learning to model in clay and produced four pieces (two heads, one torso, and an abstract swirl); these were kiln-fired, to become unglazed terra-cotta sculptures. My interest in making sculptures has continued for many years.

During brief trips to Bethesda, Maryland, I met people at NIH when I gave a seminar there. I also saw my biophysics friends from Chicago (Cole, Morales, Hearon, Podolsky, Blum, and Botts) who were then at the Naval Medical Research Institute (NMRI), located across the road from NIH; they were excellent in biophysics and biochemistry. Also in Bethesda, we visited my parents, who lived in Bannockburn, a community that my father had helped to organize as a cooperative housing development.

When we returned to New Zealand (by air this time), we found many friends pleased to see us back. Some expressed surprise that I had not taken a research position in England or the United States. We chose to return; we had built a house on the Otago Peninsula with a great view of the ocean. Also, I had accepted an obligation to return for at least 1 year after my sabbatical; this I did (during 1955–1956). However, I had overstayed my leave (for about 1 month, mainly in order to complete the manuscript of my research with Cuy Hunt). Even though I had completed three publishable papers during my leave, the university administrators had decided that I should be penalized for tardiness. This induced me to communicate with my biophysics friends at NMRI. They responded with an offer of a position for me as Head of their Biophysics Division. Before leaving New Zealand, my wife and I adopted a newborn baby girl whom we named Sara Elisabeth. Almost 5 years later, another daughter, Madelyn, was born in December 1960.

Biophysics at NMRI (1956–1957)

Arriving in Bethesda in July 1956, I soon was involved in many informal scientific seminars, both at NMRI and at NIH; it was a very stimulating research community. It had been my intention to equip a laboratory for experimental neurophysiology research at NMRI; I wrote research proposals and devoted considerable effort in determining the best items of equipment and supplies to order. Then, out of the blue, the federal government (Eisenhower Administration) imposed the startling austerity measure of an absolute freeze on all government purchases and hiring. With my experimental plans frustrated, I turned again to theoretical research. I remember having a conversation with Dick Fitzhugh at that time; we agreed that, because we both already had considerable experimental research experience, and because there were numerous colleagues who were happy to do more experiments, it was OK for us to decide to focus our attention on theoretical research. We recognized the importance of good experiments, but we also believed in the importance of theory, based on biophysical-mathematical modeling.

The new executive officer at NMRI had tried to orient me with this advice: “Basic research is OK, as long as it is not too basic.” This was my first hint that the new command at NMRI did not appreciate the strength in biophysics and biochemistry that Cole and Morales had assembled with the cooperation of the previous command. The rationale had been that excellence in basic research would provide NMRI with a valuable scientific resource, for any emergency. The new command did not accept this rationale and soon learned that top scientific talent moves elsewhere when given only lukewarm support. Cole had already moved to NIH before I arrived; Terrel Hill soon moved to the University of Oregon and later to the University of California; John Hearon was invited to form a mathematical research group at NIH. Early mainframe computers were already used by the NIH payroll office, and the director of NIH was advised by Cole and others that the NIH should have an Office of Mathematical Research, as a research resource for all of the institutes. This office was formed in 1956; I joined Hearon in December 1957.

Mathematical Research Group at NIH (1957–1994)

Dr. Hans Dewitt Stetten, the research director of the National Institute for Arthritis and Metabolic Diseases (NIAMD) offered to provide us with space and positions; thus our Office of Mathematical Research was originally attached to his office (OD) at NIAMD. There was also a very large biophysics lab in NIAMD, and Dr. Stetten invited me to consider becoming its lab chief, but I declined because by this time I knew that I much prefer to focus on my own research, with one or two colleagues, than to do administration for a large number of people. Some years later, we became the Mathematical Research Branch of NIAMD, and later, when arthritis research was split off into a new institute, we remained in what then became the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK). However, many of my research collaborations were with friends in the neurology institute (NINDB), later NINCDS. Also, when Dr. Stetten became Director of the General Medical Sciences Institute (NIGMS), J.E. (Ed) Rall succeeded him as research director of NIAMD, and later became the Intramural Research Director (Dean) of all the institutes. Here I note that brothers, Ed and Dave Rall, are distantly related to me (perhaps fifth cousins); we had not met before coming to NIH.

John Hearon provided me with complete research freedom. He was very sharp and had two Ph.D.s, one in biochemistry and another in mathematical biophysics (with Rashevsky at the University of Chicago). He was expert in the mathematical treatment of metabolic-kinetics and was helpful to me as a referee of my research manuscripts. The third person to join our group was Mones Berman, with a Ph.D. in electrical engineering; he could take charge of advanced lab equipment, but his real interest was in mathematical treatment of metabolic-kinetics and the application of computers to kinetic data. It was his early computer simulation program (SAAM, written in FORTRAN) that enabled me to do my first compartmental modeling. The fourth person to join our group was Jose Gonzales-Fernandez, who had both a medical degree from Argentina and a Ph.D. in applied mathematics from Northwestern University; he had many interests, including theory of microcirculation. Also attached to our group was John Stephenson, who had been a physicist on the Manhattan Project and then did an M.D. degree; he was supported by the Heart Institute but roomed with us. He was expert in the biophysics of kidney function. We all became friends and had many valuable interactions, in informal discussions, and in formal seminars that included other biophysicists and theoretical statisticians at NIH. Thus, we were a resource for others at NIH, as well as for each other.

Later several more people joined our group for different periods of time; these included John Rinzel, Gordon Shepherd, Steve Goldstein, Maurice Klee, John Miller, Bob Miller, John Evans, Idan Segev, Bill Holmes, Wayne London, David Lipman, and Arthur Sherman. Also, Marge Weiss, Susie Atta, Ezra Shahn, and Jeanne Altman provided valuable assistance to one or more of us with our computations, especially in the early days. When Hearon retired, I sponsored John Rinzel as Branch Chief; later, when Rinzel left NIH for a professorship at New York University (NYU), Arthur Sherman became our Branch Chief.

Membrane Time Constant of Motoneurons (1956–1957)

In 1956 several research groups (in Australia, Japan, and at NIH) recorded surprisingly rapid voltage transients in cat spinal motoneurons. These were experiments using glass micropipettes to stimulate and record from individual cells deep in the spinal cord. The point of penetration was generally assumed to be the motoneuron soma, and these transients were interpreted as properties of the motoneuron soma membrane. First Frank and Fuortes, and then Eccles (with collaborators) concluded that the membrane time constant of these motoneurons must be significantly smaller (less than half, in some cases) than the earlier estimates that were based on synaptic potentials recorded in ventral roots. In an attempt to account for this discrepancy, Eccles introduced new hypotheses about prolonged synaptic activity.

After pondering this discrepancy, I came to realize that the new time constant estimates had resulted from misinterpretation of the voltage transient. The transient had been treated as a simple exponential. That assumption would have been valid only if the motoneuron were a soma without dendrites, or if it had been possible to apply the current uniformly across all of the soma and dendritic membrane. Because neither of these options held true, it became necessary to ask how the shape of the voltage transient must be modified by the fact that current, applied inside the soma, must flow not only across the soma membrane but must also flow into the dendrites for considerable distance before flowing out across dendritic membrane.

A note to Science (Rall, 1957) made this point by contrasting two limiting cases, “soma without dendrites,” versus “dendrites without soma.” The transient in the first case is a single exponential, but in the second case it is a significantly different mathematical function. If each dendritic tree is represented simply as a very long cylinder, this function is the same as that already known to axonal biophysics from earlier studies of electrotonus in nonmyelinated axons (Hodgkin and Rushton, 1946). An intermediate case was also computed, based on the best data then available; it was assumed that the steady current into the dendrites was five times the steady current across the soma membrane; this curve lies close to the curve for “dendrites without soma” and it was suggested that, for most motoneurons, the true curve probably lies between these two. When such a transient is erroneously treated as a single exponential, an erroneously low membrane time constant is obtained. The bottom line is that when you assume an incorrect model (whether explicitly or implicitly) your interpretation of experimental data is likely to be erroneous.

Many years later, a young British physiologist told me that he remembered being in the physiology tea room at Cambridge when that issue of Science was first received. He said that there was an excited discussion (of my 1957 note) that went on for some time. I asked him how this ended. He said they concluded that my point was valid. Frank and Fuortes accepted my conclusion, as did Paul Fatt, but Eccles did not; he argued that the dendrites made only a small contribution. Regarding this issue, see a discussion by Jack and Redman in Segev, Rinzel, and Shepherd, 1995.

Theoretical Implications of Motoneuron Dendrites (1958–1960)

A detailed presentation of biophysical-mathematical theory and computations was submitted (in 1958) for publication in the Journal of General Physiology. A negative referee persuaded the editors to reject this manuscript. The fact that this referee was Eccles, was clear from many marginal notes on the returned manuscript (also confirmed by subsequent evidence). This manuscript did appear as a research report of the NMRI (Rall, 1959a). I confess that I felt rather depressed by the rejection. Fortunately, K. Frank and Bill Windle came to my rescue, by encouraging me to revise my manuscript into two papers for publication in their new journal, Experimental Neurology. One paper (Rall, 1959b) focused on steady-state current flow into dendritic trees, including implications for calculating membrane resistivity; the other (Rall, 1960) focused on transient solutions, including implications for estimating the membrane time constant.

The steady-state analysis yielded a computational algorithm for step-by-step calculation of the input resistance of a general dendritic tree having arbitrary branch lengths and diameters; this algorithm was later adopted by others in their computation packages. This paper also provided a detailed overview of the data then available and emphasized the importance of considering a reasonable range of values for the membrane resistivity and for the ratio of dendritic input conductance to soma conductance. A membrane resistivity range from 1000 to 9000 ohm(cm)squared, with a mean around 5000, was contrasted with a value of 400 to 600 estimated by Eccles and his collaborators. The dendritic/soma input conductance ratio was estimated to lie within an extreme range of 10 to 47, with a midrange from 21 to 35, to be contrasted with a value of 2.3 used by Eccles for his “standard motoneurone.” Large values for this ratio provide a measure of dendritic dominance in the responses and the functions of motoneurons.

The transient analysis yielded a better method of estimating the membrane time constant from experimental transient data. It was shown that when the log of the product: (square root of t, times the slope, dV/dt) is plotted against t, the data can be expected to fit a straight line; also, when calculated with natural logarithms, the negative slope of this line equals the reciprocal of the membrane time constant. Examples and qualifications are discussed at length in the paper (Rall, 1960). The revised membrane time constant values obtained by Eccles and collaborators were found to be 30% below my new estimates, which were made from the same data.

This may seem to be a small discrepancy, but it was very relevant to Eccles' argument for the “residual synaptic current” that he had postulated in an attempt to account for the misunderstood discrepancy. Instead of acknowledging his error, Eccles continued to publish his calculated “residual synaptic current” in many papers and reviews; later, these calculated magnitudes were reduced, and finally they disappeared, without comment. See relevant discussion by Jack and Redman in Segev, Rinzel, and Shepherd, 1995.

Because Eccles asserted that I had exaggerated the dendrites, there was a latency period during which many neurophysiologists did not know whom to believe. I found that neuroanatomists, with their knowledge of dendrites, were more ready to believe that Eccles was mistaken. As late as 1964, Eccles asserted “that synapses on dendrites are virtually ineffective if situated on the more remote regions of dendrites that are about 1 mm in length” (p. 111 in Eccles, 1964).

By 1960, I had decided not to argue further about the value of the time constant, because it was more important to focus on theoretical modeling and computation of synaptic input to different dendritic locations and on computation of different spatiotemporal input patterns. Some of this is described in the next four sections. It may be noted here that this theoretical modeling, together with the experimental testing done by my friends in the Spinal Cord Section of the Neurophysiology Lab at NIH, led to a joint paper (Rall et al., 1967), which did persuade most neurophysiologists about the significance of synaptic input to the dendrites.

D3/2 and the Equivalent Cylinder Concept (1959–1962)

Already in the 1959 papers, theory and computation of the steady-state distribution of current in the branches of dendritic trees had revealed the important role of the 3/2 power of the diameter of each branch cylinder. The mathematical treatment made use of the kind of simplifying assumptions that physicists usually make; each branch is a cylinder, and, at least at first, all branches have the same uniform passive membrane properties. Because the input conductance of a membrane cylinder depends on the 3/2 power of its diameter, it is important to consider, at every branch point of a dendritic tree, the d3/2 ratio, which is composed of the sum of the d3/2 values of the two daughter branches divided by the d3/2 value of the parent branch. In an idealized case, where this ratio is 1.0 at every branch point, the entire dendritic tree can be mapped onto an equivalent cylinder (provided also that all terminal branches terminate at the same electrotonic distance from the soma; note that dimensionless electrotonic length is the actual length divided by lambda, the length constant, which depends on the square root of branch diameter). Such a tree need not be symmetrical. Also, it is important to point out that this equivalent cylinder is valid not only for steady states but also for transient solutions of the partial differential equation.

Although I did not expect natural dendritic trees to satisfy these constraints exactly, dendritic trees of motoneurons have been found to approximate these conditions. Thus, the equivalent cylinder provides a useful model with which to compare the effects of proximal input locations with those of distal locations, where the distal input is assumed to be delivered to all distal branches at the same electrotonic distance from the soma. It may be noted that some years later, John Rinzel and I published mathematical solutions for distal input delivered to a single distal branch (Rall and Rinzel, 1973) for steady states and (Rinzel and Rall, 1974) for transients.

In 1961, Nicholas Rashevsky organized a Mathematical Biology Symposium for the New York Academy of Science. There I presented the equivalent cylinder concept and used it to provide the first computed synaptic potentials, contrasting distal with proximal synaptic input locations. Here I made explicit the mathematical treatment of synaptic excitation and synaptic inhibition, in terms of a membrane conductance change associated with an appropriate battery (reversal potential), consistent with the ideas of Fatt and Katz, and of Hodgkin and Huxley. I also derived a partial differential equation that provided for more general branching, corresponding to a tapered, equivalent noncylinder (Rall, 1962a). That more general model was used some years later, when Steve Goldstein and I explored questions about impulse propagation (including block, delay, and possible reflection of an impulse) in axons with nonuniform geometry (Goldstein and Rall, 1974); see later.

Compartmental Model of Soma with Dendrites (1962–1964)

In 1962, a Neural Theory and Modeling Symposium was held at Ojai, California; the organizers included Richard Reiss and others associated with the defense contractory, General Precision; it was also supported by the Air Force Office of Scientific Research. This may have been the earliest symposium to bring this many (about 25) neural modelers together; it was a stimulating occasion. The resulting book was published in 1964, by Stanford University Press. I presented my assumptions, for the mapping from tree to equivalent cylinder, and then introduced a compartmental model approximation to facilitate computations with different input locations and different spatiotemporal input patterns. Here I note that Mones Berman, my friend and colleague in our NIH mathematical research group, had created an early FORTRAN program for compartmental modeling of metabolic system kinetics (Berman et al., 1962). With his advice, and with logistic help from Marge Weiss (punch-card inputs were transported, by car, from Bethesda to the IBM-7090, at the old DC location of the National Bureau of Standards; there was a 24-hour turnaround to obtain printed paper output), I was enabled to do simulation computations for a soma with dendrites, approximating the equivalent cylinder model.

The particular model consisted of a chain of 10 equal compartments, where compartment #1 represented the motoneuron soma, and compartments #2 to #10 represented increasing electrotonic distance out into the dendritic trees. Computations demonstrated significant differences in the shape of the synaptic potential obtained at the soma (voltage transient in compartment #1) when the same brief synaptic input was applied at different dendritic compartments. For input located in proximal compartments (e.g., #2 and #3), the response at the soma showed a steep rise to an early peak followed by fairly rapid decay; in contrast, for input located in distal dendritic compartments (e.g., #6 and #7, or #8 and #9), the resulting synaptic potential (at the soma) showed a delayed onset, and a much slower rise to a later peak (more rounded and of much smaller amplitude), followed by slow decay. Such differences in shape can be understood in terms of electrotonic spread from the input compartment to adjacent compartments. In fact, the initial nonuniformity of membrane potential tends to equalize rapidly, such that the late decay (for times greater than twice the membrane time constant, tau) is essentially the same in all cases; this implies also that the late decay is essentially the same in all compartments, meaning at the soma and at all dendritic locations (assuming uniform membrane).

In these simulations, the synaptic conductance had a square time course; it was turned on and kept constant for 0.25 tau and then turned off. A few years later, I simulated more realistic transient synaptic conductances (Rall, 1967). Nevertheless, even the square synaptic conductance enabled me not only to demonstrate the effects of different input locations, and different spatiotemporal input patterns, but also to simulate nonlinear interactions between several synaptic input conductances, both excitatory and inhibitory.

The effects of steady synaptic inhibition at different locations upon a mid-dendritic (#5 and #6) synaptic excitatory input were compared. Distal inhibitory conductance (#9 and #10) was not effective in reducing the peak of the excitatory synaptic potential (EPSP) at the soma, but it did slightly reduce the falling phase of the EPSP. In contrast, both proximal (#1 and #2) and mid-dendritic (#5 and #6) inhibitory locations were effective in reducing the EPSP peak; the proximal location was the most effective. More complicated situations involving timing were also discussed (Rall, 1964). These results anticipated similar results that were obtained and discussed later by others.

A different compartmental model departed from the straight chain by providing branching that ended in four distal compartments. This permitted me to verify the conjecture that synaptic excitatory inputs sum linearly in the somatic EPSP when these inputs are segregated to different distal compartments; in contrast, synaptic excitatory conductance inputs combine nonlinearly when placed at a common input location (Rall, 1964).

Compartmental Models Can Be Much More General

Although these examples all assume passive membrane, it is important to note two powerful general advantages of compartmental models: (1) the simulations need not assume uniform passive membrane and (2) they are not limited to the constraints of the equivalent cylinder model. Each compartment can be different. Each can include any nonlinear membrane properties that we choose to specify. Also, each can incorporate any departure from equivalent cylinder constraints that we choose to specify.

Spatiotemporal Patterns of Synaptic Input (1962–1964)

One of the simulations, in the 1964 chapter, compared the effects of opposite spatiotemporal synaptic input patterns. The patterns made use of the four synaptic excitatory conductance input locations, A, B, C, and D used before; these are A (#2 and #3), B (#4 and #5), C (#6 and #7), and D (#8 and #9). The input sequence, A, then B, then C, then D (meaning first proximal, and then successively more distal), produced a synaptic potential at the soma whose rising phase and peak amplitude differed little from that for A alone, but the falling phase was much prolonged as a plateau with slow decay. This computed result can be understood because the effects of later distal inputs reached the soma too late to contribute to the peak, but still in time to contribute to the plateau. In contrast, the opposite input sequence, D, then C, then B, then A (meaning first distal, and then successively more proximal), produced a delayed synaptic potential that rose more slowly to a peak whose amplitude is nearly twice that for ABCD (or for A alone); it decayed without a plateau. This computed result can be understood because the effects of the distal input reach the soma with significant delay, and thus they can build upon the delayed proximal input.

Both spatiotemporal input patterns can have functional value. If the impulse threshold at the soma were between these two amplitudes, this would provide a means of distinguishing between these two patterns: DCBA would fire an impulse, whereas ABCD would not. This could be used for movement detection or for some other discrimination. On the other hand, the prolonged plateau produced by ABCD could be used to bias the soma membrane potential just slightly below threshold, in readiness for a well-timed somatic input that could trigger an impulse.

This simulation may represent the first computed demonstration of such an effect of spatiotemporal input pattern for otherwise equal amounts of synaptic input.

EPSP Shapes; Shape Index Plots; Theory and Experiment (1964–1967)

The different computed EPSP shapes caught the eye of K. Frank, who knew that Bob Burke was recording unitary EPSPs from cat spinal motoneurons. Burke had mastered the experimental technique for eliciting synaptic input delivered by a single afferent fiber of a muscle nerve in the cat hind limb, and for recording the resulting unitary EPSP in a motoneuron (Burke, 1967). Thus, we had an opportunity to compare these experimental EPSP shapes with theoretical EPSP shapes computed for different locations in the compartmental model. To facilitate the comparison, we chose two shape indices: “time-to-peak” and “half-width"; then each shape can be represented as a point in a two-dimensional plot. Later, Jack, Redman, and colleagues preferred “rise-time” to replace “time-to-peak,” because its slightly different definition made it more suited to coping with the variability of experimental EPSP shape measurements (Jack et al., 1971).

The theoretical EPSPs were made more realistic by introducing a transient time course for the synaptic conductance input. This one-parameter transient function (later named alpha-function, by Jack and Redman) rises to an early peak followed by brief decay; we used three versions: “fast,” “medium,” and “slow,” whose peak times were 0.02, 0.04, and 0.092 of the membrane time constant, tau. Thus, for tau = 5 msec, these three peak times are 0.1, 0.2, and 0.46 msec, which proved to be a reasonable range of values. Using these transient synaptic inputs, theoretical EPSP shapes (at the soma) were computed for each input location in the 10-compartment model (Rall, 1967).

A theoretical shape index locus was obtained by plotting the points defined by the paired shape index values for each theoretical EPSP, for each input location. Three loci were obtained, using the slow, medium, and fast inputs. A significantly different locus was obtained when the input was delivered uniformly to all compartments, and only the time course of the input was varied (Rall, 1967; Rall et al., 1967).

Given these shape index loci, the experimental EPSP shapes could be plotted and compared with the theoretical loci. The results were very encouraging; the range of experimental points agreed better with the loci for localized input. Although there was experimental scatter, much of this could be accounted for. The membrane time constant of each neuron had not been measured for the original set of experimental EPSPs; we had to assume a reasonable value (such as 5 or 7 msec). Later experiments by Jack et al. (1971), by Mendell and Henneman (1971), and by lansek and Redman (1973) included a time constant measurement and thus provided much closer fits with the theoretical loci. Also, some experimental EPSP shapes had larger half-widths than expected (for their time-to-peak); these could be understood as resulting from a single afferent fiber that must have delivered synapses to more than one location; such EPSP shapes were successfully simulated by computations with two or more input locations (Rall et al., 1967).

These results can be added to the list of theoretical modeling predictions that were confirmed by neurophysiological experiments. Our collaborative paper (Rall et al., 1967) also summarizes several other successful tests that we carried out at that time. Without going into further detail, I quote the final sentence of the summary to my 1967 paper: “A theme common to all of these computations and interpretations is that results, which may appear paradoxical when examined only at the soma, can be understood quite simply when attention is directed to the synaptic input location with special attention to the effective driving potential there.”

There was still one significant loose end; we did not know the actual dendritic location of the synapses that produced the experimental EPSP shapes. A new histological technique, involving horseradish peroxidase injection, was used to “demonstrate that putative la-boutons are indeed widely distributed in the dendritic trees” (Burke et al., 1979). Then, a remarkable experiment by Redman and Walmsley (1983) succeeded in combining such histology with electrophysiology (in the same motoneuron) and found agreement between the actual synaptic input locations and the theoretical location implied by two different EPSP shapes—another example of experiment confirming theory.

Extracellular Potentials During Passive Electrotonic Spread into Dendrites (1960–1962)

In the summer of 1960, I also computed extracellular potentials, with the help of Ezra Shahn and Jeanne Altmann. This was early computing with an IBM-650, using punch-card inputs. In order to find equipotential contours, we had to interpolate by hand. The first case was a simplified neuron consisting of a soma with a single cylindrical dendrite (solved with Legendre polynomials). Next, we used superposition to compute the field for a spherical soma with seven cylindrical dendrites: one polar (at 0 degrees), three equally spaced (at 60 degrees), and three more (at 90 degrees); an illustration of this can be found in the references cited later. It was assumed that the soma membrane generated an action potential and that the dendritic membrane was passive, receiving passive electrotonic spread from the soma into the dendrites. We froze the system at the instant of peak action potential and then used the distribution of membrane current density (at that instant) to define the sources and sinks of current flow in the (homogeneous) extracellular volume. We found the extracellular potential field to be negative (relative to a distant reference electrode) everywhere near the soma and proximal dendrites and found only weakly positive sleeves around the distal dendrites. These results were presented at the First International Biophysics Congress that was held in Stockholm in 1961; the Congress proceedings were published in a special issue of the Biophysical Journal (Rall, 1962b). Illustrations of these results can be found there, and also in a handbook chapter (Rall, 1977); in Rall, 1992; or in Segev, Rinzel, and Shepherd, 1995.

Because we know that sodium ion current is inward across the spherical soma membrane at peak action potential, we also know that the intracellular current flows from the soma into the dendrites; this current then flows out across the dendritic membrane, and then all of this current must flow through the extracellular volume, back to the soma surface. Thus, it should not be surprising that we find (near the soma) negative equipotential surfaces that are essentially spherical and concentric with the soma. Indeed, if the current sources were at great distance, these surfaces would be exactly spherical, concentric, and with negative polarity relative to a distant reference electrode. Because the current sources are distributed along the seven dendritic lengths, at relatively low density, small positive potentials were found only near distal dendrites; at proximal locations, the strong somatic sink outweighed the weak dendritic source. (Note also, that if the seven long cylinders are replaced by branched dendritic trees, the source current density at a branch will be significantly smaller than for the cylinder.)

These results provided me with an important insight. I had been taught that extracellular positivity was always found next to a current source; this is true for an axon in a volume conductor, but here we found it not to be true near the proximal dendrites of a multipolar neuron. Also, the concentric equipotential surfaces dominated by current to the soma bore a similarity to the “closed field” concept of Lorente de Nó (1947, 1953). Later, I learned that George Bishop had also discussed extracellular electric fields. It is noteworthy that Bishop and Lorente de Nó both worked in St. Louis at about the same time; I never met Bishop, and never learned if these two scientists had interacted at that time. Here I note that the concept of open and closed fields was relevant to my later computations of field potentials in the olfactory bulb (Rall and Shepherd, 1968), discussed in a later section.

Extracellular Diphasic Does Not Imply Impulse in Dendrites (1960–1962)

Also presented in the 1961 International Biophysics Congress were extracellular transient potentials computed for a complete action potential generated by the soma membrane, with the dendritic membrane assumed to be passive. This extracellular transient is diphasic (brief negative peak followed by a smaller positive peak) in the volume near the soma and proximal dendrites. This computed result had an important impact on the interpretations that several neurophysiologists were making with their diphasic experimental potentials, recorded near a motoneuron when it was activated (by an antidromic impulse). Some of them believed that such a diphasic (–, +) transient could be taken to provide evidence of impulse propagation in the dendrites; but now, these computations demonstrated that such a diphasic also occurs with passive dendrites that do not propagate an action potential. My result did not prove that motoneuron dendrites are passive, but it did tip the scales in a careful discussion of the issues (Nelson and Frank, 1964). This involved a significant reinterpretation of experimental observations.

A valuable biophysical insight can explain my computed result. The key is the rapid repolarization of the soma membrane by the active potassium ion current during the falling phase of the action potential at the soma membrane; this causes reversal of the direction of extracellular current flow. The negative peak potential corresponds to active sodium ion current flow inward across the soma membrane (the extracellular current flows from dendrites, radially toward the soma). The positive peak potential corresponds to active potassium ion current flow outward across the soma membrane (the extracellular current flows from the rapidly repolarized soma membrane, radially outward toward depolarized dendrites) (Rall, 1962b). These results and insights persuaded several investigators to desist from claiming that they had evidence for impulse propagation in dendrites.

A sociological note seems relevant here. In the 1960s, before the Society for Neuroscience was founded (in 1970), there were informal neurophysiology meetings held in Atlantic City, a day or two before the large Federation of American Societies for Experimental Biology (FASEB) meetings that were held there every year (in April, I believe). One of the organizers of these meetings was K. Frank; I do not remember who the others were. I do remember that many of the insights, gained by my interactions with K. Frank's spinal cord research group, were presented to the wider neurophysiological community at these meetings. These meetings augmented the scientific grapevine by which new insights were disseminated.

Farm Family (1963–present)

In 1963, it happened that four NIH families together bought a 500-acre farm located about 60 miles west of NIH, in Washington County, Maryland. Two old farm houses had electricity, but no indoor plumbing and no telephone. Lack of telephone was important to having quiet weekends, away from NIH. It was mostly woodland and pasture; crops were corn and hay; repairing fences was a regular activity. We managed a small herd of cattle with the help of our neighbors, the Poffenberger family. Some skeptics thought that this cooperative effort could not last, but it has lasted for more than 40 years. Our farm family consisted of Jean and Barry Blumberg, Caroline and Ed Rall, Jean and Jacob Robbins, Ava Lou and me, all with children who enjoyed the farm. Today, my daughter Sara lives on the farm with her daughter, Megan, and with four dogs and four horses (she has a job in Hagerstown). Sara and Ed Rall (the younger) now do much of the managing.

International Brain Research Organization (IBRO), NAS-NRC Committees, Society for Neuroscience (1963–1972)

It must have been in the mid-1960s that I was invited to join the Biophysics Panel of IBRO. I attended a meeting in Munich, where one felt some East-West tensions; I remember speaking for international cooperation in scientific research. I was also a member of two NAS-NRC committees; one was for liaison with IBRO. The other was a Committee for Brain Sciences, which engaged in several projects, including founding a new society (originally to be named Society for Brain Sciences); when I voiced a preference for the word, “neuroscience,” the other committee members agreed. We subsequently signed the Articles of Incorporation, becoming the Founders of the Society for Neuroscience. Some critics regarded this new society as superfluous. The first annual meeting had about 1000 participants; recently that number has swelled to around 30,000. I was elected to the first National Board and also held office in the local (Potomac) chapter. Looking back, my role has been as an independent scientist; I did not find myself drawn to administration or committee work.

The Role of Mathematical Theory in the Neurosciences (November 1968)

In 1968, the Committee for Brain Sciences received a draft statement about the present and future complexion of brain sciences. Because this statement included no mention of mathematics, I felt the need to prepare the following statement (that I just rediscovered among the few files I preserved in my retirement):

The development and future integration of the brain sciences must be viewed as a very long range project in which mathematics is bound to play a fundamentally important role. The role of mathematics in modern theoretical physics is unquestioned; yet the central nervous system is much more complex than the well-studied systems of physics.

Although mathematical and biophysical theories are already well-established in some areas of basic neuroscience, many problems in the neurosciences are not yet ready for mathematical theory. Also, it seems likely that future theory will depend partly upon mathematical methods developed specifically for the neurosciences; we cannot expect to leap to this future level of sophistication overnight. In any case, there is much that can be done, and is being done now, with the mathematical tools already available.

The present task is to explore and develop theoretical models in areas where they can be tested experimentally, and can provide new insights. The future development of basic theoretical neuroscience depends not only upon new data and new hypotheses; it depends upon careful exploration and evaluation of quantitative theoretical predictions coupled with carefully planned experiments. Sustained interaction between well conceived theory and experiment can be expected to lead to new syntheses of fundamental understanding.

The previous statement is on one page; it was followed by two pages that briefly describe seven examples “of theoretical neurophysiology in which mathematical formulation plays an important role.” The best of these was the Hodgkin-Huxley achievement. Here, I do not burden you with the diverse other six, but note that two references were added, as sources for additional detail (Harmon and Lewis, 1966; MacKay, 1968).

Theoretical Reconstruction of Field Potentials in the Olfactory Bulb (1963–1964)

The field potentials recorded in the olfactory bulb of rabbit by Gordon Shepherd in his thesis research with Phillips and Powell, in Oxford, provided an unusual theoretical modeling challenge that required me to go beyond my earlier modeling efforts. Here, the experiment provided simultaneous action potentials in a large population of mitral cells.

These mitral cells happen to be arranged in an almost spherical cortical layer, known as the mitral body layer (MBL). Their apical dendrites extend more or less radially outward into a layer known as the external plexiform layer (EPL), and end in glomeruli where they receive synaptic input from the olfactory nerve; these glomeruli form an almost spherical outer layer, the glomerular layer (GL). Deeper (radially inward from the MBL) lies a volume containing the axons of the mitral cells, and the cell bodies of a very large population of granule cells; this is known as the granular layer (GRL). It should be added that the granule cells have dendrites (not axons) that extend throughout the GRL, and through the MBL into the EPL, where they intermingle with dendrites of the mitral cells.

To a first approximation, this cortical system can be idealized as having complete spherical symmetry, where the layers are spherical shells, and where the dendrites are oriented radially. Such symmetry allows us to reduce a three-dimensional field to one dimension, the radial dimension. Then we introduced the concept of punctured spherical symmetry, for two reasons: (1) the olfactory bulb is indeed punctured by the lateral olfactory tract, which contains the axons of the mitral cells, and (2) the experimental field potentials at the bulb surface were not zero (relative to a distant reference electrode), whereas zero is expected if there were a completely “closed field” (Lorente de Nó, 1947, 1953). Punctured symmetry provides an extracortical path for current to flow from the outer surface (GL) around (in the extrabulbar volume) to and through the puncture, and into the deep edge of the deep layer (GRL) of the cortical system. At some point, this path must be equipotential with the distant reference electrode; this provides the basis for a “potential divider” correction, which proved essential to the success of our simulations (Rall and Shepherd, 1968).

In the experiments of Philips, Powell, and Shepherd (1963), a sharp electric shock was applied to the lateral olfactory tract, such that a synchronous volley of antidromic impulses reached the mitral cell bodies and produced simultaneous action potentials in the mitral cell population. The field potentials generated by this activity were recorded by an extracellular electrode, placed at many depths along the electrode path into the olfactory bulb; these recordings were made relative to a distant reference electrode. Reproducible patterns of responses were recorded at specific depths, which they carefully correlated with the histological layers. Thus, our task was to try to reconstruct (simulate) the voltage transients that they had recorded at depths corresponding to the layers, GL, EPL, MBL, and GRL, along the radial dimension of our cortical model.

Gordon Shepherd and I devoted a substantial part of 2 years (1963 and 1964) in testing and fine tuning our simulations on the Honeywell 800 computer then at the NIH (still using punch-card inputs). I programmed the computation in Honeywell Algebraic Compiler (HAC), which was essentially the same as IBM-FORTRAN. We used a compartmental model of a mitral cell, where a chain of three small axonal compartments was attached to a large compartment representing the soma; these four compartments were programmed with excitable membrane properties that could generate and propagate an action potential. The soma was also connected to a chain of 5 to 10 dendritic compartments; these were usually assumed to have passive membrane properties, but we also did a series of computations with excitable membrane properties in the dendrites. We did not use the Hodgkin-Huxley equations to model the excitability properties, for two reasons: (1) their original theoretical parameters had been determined for squid membrane, and the correct parameter values for mammalian neurons were unknown, and (2) their set of equations would have added a major computational load to an already complicated computation (on an early computer). Fortunately, I succeeded in devising a pair of nonlinear differential equations that captured the essence of the Hodgkin-Huxley model; it generated a brief excitable conductance transient (corresponding to Na ion permeability), and a slightly delayed quenching conductance transient (corresponding to K ion permeability). This model is described under methods in Rall and Shepherd, 1968; it is an understatement to note that much trial and error was required to find a good set of model parameter values.

With this model, we could simulate the following sequence of events: propagation of an action potential along the three axonal compartments, and the resulting action potential in the soma compartment, together with the passive electrotonic spread of current and of membrane depolarization into the dendritic compartments. This sequence was assumed to occur in all of the mitral cell population. Thus every mitral cell is assumed to provide the same radial distribution of current sources and sinks; these sources and sinks are the generators of extracellular current. For closed spherical symmetry, the extracellular current is constrained to flow along radii in the extracellular space between the dendrites; thus one can compute the extracellular potential (relative to the bulb surface) for all radial locations and at all times. For punctured spherical symmetry, the primary extracellular current is reduced by the amount of secondary extracellular current that flows outside the bulb and through the puncture; the computed values of extracellular potential in the bulb must be adjusted as described in the method section of Rall and Shepherd, 1968.

This computation succeeded in simulating both the large (–, +) diphasic potential recorded at the MBL level, and the smaller, simultaneous (+, – ) diphasic potential recorded at the GL (outer surface). Here, as with the motoneuron computations, the (–, +) diphasic recorded near the soma occurs without impulse propagation in the dendrites. We also made computations with excitable dendrites and found that these were successful only if the excitability was set very low. The explanation, with passive dendrites, is essentially the same as given earlier for the motoneuron. We distinguish two time periods. In Period I, the soma membrane is rapidly depolarized (by inward Na ion current); in Period II, extracellular current is reversed because the soma membrane is rapidly repolarized (by outward K ion current), while the passive dendrites remain depolarized. Thus, antidromic activation of the mitral cell body population accounts for Periods I and II of the recorded field potentials. However, in the following time period, designated Period III, the distribution of potential cannot be generated by mitral cell activity; see next.

Period III Must be Generated by the Granule Cell Population (1964)

The recorded field potentials have a significantly different depth distribution during Period III. They exhibit a large positive potential, deep in the GRL, coupled with a negative potential in the EPL. This implies that significant extracellular current must flow from extensive current sources lying deep in the GRL, through the MBL, to current sinks in the EPL. The mitral cell population cannot generate significant current deep in the GRL, because there they have no dendrites, only axons whose large core resistance severely limits the current they produce. (We estimated, from anatomical measurements, that the combined axonal core resistance is at least 25 times the combined dendritic core resistance.) Anatomically, there is no candidate other than the large granule cell population, whose dendrites do extend the full distance, from deep GRL into outer EPL.

For our theoretical model, we lumped the granule cell dendrites into equivalent cylinders that extend radially over this full distance. Then we represented this as a 12-compartment model, where 6 compartments are assumed to be in the EPL, where they are assumed to receive synaptic excitation, while the other 6 compartments are assumed to be in the GRL, where they are assumed to receive no synaptic input.

Computations with this model succeeded in producing good agreement with the experimental field potentials during Period III, provided that an appropriate potential divider correction was included. It is important to note that excitatory input to the deep (GRL) compartments would not have fit the data; this ruled out an earlier idea that granule cells might receive their input from axon collaterals in the GRL. Because axon collaterals are not present in the EPL, we needed to consider other sources of synaptic input in the EPL.

Dendrodendritic Synapses in the EPL (1964–1966)

Because the EPL consists mainly of large numbers of dendrites belonging to two cell populations, mitral cells and granule cells, we were forced to consider the possibility that the synaptic excitation of many granule cell dendrites during Period III must be provided by synaptic contacts from the secondary dendrites of mitral cells. Although such dendrodendritic synapses were unprecedented, we had two good reasons for entertaining this idea: (1) the mitral secondary dendrites were being depolarized (during Periods I and II) by electrotonic spread from the action potential at the mitral cell bodies and (2) then the granule cell dendrites in the EPL are depolarized by synaptic excitatory input in Period III, and there are no other cells in the EPL that could deliver this synaptic excitation (August 1964 lab notes).

Gordon Shepherd also knew that many mitral cells are inhibited at times corresponding to Period III, and it had been previously assumed that the granule cells might deliver inhibitory synaptic input to the mitral cells (in response to axon collaterals of mitral cells). But here we had depolarization of the granule cell dendrites, just at the time that synaptic inhibitory input was received by the mitral cells; we could not resist considering the possibility of dendrodendritic synaptic inhibition, delivered by dendrites of granule cells to dendrites of mitral cells. We even wondered if a dendrodendritic contact could be specialized to perform both functions: synaptic excitation, from mitral to granule, followed by synaptic inhibition, from granule to mitral (August 1964 lab notes).

The answer was provided by electron microscopy in March 1965. Tom Reese and Milton Brightman, working independently at NIH, had begun research on the olfactory bulb of rat. Gordon Shepherd, who was doing light microscopy measurements on the bulb, had asked them to let us know if they found unusual synaptic contacts in the EPL. Several months later, they did. They found dendrodendritic contacts of two kinds, which were sometimes seen side-by-side in a single tissue slice, but more often neighboring contacts were found in reconstructions from serial sections. What was most remarkable was that they found that the polarity of these contacts (judged by histological criteria) was always what we had needed for our model: the mitral-to-granule contacts were always excitatory, and the granule-to-mitral contacts were always inhibitory.

This was exciting news. Gordon Shepherd and I had entertained a rather heretical conjecture about dendrodendritic synapses (in both directions), based on a theory that combines electrophysiology, gross neural anatomy, and biophysics, and now we found this conjecture confirmed by subsequent electron microscopy.

Then we learned that a few others had also seen such contacts in the EPL, but they did not know what to make of them. Someone commented that this looked like a short circuit. Our answer to that notion was to point out our functional interpretation: first synaptic excitation, from mitral to granule, then subsequent synaptic inhibition, from granule to mitral. Theory and experiment fitted so well that we agreed to write a joint (four author) paper, which we submitted as a note to Science in 1965. It was rejected because the referee found it “not of general interest.” William Windle did appreciate our joint manuscript; it appeared in Experimental Neurology a year later (Rall, Shepherd, Reese, and Brightman, 1966).

Reese and Brightman presented their electron microscopy results, together with our interpretation of their function, to an anatomy meeting in Miami, in April 1965. At first, some anatomists protested that these were not dendrites, because there had been a dogma that dendrites only receive synaptic inputs; if a process sends, they argued, it cannot be a dendrite. But, with time, such protests subsided. Our case was strong; furthermore, dendrodendritic synapses were also being found in other parts of the nervous system.

In our case, we had demonstrated a new pathway for recurrent inhibition, and for lateral inhibition. Also, this had important implications for neuronal interactions. Previously, neural circuits depended entirely upon axons delivering all-or-none action potentials to their synaptic contacts with the soma or the dendrites of other neurons. Now, with dendrodendritic synapses, we can have graded interactions that are not mediated by axons or by action potentials. The implications for functional interactions, and for neural circuit modeling, are immense.

Here is a note about the neuroscience grapevine. In 1965, I attended the International Physiological Congress in Tokyo. When I visited Osaka, my friends told me that I must visit Professor Hama. When I did so, Hama promptly handed me a large photographic print. As I looked at it, I could see that it was a section in the EPL that was simply loaded with very clear dendrodendritic synapses. There was a large grin on his face. I had not presented the dendrodendritic story at the congress, and our publication did not appear until 1966, but he obviously had heard about our research, presumably from reports about the presentation Reese and Brightman made in Miami, April 1965.

International Symposia (1969)

Two excellent symposia were held in 1969. The Neurosciences: Second Study Program, organized by F.O. Schmitt, was held in Boulder, Colorado. It included many interesting lectures and discussions, and included our olfactory bulb story in two lectures (Shepherd, 1970; Rall, 1970a). A symposium on Excitatory Synaptic Mechanisms, organized by Andersen and Jansen, was held at Sandefjord, near Oslo, Norway. My paper reviewed the equivalent cylinder concept, the compartmental model, and the EPSP shape theory and experiment (Rall, 1970b). Another paper (Lux et al., 1970) included anatomical measurements that supported the equivalent cylinder concept; this paper also presented a table that summarized careful estimates of membrane resistivity and electrotonic length (L) using both anatomy and electrophysiology. Their results confirmed the relative constancy of electrotonic characteristics despite variation in cell sizes, making reference to Burke, 1969 and Nelson and Lux, 1970. A paper by Jack, Miller, Porter, and Redman (1970) summarized their study of 252 EPSPs in 169 motoneurons, in which they estimated the locations of the synaptic inputs on the dendrites, making comparisons for afferent fibers of different velocity and also for homonymous versus heteronymous fibers.

Equalizing Time Constants and Electrotonic Length, L (1962–1969)

Although the essential results were already contained in the transient solutions presented in Rall, 1962a, my involvement in several different collaborations, during the 1960s, resulted in publication delays. Completing the EPSP shape story (published in 1967), delayed the completion of the Olfactory Bulb Theory (published in 1968), and both of these delayed completion of my demonstration that equalizing time constants could be used to estimate the electrotonic length, L, of an equivalent cylinder (Rall, 1969a).

Transient solutions of the partial differential equation (cable equation), for a finite length of the equivalent cylinder, can be obtained by the method pioneered by Fourier, which is now common in physics and applied mathematics. If the initial condition is a uniform membrane potential over the full length, then this potential decays uniformly, with an exponential decay governed by the passive membrane time constant, tau-m, which is also designated tau-O to distinguish it from several smaller equalizing time constants, tau-N, where N can be 1, 2, 3, etc. When a local current injection, or synaptic input, produces a nonuniform distribution of membrane potential along the cylinder, the nonuniformity decays more rapidly than the final uniform decay. This is due to rapid spread from the more depolarized regions to the less depolarized regions. This equalizing spread is governed by the equalizing time constants, whose values depend upon the electrotonic length, L, of the cylinder. L is a dimensionless length defined by the actual length (e.g., in mm) divided by the length constant, lambda. The mathematical theory provides exact expressions for the equalizing time constants, such that the ratio of tau-O to any measured tau-N can be used to calculate the value of L (Rall, 1969a).

This method was used successfully by numerous neurophysiologists (e.g., Nelson and Lux, 1970; Lux, Schubert and Kreutzberg, 1970; Burke and ten Bruggencate, 1971). For many motoneurons, L values in the range from 0.6 to 1.5 were reported. Such values were in agreement with my earlier attempts to estimate L from anatomical data, using my estimate of reasonable values for membrane resistivity (Rall, 1959b). (Note that the much larger L values, inferred by Eccles, were due to his membrane resistivity values that were 10 times too small.) Although the anatomical approach is basic, this electrophysiological method proved to be much simpler and became widely used.

This theoretical paper also presented mathematical solutions for the case where a lumped soma is attached to one end of the cylinder, and then for several cylinders attached to a common lumped soma. A different set of solutions was presented for the case of a voltage clamp applied to the neuron soma. These have the advantage of avoiding complications that may result from electric shunting of the soma membrane at the site of micropipette penetration. Numerous numerical examples, throughout this paper, serve to clarify the issues (Rall, 1969a).

A companion paper, appearing in the same issue of the Biophysical Journal, provided solutions for the three-dimensional problem of a membrane cylinder placed in a large extracellular volume. It was a response to a physicist friend (John Blair, a Yale classmate, and Manhattan Project alumnus) who had commented that this problem could be solved by means of Bessel functions. Very briefly, this solution contains additional time constants for equalization around the circumference of the cylinder. Such equalization was found to be extremely rapid (in microseconds). The conclusion was that the one-dimensional solutions, with their theoretical time constants (depending on L), are all we need for most electrophysiological purposes (Rall, 1969b).

Theory for Input to a Single Branch of a Dendritic Neuron Model (1969–1974)

Because dendritic branches had been collapsed to an equivalent cylinder in my earlier theoretical studies (Rall 1962, 1964, 1967, 1969), it became important to me to undo this collapse and consider what happens in the individual branches when an input is delivered to a single branch. Then we could address questions about how much the input resistance is increased by this segregation, and how the resulting voltage becomes increased locally and then attenuates from the input site to the soma; voltage attenuation also occurs in the other branches of the input tree, as well as in the other trees of the neuron model. Although John Rinzel and I obtained most of these results in 1969, we did not finish getting them ready for publication right away. (The delay was partly due to the fact that Rinzel returned to NYU in 1970, to complete his Ph.D. in applied math.) Our steady-state analysis was published first (Rall and Rinzel, 1973) and the transient analysis was published a year later (Rinzel and Rall, 1974).

The key to making the mathematics tractable was to preserve the equivalent cylinder constraints on branching and also to assume symmetry of branching. This idealized model permitted us to obtain analytical solutions, both steady state and transient. Because we had analytical solutions, we did not need compartmental models for this idealized case.

Our idealized neuron model was composed of several equivalent dendritic trees (N in number); the input tree had several orders of symmetric branching (M in number). An explicit example, with N = 6 and M = 2, is illustrated in Figures 1, 2, and 3 of Rall and Rinzel, 1973. It is explained, with the help of those figures, how we made repeated use of the principle of superposition to (piecewise) construct a solution for input to a single branch. This set of superpositions was conceived intuitively, but then we actually carried it out, first for the steady-state solution and later for the transient solution.

Steady-State Solutions for Input to a Single Branch (1969–1973)

A dramatic aspect of the steady voltage attenuation calculations was found when comparing the input branch with its sister branch (which received no input). Although these two branches have exactly the same length and diameter, the calculated voltage attenuation is extremely different. This provides a warning to anyone who thought that voltage attenuation along a branch would depend only on its length and diameter (given equal membrane properties).

The input branch shows a very steep voltage gradient, because all of the applied current flows through its core resistance and onward. The sister branch (which is terminated by a sealed end) has very little current flowing through its core resistance; no current flows out of the sealed end, and very little current flows across its membrane. This difference is due to the boundary conditions: The input branch current finds ample input conductance at its output end (the branch point), while the sister branch finds zero input conductance at its output end (the sealed terminal). Similar results are seen also for the first-cousin and second-cousin branches. Understanding this result is important because it holds also for dendritic spines; there can be large voltage attenuation in the spine-stem of a spine that receives input and very little voltage attenuation in the spine-stem of a spine that receives no input. The theory provides expressions for the ratio of input resistance at a terminal branch to the input resistance at the soma, and for steady-state voltage attenuation of voltage from the input site to the soma. These expressions have been used to calculate a table of these values for different sets of the parameters, L, M, and N. The input resistance ratio is always smaller than the attenuation factor. This means that if we compare the steady voltage (e.g., 1 mv) at the soma (produced by injection of a steady current at the soma) with the steady voltage (e.g., 15.5 mv) at a branch terminal (due to injection of equal steady current to that branch terminal), the attenuation factor (e.g., 23.9) means that this branch input alone would produce a steady voltage at the soma of 15.5/23.9, which is about 2/3 of the reference value for direct input to the soma (e.g., for L = 1, M = 3, N = 6). Thus, the distal input does deliver less to the soma than an equal soma input, but 2/3 for the steady state is not negligibly small; many such contributions could sum effectively at the soma. Note that, for brief transients, the attenuation is more severe (Rinzel and Rall, 1974).

For the steady-state results, who could have guessed that, when L is doubled from 1.0 to 2.0, the attenuation factor increases roughly fivefold, while the input resistance ratio is roughly doubled. When the number of trees, N, is increased from 6 to 10, both quantities increase roughly by the factor, 10/6. When the orders of branching, M, are increased from 3 to 7, both quantities are increased nine- or tenfold, which can be attributed mainly to the smaller diameters of the higher order branches.

The terminal branch input resistance values are estimated to lie in the range from 40 to 750 megohms, depending on the size of the motoneuron. Generalization of the theory to include mid-dendritic input sites and unequal branching are solved in the Appendix of Rall and Rinzel, 1973.

An important functional consequence of the large local depolarization produced by synaptic excitation at a distal branch is that nonlinearity of local summation is increased (because the local depolarization reduces the effective synaptic driving potential). Numerical examples are provided. As was already pointed out in Rall et al., 1967, nonlinearity of EPSP summation seen at the soma can be understood as originating between neighboring distal synaptic inputs; it thus provides evidence of synaptic activity at neighboring distal dendritic locations. However, when synaptic inputs are on widely separated branches, their effects do sum linearly at the soma, as noted previously, from compartmental computations (Rall, 1964).

The application of these results to cat spinal motoneurons is discussed in relation to new experimental evidence that the equivalent cylinder constraints are approximately satisfied and that L-values range between 1 and 2, with a mean around 1.5; (Nelson and Lux, 1970; Burke and ten Bruggencate, 1971; Jack et al., 1970, 1971; Lux et al., 1970; Barrett and Crill, 1971).

Transient Solutions for Input to a Single Branch (1969–1974)

By using the same idealized assumptions, and the same system of superpositions of component solutions (as for the steady-state problem), we obtained mathematical expressions for the “response function,” which defines the transient membrane potential at every location in the model neuron, in response to injection of an instantaneous point charge at the terminal of a single branch. For our computations, we used two different mathematical expressions: one infinite series converges best for large values of T, while the other converges best for small values of T; (they agree for midvalues of T). The computations, although formidable, were easy for John Rinzel.

In order to compute the response for any specified input function (time course), one must compute the mathematical convolution of this function with the “response function.” This we did to provide several numerical examples and illustrative figures. For example, Figure 3 of Rinzel and Rall, 1974 illustrates an input current function that peaks at T = 0.02 (applied at a branch terminal of a model neuron with N = 6, M = 3, L = 1); the voltage transient at this branch terminal peaked at T = 0.04, while the much attenuated voltage transient at the soma peaked at T = 0.35; the attenuation factor for peak voltage was 235, which is nearly 10 times greater than the 23.9 value found for the steady state. Peak values and attenuation factors at several other locations can be found in Table 1 of Rinzel and Rall, 1974. A peak time, T = 0.12, in the sister branch implies rapid voltage equalization between the sister and input branches.

Also, although there is severe attenuation of voltage transients from branch input sites to the soma, the fraction of total input charge actually delivered to the soma (plus other trees) is about one half. Details of charge dissipation are presented for all branches and trees. Details are also presented to illustrate the nonlinearities found when synaptic input is treated as a conductance transient; the key is that the effective synaptic driving potential is reduced by local depolarization.

It is important to note that many of the issues discussed in this paper were also discussed by Redman (1973), Iansek and Redman (1973), and Barrett and Crill (1974) showing that several investigators were almost simultaneously tuned to these issues.

Chapter in Handbook of Physiology (1974–1977)

It must have been in 1973 or 1974 that Eric Kandel invited me to contribute a chapter, “Core Conductor Theory and Cable Properties of Neurons” for The Nervous System, Vol. 1, Cellular Biology of Neurons that he was editing for a new edition of the multivolume Handbook of Physiology, edited by Brookhart and Mountcastle for the American Physiological Society. This volume was published in 1977. Kandel had previously been at NIH; he had attended some of my seminars there, and we had discussed the relation between theory and experiment on several occasions.

I put much effort into writing a comprehensive chapter (58 large pages) that included historical background, careful definitions and derivation of the cable equation, with tables of cable parameters for invertebrate axons, for frog myelinated axons, and for cat spinal motoneurons. It also presented the assumptions and results of several of my modeling efforts of the 1960s and early 1970s: the equivalent cylinder model, compartmental models, the effects of different dendritic input locations, and different spatiotemporal input patterns, as well as the comparison of experimental, unitary EPSP shapes with theoretical EPSP shape loci, with discussion of implications. The computed extracellular (–, +) diphasic was presented and discussed (in relation to passive dendrites), as were the computed extracellular fields for a single multipolar neuron and for populations of mitral cells and granule cells in an idealized olfactory bulb. Dendrodendritic synapses were discussed. Mathematical solutions for transients in cylinders of finite length-L were presented and used to explain the relation between L and the equalizing time constants. Results for voltage clamp at the soma and also the results for input to a single branch of a multibranched neuron were included. Finally, there was an updated discussion of the interrelations between neuron model parameters. This chapter tried to be useful to those who wished to understand the biophysical approach to neurons (Rall, 1977).

Action Potential Shape and Velocity, Changed by Nonuniform Geometry (1973–1974)

Steve Goldstein had a degree in electrical engineering before he did his M.D. at the University of Chicago; he visited our group during a quarter off, and then came as a research fellow for 2 years. We decided to study the propagation of action potentials in axons in the vicinity of axonal branch points, and also for both abrupt and tapering changes in diameter. We used the action potential model that I had invented for the earlier olfactory bulb simulations; one nonlinear differential equation simulates the brief Na ion conductance transient of the Hodgkin-Huxley model; the other simulates the slightly delayed K ion conductance transient of the H-H model. These nonlinearities have the advantage of being polynomial, rather than exponential, which contributes to computational efficiency.

Our first example was to compute the changes in action potential shape and velocity with approach to a sealed end of a long uniform cylinder. Note that the slope, dV/dx, is zero at a sealed end; note also, that a zero slope occurs at the point of collision of two action potentials traveling in opposite directions, in a long uniform cylinder. We found that the action potential increases its peak height and its velocity as it approaches (within a distance, ½ lambda) the sealed terminal, or point of collision; the half-width is decreased. These computed results can be explained in terms of physical intuition, as follows. The propagation of an action potential involves core current that extends ahead for some distance; this current crosses the extensive membrane ahead at relatively low current density, causing passive membrane depolarization, that finally reaches excitation threshold (which ensures onward propagation). Such leading core current cannot flow beyond the sealed end; it must flow out across the near membrane at high current density; thus, the near membrane reaches threshold sooner, and the peak is higher, than when far from a sealed end.

Similar physical intuition applies when an action potential propagates toward a point of step decrease in cylinder diameter, where the core resistance increases step-wise. The computed results showed the expected increase in peak and velocity as the impulse approaches the step; however, beyond the step, we found reduced action potential velocity in the thinner cylinder, with its larger core resistance (and smaller lambda). It is interesting that (when well beyond the step) this action potential has the same time course as before. Its shape is the same in the time domain, but it is significantly changed when computed in the length domain (its shape is more narrow). These effects were computed for three different diameter ratios (Goldstein and Rall, 1974).

For a step-wise increase in cylinder diameter, computations showed a decrease in velocity with approach to the step. Propagation onward was blocked if the diameter increase was too large (a diameter ratio of 3.5, for these action potential kinetics). Also, propagation onward at increased velocity was found for smaller diameter increase. We computed illustrations of the shape changes in both time and length domains.

Most fascinating was an intermediate case (a diameter ratio of 2.5), which showed delay (instead of block) followed by both forward and reverse propagation. The computed results are clear and were illustrated. The physical intuitive explanation hinges on the delicate fact that the delay was sufficient for the upstream membrane to recover from its refractory period (which always follows immediately after generating an action potential). This meant that when the membrane downstream, beyond the step, fired its delayed action potential, this produced sufficient current to bring the recovering membrane (upstream) to threshold, such that two action potentials were able to propagate, one forward and one backward. This was of great interest to many neurophysiologists. Actually, Shepherd and I had seen something similar in our computed antidromic activation of mitral cells; a delay in impulse invasion of the soma resulted in back propagation. Also Zeevi (personal communication) had an example of “decremental reverse conduction” in his Ph.D. thesis (Zeevi, 1972), and something similar was reported by Khodorov et al. (1969).

We also did computations for taper, and for branching, and provided discussion of various functional implications. In particular, there is a discussion of filtering and of issues involved in preferential propagation into different branches (Goldstein and Rall, 1974). Steve Goldstein subsequently did a neurology residency at Johns Hopkins and then entered private practice in neurology.

Computed Extracellular Potentials for Open Cortex (1974–1977)

Because Maurice Klee had done his Ph.D. thesis in an electrical engineering department (advised by Plonsey), doing theory and computations of extracellular fields, we found it strategic to revisit the subject of punctured spherical cortical symmetry. Thus we could test the validity of the “potential divider” approximation that was used earlier for the olfactory bulb simulations (Rall and Shepherd, 1968).

We started by defining, computing, and illustrating the problem for a hemispherical cortex. We also solved two other cases: a more nearly completely spherical cortex (radius from 0 to 135 degrees), and a less complete cortex (radius from 0 to 45 degrees). We illustrated these fields as equipotential contours. We also found the “potential divider” ratio that fits each of these three cases and discussed the validity of the approximations made earlier for the olfactory bulb. Although we expected agreement, it was satisfying to have physical intuition confirmed by a rigorous computation. This research was done mostly in 1974, but publication appeared in 1977 (Klee and Rall, 1977). Here I note that theory and computation of extracellular fields generated by neurons were presented by a few others around this time (e.g., Plonsey, 1964, 1969; Pickard, 1971; Rosenfalck, 1969, Ph.D. thesis).

Trauma Caused by Cataracts and Disastrous Surgery (1977–1978)

In retrospect, it is clear that my research momentum took a big hit, when routine cataract surgery (March 1977) resulted in the complete loss of vision in my left eye. The vitreous had became infected; a vitrectomy resulted in retinal detachment; surgery to reattach the retina was only briefly successful; after 2 months of effort, this eye was pronounced phthisic (i.e., shot). My right eye also had a cataract; it was axial and it multiplied images of the moon, when I looked at it. Surgery was needed in 1978; fortunately, Professor A.E. Maumenee, head of the Wilmer Eye Institute at Johns Hopkins, performed successful surgery. I do treasure my aphakic right eye. Because my cataracts were so early (in my 50s, whereas my father had his in his 70s), I suspect that this may have resulted from exposure of my eyes to soft x-rays, during long-duration experiments performed for the Manhattan Project (Rall, 1946). The overall trauma was more than my wife's anxieties could handle, resulting in the end of our marriage.

I was not ready for marriage again until 1983, when I married Mary Ellen Condon. She is a historian who did her Ph.D. in London. We share interests in music and theatre, in academic writing, and in art and nature. This summer (2005) we are both under pressure to meet writing deadlines before departure on a trip to Australia, to participate in Steve Redman's retirement symposium on Heron Island; also, a side trip to New Zealand gives me a chance to revisit the Otago Peninsula and, also, the Fiordland National Park.

Symposium on Neurons Without Impulses (1979–1981)

Invitation to participate in a symposium, held at the University of York in April 1979, stimulated me to review my research and prepare my contribution. Gordon Shepherd also made an important contribution in his review chapter. Most of the meeting was devoted to invertebrate examples. The resulting book was published in 1981; in the preface, the editors remarked “It was in the vertebrate olfactory bulb that extensive evidence of graded interactions between neuron dendrites was first found in the mammalian brain.” My chapter also included some modeling results for a nonspiking interneuron of locust, which had been carefully studied by Burrows and Siegler, at Cambridge, as well as other modeling results, done with Rinzel and Bob Miller, for a photoreceptor studied by Dan Alkon at Woods Hole in a nudibranch mollusc. These were presented as examples of how our neural modeling methods could be applied to different neurons (Rall, 1981).

Comment on Symposia

It happened that some of my major results were first published as chapters of volumes that resulted from symposia. If an invitation to a symposium came just as I was getting a new result, this would often be presented there. This helped keep up the research momentum, but then a full presentation of the results did not get published in a regular scientific journal, especially because the journal did not choose to publish research that had been previously published. This was one reason that my friends took the trouble to include some of these chapters in Segev, Rinzel, and Shepherd, 1995.

I also attended several Gordon Conferences (summer in New England) and also several Winter Conferences on Brain Research (in Colorado), and Neuroscience Workshops (in Boston). These had two special advantages: (1) they did not require a chapter for a book and (2) they did offer opportunity for investigators from different parts of the country to interact informally.

Dendritic Spines Re Plasticity and Learning (1969–1978)

Although the granule cells of olfactory bulbs have spines (or gemmules) that participate in the dendrodendritic synaptic interactions, we did not do detailed spine computations at that time. It was during a workshop organized by the Scheibels in 1968 that I was urged by Arnie Scheibel and Dom Purpura to apply my theoretical approach to dendritic spines. It was probably in 1969 that John Rinzel and I started to look at this problem, along with input to a single dendritic branch. The biophysics and implications of this research were presented briefly at two major meetings: an International Physiological Congress, and the first annual meeting of the Society for Neuroscience; both abstracts are dated 1971. More detail appeared later in two rather obscure publications: one is a Brain Information Research Report of a symposium organized by Chuck Woody at UCLA (Rall, 1974), and the other is a festschrift for Archie McIntyre, edited by Bob Porter and published by Cambridge University Press (Rall, 1978). The 1974 report has been reproduced in Segev, Rinzel, and Shepherd, 1995.

Many spines have long, thin spine stems whose large core resistance can be expected to produce significant voltage attenuation, from the spine head to the point where the spine stem is attached to the neuron (Chang, 1952). Our steady-state analysis (for passive spines) brought our focus upon the ratio of the spine stem resistance to the input resistance at the branch to which it is attached. When this resistance ratio is 0.01 or less, steady voltage at the spine head is delivered to the branch without significant attenuation; then a synapse on the spine head is equal to a synapse directly on the branch. However, when this resistance ratio is 100 or more, the voltage attenuation is so severe that negligible voltage is delivered to the branch; then a synapse on the spine head is ineffective.

Thus, we were able to identify an intermediate range, especially from 0.1 to 10, for this resistance ratio, where the attenuation ranges approximately between 10% and 90%. We labeled this as a possible “operating range” for plasticity and learning. The concept was that if spine stem resistance can be adjusted, this can change the weight of a synapse. If the relative weights of many synapses can be adjusted, this could be part of a means to accomplish plasticity and learning.

It was interesting that, at least in some neurons, long, thin spine stems were more common on distal dendritic branches (with large input resistance), whereas less long ones were located at more intermediate branches (with smaller input resistance). This suggested that possibly both of these could be in their “operating range.” This was encouraging at that time, but I have been told that some other data do not support this particular idea.

In this research report, we also included computations for transient potentials and found that a similar “operating range” holds also for the much larger attentions that occur with transient potentials. Here I note that my colleagues, Holmes and Levy (1990), shifted their theoretical focus from electric resistance to diffusional resistance in the spine stem (effect on calcium ion concentrations; see also Holmes, 1990).

Excitable Dendritic Spines, Synaptic Amplification (1974–1985)

Although we and others had speculated about possible effects of placing excitable membrane properties in a spine head, and Julian Jack had included some astute steady-state considerations in Jack, Noble, and Tsien, 1975, as far as we know, no one had done detailed transient computations with excitable spine heads until around 1983; see discussion by Shepherd on pages 404–406 of the book Segev, Rinzel, and Shepherd, 1995. Computations by Brayton and Shepherd used an IBM modeling program, ASTAP; Don Perkel and his son, David, used their modeling program, MANUEL, whereas John Miller (with Rinzel and me), used an electrical engineering modeling program, SPICE (with some adaptation by Barry Bunow). Related computations were done by Wilson (1984) and by Koch and Poggio (1983). At a neuroscience meeting held in 1984, two presentations were so similar that we agreed to publish our papers together; they appeared in Brain Research (Perkel and Perkel, 1985; Miller, Rall, and Rinzel, 1985).

For carefully chosen sets of theoretical parameters, we all found that, with excitable membrane at the spine head, a synaptic excitatory input can result in an action potential at the spine head and that this delivers a significantly amplified depolarization to the spine base. In our published example, the EPSP peak (at the spine base) was 6.5 times that for a passive spine head; together with the increased duration of this EPSP, this meant a 10-fold amplification, in terms of the charge delivered to the spine base (Miller, Rall, and Rinzel, 1985).

We also discussed the dependence on spine stem resistance; if this is too small, the depolarization at the spine head may not reach the threshold for an action potential; if it is too large, the increase of voltage in the spine head is limited (by the synaptic reversal potential), and also, the voltage attenuation by the spine stem is large. Over an intermediate range of parameter values, the spine stem could be a locus for plasticity (as previously noted for passive spines).

Local Interactions in Clusters of Excitable Spines (1985–1987)

Further insights were gained when Idan Segev and I explored interactions between spines (both passive and active) within the clusters of spines located on distal dendritic branches. One insight had to do with the economics of Na channels in dendrites. Because the spine stem resistance semi-isolates the spine head membrane from the dendritic branch membrane, this changes the efficacy of Na channels on the spine head. The number of channels sufficient to generate an action potential at the spine head is much too small to generate an action potential on the branch because of the large membrane surface that provides a large conductance load. Also, doubling this number of channels on one spine head does not double the result, whereas giving these extra channels to a neighboring spine head does double the result delivered to the branch (assuming that both spines receive equal synaptic input). This means that, if you have a limited number of Na channels (for the dendrites), the optimal design would allocate them entirely to the spine heads, with a threshold number of Na channels in as many spine heads as possible.

Another insight had to do with the input resistance at distal branches. A large input resistance increases the amount of local depolarization of the branch membrane. Because of negligible attenuation of voltage from this local depolarization into neighboring spine heads, it can happen that the local depolarization produced by two or three synaptically excited spine head action potentials can cause a threshold amount of depolarization to spread into neighboring spine heads (which did not receive synaptic input). Those spine heads (which are excitable) will then produce their action potentials (with a slight delay). These additional action potentials provide further amplification of the original synaptic input (Rall and Segev, 1987).

We provided examples in which a threshold depolarization spreads into a distal sister branch, thus firing the excitable spines in this branch and providing significant amplification at the point where these two branches meet. Such action potential spread would occur only (centrifugally) into distal branches; it would not occur (centripetally) toward the soma, because of the asymmetry of attenuation in branched trees noted earlier (Rall and Rinzel, 1973). Synaptic input to passive spine heads in the sister branch can, in some cases, facilitate reaching threshold in the active spine heads; conversely, well-timed synaptic inhibition can prevent this. Such considerations support a concept of possible logical processing in the distal dendrites of a neuron.

Many of these results were presented at a symposium on Synaptic Function, sponsored by the Neurosciences Research Foundation (in 1986); the book appeared in 1987, edited by Edelman, Gall, and Cowan. Our chapter provided detailed illustrations and discussion of the results and insights summarized previously (Rall and Segev, 1987).

Space-Clamp Problems with Voltage Clamp Applied to Neurons (1984–1985)

A 1984 symposium on voltage and patch clamping stimulated me, together with Idan Segev, to explore the mathematics and compute examples of what to expect when a voltage clamp is applied to the soma of a dendritic neuron. Early solutions and time constants had already been included in Rall, 1969. We knew that a clamp at the soma cannot clamp the dendrites, but asked what does it do. We found that for very short dendritic trees (L < 0.2), both direct current (DC) steady states and low-frequency alternating current (AC) steady states are nearly space-clamped (within 2% error) but that much larger error occurs for larger L and for higher frequencies. The DC steady-state solution provides the basis for estimating the dendritic synaptic equilibrium potential from the reversal potential observed at the soma. The AC steady-state solution provides expressions for the decrement of amplitude (and increasing phase lag) with distance, at different frequencies. The transient response, at all dendritic locations, for a voltage clamp step at the soma, defines how the distal dendrites charge less rapidly than the proximal dendrites. Theoretical transfer functions permit one to compute the time course of synaptic current (at a specified dendritic location) from the current detected at the soma, by the voltage clamp (Rall and Segev, 1985).

Two Book Chapters to Be Noted (1989, 1991)

In 1989, the first edition of Methods in Neuronal Modeling, edited by Koch and Segev, included my 51-page chapter entitled “Cable Theory for Dendritic Neurons,” which provided a fairly comprehensive presentation of the equations, results, and insights gained from my dendritic modeling efforts (Rall, 1989). The following chapter (Segev, Fleshman, and Burke, 1989) provided details of compartmental modeling methods. Later, in the second edition of this book, my chapter included some additions and revisions carried out with a coauthor (Rall and Agmon-Snir, 1998).

In 1991, an autobiographical chapter, “Path to Biophysical Insights about Dendrites and Synaptic Function” was published in The Neurosciences: Paths of Discovery, II, edited by Samson and Adelman (Rall, 1991). This aimed to give my personal perspective on my research path. Although that was written 15 years ago, it obviously must have much in common with the present essay. These chapters do include key illustrations.

Equalizing Time Constants and Electrotonic Length in Branched Neurons (1987–1992)

The earlier relation between L and the equalizing time constants was strictly valid only for a single cylinder of finite length. We knew that a multipolar neuron with extensive branching must have many additional time constants. Most of these would have zero coefficients in transients initiated at the soma; however, some of these coefficients will not be zero, especially in transients produced by input delivered to individual branches.

The mathematical details are presented, illustrated, and discussed in Holmes, Segev, and Rall, 1992. Many of these computations made use of a supercomputer located at the Frederick Cancer Research Facility. This computing power was needed, for example, to simulate one motoneuron (with detailed morphology) represented by 732 compartments. A different branched model involved 169 compartments; this model confirmed the insight that many of the time constants, produced by the mathematical solutions, can be interpreted as corresponding to voltage equalization from the tip of a distal branch (of one dendritic tree) to the soma, and all the way out to the tip of a distal branch of a different dendritic tree; each pair of such branches contributes an equalizing time constant, but their coefficients tend to be small in most transients.

In a closely related paper (Holmes and Rall, 1992b) we present a “constrained inverse computation” for compartmental models. To solve for N unknown electrotonic parameters, we must have at least N independent experimental quantities We showed that the solution is nonunique if the data are only electrophysiological; uniqueness requires that morphological data be included. Many examples are presented and discussed.

In another related paper (Holmes and Rall, 1992a) we deal with the effect on electrotonic length estimates of such complications as dendritic taper or somatic shunt. Many examples are presented and discussed. It is concluded that the standard formula for computing L underestimates L when dendrites taper, and overestimates L when a soma shunt is present. Methods to deal with these problems are provided.

Workshop and Resulting Physiological Review (1987–1992)

An intensive workshop, limited to six participants, was held in New York in 1987; it was sponsored by the Neurosciences Research Foundation (Edelman and Gall) at Rockefeller University. The participants were Bob Burke, Bill Holmes, Julian Jack, Steve Redman, Idan Segev, and myself. All of us were working on related problems, and it seemed a good time to exchange ideas and assess where our research stood at that time. I believe that we all enjoyed this occasion very much. A joint writing effort produced a draft manuscript that was distributed among the authors and some friends (in May 1988), but final revisions were delayed. Later, an invitation to contribute to a special issue of Physiological Reviews, commemorating the pioneering research contributions of Hodgkin, Huxley, and Katz, was accepted with the understanding that our draft manuscript was to be updated and completed. We all added illustrations and discussion; part of my effort was shared with Steve Redman during a 3-month visit to Canberra; Bob Burke helped me with the final wrap-up.

This was published in 1992. The title and focus of our review was “Matching Dendritic Neuron Models to Experimental Data.” In this review (26 large pages), we provide some history and discuss early simplifying assumptions, together with new evidence for nonlinearities and voltage dependent membrane conductances. We present an example (provided by Burke and his colleagues) of the branching details of a cat alphamotoneuron, together with a corresponding model consisting of a soma with 777 cylindrical branch elements, and discuss the steady-state solution, plus our best estimates of membrane resistivity, core resistances, lambda values, and how to calculate the input conductance of such neurons and models. A table summarizes parameter estimates and experimental data for six alpha-motoneurons of three different types. We discuss complications and methods for dealing with them. We discuss several robust parameter ratios for different neuron types. We also present and discuss a pyramidal cell model (provided by Jack and his collaborators). We review several of the uncertainties that complicate the estimation of neuron parameters. We touch on the nonuniqueness of solutions, and discuss the “constrained inverse” problem, noted previously and discussed further later.

One point that we all agreed to was the following: It is essential to have a firm grasp of the consequences of neuron morphology on electrotonic properties, using passive membrane assumptions, before adding the next layer of problems posed by nonlinear membranes. Given this foundation, modern computational techniques should make it possible to build realistic, nonlinear neuron models, as experimental research provides us with constraints about the properties and local densities of these channels for different neuron types (Rall et al., 1992).

Nonuniqueness and “Constrained Inverse” Computation (1962–1994)

In the 1960s, Mones Berman and I (together with others in our group) had a number of discussions about the issue of nonuniqueness of solutions obtained by modeling and computation. At our 1987 workshop, Jack presented particular examples of nonuniquenss that had been explored by one of his students; for example, the ratio between two parameters could be determined but not the separate parameter values. At the same time, other examples of this became apparent as Holmes, Segev, and I explored the “constrained inverse” computation, for models with very large numbers of compartments.

There is first the issue of how well an idealized model corresponds to the biological object of study. By our choice of simplifying assumptions, we reduce the number of unknowns to be determined by fitting the data. The hope is to evolve a model which fits data from a variety of experiments (using the same object or system).

A model that specifies a soma with different membrane properties, and shunted (by leakage around the microelectrode), requires more model parameters (and hence more unknowns) than does a uniform cylinder, or chain of equal compartments. A forward computation uses estimated values for all of these parameters (to compute voltage transients and input resistance). An inverse computation attempts to work backward, from experimental data, to the best set of parameter values (that fit the data); this can be done by trial and error, which can be computed systematically. This we call the “constrained inverse” computation, which Holmes programmed for a supercomputer; see previous references, and a useful description in Holmes and Rall, 1992c.

Solutions for Transients in Arbitrarily Branching Cables (1992–1994)

A remarkable mathematical success was achieved by Julian Jack's group in Oxford. Two papers by Major, Evans, and Jack (1993a, 1993b), together with two more (Major, 1993; Major and Evans, 1994) presented analytical solutions for the general problem of arbitrary branching. John Rinzel and I had solved a simpler problem, which did include branching details but took advantage of symmetric branching, assumed to satisfy the d3/2 constraint for an equivalent cylinder. Here, Major et al. had solved a much more difficult problem and applied this to pyramidal neurons (Major, 1992; Major, Larkman, Jonas, Sakmann, and Jack, 1994). The editors of the Biophysical Journal invited me to provide an appreciative commentary on the two 1993 papers (Rall, 1993).

These transient solutions consist of infinite series of terms having different time constants, as is true also for the arbitrary compartmental model solutions of Holmes, Segev, and Rall (1992). It would be interesting to compare solutions obtained by both methods for equivalent arbitrary branching. One limitation does apply to both of these analytical solutions; they both assume uniform passive membrane. If one needs to include nonlinear membrane properties, one cannot use these analytical solutions, but one can perform computations with a compartmental model that specifies these complications.

Perspective on Neuron Model Complexity (1995)

Michael Arbib invited me to write a short essay for his Handbook of Brain Theory and Neural Networks (1st edition, 1995; 2nd edition, 2002). I chose to discuss model complexity. With improved anatomical methods, and with increased computing power, there is a temptation to create neuron models consisting of hundreds of compartments. Such a model can have far too many degrees of freedom. One can reduce this number by means of simplifying assumptions: specify many compartments to have the same passive membrane properties, reduce the number of compartments, or both.

My preference is to use the fewest compartments that represent the most essential morphological aspects of the neuron and also represent what is known about different membrane properties, or synaptic input distributions, for different areas of the neuron. With fewer degrees of freedom, there is more chance of gaining functional insights.

Nerve-net modelers often represent a neuron as a binary unit; this ignores the richness of biological neurons. I believe it is important to work with neuron models that can receive synaptic inputs on different dendrites, and perhaps on dendritic spines (both passive and excitable), and perhaps also with dendrodendritic synapses. Then, when one has succeeded in modeling an interesting behavior for one neuron, or for a network of such neurons, ask what happens to the simulation when all dendritic compartments are lumped together with the soma. I expect that the interesting behavior will disappear. The more good demonstrations we can provide, the more we establish the need for models that are not too reduced.

This essay provides several examples that can meet that test. The computation of spatiotemporal patterns of synaptic input to dendrites (Rall, 1964) and of dendrodendritic synaptic interactions in olfactory bulb (Rall and Shepherd, 1968) are discussed. A 19-compartment model of rhythmogenesis (Traub et al., 1991) is compared with a 2-compartment model by Pinsky and Rinzel, 1994; this example demonstrates that at least two compartments are required to separate the synapses and membrane properties of soma versus dendrites in order to get the rhythmic behavior.

I prefer intermediate models with few compartments, for two important reasons: (1) it helps sharpen our intuitive understanding about what is essential to obtaining the behavior of interest and (2) it can greatly facilitate computations with networks composed of such neuron models. This essay closed with remarks about having enjoyed the creative activity inherent in pioneering dendritic neuron modeling. This essay remained unchanged in the second edition of Arbib's handbook (Rall, 2002).

Late Comments

In 1994, I felt very touched when the six editors of the Journal of Computational Neuroscience dedicated their first issue to me. Also, in 2004, Gordon Shepherd kindly dedicated the fifth edition of his The Synaptic Organization of the Brain to me.

In April, 2005, I had the pleasure of participating in a “School of Dendrites,” held in Jerusalem by the Israeli Institute for Advanced Studies, organized by Sakmann and Segev. We had 120 graduate students, 80 from Israel, and 40 from Europe and the United States. I enjoyed hearing about much remarkable recent research and was awed by how much this field of research has grown in my lifetime.

Retirement (1994–present)

I retired from NIH in 1994, at age 72. Although there were some loose ends, such as revisions of earlier chapters, I was happy to have more time for my sculptures. There were several pieces that needed some additional work; this was done in time for a show of 14 pieces, displayed for about 75 friends and family (at our home in Maryland, September 1998). We moved from Maryland to Charlottesville, Virginia (in August 2000), in order to supervise the construction of a home at Wintergreen Mountain Village, in the Blue Ridge (completed August 2001). We have a great view (of several mountains, with granite boulders and oak trees in the foreground); we feed lots of birds and squirrels. We occasionally drive to D.C. and Maryland, for the Washington National Opera and for visits with relatives and friends.

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Mark R. Rosenzweig

BORN:

Rochester, New York

September 12, 1922

EDUCATION:

University of Rochester, B.A. (Psychology, 1943)

University of Rochester, M.A. (Psychology, 1944)

Harvard University, Ph.D. (Psychology, 1949)

APPOINTMENTS:

Harvard University, Research Fellow (1949)

University of California, Berkeley (1950)

HONORS AND AWARDS (SELECTED)

Editor, Annual Review of Psychology (1968–1994)

National Academy of Sciences, USA (1979)

Doctor Honoris Causa, Université René Descartes, Université de Paris (1980)

Distinguished Scientific Contribution Award, American Psychological Association (1982)

Distinguished Alumnus Award, University of Rochester (1984)

Founding Chair, U.S. National Committee for the International Union of Psychological Science, National Academy of Sciences/National Research Council (1985–1988)

Doctor Honoris Causa, Université Louis Pasteur, Strasbourg, France (1987)

President, International Union of Psychological Science (1988–1992)

William James Fellow, American Psychological Society (1989)

Berkeley Citation, University of California (1992)

Distinguished Contribution to International Psychology Award, American Psychological Association (1998)

In his early studies, Mark Rosenzweig discovered brain mechanisms of auditory localization and of the precedence effect in localization. He is best known for research with collaborators that was the first to demonstrate neurochemical and neuroanatomical plasticity of the brain in response to differential experience. These discoveries changed the thinking of neuroscientists and others about the brain.

Rosenzweig and collaborators also investigated the neurochemical processes underlying the successive stages of memory formation.

Mark R. Rosenzweig

Preparing this account brings back the excitement of discovering unexpected aspects of the nervous system as well as the satisfaction of systematically testing alternative hypotheses. It also shows occasions when I failed to follow up leads or insights that later proved important.

Family Background and Early Education

I do not know of any scientists among my forebears, but there were relatives noted for logical reasoning and skill in use of language. Perhaps that heritage, combined with fortunate circumstances, was enough to permit me a scientific career.

My grandparents emigrated from Russia to the United States in the 1880s. My father and his two brothers became lawyers; their four sisters were office workers. My father was known for keen legal analysis and for activity in community affairs. My mother grew up in Buffalo, New York, at that time a city with a large German-speaking population. She received high school diplomas in both German and English, and she was always interested in languages. She and my father were actively engaged in my sister's education and my own. They played word games with us to improve our vocabularies. We enjoyed a warm family life.

I was born and grew up in Rochester, New York and went to public schools where I was valedictorian in both grammar school and high school. In high school, I was selected for the Honor Work Program, a program for highly achieving students. In this program we were allowed to complete the curriculum according to our own schedules and to spend the rest of the time on individual or joint projects, such as chemical experiments, library time, writing and presenting skits, or cartooning.

College

In fall 1940 I entered the University of Rochester. In some ways I found college a letdown after the high intensity of the Honor Work Program. I was not sure what to make my major field. Courses in history interested me strongly, but the introductory course in psychology fascinated me, and I decided to major in psychology. The chair of the Department of Psychology, Elmer A.K. Culler, and some of his colleagues, including K.U. Smith, specialized in physiological psychology. The attack on Pearl Harbor and the entry of the United States into the war occurred during my sophomore year. Because of poor vision, I could not qualify for officer training, so I decided to continue my studies as long as possible. By taking a heavy program, I earned the B.A. in 1943 and then continued work toward the M.A.

A major area of research in the department was auditory perception and its physiology. We benefitted from the collaboration of Karl Lowy, an otolaryngologist with a strong scientific background, and summer visits by auditory physiologist Harlow Ades. I chose an M.A. research project that fit into the program of the laboratory, but the results yielded the first surprise in my research career. I trained cats to respond to a change in intensity of an auditory stimulus and then planned to map the frequency representation of the auditory cortex by removing areas of cortex and finding frequencies to which the cats could no longer respond. First, as a test, I removed the entire primary auditory area, and I found that the cats were still able to respond to stimuli throughout the frequency range! Auditory cortex was not required for intensity discrimination. Later it was found that auditory cortex is necessary for accurate auditory localization. I completed requirements for the M.A. before being drafted in 1943. A report based on my M.A. thesis, written during naval service, was my first scientific publication (Rosenzweig, 1946).

Naval Service

Dr. Lowy had arranged for me to join a Navy physiology laboratory in Bethesda when I would be drafted. I had visited the laboratory, and all seemed to be in order. But when I was drafted, the Navy needed technicians for its radar program. Some electronic training in my M.A. program showed in my record, so I spent the next 2 years training and serving as a radio technician (the word radar was not public yet). Despite the poor vision that kept me out of officer training, my service involved reading detailed, finegrained electronic circuit diagrams. While I was stationed at the Anacostia Naval Base in Washington, DC, President Roosevelt died, and I marched in his funeral procession. Later I shipped out across the Pacific and was stationed on a seaplane tender in Tsingtao Harbor, China.

The tender served the seaplanes that brought mail to us and other naval vessels in Tsingtao harbor, a somewhat circuitous function. This was my first experience in another country, and I tried to make the most of it. I arranged on days of liberty to be shown around the city and nearby countryside by members of the staff of a small advertising newspaper intended for American servicemen, in exchange for improving the writing of the newspaper. The Chinese staff helped me to understand Chinese customs and architecture.

The Years at Harvard

Doctoral Studies at Harvard

While still at the University of Rochester, I had applied for entrance to the doctoral program in psychology at Harvard and had been accepted. Soon after my discharge from the Navy in the spring of 1946, I entered Harvard in the fall, where I did research in the Psycho-Acoustic Laboratory. Professor Edwin Newman enlisted me to do research on dichotic listening in human subjects for a project that he and Professor Hans Wallach had devised. This research provided the empirical basis for a well-known paper on the precedence effect in auditory localization (Wallach, Newman, and Rosenzweig, 1949).

Some graduate courses or seminars at Harvard were particularly impressive. In the summer of 1947, Donald O. Hebb came as a visiting faculty member and taught a seminar, using as textbook a mimeographed version of The Organization of Behavior: A Neuropsychological Theory, which had not yet found a publisher. I wish I had had the foresight to save that historical version. I also enjoyed Edwin G. Boring's seminars in the history of psychology, and later I was to write some articles on history of psychology and neuroscience.

Dr. Robert Galambos joined the laboratory as a research associate in 1947 and I learned electrophysiological recording from him. Professor Georg von Békésy joined the laboratory in 1947; in 1961 he was awarded the Nobel Prize in Physiology or Medicine for his research in the physiology of audition. Von Békésy suggested I learn histological techniques with him to aid him in his research, but I did not want to be diverted from the research I had begun on the neurophysiology of binaural perception in the cat, so I declined his offer. Had I accepted it, my research career might have gone off in a different direction.

Békésy impressed me strongly with his insistence on finding alternative ways to test a hypothesis and not being content with any single test, and I have tried to follow that practice. Later on, during a few returns to Cambridge, I benefitted from conversations with him.

Late in his career, Békésy took a professorship at the University of Hawaii. In Honolulu for a meeting in 1972, I heard that he was gravely ill, and I went to see him in the hospital. Békésy was heavily sedated, and his voice seemed to come from far off. He surprised and shocked me by murmuring, “I wasted my life studying audition. I should have studied pain.”

In the research on binaural perception, I investigated how the electrophysiological responses evoked by stimulation of the two ears interacted at the auditory cortex. Because the responses were variable, I measured and averaged many responses for each stimulus condition, in effect acting as a living example of the later-to-be-invented computer of averaged transients. The results demonstrated that each ear is represented at the auditory cortex of each hemisphere but significantly more strongly in the contralateral hemisphere. They also showed that when the two ears were stimulated with dichotic time differences as little as microseconds, the response to the earlier stimulus partially inhibited the response to the later one. The relative size of responses at the two hemispheres indicated which ear was stimulated first and by how much. These findings were used to interpret dichotic-listening effects in human observers. Brain responses to closely successive dichotic stimuli suggested a mechanism for the precedence effect. I presented and defended my doctoral thesis in 1949 and remained another year at Harvard as a postdoctoral fellow to round out some aspects of the research.

During my postdoctoral year I taught the undergraduate course in physiological psychology. Some graduate students in the Department of Social Relations wanted to enroll in the proseminar in physiological psychology, but they were refused because feelings were still raw between Psychology and the recently formed Social Relations. I was told that if I wished, I could give them a noncredit seminar, which I did. One of those students was James Olds, who later went on to do postdoctoral research with Hebb at McGill. He and Peter Milner became famous for discovering “pleasure centers” (reinforcement centers) in the rat brain. In later years, Olds always addressed me as “Professor” in recognition of the seminar he took with me.

My 1949 doctoral thesis also demonstrated that electrodes placed on the skull could pick up electrical activity of all the auditory stations from the cochlea to the cortex. I noted that in his unpublished 1941 doctoral dissertation, J.E. Hawkins had shown that short-latency auditory deflections recorded at the cortex were subcortical in origin because they persisted after ablation of the cortex. In a publication based on my thesis I called attention to the fact that “the activity of subcortical centers can be studied without surgical invasion of the nervous system” (Rosenzweig, 1951, p. 148). At the time, I did not make much of this, and I did not follow it farther. Only later did others realize that these responses could be used to test the integrity of successive stations of the auditory system in infants and in adults with hearing impairment.

Starting in the 1970s, Robert Galambos and members of his group developed this into a practical hearing and neurological test and began using it to identify newborns with hearing loss. Now such tests are mandatory for infants in most of the United States so that problems of hearing can be detected and remedied early.

Marriage

While at Harvard I met my future wife, Janine Chappat, a young French scholar who was doing postdoctoral research in education and cultural anthropology. Janine had been studying at the University of Oxford, England, when the sudden defeat of France in 1940 made it impossible for her to return there, and the occupation of northern France led to her classification in England as an enemy alien. Although friends in England were very hospitable and supportive, Janine decided to continue her studies in the United States. When I met her, she had recently concluded 2 years of fieldwork in New Mexico, supervised by anthropologist Clyde Kluckhohn, studying how children of Anglo, Hispanic, and Navajo communities learned about the other groups.

Janine and I married in the summer of 1947, and we have shared a life of love and mutual support. We had a brief honeymoon in France where Janine was reunited with her family for the first time after the war. That was the first of our many trips to France, including some halfsabbatical leaves. It paved the way to my doing research later with French colleagues and lecturing in French, and it was one of the factors that led me to become active in international psychology. (My activities in international psychology have been reported elsewhere [Rosenzweig, 1998].)

While in Paris in 1947 I paid my respects to Professor Henri Piéron at the Collège de France. Piéron was well known for his research in sensory physiology, and he was a leader in international psychology. He had been president of the 11th International Congress of Psychology in 1937, and he was soon to become the first president of the International Union of Psychological Science, 1951 to 1954. France in 1947 was still suffering from the aftermath of the war. Rationing was still in force, and the general mood was gloomy. Pieron shared that sentiment. Leading me to a window at the back of the Collège de France, Piéron pointed down to an abandoned excavation with muddy water in the bottom. “That was to have been our new laboratory,” he said, “but now it will never be built.” Fortunately that pessimism was excessive, because the overall situation soon improved, and French psychology and neuroscience rebounded.

In the summer of 1949, because of Janine's skills in French and anthropology, we took part in an anthropological/sociological survey in southwestern Nova Scotia, conducting interviews in the string of Frenchspeaking villages that line the shore of the Baie Ste. Marie. This was the Acadian country of Longfellow's Evangeline. The French spoken there gave us many surprises because some words had meanings that had changed over the centuries in France, and there were many maritime terms (e.g., “Debark from bed.” “Moor (tie) one's shoelaces."). We welcomed the birth of our first child, Anne Janine, in 1950 while we were still at Harvard. She celebrated her first birthday in Paris. Then we drove from Massachusetts to California, with Anne walking much of the way in her playpen in the back of our Plymouth Suburban. Suzanne Jacqueline was born in 1952 and Philip Mark in 1955, and we have six grandchildren. When our children were young, we spoke only French at the dinner table so they would be bilingual. This also resulted in my learning French backwards, so to speak, adding an underpinning of children's sayings and games to my adult French. (A further benefit of mastering French was that it gave me another language in which to make puns.)

Later, as I gave research papers abroad and as I became active in the International Union of Psychological Science (IUPsyS), our children accompanied us on visits to 10 countries. The children developed a taste for travel and, among them, later learned Chinese, German, and Spanish to supplement their English and French. Our daughter Anne, a lawyer, is active in international organizations that foster human rights and labor rights. She and her husband travel abroad frequently. Our daughter Suzanne and her husband enjoy travel, and they have instilled this in their four wonderful children. Our son is a professor at the Institute for Management Development in Lausanne, Switzerland, and he conducts workshops in many countries. He and his wife have two wonderful bilingual children.

Appointment at the University of California, Berkeley

During 1948 to 1949 the well-known psychologist Edward C. Tolman spent the academic year at Harvard, shut out of his office at the University of California when he and a few other professors refused to sign a loyalty oath required by the regents. Early in 1949 he interviewed me and some others for an opening at Berkeley in physiological psychology. After some correspondence, I was offered a position as assistant professor. Now I felt a dilemma because the American Association of University Professors had censured the regents of the university because of their actions.

I consulted Professor Tolman, and he replied generously, “If you are interested in the position, take it. There are enough senior professors to maintain the fight against the loyalty oath, and we don't want to cripple the future of the university by stopping recruitment of young people.” So I accepted the position but arranged to remain at Harvard for one more year. Tolman's stance as a nonsigner of the oath was later justified by the courts. Although the Regents of the University of California claimed that all academic appointments were for one year only and did not have to be renewed, the judges found that in practice the university did have tenure, and they ordered the non-signers reinstated.

During my last spring at Harvard, David Krech of the psychology department at Berkeley spent a few months there, and we became acquainted. He, like Tolman, was a nonsigner of the California Loyalty Oath and was returning from a year spent in Europe. Krech and I were later to collaborate at Berkeley.

Research at Berkeley, The Early Years

Arrival at Berkeley

Soon after my arrival at Berkeley, I established a laboratory to continue research on neural mechanisms of binaural perception. To determine the contributions of different neural stations to binaural perception, my students and I recorded electrophysiological responses at different levels of the nervous system as we delivered dichotic stimuli to anesthetized cats, and we published several papers on the results. I summarized some of this research in a Scientific American article (Rosenzweig, 1961). I also conducted research on other topics, including perception of words as a function of their frequency of usage, word association, and history of topics in psychology, but soon another intriguing topic began to occupy me increasingly.

Edward Tolman

First, however, I should add a little more about Edward Tolman who was a major influence on me and on the study of learning and memory. At a time when behavioral psychology reigned in the United States, Tolman was a “cognitive behaviorist,” and his work prefigured the cognitive movement. Also, at a time when investigators were searching for THE key to learning and memory, Tolman (1949) held that there are many kinds of learning, and there may be many mechanisms of memory. Tolman's eminence in research was reflected by his election as president of the American Psychological Association (1937) and as vice president of the American Association for the Advancement of Science (1942). The 14th International Congress of Psychology was to have been held in the United States in 1954 and Tolman was to have been its president, but partly because anticommunist legislation in the United States would have made it difficult for many foreign psychologists to attend, the congress was shifted to Canada, and Tolman was copresident along with Canadian psychologist Edward A. Bott. Although Tolman had many productive students, he did not try to establish a school but instead encouraged students to pursue their own directions.

In 1958 Krech and I headed a committee to arrange to have a portrait painted of Tolman, and the artist had completed the face and hands when Tolman died in 1959. On one of my last visits to Tolman at his home, he recalled visiting a retired colleague at another university and walking with him down a corridor where the colleague's portrait hung. “Wouldn't that be embarrassing,” Tolman reflected, “to walk under one's own portrait?” Tolman might have been even more embarrassed at the thought that the portrait hangs in the lobby of Tolman Hall, the building that was named for him in 1962.

Beginning the Search for Neural Correlates of Problem-Solving Behavior

Soon after I arrived at Berkeley, my colleague David Krech asked me to consider with him what might be neural mechanisms of the individual differences in tests of problem-solving behavior he had been finding among rats of inbred strains. As a “ratrunner” of long standing, he had been impressed by sizable individual differences of problem-solving ability among rats of the same strain, sex, and age. I suggested that we might investigate whether individual differences in cortical acetylcholine metabolism might correlate with individual differences in problem-solving ability. Krech turned to his friend Melvin Calvin, head of the campus Laboratory of Chemical Biodynamics, and Calvin agreed to encourage any of the younger chemists in his laboratory to collaborate with us, if the project interested them. So one noon in the fall of 1953 I met in the Faculty Club for lunch with three chemists and explained our project. One of them, Edward L. Bennett, decided that it might be interesting to collaborate with psychologists for a few months, and thus began a fruitful collaboration that lasted for over 40 years. We benefitted from the continued interest and support of Professor Calvin.

Status of the Field in the 1950s

Reviewing briefly the state of the field will provide some context for our research. It may also help to explain the skeptical initial reaction to our discoveries. In the 1950s pessimism prevailed about being able to discover the neural bases of learning and memory. For example, Karl S. Lashley, in a highly critical review in 1950, surveyed the literature on possible synaptic changes as a result of training and concluded that there was no solid evidence to support any of the “growth” theories. Specifically, Lashley offered these criticisms: (1) Neural cell growth appears to be too slow to account for the rapidity with which some learning takes place. (We will return to this point later.) (2) Because he was unable to localize the memory trace, Lashley held that there was no warrant to look for localized changes.

I witnessed the vehemence of this opinion at a small, informal lunch in New York in 1950 during a meeting of the Association for Research in Nervous and Mental Diseases. When someone asked Lashley his opinion of Hebb's recently published book, Lashley stated sharply that the ideas in the book were garbled versions of his own ideas that Hebb had misunderstood. A few years later, Hans-Lukas Teuber stated in his Annual Review of Psychology chapter on physiological psychology that

The absence of any convincing physiological correlate of learning is the greatest gap in physiological psychology. Apparently, the best we can do with learning is to prevent it from occurring, by intercurrent stimulation through implanted electrodes..., by cerebral ablation..., or by depriving otherwise intact organisms, early in life, of normal sensory influx (Teuber, 1955, p. 267).

Edwin G. Boring, the historian of psychology with whom I studied in the latter 1940s, also testified to the lack of progress on this problem in the 1950 edition of his history of experimental psychology:

Where or how does the brain store memories? That is the great mystery….The physiology of memory has been so baffling a problem that most psychologists in facing it have gone positivistic, being content with hypothesizing intervening variables or with empty correlations (Boring, 1950, p. 670).

In general it seems safe to say that progress in this field is held back not by lack of interest, ability, or industry but by the absence of some one of the other essentials for scientific progress. Knowledge of the nature of the nerve impulse waited on the discovery of electric currents and galvanometers of several kinds. Knowledge in psychoacoustics seemed to get nowhere until electronics developed. The truth about how the brain functions may eventually yield to a technique that comes from some new field remote from either physiology or psychology. Genius waits on insight, but insight may wait on the discovery of new concrete factual knowledge (Boring, 1950, p. 688).

In fact, some major advances were already beginning to occur in research on the neural mechanisms of learning and memory. Some of these resulted from applications of recently developed techniques such as single cell electrophysiological recording, electron microscopy, and use of new neurochemical methods. Another major influence encouraging research on neural mechanisms of learning and memory was Donald O. Hebb's monograph, The Organization of Behavior, that was finally published in 1949.

Hebb was more positive about possible synaptic changes in learning than his mentor Lashley. Hebb noted some evidence for neural changes and did not let the absence of conclusive evidence deter him from reviving hypotheses about the conditions that could lead to formation of new synaptic junctions and underlie memory. In essence, Hebb's hypothesis of synaptic changes underlying learning resembled William James' formulation of 1890:

When two elementary brain-processes have been active together or in immediate succession, one of them, on recurring, tends to propagate its excitement into the other (James, 1890, p. 566).

And this in turn resembled the still earlier formulation of associationist philosopher Alexander Bain:

for every act of memory, every exercise of bodily aptitude, every habit, recollection, train of ideas, there is a specific grouping or coordination of sensations and movements, by virtue of specific growths in the cell junctions (Bain, p. 91).

Hebb's “dual trace hypothesis"—that a labile short-term memory trace may be followed by a stable long-term trace—also resembled the “consolidation-perseveration” hypothesis of Müller and Pilzecker (1900). Much current neuroscience research concerns properties of what are now known as Hebbian synapses. Hebb was somewhat amused that his name was connected to this resurrected hypothesis rather than to concepts he considered original (Milner, 1993, p. 127).

Still, a decade after Hebb had revived these long-standing hypotheses, the postulate of use-dependent neural plasticity had not yet been demonstrated experimentally. This was to change in the early 1960s when our group announced that both formal training and informal experience in varied environments led to chemical (Krech, Rosenzweig, and Bennett, 1960) and anatomical plasticity of the brain (Rosenzweig, Krech, Bennett, and Diamond, 1962). Soon after came the reports of Hubel and Wiesel that occluding one eye of a kitten led to reduction in the number of cortical cells responding to that eye, but only if the occlusion occurred during an early critical period (Wiesel and Hubel, 1963, 1965; Hubel and Wiesel, 1965).

A Failed Approach

Attempts to explain learning and perception in terms of fields of neural activity persisted through much of the 20th century. To explain conditioning, Pavlov posited fields of excitation and inhibition irradiating across the cerebral cortex. In 1940 Hilgard and Marquis criticized these concepts as being purely inferential and lacking any accepted neurophysiological foundation.

Wolfgang Köhler called on a similar field theory to explain phenomena of visual perception. I heard prominent scientists criticize this concept. In 1959, when Köhler was inducted as president of the American Psychological Association, the outgoing president, Harry Harlow, praised Köhler's accomplishments. That evening, Harlow told me, “That was the hardest thing I ever had to do,” because he thought so little of Köhler's work.

Lashley disproved Köhler's field theory by an experiment in which he implanted metal foil over the visual cortex of rats. Although the foil would have distorted any electrical fields, it did not impair the ability of the rats to make correct visual discriminations. Shortly after Lashley's death, some of his former students published a volume of his main papers. Surprised to find the metal-foil experiment missing from the volume, I queried Donald Hebb, one of the editors. Hebb replied that Köhler's field theory was too silly to merit a refutation. When Köhler lectured once at Berkeley about his field theory, vision scientist Gordon Walls questioned whether Köhler understood that in the human brain the primary visual fields of the two hemisphere lie closely parallel on the inner surface near the occipital pole. Because of this juxtaposition, electrical fields from the visual cortex in one hemisphere would interfere with perception mediated by the other hemisphere, which is not the case.

Hans Wallach, who had collaborated with Köhler in Germany and again in the United States, told me that he regretted that Köhler had wasted his time theorizing about electrical fields of the cortex rather than pursuing research in areas that he knew better.

Unexpected Discovery of Brain Plasticity

Our Approach and Early Findings

The strategy of our group was stated in a symposium paper I gave in 1955: We proposed that to find “changes in the nervous system that accompany learning” a “biochemical analysis which could integrate changes over thousands of neural units might provide an entering wedge.” Further analysis might then focus more narrowly on the exact sites of change (Rosenzweig, Krech, and Bennett, 1958b, p. 367).

We decided to use the activity of the enzyme acetylcholinesterase (AChE) as an index to acetylcholine (ACh) metabolism. We hypothesized, wrongly as it would turn out, that AChE was a stable characteristic of the individual. Measurement of AChE activity was feasible with a recently devised automatic titration apparatus. Our first experiments attempted to account for individual differences in behavior in Krech's “hypothesis” apparatus. This was a four-unit Y-maze that was unsolvable because the correct visual and spatial cues were changed on successive trials. Nevertheless, rats tended to show hypotheses, that is, they would show runs of choices in which they favored visual hypotheses (light or dark) or spatial hypotheses (right or left). As subjects, we used mainly two strains of rats maintained by the department: the Sl strain (descendants of rats that had been selectively bred in the 1930s for maze-bright behavior by our Berkeley colleague Robert C. Tryon) and the S3 strain (descendants of Tryon's maze-dull strain).

Findings we published during the first few years of our research provided baselines for unexpected discoveries we were soon to make. This provided an illustration of Louis Pasteur's dictum: “Chance favors the prepared mind.” Some of the main early findings were these:

Within both the Sl and S3 strains, there are significant correlations between behavioral scores and cortical AChE activity (Rosenzweig, Krech, and Bennett, 1958a, 1960), thus justifying the original purpose of this project.

There are significant strain differences in cortical AChE activity, with the S1 (maze bright) strain showing significantly higher values than the S3 rats (Bennett, Rosenzweig, Krech, Karlsson et al., 1958).

AChE activity differs significantly among regions of the cortex (Bennett, Krech, Rosenzweig, Karlsson et al., 1958), although previous investigators had concluded that there were not significant regional differences. The enzyme lactic dehydrogenase did not show such differences, nor differences between the Sl and S3 strains, so the correlations between AChE activity and behavior could not be ascribed to general differences in cerebral metabolic levels (Bennett, Krech, Rosenzweig, Karlsson et al., 1958).

Cortical AChE activity increases with age in the rat until about 100 days and then declines (Bennett et al., 1961).

At the start of our work we assumed from work of others that AChE would provide an index to metabolism of the ACh system, and we later obtained direct support for this, finding that brains of S1 rats showed significantly higher concentrations of ACh than did brains of S3 rats, just as the S1s showed significantly greater AChE activity (Bennett, Crossland, Krech, and Rosenzweig, 1960).

Early Finding of Plasticity of Brain Chemistry

To try to explore further the correlations between behavior and brain chemistry, we tested different groups of rats in different spatial mazes, and we obtained a surprising result. As I reported at a symposium at the University of Pittsburgh in 1958, there were systematic differences among the cortical AChE values of rats that had been tested in different apparatuses (Rosenzweig, Krech, and Bennett, 1961). We had been assuming that the brain AChE value of an animal was an independent variable, but now it appeared that the value depended in part on the experience the animal had undergone! To test further this unexpected finding, we compared animals subjected to behavioral tests with animals not subjected to testing, and we found the tested animals to differ significantly from the untested in cortical AChE activity.

Rather than continue the expensive process of testing animals in various mazes, we then decided to explore the results of informal learning by placing rats for prolonged periods in environments that were either more enriched or more impoverished than the standard colony (SC) housing of three rats to a cage. For the enriched condition (EC), we placed 10 to 12 rats in a large cage provided with varied stimulus objects, as students of Hebb had done (Forgays and Forgays, 1952). We also gave this group a small amount of maze training. For the impoverished condition (IC) we placed rats in individual cages. In initial experiments of this sort, we placed littermates in the three conditions at weaning, at about 25 days of age, and we kept them there for 80 days. Analysis of cortical samples at the end of the period showed significant differences among the groups: Contrary to our expectation, AChE activity per unit of tissue weight in the cerebral cortex was significantly lower in EC than in IC animals, with SC being intermediate. In the rest of the brain, however, AChE activity was significantly highest in the ECs and lowest in the ICs.

Surprising Discovery of Plasticity of Brain Anatomy

Another surprise helped us to interpret this unexpected result. After years of dividing AChE activity by tissue weight of each sample to obtain enzymatic activity per unit of tissue weight, we were astonished to find that the tissue weights of the samples differed significantly among experimental groups! Specifically, for a cortical tissue sample of fixed surface area, the weight was greatest for EC rats and least for IC rats (Rosenzweig, Krech, Bennett, and Diamond, 1962). So the anatomy as well as the chemistry of the brain was altered by experience! This effect was larger in the occipital region than in other regions of the cortex. Subsequent work showed that the increased weight of cortex in the EC rats was paralleled by increased protein in the samples (Bennett, Diamond, Krech, and Rosenzweig, 1964). Anatomical measurements of brain sections showed the cortex of EC rats to be significantly thicker than that of IC rats, by about 5% (Diamond, Krech, and Rosenzweig, 1964). This difference was not large, but because the brain shows relatively little anatomical variability, it was highly significant statistically.

We and coworkers also found that enriched experience in rats led to increased amounts of RNA (Ferchmin et al., 1970; Bennett et al., 1976) and increased expression of RNA in rat brain (Grouse et al., 1978). We also found that maze training caused differences not only in brain anatomy but also in cortical RNA/DNA ratios (Bennett et al., 1979).

Having found differences in gross anatomy of the brain caused by differential experience, we then proceeded to investigate more detailed neuroanatomical features. In a review article in the Scientific American (Rosenzweig, Bennett, and Diamond, 1972), we described several such neuroanatomical differences induced by enriched experience in the occipital cortex:

The cross-sectional area of cortical pyramidal cell bodies increased significantly (by about 13%). For more on this effect, see Diamond, Johnson et al. (1975).

The number of neurons per unit of volume of occipital cortex decreased slightly with enriched experience, probably because the number of neurons remained fixed while the thickness of the cortex increased.

On the contrary, the number of glial cells per unit of volume of cortex increased significantly (by 14%).

Pyramidal neurons of EC rats showed significantly more dendritic spines than those of IC rats, especially on the basal dendrites. For more detail on this effect, see Globus et al. (1973).

The size of synaptic junctions increased significantly. See also West and Greenough (1972).

Our Finding Countered the Dogma of Fixity of Brain Weight

Our finding of changes in cortical weights with differential experience ran counter to the established dogma that brain weights are strictly fixed. Consider, for example, the following quotations from the outstanding neuroanatomist Santiago Ramón y Cajal (Cajal, 1894), which turned out to be pertinent to our research in more than one way:

If we are not worried about putting forth analogies, we could say that the cerebral cortex is like a garden planted with innumerable trees—the pyramidal cells—which, thanks to intelligent cultivation, can multiply their branches and sink their roots deeper, producing fruits and flowers of ever greater variety and quality (Cajal, 1894, p. 467).

But Ramón y Cajal then considered an obvious objection to his hypothesis:

You may well ask how the volume of the brain can remain constant if there is a greater branching and even formation of new terminals of the neurons. To meet this objection we may hypothesize either a reciprocal diminution of the cell bodies or a shrinkage of other areas of the brain whose function is not directly related to intelligence (p. 467).

To preserve the supposed fixity of brain volume, Ramón y Cajal hypothesized a diminution of cell bodies to compensate for the greater branching of neurons, but as we found, the cell bodies increase in volume with enriched experience. His other hypothesis, that other regions of the brain shrink as the cortex expands, may be supported by our finding of diminution of the noncortical parts of the brain as a consequence of enriched experience. Nevertheless, we found an overall increase in brain weight (and presumably in brain volume), overthrowing the longstanding dogma of fixity of the brain.

Cerebral Effects of Experience Occur Rather Rapidly, Across the Life Span, and in Many Species

Originally we placed rats into the differential environments at weaning and kept them there for 80 days, because we wanted to allow a good chance for effects to occur. Having found clear effects of differential experience on brain measures, we then tried varying both the age at onset and the duration of differential experience. We obtained similar cerebral effects in rats assigned for 30 days to the differential environments (EC vs IC) either as 50-day juveniles or as 105-day young adults. Walter H. Riege (1971) in our laboratory found similar effects in rats assigned to the differential environments at 285 days of age and kept there for periods of 30, 60, or 90 days. Although the capacity for these plastic changes in the nervous system, and for learning, remain in older subjects, the cerebral effects of differential experience develop somewhat more slowly in older than in younger animals, and the magnitude of the effects is often smaller in the older animals. The fact that cerebral effects of differential experience occur across the entire life span marks a strong difference from the effects reported by Hubel and Wiesel that can be induced only during an early critical period.

Further work showed that 2 hours a day in the differential environments over a period of either 30 or 54 days produced cerebral effects similar to those of 24-hour-a-day exposure for the same number of days (Rosenzweig, Love, and Bennett, 1968). Just 4 days of differential housing produced clear effects on cortical weights (Bennett et al., 1970) and on dendritic branching (Kilman et al., 1988). Ferchmin and Eterovic (1986) found that four 10-minute daily sessions in EC significantly altered cortical RNA concentrations.

Experiments with several strains of rats showed similar effects of EC versus IC experience in both brain values and problem-solving behavior, as reviewed by Renner and Rosenzweig (1987, pp. 53–54). Similar effects on brain measures have been found in several species of mammals—mice of several strains, gerbils, two species of ground squirrels, cats, and monkeys (reviewed by Renner and Rosenzweig, 1987, pp. 54–59). Further work has extended these brain effects to birds, fish, fruit flies, and spiders. The ubiquity of effects across species led neurobiologist Abdul Mohammed to exclaim that these effects occur “from flies to philosophers” (Mohammed et al., 2002, p. 127).

Control Experiments Verified that the Cerebral Effects Were Caused by Differential Experience and Not by Other Variables

It was possible that the unexpected cerebral effects were not the result of differential experience but of other aspects of the experimental situation, so we promptly ran a number of experiments to control for other possible causes. The results of the control experiments did not support the importance of any of the other variables, as the following examples show.

Handling. Handling rats, particularly young ones, is known to increase the weight of their adrenal glands. Because the EC rats were handled more often than SC or IC rats, perhaps cerebral differences were caused by handling or stress. In control experiments, some rats were handled for several minutes each day for either 30 or 60 days; littermates were never handled. No differences developed between the handled rats and the unhandled ones in brain weight or brain enzyme activity, although there were differences in adrenal weights. In further experiments, rats in both EC and IC were handled once a day, and the usual brain differences were found at the end of the experimental period (Rosenzweig, Krech, Bennett, and Diamond, 1968).

Stress. Stress might have been a cause of the cerebral effects we found. IC rats might have suffered from “isolation stress” and EC rats might have suffered from “information overload.” To test the possible effects of stress on brain measures, we conducted five experiments in which some rats were given intermittent unavoidable electric shocks for 12 minutes daily. At the same time, littermate controls were placed in similar enclosures but with no shock and in a different room. Although the stress of shock affected body weight and adrenal weight, it had little effect on brain measures. None of the four cortical regions showed a significant difference. Total cortex did weigh 2.3% less in the shocked rats (p < 0.05), but when allowance was made, through analysis of variance, for the reduction in body weight in the shocked rats, the difference shrank and became nonsignificant. Even if the absolute weights were considered, the pattern of differences over cortical areas did not parallel that of EC-IC differences. AChE activity was analyzed in only one of these experiments. It showed no significant difference between shocked and control rats for any brain region. For more on experiments on possible effects of stress on brain measures, see Rosenzweig, Bennett, and Diamond (1972b) and Rosenzweig and Bennett (1976b).

In a later experiment, Riege and Morimoto in our laboratory subjected some rats to a daily period of stress in which they were briefly tumbled in a revolving drum or given a mild electric shock. They also kept rats in EC and IC. There was a clear double differentiation in effects: The stress was effective in producing a significant increase in the weight of the adrenal glands, but it did not cause changes in the brain measures we studied. Meanwhile, the environmental EC-IC treatment produced the usual brain effects but did not affect adrenal weights (Riege and Morimoto, 1970).

The experiments on stress also included the variable of handling because the stressed rats were removed from their cages daily and taken to another room for the stress treatment, while the control rats remained in their cages. We concluded, therefore, that the combination of stress and handling did not give rise to the EC-IC brain effects.

Accelerated Maturation. Some of the changes we found between EC and IC rats go in the same direction as changes that occur in normal maturation—greater cortical weight, greater glial/neural ratio, and fewer neurons per unit of cortical volume. Thus, it seemed possible that enriched experience accelerates maturation or that impoverished experience retards it. But we found that some changes with enriched experience go in the opposite direction from what is found in normal growth. Also, as we have seen previously, typical EC-IC brain effects can be induced in animals placed in the differential environments as adults. Thus, the EC-IC differences cannot be attributed to differences in rate of maturation of animals in the differential environments.

Differential Locomotion. Rats in an EC cage are more active than those in IC, so we wanted to determine whether locomotor activity might account for the EC-IC effects. In our initial publication on the EC-IC effects, we reported a control experiment in which some IC rats had free access to a running wheel while others were never allowed such access. The experimental (running wheel) rats averaged more than 100,000 revolutions during the experimental period. At the conclusion of the 80-day period, there was no significant difference in AChE measures between the experimental and control groups; the small differences found were opposite in direction from those seen in EC-IC groups (Krech, Rosenzweig, and Bennett, 1960).

Hormonal Mediation. Although stress had been ruled out as the cause of the EC-IC cerebral effects, other hormones might have mediated these effects. We therefore tested the hypothesis that the pituitary gland is essential to occurrence of these effects (Rosenzweig, Bennett, and Diamond, 1972b). The pituitary was chosen not only to eliminate its secretions but also to control for effects of glands controlled by feedback relations with the pituitary—the thyroid, the adrenal cortex, and the gonads.

Three experiments were run, and results were analyzed only for those animals in which we could verify complete hypophysectomy at sacrifice. Although hypophysectomy stunts bodily growth and reduces brain growth somewhat, significant EC-IC differences nevertheless occurred in both the brain weights and brain chemical measures of the operated as well as in the control animals. We therefore did not pursue further experiments in the endocrine direction.

Skepticism and Incredulity Greeted Our Initial Reports of Brain Plasticity

Our first reports that differential experience induces measurable changes in the brain were greeted with skepticism and incredulity. The responses reminded me of an old story: A villager was accused of returning a borrowed teapot in poor condition. Vehemently he replied, “In the first place, I never borrowed it; in the second place, I returned it in perfect condition; in the third place, the teapot was already dented when I got it!” Thus, on the one hand, some critics told us that such changes could not exist. On the other, we were told that it is well known that one can induce changes in a rat's brain just by looking at it cross-eyed. We were asked whether changes were found in the thickness of the soles of the paws and in all other tissue of ectodermal origin. At a meeting where I reported on increase in number of synaptic contacts (dendritic spines) with experience, John C. Eccles stated his firm belief that learning and memory storage involve “growth just of bigger and better synapses that are already there, not growth of new connections” (1965, p. 97). Donald Hebb, whom I had gotten to know better when he spent the summer of 1953 as a visiting professor in Berkeley and with whom I maintained contact, cautioned me that the more important the claim, the more carefully one must test it.

Beyond normal scientific caution, questions of turf may have been involved. I have the impression that neurophysiologists were reluctant to believe that psychologists and their collaborators could be the first to present evidence of changes in the brain as a result of experience.

Over the next several years, reports of replications and extension by us (e.g., Bennett et al., 1964) and by others (e.g., Altman and Das, 1964; Geller et al., 1965; Greenough and Volkmar, 1973) gained acceptance for the idea that training or differential experience could produce measurable changes in the brain. Thus in 1972 neurobiologist B.G. Cragg wrote “Initial incredulity that such differences in social and psychological conditions could give rise to significant differences in brain weight, cortical thickness, and glial cell numbers seems to have been overcome by the continued series of papers from Berkeley reporting consistent results. Some independent confirmation by workers elsewhere has also been obtained” (Cragg, 1972, p. 42).

Enriched Environments and the Brain

Our Work Introduced Enriched Environments to the Neuroscience Community

We did not invent the concept of the “enriched environment,” but I believe that our publications introduced the concept and the term to the neuroscience community. Our first paper with “enriched and impoverished environments” in the title appeared in 1962 (Krech, Rosenzweig, and Bennett, 1962). In the National Library of Medicine website, PubMed, the first citation for enriched environment is a paper from our group (Diamond, Krech, and Rosenzweig, 1964). This was followed later the same year by a paper by Altman and Das (1964), which cited four of our papers (1960 to 1964) showing effects of enriched environments on brain chemistry and brain anatomy. Our first papers reporting effects of environment on brain plasticity had used the term “environmental complexity” (Krech, Rosenzweig, and Bennett, 1960; Rosenzweig, Krech, Bennett, and Diamond, 1962). The next PubMed citation for enriched environment after 1964 was another paper from our group (Diamond et al., 1966). The period 1970 to 1974 showed seven citations for enriched environment, and thereafter the citations to this term increased exponentially, reaching 46 for 1995 to 1999 and 122 for 2000 to 2004.

Although the term “enriched environment” has become widely used, there is no standard definition for it and some investigators avoid it, preferring “complex environment.” We tried to make clear from the beginning that our enriched laboratory environment is enriched only in comparison with the standard animal colony cage. A natural environment may be much richer in learning experiences than even an enriched laboratory environment. For inbred laboratory animals, however, it is no longer clear what the natural environment would be. Laboratory rats and mice have been kept for more than 100 generations in protected environments, and inbreeding has made their gene pool different from the natural one.

We tried in two ways to ask how our enriched laboratory environment might compare with the natural environment. First, we tried raising laboratory rats in a seminatural outdoor environment at the Field Station for Research in Animal Behavior of the University of California at Berkeley. This environment consisted of a 30 × 30 foot concrete enclosure filled with dirt to a depth of 2 feet above the concrete base and with screening over the top. Food and water were provided ad lib, and a few stimulus objects were placed in the enclosure. For a diagram of this environment, see Rosenzweig, Bennett, and Diamond (1972b, p. 24). Groups of a dozen male laboratory rats thrived in the outdoor setting and, when the weather was not too wet, dug burrows, something their ancestors had not been able to do for more than 100 generations. In each of eight experiments, the rats kept for 1 month in the outdoor setting showed greater cortical development than their littermates that had been kept in enriched laboratory cages. This indicates that even the enriched laboratory environment is indeed impoverished in comparison with a natural environment. We had hoped to test the rats from the outdoor environment to find whether their increased cortical development was accompanied by increased problem-solving ability. Unfortunately, however, in the outdoor setting the rats became too savage to handle, so we were unable to conduct behavioral tests with them.

In a second attempt to compare effects of laboratory and natural environments on brain development, we used Belding's ground squirrels (Spermophilus beldingi), in collaboration with our colleague Paul Sherman who was studying a population of the squirrels in the Sierra near Tioga Pass, California. Feral ground squirrels, unlike laboratory rats, have not been altered by living for many generations in captivity. We live-trapped pregnant ground squirrels in the Sierra and brought them to the field station in Berkeley. The young were weaned at about 30 days of age and assigned to EC and IC conditions where they were kept for 40 days. Ten male and 10 female squirrels were in each condition. Just before sacrifice, feral (F) juveniles of the same age were live trapped where the pregnant ground squirrels had been obtained, and their brains were analyzed along with those of the EC and IC squirrels. In weights of cerebral cortex, values from F and EC squirrels were equal, and both exceeded the IC squirrels significantly ([F = EC] > IC, p < .01). In total RNA of occipital cortex, (F = EC) > IC, p < .05. In total DNA of occipital cortex, F > (EC = IC), p < .05. In skeletal development, measured by hindfoot length, F > EC > IC; F > IC, p < .01. Thus, in two out of three brain measures, EC squirrels equalled F squirrels, although F exceeded EC in skeletal development (Rosenzweig, Bennett, and Sherman, 1979). A further study substantially replicated these findings (Rosenzweig, Bennett, Sherman, and Alberti, 1980). At least in the case of ground squirrels, the laboratory enriched environment seemed to support brain development as well as did the natural environment. Clearly, the difference between results of the studies with rats and ground squirrels shows that this question still lacks a general resolution. Nevertheless, this has not prevented the increasing use of enriched laboratory environments.

The latter study (Rosenzweig et al., 1980) also showed plastic responses of the brain during hibernation. For this study, ground squirrels were livetrapped at about 80 days of age. Some were sacrificed for baseline values and others were placed for 5 months in EC or IC cages or in a cold room at 5°C where they hibernated. The nonhibernating squirrels continued to gain in brain and body weights during the experimental period, whereas the hibernators lost in both, showing significant decreases in weights of certain brain regions (hypothalamus, caudate nucleus, and medulla), and decreases of DNA in these regions, indicating loss of cells.

Enriched Experience Improves Ability to Learn and Solve Problems

Hebb (1949, p. 298) reported briefly that when he allowed seven laboratory rats to explore his home for some weeks as pets of his children and then returned the rats to the laboratory, they then showed better problem-solving ability than most rats that had remained in the laboratory throughout. Moreover, he stated, although he did not present evidence for this, that they maintained their superiority or even increased it during a series of problems in the Hebb-Williams maze. Hebb (1949, pp. 298–299) concluded that "the richer experience of the pet group during development made them better able to profit by new experience at maturity—one of the characteristics of the 'intelligent' human being” (italics in the original). Thus, the results seemed to show a permanent effect of early experience on problem-solving at maturity, and this conclusion continues to be cited.

We and others have confirmed the first conclusion of Hebb's exploratory study; that is, experience in an enriched environment improves learning and problem-solving on a wide variety of tasks, although such differences have not been found invariably. The more complex the, task, the more likely it is that animals with EC experience will perform better than animals from SC or IC groups (Renner and Rosenzweig, 1987, pp. 46–48).

We were unable, however, to replicate Hebb's report that over a series of tests, EC rats maintain or even increase their superiority over IC rats. On the contrary, we found that IC rats tend to catch up with EC rats over a series of trials in a test; this occurred in three different tests, including the Hebb-Williams maze (Rosenzweig, 1971, p. 321). Thus, we did not find that early deprivation of experience caused a permanent deficit, at least for rats tested on spatial problems. Rather, the rats showed a persistent capacity to benefit from experience.

Somewhat similarly, decreases in cortical weights induced by 300 days in the IC (vs the EC) environment were overcome by a few weeks of training and testing in the Hebb-Williams maze (Cummins et al., 1973). Similarly, Fuller (1966) found restricted experience beagles to be inferior to pets in reversal learning, but only on the first five reversals; thereafter there was no significant difference.

Enriched Environments as Therapy, in Animals and People

Once the brain was seen to respond to environmental influences not only in young but also in mature animals, investigators soon began testing whether environmental enrichment might aid recovery from brain disorders that have identifiable neuropathy. An intriguing report of 1964 stated that an enriched environment aided rats in recovering from effects of neonatal cortical lesions (Schwartz, 1964). We began in 1974 to replicate and extend this effect (Will et al., 1977), and research along this line continues. One of the major questions is the extent to which experience actually aids in recovery or only in compensation for the effects of brain injury. At a minimum, in people behavioral techniques aid the quality of life of patients with injuries of the brain or of the spinal cord. Beyond this, there may be interaction between the physiological and behavioral interventions. By 1976 an edited volume was published entitled Environments as Therapy for Brain Dysfunction (Walsh and Greenough, eds.), treating such topics as recovery from brain injury, malnutrition, endocrinopathies, and sensory deprivation. Chapters considered the relevance, generalizability, and limitations of animal models for therapy, and work on these questions continues. Investigators have asked which is most effective in promoting recovery from brain injury in an animal's environmental enrichment, physical exercise, or formal training? A review of research on this topic during the period 1990 to 2002 shows that enriched experience is the most potent of these treatments (Will, Galani, Kelche, and Rosenzweig, 2004).

Soon after we began publishing on effects of differential environments on brain and behavior, people began asking us about possible applications to human behavior, all the way from child development to successful aging. Thus, in 1965 I was invited to address the Division of Child Psychology at the American Phychological Association (APA) convention (Rosenzweig, 1966). Many of the developmental psychologists who attended my talk were surprised to learn that an enriched environment stimulates brain growth not only in infant but also in adult rats. On such occasions I was always careful to point out limitations in what we had found and to be cautious about extrapolations of animal research (e.g., Rosenzweig, Bennett, and Diamond, 1972b, p. 28). Nevertheless, invitations to speak and write about possible applications continued to come, and I accepted many of them (e.g., Rosenzweig, 1976, 1979, 1980, 1981a, 1981b, 1986, 1999a, 1999b, 2002; Rosenzweig and Bennett, 1979). At an international symposium on cognitive decline in old age, I summarized the research as follows (Rosenzweig and Bennett, 1996, p. 63):

It's a fortunate person whose brain

Is trained early, again and again,

And who continues to use it

To be sure not to lose it,

So the brain, in old age, may not wane.

Although I did not do research on effects of environment with human subjects, I was active in an innovative program to promote higher education for disadvantaged and under-represented youth. In 1964 physicist Owen Chamberlain and I became cochairs of the newly established Berkeley faculty Special Opportunity Scholarship Committee. We obtained faculty and university financial support for an on-campus summer precollege program for promising high school students and continued that with a year round contact program. This soon became a federal Upward Bound program. After a few years, for the students who completed the preparatory program we were able to secure admission to the University of California and to other universities and colleges; they became the first in their families to obtain higher education. The faculty committee, renamed in 2005 as the Committee on Student Diversity and Academic Development, continues its work. The favorable results it has obtained suggest that even at high school age, students from family backgrounds and high schools that do not predispose to postsecondary education can be prepared and encouraged to undertake successful college studies. The results also suggest that public schools are falling short of what they should accomplish.

I did in fact attempt to do research on the effectiveness of the Special Opportunity Scholarship program. After the program had been going for a few years, I proposed to the faculty committee that we attempt to measure the effectiveness of the program in the following way: Each year we would draw up a pool of twice as many candidates as the program could accommodate, and then we would select at random those to be accepted. Both those accepted and those rejected would then be followed up over the next 6 to 10 years to determine whether the program was making a difference. I was unable, however, to convince my fellow committee members that such research was appropriate, so the attempt was not made.

Should All Laboratory Animals Be Housed in Enriched Environments?

There is a growing movement to house all laboratory animals in enriched environments, with exceptions only for specific research purposes. Some proponents cite evidence from work such as ours that indicates that enriched experience is necessary for full growth of the nervous system and behavioral capacities, as well as for animal well-being. Others favor this as part of the movement to improve animal welfare.

The history of enriching environments of the laboratory animals goes back at least to psychologist Robert Yerkes' work with primates in the 1910s to 1920s. Hebb, who did research at the Yerkes primate laboratory, helped to extend the concept of enrichment to laboratory rodents in the 1950s. Our publications, beginning in 1960, popularized use of enriched environments by showing that they contributed to full development of the brain as well as to behavioral capacities. Providing enriched environments is not without its problems. For one thing, definitions of enrichment vary, although most attempt to foster species-specific behaviors. It is important for investigators to avoid the temptation to anthropomorphize in choosing enriched conditions. Thus, it is amusing to see photographs of enriched environments for laboratory rodents that show cages filled with brightly colored objects. Although the colors may be attractive to the researchers, they do nothing for rats or mice who do not discriminate hues. There are also concerns because enriched environments are more expensive than standard housing: They take up more space and require more care.

Some investigators have expressed concerns that enriched environments may differ among laboratories and thus decrease the reproducibility of results. In a recent attempt to deal with these concerns, investigators from three laboratories performed an experiment in which they raised female mice of two inbred strains in either standardized cages or following an enrichment protocol. They then tested the mice on four common behavioral tests. The results were highly consistent, indicating that standardization among laboratories was almost as good as within laboratories (Wolfer et al., 2004). The authors note that it remains to be seen whether similar results would also be obtained for male mice who may respond to enrichment with increased dominance behavior and aggression.

The growing concern about enriched environments is shown by ILAR, the journal of the Institute for Laboratory Animal Research, which devoted its Spring 2005 number to this topic. The 12 articles in this issue range from enriched housing for laboratory rodents to enriched housing for nonhuman primates, and from theoretical to practical concerns.

In the near future, whether to use enriched environments may no longer be a matter of choice for the individual investigator or research unit. Enriched environments are part of revisions of animal welfare standards that the Council of Europe is preparing as recommended practices for its 45 member nations, and these standards could affect practices in other countries as well. The website of the Council of Europe reports that a working party, at a meeting of September 22 to 24, 2004, completed a revision of its recommendations for protection of vertebrate animals used for experimental and other scientific purposes and submitted it for adoption. The changes proposed include not only increasing the minimum recommended cage sizes but would also require that laboratory animals be housed in enriched environments that permit the expression of normal behaviors.

Whatever the fate of regulations concerning enriched environments, the clear evidence of the importance of animal environments in determining the results of research shows the necessity of describing animal housing clearly and accurately in all reports of research.

Stimulant Drugs Enhance Effects of Environment on Recovery

Our finding that a daily 2-hour period of exposure to EC was sufficient to produce cerebral effects allowed us to test whether stimulant drugs altered brain measures directly or only in conjunction with EC. In this research, we gave some animals a low dose of methamphetamine just before putting them into EC for a daily 2-hour period, whereas other animals received the drug at a different part of the day when they were in their individual home cages. The drug enhanced cortical weight only when it was active during the daily EC period (Bennett, Rosenzweig, and Wu, 1973). The drug-environment interaction was even clearer with shorter daily periods of EC or in shorter-duration experiments. Effects on AChE measures were somewhat larger, but not significantly so, in the drug-EC groups. A low dose of the depressant pentobarbital sodium reduced the effect of EC experience on cortical weights, but again only if the drug was active during the daily period of EC. Thus, it was the combination of drug and environment that counted in determining cortical weights.

Considering this finding and research on recovery of function, we proposed testing “whether the conjunction of enriched environment and an excitant drug may be even more favorable for recovery from brain damage than is either treatment alone” (Bennett, Rosenzweig, and Wu, 1973, p. 327). We did not follow our own suggestion, but in the last two decades others have conducted fruitful research on this topic with both animal subjects and human patients.

In an early study of this sort, Feeney et al. (1982) removed motor cortex unilaterally in rats and studied their behavior 24 hours later in locomotion on a narrow beam. After a single trial, subgroups received either a single daily injection of saline, a low dose of amphetamine, or the depressant haloperidol. Further tests of locomotion showed that amphetamine improved recovery, while haloperidol impaired it, in relation to the saline controls. Confining the animals in a small cage to prevent locomotion for 8 hours after drug administration blocked the effects of the drugs, so they were effective only in combination with behavioral practice.

Reviews of research with both animal and human subjects have shown the generality of these effects (e.g., Davis et al., 1987; Feeney, 1997, 1998; Goldstein and Hulsenbosch, 1999). More recently, Walker-Batson has reported that amphetamine plus intensive speech therapy aids recovery from aphasia (Walker-Batson et al., 2001), and Walker-Batson and her colleagues have reviewed neuromodulation paired with learning in rehabilitation for various deficits resulting from stroke (Walker-Batson et al., 2004).

An obvious extension of this research would be to combine enriched experience or training with other pharmacological treatments. Hamm et al. (2000) reviewed research in which traumatic head injury in rats was followed by a number of different drug treatments, including agents that affected the monoamine system, the cholinergic system, the glutaminergic system, nerve growth factor, and basic fibroblast growth factor. Each agent led to some improvements, but none was as effective as exposure to an enriched environment. It will be interesting to see results of research that combine some of these pharmacological treatments with enriched experience.

In attempts to promote recovery from brain damage, some neuroscientists are transplanting fetal brain cells into the region of a brain lesion. Some investigators have studied the separate and the combined effects of enriched environment and neural transplants (e.g., Kelche, Dalrymple-Alford, and Will, 1988). Under some conditions, neither the enriched experience nor the transplant alone had a beneficial effect, but the combination of the two treatments yielded a significant improvement in learning. Further work indicates that formal training of rats may be more effective than enriched environment in promoting the effects of brain cell grafts on recovery of learning ability (Kelche et al., 1995). These results of animal research may find application in attempts to aid human patients. Perhaps the differences among clinics in success of brain cell grafts reflect, in part at least, the kinds and amounts of training and stimulation given the patients; this may interact with the skill of the neurosurgeon. The combination of brain implants with training and stimulation may become an increasingly important area of interaction between research and application in the field of plasticity of brain and behavior.

Recent Research Involving Enriched Environments Falls into Three Main Categories

Research for the period 2000 to 2004 that involves enriched environments falls into three main categories, two of which were pioneered by work of our group:

By far the most frequent category is enriched environment as therapy. This has been studied recently for many kinds of brain injury, including trauma, brain infarcts, focal ischemia, and transient global ischemia. Spinal cord injuries have also been studied. In addition to injury, other studies have taken up therapy for cocaine exposure, epilepsy, prenatal stress, immune challenges, and lead poisoning. Although most of this research uses animal subjects, some is being done with human subjects.

The next most frequent category is effects of enriched environments on gene expression. This was anticipated by our studies showing greater expression and variety of RNA in EC than in IC animals.

The third most frequent category of recent research involving enriched environments concerns effects of environmental treatments on neurogenesis. A group including Marian Diamond was the first to report that EC increased neurogenesis in the dentate gyrus of adult rats (York et al., 1989).

Other groups in addition to ours have recently written reviews of the neurobiological effects of enriched environments and have extended the research into new directions, notably Mohammed et al. (2002) and also Rampon and Tsien (2000) and van Praag, Kempermann, and Gage (2001).

The Neurochemical Cascades that Underlie Learning and Memory Formation

Similar Neurochemical Cascades Underlie Different Kinds of Learning and Occur in Different Species

Having found that learning or enriched experience led to plastic changes in the nervous system, Edward Bennett and I decided to try to find the mechanisms that lead to such changes. We had found early that enriched experience causes increased rates of protein synthesis and increased amounts of protein in the cortex (Bennett et al., 1964a). Later, others reported that imprinting increased the rates of incorporation of precursors into RNA and protein in the forebrain of the chick (Haywood et al., 1970), and, as mentioned previously, we and coworkers found that enriched experience in rats led to increased amounts of RNA in rat brain. We viewed these and related findings in the light of the hypothesis, perhaps first enunciated by Katz and Halstead (1950), that protein synthesis is required for memory storage.

Tests of the protein synthesis hypothesis of memory formation were initiated by Flexner and associates in the early 1960s (e.g., Flexner et al., 1962, 1965), but the interpretation of the findings was clouded by serious problems. The research involved administering to experimental subjects an inhibitor of protein synthesis at various times close to training, while control subjects received an inactive substance, and comparing test performance of experimental and control subjects at a later time. Unfortunately, the inhibitors of protein synthesis then available for research (such as puromycin and cycloheximide) were rather toxic, which impeded experiments and complicated interpretation. Also, it appeared that inhibition of protein synthesis could prevent memory formation after weak training but not after strong training (e.g., Barondes, 1970).

A recently discovered protein-synthesis inhibitor, anisomycin (ANI), helped to overcome these problems. Schwartz et al. (1971) reported that ANI did not prevent an electrophysiological correlate of short-term habituation or sensitization in an isolated ganglion of Aplysia, but they did not investigate whether ANI could prevent long-term effects.

Then Bennett discovered that ANI, administered shortly before training, prevents formation of long-term memory (LTM) in rats (Bennett, Orme, and Hebert, 1972). This opened the way to resolving the main challenges to the protein-synthesis hypothesis of formation of LTM. ANI is much less toxic than other protein synthesis inhibitors, and giving doses repeatedly at 2-hour intervals can prolong the duration of cerebral inhibition at amnestic levels. By varying the duration of amnestic levels of inhibition in this way, we found that the stronger the training, the longer inhibition of protein synthesis had to be maintained to prevent formation of LTM (Flood et al., 1973, 1975). We also found that protein must be synthesized in the cortex soon after training if LTM is to be formed; short-term memory (STM) or intermediate-term memory (ITM) do not require protein synthesis (e.g., Bennett et al., 1972; Mizumori et al., 1985; Mizumori et al., 1987). From the time that Bennett showed the value of ANI is studying formation of LTM, this agent has been in frequent use for this purpose.

We then designed further studies to find the neurochemical processes that underlie formation of STM and ITM. Lashley's concern, mentioned previously, that some kinds of memory appear to be formed too quickly to allow growth of neural connections, ignored the distinction between STM and LTM, even though William James (1890) had already distinguished between these stores (although under different names). Observing this distinction was necessary if one was to look for different mechanisms of the two kinds of memory traces that Hebb distinguished: transient, labile memory traces, on the one hand, and stable, structural traces, on the other.

Much of our work on the neurochemistry of STM and ITM was done with chicks, which have several advantages for this research, including the following: The chick system is convenient for studying the stages of memory formation because chicks can be trained rapidly in a one-trial peckavoidance paradigm and can be tested within seconds after training, or hours or days later. Large numbers of chicks can be studied in a single run, so one can compare different agents, doses, and times of administration within the same batch of subjects. Unlike invertebrate preparations, the chick system can be used to study the roles of different vertebrate brain structures and to investigate questions of cerebral asymmetry in learning and memory. The chick system permits study of learning and memory in the intact animal. The successive neurochemical stages occur more slowly in the chick than in the rat, thus allowing them to be separated more clearly. We have stated further advantages elsewhere (e.g., Rosenzweig, 1990; Rosenzweig et al., 1992).

Although some amnestic agents, such as ANI, diffuse readily throughout the brain, we found that others affect only a restricted volume of tissue at amnestic concentrations (Patterson et al., 1986). We employed such agents to reveal the roles of different brain structures in different stages of memory formation (e.g., Patterson et al., 1986; Serrano et al., 1995).

Using the chick system, several investigators have traced a cascade of neurochemical events from initial stimulation to synthesis of protein and structural changes (e.g., Gibbs and Ng, 1977: Ng and Gibbs, 1991; Rose, 1992a, 1992b; Rosenzweig et al., 1992). At some if not all stages, parallel processes occur. Briefly, here are some of the events: The cascade is initiated when sensory stimulation activates receptor organs that stimulate afferent neurons by using various synaptic transmitter agents such as ACh and glutamate. Inhibitors of ACh synaptic activity, such as scopolamine and pirenzepine, can prevent STM. So can inhibitors of glutamate receptors, including both the NMDA and AMPA receptors. Alteration of regulation of ion channels in the neuronal membrane can inhibit STM formation, as seen in effects of lanthanum chloride on calcium channels and of ouabain on sodium and potassium channels. Inhibition of second messengers is also amnestic, for example inhibition of adenylate cyclase by forskolin or of diacylglycerol by bradykinin. These second messengers can activate protein kinases—enzymes that catalyze addition of phosphate molecules to proteins. We found that two kinds of protein kinases are important in formation, respectively, of ITM or LTM. Agents that inhibit calcium calmodulin protein kinases (CaM kinases) prevent formation of ITM, whereas agents that do not inhibit CaM kinases but do inhibit protein kinase A (PKA) or protein kinase C (PKC) prevent formation of LTM (Rosenzweig et al., 1992; Serrano et al., 1994). From this research, Serrano et al. (1995) in our laboratories were able to predict for a newly available inhibitor of PKC, chelerythrine, its effective amnestic dose and how long after training it would cause memory to decline.

One-trial training leads to increase of immediate early gene messenger RNA in the chick forebrain (Anokhin and Rose, 1991) and to increase in the density of dendritic spines (Lowndes and Stewart, 1994). Many of these effects occur only in the left hemisphere of the chick or are more prominent in the left than in the right hemisphere. Thus, learning in the chick system permits study of many steps that lead from sensory stimulation to formation of neuronal structures involved in memory.

The neurochemical cascade involved in formation of memory in the chick was soon shown to be similar to the cascade involved in long-term potentiation in the mammalian brain (e.g., Colley and Routtenberg, 1993) and in the nervous systems of invertebrates (e.g., Krasne and Glanzman, 1995). DeZazzo and Tully (1995) have compared STM, ITM, and LTM in fruit flies, chicks, and rats. Tully et al. (1996) have shown that the three stages of memory in the fruit fly depend on three different genes.

The fact that similar neurochemical cascades are involved in memory formation in mammals, birds, and invertebrates should not be interpreted to mean that this is the only sequence of events that underlies memory formation. In fact, research has borne out Tolman's prescient 1949 insight that there may be many mechanisms of memory. For example, whereas induction of long-term potentiation (LTP) requires activation of NMDA receptors in some parts of the brain, it can occur in other regions after inhibition of NMDA receptors, and in those regions activation of opioid receptors is required for LTP induction. We also found that opioid agonists tend to impair, and opioid antagonists to enhance, memory formation. We found that different opioids appear to modulate formation of different stages of memory (e.g., Colombo et al., 1992, 1993; Patterson et al., 1989; Rosenzweig et al., 1992). Neuroscientist Seymour Kety foresaw the finding of multiple mechanisms of memory formation in the 1970s, as the following quotation shows:

So profound and powerful an adaptation as learning or memory is not apt to rest upon a single modality. Rather, I suspect that advantage is taken of every opportunity provided by evolution. There were forms of memory before organisms developed nervous systems, and after that remarkable leap forward it is likely that every new pathway and neural complexity, every new neural transmitter, hormone, or metabolic process that played upon the nervous system and subserved a learning process was preserved and incorporated (Kety, 1976, pp. 321–322).

Parts of the Neurochemical Cascade Can Be Related to Different Stages of Memory Formation

Some of the difficulty in attempting to relate parts of the neurochemical cascade to different stages of memory formation comes from problems of defining stages of memory, as I have discussed more fully elsewhere (Rosenzweig et al., 1993). Consider, for example, some very different notions about the duration of STM. Early investigators of human STM (Brown, 1958; Peterson and Peterson, 1959) reported that it lasts only about 30 seconds if rehearsal is prevented. Agranoff et al. (1966) reported that in goldfish, if formation of LTM is prevented by an inhibitor of protein synthesis, STM can last up to 3 days, although normally LTM forms within an hour after training. Kandel et al. (1987) wrote that in Aplysia, “A single training trial produces short-term sensitization that lasts from minutes to hours” (p. 17) and that long-term memory is “memory that lasts more than one day” (p. 35). Rose (1995) suggested that, in the chick, memories that persist only a few hours involve a first wave of glycoprotein synthesis; whereas “true long-term memory” requires a second wave of glycoprotein synthesis, occurring about 6 hours after training.

Instead of considering that STM can last several hours or even a day or more, it is useful to posit one or more intermediate-term memory (ITM) stages occurring between STM and LTM, as some theorists have done since the 1960s (e.g., McGaugh 1966, 1968). Thus, Gibbs and Ng (1977) referred to a “labile” stage occurring between STM and LTM and later (e.g., 1984) called this the intermediate stage of memory. My coworkers and I have discussed mechanisms of STM, ITM, and LTM in a series of papers (e.g., Rosenzweig et al., 1984, 1992, 1993; Mizumori et al., 1987; Patterson et al., 1988). In investigating effects of protein kinase inhibitors (PKIs) on memory formation in chicks, we reported that those agents that inhibit CaM kinase activity disrupt formation of what some workers with chicks identify as ITM (lasting from about 15 min to about 60 min posttraining); those agents that inhibit PKC, PKA, or PKG but do not inhibit CaM kinase disrupt the formation of LTM (Rosenzweig et al., 1992; Serrano et al., 1994). Other investigators prefer to refer to different phases or stages of LTM rather than use the expression ITM. Thus, studying the LTP analog to memory in slices of rat hippocampus, Huang and Kandel (1994) reported findings similar to those of Rosenzweig et al. (1992) and Serrano et al. (1994) with regard to the roles of two classes of protein kinases: Inhibitors of CaM kinase activity disrupted what Huang and Kandel called a transient early phase of LTP (E-LTP), evoked by moderately strong stimuli and lasting from 1 hr to less than 3 hr after induction of LTP; agents that inhibited PKA but did not inhibit CaM kinase disrupted the formation of what they called a later, more enduring phase of LTP (L-LTP), evoked by strong stimulation and lasting at least 6–10 hr. Weak stimuli evoke only short-term potentiation (STP), lasting only 20–30 min. As mentioned above, Rose (1995) suggests that in the chick, a kind of LTM that lasts a few hours involves a first wave of glycoprotein synthesis, whereas “true long-term memory” requires a second wave of glycoprotein synthesis, occurring about 6 hr after training. Rather than call the memory associated with Rose's first 6-hr-long wave a form of LTM, I believe it is better to designate it by a special term, such as ITM, and to note that there is an earlier STM lasting only a few minutes, as has been shown in many experiments with the chick. The findings in this area, in my opinion, support the hypothesis of at least three sequentially dependent stages of memory formation, each dependent on different neurochemical processes.

Writing, Editing, Publishing

I succeeded in writing up most of my research promptly and encouraged my students to do the same, believing that science does not exist until it is published. In addition to research, much of my work has involved writing, editing, and publishing, so I will conclude with a bit about these activities.

In 1968 my Berkeley colleague Paul Mussen was invited to be editor of the Annual Review of Psychology, and he invited me to share the editorship. The annual meetings of the editorial committee, in which we reviewed progress in the main fields of psychology and decided whom to invite to write chapters, were stimulating occasions. After five years of collegial joint editorship, Paul retired as coeditor and was succeeded by our former Berkeley colleague, Lyman Porter. Porter and I continued as coeditors through 1995. One of my innovations was to have a chapter on psychology in the host country of the congresses of the International Union of Psychological Science (IUPsyS) and the International Association of Applied Psychology. Thus, every two years, readers were informed about psychology in another country.

In the 1970s, a failed publication gave rise indirectly to an influential conference volume. I took part in 1973 in a symposium of the American Association for the Advancement of Science (AAAS) and was disappointed when the promised publication did not materialize. But in the audience at the symposium was an officer of the National Institute of Education (NIE), and he invited me to organize, with financial support from the NIE, an international conference that would summarize and evaluate the current status of research on learning and memory and their neural bases. I asked my chemist collaborator Edward L. Bennett to cochair the conference. We recruited an outstanding group of contributors and spent June 24–28, 1974 presenting and discussing at the conference center in Asilomar, California. The large proceedings volume appeared in 1976 (Rosenzweig & Bennett, Eds.).

From the start of my appointment at Berkeley I taught the course in what was then called physiological psychology. After he joined the department, Arnold Leiman alternated with me in teaching the course. We were not satisfied with existing textbooks in the subject, so Arnie and I wrote our own text, which first appeared in 1982; a second edition appeared in 1989. Arnie had an unmatched scholarly mastery of the field, and he was a gifted teacher, but he was a slow writer. We then changed publishers and gained a talented third author, our Berkeley colleague S. Marc Breedlove, for our next edition (Rosenzweig, Leiman & Breedlove, 1996). The book was adopted widely, and successive editions followed. After Arnie's death, we invited Neil V. Watson to be our coauthor. Meanwhile, Marc Breedlove had left Berkeley, so it was no longer possible just to go down the hall to discuss some aspect of the manuscript. Instead we collaborated by e-mail, FedEx, and phone. It has been a pleasure to reach students in many countries of the world through the text. Translations of the text have been made into French, Italian, Portuguese, and Spanish, further increasing our scope.

In 1990–1991, as president of the IUPsyS, I conducted a survey about psychology and psychological research among our national member societies. I then edited a volume that described and evaluated the status of psychology internationally (Rosenzweig, Ed., 1992). Later, Kurt Pawlik, my successor as president of IUPsyS, and I organized and edited the International Handbook of Psychology with 51 chapters surveying all of modern psychology, written by authors from 19 countries (Pawlik & Rosenzweig, Eds., 2000).

To mark the first half century of the IUPsyS, its executive committee asked me and a few colleagues to write the History of the International Union of Psychological Science (Rosenzweig, Holtzman, Sabourin & Bélanger, 2000). This covered the history, not only since the formal founding of the union in 1951, but going back to the first International Congress of Psychology in 1889 and to the International Congress Committee that organized 12 successive international congresses through 1951. We combed the published records and the extensive archives of the union, but wished we could have consulted some recently deceased colleagues who spanned the transition from the International Congress Committee to the formation of the union. This convinced me of the importance of leaving autobiographical accounts and of contributing personal records to archives.

Acknowledgments

It is a pleasure for me to acknowledge that in my publications and in my research I have benefitted from association and collaboration with many gifted and stimulating collaborators. My hearty thanks and deep appreciation go to all of them, and especially to Edward L. Bennett, S. Marc Breedlove, Marian C. Diamond, David Krech, Arnold L. Leiman, Paul Mussen, Kurt Pawlik, and Bruno Will. My appreciation also goes to the talented students, post-doctoral fellows, and skillful assistants who worked with me. I also want to acknowledge indispensable financial support from a number of agencies and organizations: March of Dimes; Miller Institute for Basic Research in Science, University of California; National Institute of Drug Abuse; National Institutes of Health, U.S. Public Health Service; National Institute of Mental Health, U.S. Public Health Service; National Science Foundation; Office of Education; U.S. Atomic Energy Commission.

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Arnold Bernard Scheibel

BORN:

New York, NewYork

January 18, 1923

EDUCATION:

Columbia College, B.A. (1944)

Columbia University College of Physicians and Surgeons, M.D. (1946)

University of Illinois, M.S. (neuroanatomy) (1953)

APPOINTMENTS:

University of Tennessee College of Medicine (1952)

University of California, Los Angeles, (UCLA) School of Medicine (1955)

Director, Brain Research Institute, UCLA (1987–1995)

HONORS AND AWARDS (SELECTED)

John Simon Guggenheim Fellow (1953–1954)

George H. Bishop Lectureship, Washington University (1967)

Distinguished Graduate Student Teaching Award, UCLA (1977)

Fellow, American Academy of Arts and Sciences (1981)

Fellow, Royal Norwegian Academy of Sciences (1983)

Scientist of the Year, Alzheimer's Disease Research Association (1988)

The Harriet and Charles Luckman Distinguished Teaching Award, UCLA (1997)

The California Biomedical Research Association Distinguished Service Award (1998)

Distinguished Life Fellow, American Psychiatric Association (2003)

Research Pioneer Award, Alzheimer's Disease Research Association (2004)

Arnold Scheibel is known for his studies of the detailed architecture of the spinal cord, brain stem, and cerebral cortex and introduced the module concept into central nervous system research. His description of the recurrent axonal projection of the nucleus reticularis thalami led to the gatelet theory of selective attention. His Golgi studies of human brain tissue extended our knowledge about the nature of neuronal changes in senile brain disease and in schizophrenia. He demonstrated correlations between human cognitive activity and structural change, and emphasized the role of plasticity in the living reactive brain.

Arnold Bernard Scheibel

Patterns in Neuropil, or “passion in neuropil” as some friends interpreted it, was the title of my first and longest lasting research grant from the National Institutes of Health. The title spelled out the thrust and excitement that I have always felt for the fine structure in the nervous system. The fact that definable organizations of neurons, dendrites, and axons—the formal minuet of cerebellar Purkinje cells, the stately files of neocortical pyramids with their cathedraI-like dendritic arches, the overlapping swirls of inferior olive cells, or the town and country spotting of cell villages throughout the brainstem core—might serve as vital substrates for cognition and behavior has, over the years, held me spellbound. With this in mind, I am grateful to the editor of The History of Neuroscience in Autobiography and the Society for Neuroscience for their invitation to look back over a period of more than half a century and share memories.

In the Beginning

Both sides of my family arrived in the United States in the decades after the Civil War. I should know when, but when one is young, one's forebearers seem uninteresting, and when one is old enough to care, the sources are gone. My maternal grandmother's family came from what was then part of southern Germany. My father's family emigrated from the old Austro-Hungarian Empire. Dad's family may have been vintners and there is apparently still a Scheibel aperatif or liqueur that is locally available in central Europe. Several of Dad's uncles were architects who practiced in the Cleveland-Youngstown area and this flair with a pencil did not escape him. (I often wonder whether my own preference for neurohistology and neural circuitry, the fine architecture of the nervous system, was not another and somewhat more derivative expression of that same gene line.) Although Dad trained to be an architect, he quickly found that he was better able to support his family by working in the “front office". And so he became an advertising and sales manager at a time when that was still a fairly exotic occupation. Among the experiences he shared with me was his being at the airfield on a foggy morning in 1927 when Lindbergh took off for Paris. Lindbergh was wearing a Bulova watch that Dad had just strapped on his wrist, a model that was then sold widely and successfully as the “Lone Eagle.”

Although Mother's education was cut short by financial reverses in her family (my maternal grandfather was saintly but not a business man), she remained until almost the end of her life an indefatigable reader and much of my interest in history and biography comes from her. During Mother and Dad's lives together, they had many differences but were in complete accord as to the importance of education for their young people.

I was born in the northwest part of New York City and spent the first 24 years of my life in Manhattan and the Bronx. Although one of the largest cities in the world, it was still thought of (in its pre-Big Apple days) as “little old New York” by its inhabitants and that is still the way I remember it. I was my parents' only child but when I was 5, my aunt died in childbirth and her newborn son was raised by my parents. The grief surrounding the death of my aunt pervaded the family for a number of years and, coming as it did in the latter part of 1928, it is somehow mixed in my mind with the gathering anxiety and suffering that followed the stock market crash and Great Depression, which followed shortly thereafter. As a “child” of the Depression, I still fancy I see its carryover in my unwillingness to spend money on myself. My cousin Milton, who became in every sense my brother was always gifted, always passionate, seldom predictable. Unlike me, he was excellent in chess, good in mathematics, and a bit of a rebel. He became an economist and spent part of his adult life in Washington as Executive Assistant Secretary for Defense under several administrations.

The most vivid memories of my childhood are those of the books that my dad arranged to come my way once I learned to read. The Mysterious Universe by Sir James Jeans leaves a special impress, with its discussions of recently discovered red giants like Betelguese and Antares, and the great matrix of dust that seemed to fill the galaxy. I also recall short biographies of the presidents, several lives of Lincoln, and Compton's Pictured Encyclopedia, which became my bible (and then Milton's) for several years. Interestingly, I remember no introductions to biology or much curiosity on my part in this direction (with the possible exception of Paul deKruif's Microbe Hunters). Outdoor sports were far down the list of encouraged activities. For my parents, life was a serious business and play was at best a slightly disreputable way of taking a necessary break from meaningful work. I am afraid that I was raised with the idea that professional athletes were little better than ne'er-do-wells or “bums.” Under these conditions, it is not surprising that my graduation from Columbia College hung in the balance until I learned to swim (still a prerequisite for graduation at that time).

I remain perpetually grateful to my parents for their commitment to my education. The middle 1930s were marked by two educative experiences that still live vividly for me. One was the trip around the country that we took by car in the spring of 1934. Dad was “between position” in those deep Depression days and they accordingly decided that it might be the time to kick over the traces for a few months. They assumed that I would learn more this way than I could possibly gain in my 6th grade school class. Considering that the vehicle of choice was a 1928 Nash without springs and an effective top speed of 38 mph, it was a valiant decision.

In the nation's capital, it was a fortunate 11-year-old who could sit and listen while the United States Senate debated the proposed independence of the Philippine Islands or watch great jurists such as Brandeis, Cardoza, and Hughes (still meeting in the old Senate Chamber) consider the constitutionality of New Deal legislation. Further in our course toward the southwest lay the battlefields of the Civil War, Mississippi paddle wheelers, the gathering threat of the Dust Bowl, the memories of Tombstone, Arizona, and the citrus-loaded valleys of California. Luckiest of all was the fact that we made the trip just before the “homogenization of America” began. Aside from a few of the “new fangled” tourist cabins, the hotels or boarding houses we stayed in were often those that dated from frontier days. Another 10 years and they would all be gone, swallowed up by the omnipresent Hiltons, Sheratons, Best Westerns, and Holiday Inns.

The other lucky break was winning a scholarship at Horace Mann, a small, private middle school–high school at the northern edge of New York City. Rigorous discipline, sometimes great teaching (with the unfortunate exception of biology), small classes (five of us struggled through 4 years of Latin together), and a very active sports and extracurricular program helped me begin to spread my wings. I liked drama, writing, and illustration and actually took up track and tennis. The pattern continued at Columbia College, the (then) surprisingly small college arm of Columbia University, to which I also won a scholarship. Immature as I was through my college years, I still recognized the privilege of being exposed to instructors such as Lionel Trilling, Mark Van Doren, and Charles Frankel. It was a heady time, but I still was not sure where I was going.

As a liberal arts major, I took a short science sequence put together for those who would presumably have nothing further to do with these fields. The opening salvo here was a semester of physics taught by Professor John Dunning, then already deeply involved in the mysterious “Manhattan Project” going on behind plywood partitions just down the corridor in Pupin Hall. Things began to look up with geology and improved still more as fossils and life forms became the focus. I think I began to realize at that point that the study of living things was more interesting than I could have guessed. The strongly negative impression that had followed me from my unfortunate high school biology classes began to dissolve and I realized—almost reluctantly—that perhaps what I had been reading in my Great Books classes, about the appropriate study of mankind being man, might just be true.

Another conditioning factor was the approach of the war. With the attack on Pearl Harbor at the end of 1941, most of us became concerned with the relevance of what we were doing—or planning to do—in a nation now fully committed to a war effort for an indefinte period. Medicine now seemed to me to be the best way to combine my burgeoning interest in biology with a profession that would be useful and intellectually challenging. I was hardly equipped for medical school, having carefully avoided all premedical classes until that point. With a little advice from the pre-med advisor, a kindly organic chemist named Powell, I arranged to take the requisite 2 to 3 years of required courses in a hectic 15 months. These included biology, comparative zoology, embryology, organic chemistry, and qualitative analysis and they were taken whenever I could find a session scheduled. I attended extension evening classes, summer school, and a few graduate level classes. I remember taking the two-semester zoology course out of sequence, the second term before the first. It was certainly the hardest period of study I had yet known—and I found it exhilarating. With war pressures rising, Columbia offered a “professional options” program for those who planned to go on to graduate school. It was essentially a “4 years in 3” program, which allowed the first year of the following graduate experience to be counted as the final college year. I believe this was partly in response to the government's need for young physicians and was followed by a similar “4 years in 3” compression in professional school. I was fortunate enough to be accepted at Columbia University Medical School (College of Physicians and Surgeons) and started with my class in April of 1943. With bitter fighting going on in the Mediterranean and the Pacific, and with the invasion of Europe certain to follow, we were a busy, anxious group in our first anatomy laboratory.

Medical School and Beyond

Our class at P & S was one of the brightest, most articulate groups that had ever been selected. The sense of intellectual competition was also spurred by the rumor, probably incorrect, that the lowest 5% of the class each year would end up in the South Pacific! After the first 3 months of work, we were given the option of joining the Army or Navy and being sent back to school at the expense of the Armed Forces, with the agreement that we would spend 2 or more years in service as physicians once our training was complete. Because medical school costs, even then, were not inconsequential, most of us selected this option. I think the majority of us chose the Army although it was later agreed by all that the V 12 naval uniforms cut a far more rakish figure. After several weeks of tests and training at Camp Upton, a barren, barracked waste on Long Island where we were immensely unpopular with the Regular Army personnel (our unofficial title was “those damned college f…") we returned in uniform with our Army Specialized Training Program (ASTP) patches on our shoulders. Our orders to salute all officers, domestic and foreign, led to our saluting many a surprised doorman until we learned the difference. Another aspect of our new status, was the diet of frequent training films (primarily on the evils of gonnorhea, syphilis, and unwashed mess kits) and the almost daily training parades held in the Armory, which just happened to be across the street from the medical school. Because we took turns drilling our student platoons, precise maneuvers were infrequent and marching catastrophes certainly not unknown. Our commanding officer, a gentle, Regular Army major who must have wondered what he had done to deserve this assignment, seemed resigned to the martial incompetence that surrounded him.

Like most other medical schools of the time, P & S had lost many of her clinicians to the war effort, and the compressed 4 years in 3 schedule put further demands on an overworked faculty. In retrospect, our teaching was spotty and a bit ataxic. I recall in particular our course in basic neurology—a fusion of neuroanatomy, a little neurophysiology, and a dash of clinical application. Six or eight neurology and neurosurgery faculty, some well within the category of “grand old men in the field,” shared the lecture load—and indeed, the lectures came across as if they were a load to them. It was an unfortunate introduction to the field. After the course, I made the first conscious decision about my future that I can remember making, namely whatever I did with my later life in the medical profession, it would have nothing to do with structures above the neck!

Instead of a summer vacation between the school years, there was a 2 week break. Between first and second years, a number of us were asked whether we would like to help out in anesthesia because the operative staffs were so thinned by the war. I think we were asked because we had just finished our course in general physiology and were thought to be knowledgeable about processes such as respiration. In any case, I found myself one morning administering ether (there were few other choices for a deep anesthesia in 1944) for a “partial gastrectomy” who also had some type of coronary insufficiency. The surgery was being performed by one of the distinguished gastrointestinal surgeons of the day, Dr. A. McGee Harvey, a physician who also deserves sainthood as we shall see in a moment. My understanding of basic physiology was shaky and my estimates of the depth of anesthesia of my patient at best approximate. While worrying about his cardiac status, I made what I thought was a useful discovery. Once under anesthesia, a patient could apparently be maintained exclusively on oxygen! His color had improved, and the operative proceedure seemed to be going well. Dr. Harvey had gotten to the point where the stomach, suitably isolated and clamped, was folded back on the sterile field and ready for excision. At this critical point, the patient moved slightly, then threw his legs off the operating table and began to sit up. Instruments clattered to the tile floor and there were audible gasps from the operating group. Dr. Harvey then proved the appropriateness of his candidacy for sainthood with the following comment, “Doctor, I think your patient is a bit light.” I need hardly add that a good deal of ether was used for the rest of the procedure. In thinking back over episodes like this in those pressured but fortunately less litiginous times, one cannot help but compare them with present concepts of medical ethics and professional oversight.

Another measure of medical training of the 1940s that comes to mind was our experience with “chest medicine,” managed far downtown at the old Bellevue Hospital facility. Chest medicine was then virtually synonymous with tuberculosis, and the terrible open pulmonary lesions that characterized so many of the hospitalized patients were a real threat to students and staff in those preantibiotic days. Some of us felt protected by the unspoken assurance that doctors never picked up infections from their patients. Others of us, including myself, were not so sanguine. While I was working at Bellevue I followed my own version of a physical exam, which in these cases consisted primarily of percussion and auscultation of the chests of the unfortunate patients followed by demonstration or report to our attending physician. I would hyperventilate in the hall outside the room for a moment or two, then, while holding my breath, hurry in to percuss half the chest. After a brief return to the hall for more oxygen, I would return to the other half. Instructions to the patient were always managed in a low voice in order to lose as little oxygen as possible. Usually half a dozen trips in and out sufficed to finish the examination of one patient. In retrospect it seems absurd although the danger and anxiety were real enough. Several of our classmates became tuberculosis skin-positive after this experience and I believe one of us developed overt disease.

I wish I could report that the teaching of clinical medicine was inspiring. There is no doubt that the P & S faculty were usually of international caliber—with names such as Cournand and Richards for respiration and blood gases, Hanger and Patek for liver disease, Atchley for body fluids and electrolytes, and Loeb for early work with corticoids coming naturally to mind. But many of them also seemed remote and unapproachable and far from representing the human component in medicine that I expected. This memory has remained with me to serve as a constant reminder when I deal with patients or students.

Even with the uneven quality of the teaching experience, there was no doubt in my mind that I had made the right choice and that medicine was the greatest of the humanities. My interests flowed in the direction of internal medicine and with the fairly recent arrival of objective measuring devices such as the electrocardiograph, cardiology seemed increasingly attractive. My 15-month, mixed internship at the old Mount Sinai Hospital in New York (it was not yet a medical school) was a powerful experience during which I began to taste the rewards and anxieties of patient responsibility. The major attending physician on our medical service was the Dutch physician, Dr. I. Snapper who taught us an important lesson in what he called the fundamental rule of life—the rule of “autas.” Loosely translated (I believe very loosely!) this means “do it yourself.” Accordingly, in addition to the physical workup, we did all of our own laboratory work during the first evening and night after hospital admission. It was not at all unusual for me to have the unfortunate new patient under the fluoroscope screen at one in the morning.

On some occasions, the etiology of the patients' illnesses were sufficiently baffling to warrant the call for outside consultants. On the occasions when the consultant was a psychoanalytically trained psychiatrist, I was intrigued to see how easily a rich substrate of emotionally laden and possibly clinically relevant material could be obtained, often from the most unlikely looking patient. My few hours of psychiatric exposure at medical school clearly had not prepared me for the apparent breadth of emotional “disease” and psychopathology behind every clinical entity. It was an eyeopening experience and led me to consider psychiatry instead of cardiology as my future speciality. I think I would have preferred to finish residency training in internal medicine before going on to psychiatry, but these were unusual times. It was 1946–1947 and many young medical officers were returning from their stint in the recent war and it was appropriate that they get first shot at the house staff slots. Furthermore, I had the obligation of 2 years of Army medical service before me. I learned to my surprise that because the Army needed more psychiatrically trained physicians to help serve the returning veterans, they would prefer if I took an extra year of training. The prospect of doing something more exciting than routine physical examinations was enticing, and so I was determined to find a year of resident training in psychiatry before presenting myself to the Army. Again, the number of first-year residency slots in psychiatry were limited, but I found one open at the new Psychiatry Service at Barnes and McMillan Hospitals of Washington University in St. Louis. The young emigrant from New York City presented himself there at the end of June 1947, and the pattern of life changed forever.

Into the Realm of the Mind

Psychiatric training was both a challenge and a shock. The department was new, led by a genial lipid chemist named Ed Gildea, and the faculty were mainly local practitioners who were not primarily interested in teaching. The predominant psychiatric school they claimed to represent was Meyerian biological psychiatry although none of us could find out exactly what that meant. Schooled as I was in the medical model of disease, the more amorphous conceptual approach was difficult to comprehend. In those pre-psychopharmacology days, our only therapeutic tools were chloral hydrate and amytal, insulin and electric shock, and psychotherapy. And the latter was the most baffling of all. As I recall, it took a “strike” by some of the house staff to convince the faculty to bring in a couple of local analysts to enlarge our experience in dynamic psychotherapy.

Nevertheless, the year served its purpose and by the time I departed for armed service, I knew the rudiments of my new profession. I might add that while at Washington University, I had occasional, fleeting contact with electrophysiologists George Bishop and James O'Leary. I did not have the time or the courage to explore what they were doing, but it was enough to alert me to the fact that there might be other approaches to the riddle of brain and mind.

My 2 years of active service with the Army Medical Corps, spent at Brooke General Hospital in San Antonio, served four important functions. It allowed me to broaden and reinforce my knowledge of the field of clinical psychiatry, including an unexpected foray into the new field of child psychiatry. It enabled me to meet and marry my first wife Madge, or Mila as most people knew her. I learned the rudiments of portrait painting. And it convinced me that the full-time practice of psychiatry, at least as I had so far experienced it, was not going to satisfy me.

The foray into child psychiatry was especially unexpected. Our commanding officer, a handsome white-haired gentleman, Colonel Rawley Chambers, was apparently advised by Army Headquarters that his unit would have the honor of developing the first child guidance clinic in an army general hospital setting, an obvious mechanism to provide better service to families who were part of the still large peacetime army. The colonel informed us of this decision from above and also of the fact that I would be the medical officer in charge. When I pointed out that I knew nothing of the field, the colonel suggested that I become informed immediately! I read the only book on the subject in the hospital library and so, by act of Congress, became a child psychiatrist. Working with a small staff of psychologists and social workers, things turned out far better than one would have expected, so much so in fact that I became the local authority on the subject and before leaving the service, was asked by the Hogg Foundation to open a child guidance clinic in Austin—presumably the first such facility in Texas. Fortunately, I had the good sense to decline this generous, if misguided, offer.

As already mentioned, I continued to have the uneasy feeling that what I was doing was not sufficiently entraining. Something was missing. I shared these concerns with our local consultant, Dr. Melvin Thorner, who suggested that I consider a year or two in a research laboratory. We discussed a few possibilities, the only one that I knew being the Bishop and O'Leary group in St. Louis. When Thorner mentioned Warren McCulloch in Chicago, I went to the literature and was impressed by the excitement of his ideas. After a brief visit to McCulloch's basement laboratory at the Illinois Psychiatric Institute, I found the man as stimulating as his writing and so, at the end of June 1950, Mila, my brand new wife, and I set out for Chicago. The day after I was placed on inactive service and left San Antonio, the North Korean Army attacked South Korea and all armed forces appointments were frozen for the duration!

Mid-August in Chicago was not the best time to show up for work in a laboratory. Most of the staff were on vacation or at meetings. McCulloch had arranged that I relearn my neuroanatomy with a neuropathologist, Dr. Ben Licbtenstein who kindly gave me time and interest—gifts that I will always cherish. Mainly, I had come into possession of something I had never owned before—free, unstructured time. Rather uncertainly at first, I began to spend half days and then full days in the University of Illinois library, reading about this new field of brain research that I had dared wander into. I do not remember the process or progression, but pretty much by chance I sat down with the two-volume work, Histologie du System Nerveux by Ramon y Cajal (1911). I leafed through it noting that my French was just adequate to the task.

The next few days came as close to being a transforming experience as I ever hope to know. I had just looked into my own version of Chapman's Homer! Here were images of neural structure and circuitry that must form the substrate for all of the behavior and all of the cognitive and emotional capabilities that I had ever considered. I was entranced by the beauty and intricacy of the drawings, and by the Golgi technique that made them possible. As soon as McCulloch returned to the laboratory, I told him about my enthusiasm for neural architecture. He liked the idea and suggested I immediately go down to see Heinrich Kluver at the nearby University of Chicago. Apparently the word was out that Kluver had just devised a stain that revealed fine structure in an exciting fashion. It turned out to be the new Kluver-Berrara stain, resembling a combination of Nissl and Weil preparations in the same section. It was clearly going to be a powerful control method, but nothing like the precious Golgi that I had just discovered. Again at McCulloch's suggestion, I went crosstown to the Northwestern Medical School to see Ray Snider, a neurophysiologist whose wife had worked with Lorente De No, one of the last great practitioners of the Golgi method, and a student of Cajal. With the Cajal-Lorente version of the Golgi method in my hand, I suddenly felt tied into the long and prestigious tradition of classic neurohistology. Dr. Snider was both interested and hospitable and allowed me to come to his lab twice a week from that time on. This provided me with my first halting essay into animal neurophysiology. Unfortunately we tackled a problem—the direct current (DC) shifts in cerebellum—that was rather intractable for the time, given the primitive state of our recording equipment and our own insensitivity to the need for non-polarizing electrodes. Nonetheless I am grateful to Ray for his patience and the opportunity to share ideas.

The McCulloch laboratory was dominated by Warren whose broad interests and almost poetic approach to the brain set a tone, if not exactly a work program, for us all. He was famous for his rejoinder to those who could not follow his ideas—"Don't bite my finger, look where I'm pointing.” A group of equally interesting younger workers surrounded him and tried to match experiments to his ideas—men such as Jerry Lettvin, Paul Dell, Pat Wall, Turner MacLardy, and the mathematician Walter Pitts—all of whom were productive on their own. I can still see Warren's tall, somewhat stooped, tweed-clad figure striding the halls of the basement lab, talking animatedly to anyone who would listen. He provided me with a unique introduction to the world of brain research. (Note that the term neuroscience was not to come into existence for another 10–15 years.)

In selecting an area for my own first neurohistological research project, my discussions with Ray Snider and Warren led to the brainstem reticular formation. Horace W. (Tid) Magoun had just departed from Chicago (to everyone's astonishment) for the west coast to become the Chair of Anatomy at the new UCLA School of Medicine and had left as his legacy exciting new ideas on the role of the reticular core of the brainstem. With Ruth Rhines (Rhines and Magoun, 1946) he had demonstrated the downstream modulatory control exerted by the core on spinal mechanisms. Working with Giuseppi Moruzzi (Moruzzi and Magoun, 1949), he had shown the role of the core in controlling cortical excitability and, by inference, levels of consciousness. Little was known of its internal structure and connections save what Cajal (Ramon y Cajal, 1911) had shown about the former and Papez (Papez, 1926) using the venerable Marchi method, about the latter. It seemed like the ideal subject matter for a psychiatrist seeking substrate!

Space was made for me “upstairs” in the neuropathological laboratory of Dr. Ben Lichtenstein, where I experienced the initial emotional highs and lows that the notoriously fickle Golgi method could trigger. But, when it worked, it was beautiful and it took me into a new world—the world of neuropil. Then, and for some years thereafter, I did all of my own cutting and processing and, in retrospect, these were the most enjoyable of my research years. One literally knew each section as it came off the microtome and carried it individually through the processing fluids. There was nothing quite like the excitement of “that first look” while the mounting medium was still wet, to see what surprises might lurk therein. Because each Golgi impregnation showed, at best, a small vignette of the neuropil fields that lay before one, reconstruction of the architecture of the entire field was truly a cognitive enterprise—a great spatial reconstruction based on the synthesis of image fragments and intuition. I have worked subsequently with other techniques such as evoked potentials, extra- and intracellular microelectrophysiology and immunohistochemistry, but I know of no excitement and satisfaction such as that offered by the Golgi method. It represented a kind of melding of science and art that seems to have less place in today's research.

During our first 5–6 months in Chicago my wife Mila, a talented and sensitive psychotherapist, worked as a psychiatric social worker at the Great Lakes Naval Training Station, north of Chicago. Poliomyelitis struck her in December. She survived with moderate sequelae but a long delayed postpolio syndrome (not recognized in those pre-Salk and Sabin days) took its eventual toll. During her long recovery, she became increasingly interested in the neurohistological work that I brought home to be close to her. With an old, late 19th century sliding microtome that I had bought from a German refugee scientist, we set up a tissue processing “line” on the dining room table. Mila learned fast and thus began a collaboration that was to continue for some years while her health permitted. Because she did not read French, I began to translate relevant portions of the Cajal Histologie for her until, over the years, we had a considerable portion of the twovolume classic in accessible (if at times somewhat stilted) English. More recently, the job has been accomplished with elegance by the Swansons. By early spring, we felt that we might have enough data to present and, because Mila now seemed well enough to travel, we sent our abstract to the American Anatomical Society, which met in Detroit in 1951 (the Society for Neuroscience did not yet exist). It was a fairly primitive description of dendrite fields in the medullary reticular formation but it did give us the chance to see and hear many of the prominent people in our new field. It was a particular thrill to meet Dr. Magoun, who expressed interest in following our work.

As the work on internal architecture of the reticular core proceeded (along with many sideward glances at the seductive cerebellar cortex), it became clear that we could not tell where the downstream effects carried by the reticulospinal tracts, as earlier defined by Papez (Papez, 1926), were implemented. The Marchi tracking method used by Papez became silent when the terminal, nonmyelinated parts of each axon were reached, and the Nauta methods for impregnating degenerating presynaptic terminals were still several years in the future. While searching, I found in some obscure source that now eludes me reference to a staining method devised by Rasdolsky that was supposed to polychromatically stain degenerating terminals. If this could be made to work, we could throw light on how the descending Magoun and Rhines effects were implemented.

With this as our goal, I arranged with the technician in Warren's lab to have a sterile setup in the operating room ready for us at the end of the working day. Mila and I would come down after 5 PM when the coast was clear and make lesions in appropriate sites of the brainstem of a series of cats. Finishing by 10 PM or so, I would then take my wife out for a Chinese dinner, our cat still sleeping off its anesthetic, well swaddled on the back seat of the car. Thus each recovering animal got several days of home attention and personal nursing, while our apartment built up a backlog of fleas. The Marchi technique provided few difficulties but the Rasdolsky counterstain refused to work, so nothing new was found.

Among the distinguished faculty then working at Illinois Neuropsychiatric Institute were the neuroanatomist and then editor of the Journal of Comparative Neurology, Gerhard Von Bonin, and the neurocytologistneurosurgeon, Percival Bailey. Both of these men had the patience to sit through my one and only presentation in Warren's lab and both were supportive. Dr. Von Bonin told me he would like me to read a manuscript that had just been submitted for publication(!), and Dr. Bailey complemented me on having “sitzfleisch.” I am very grateful to both of these men, for their encouragement and support over the years.

Although I now had a National Institutes of Health (NIH) fellowship and planned to work for a full 2 years in McCulloch's laboratory, it became clear to me that we must not spend another winter in Chicago. The painful muscle spasms that had characterized the early phase of Mila's polio, unaccountably continued and were exacerbated by cold weather. At Dr. Magoun's invitation, I made a quick trip to California but felt that there was, as yet, no lab space where Mila and I could work together. The medical center was still a large excavation in the hill overlooking Westwood, and Magoun's group traveled all the way to Long Beach several times a week to do their experimental work. The only other direction to seek a warm climate was south and after a bit of looking, I decided on the University of Tennessee Medical Center at Memphis. Here I was fortunate enough to be given joint appointments in the Departments of Psychiatry and Anatomy, and Mila and I were given our own small laboratory. Drs. Theron Hill, Chair of Psychiatry, and Roland Alden, Chair of Anatomy, saw to it that we had what we needed to start work until our first grant came through.

In Memphis, I worked on my psychiatric ward all morning, then joined Mila during the afternoons and evenings in the laboratory. This was a time of intensive work and continuous excitement. In addition to drawing the relevant Golgi material, I did all of our own photography including development and printing, both in black and white and in color. As we pushed ahead slowly with the reticular core, trying to understand the patterns of axonal neuropil and the distribution and length of axon trajectories, it became clear that the reticular formation was not rich in short-axoned cells as generally believed. In fact we found none. Local collateralization seemed to account for “neighborhood circuitry.” At the same time, adjacent structures often stained brilliantly and as a result, our first two full-length papers were on the cerebellar climbing fiber (Scheibel and Scheibel, 1954) and the inferior olive (Scheibel and Scheibel, 1955) The latter became the basis for a Master of Science degree in Anatomy that the University of Illinois awarded me early in 1953. The former described one of Mila's earliest findings, a climbing fiber collateral to the large Golgi type II cell of the cerebellum. John Szentagothai saw our paper (they were both published by Von Bonin in the Journal of Comparative Neurology) and generously coined the name “Scheibel collateral.” Collaterals were also found extending to basket and stellate cells, thereby appreciably expanding the influence of climbing fiber input to the inhibitory systems of the cerebellar cortex. The reticular core material slowly matured and at the next American Anatomical Society meeting, Mila and I gave our only “back to back” presentations. She talked about patterns of axonal output and I about input. I think that the concept of “the Scheibels” first took form here and became a cherished part of our life together as long as she lived. Although we did not think of Memphis as our final home, it provided us with experience on how to manage a simple laboratory operation and gave us the time to think and work together. But, unknown to us, other things were brewing.

Overseas

To my great surprise, I received a letter from Percival Bailey, suggesting that we consider a Guggenheim Fellowship year overseas, and the intimation that he would support our application. This remarkably generous offer was too good to miss, even though I had some concerns as to whether Mila could handle the day to day stress of a foreign lifestyle. Feeling that our greatest need was some electrophysiological experience to enable us to begin to correlate our anatomical data with function, we applied to work with Ragner Granit at the Royal Caroline Institute in Stockholm. Granit suggested rather that we should work with his young anatomist colleague, Bror Rexed, who had recently described the laminar organization of the spinal grey matter. This would not have supplied the research need we were trying to fill, and at the same time, I began to realize that living in Stockholm would not be unlike living in Chicago, from whose rigors we had recently escaped. Looking southward again, an obvious solution presented itself. Moruzzi, in Pisa, who had worked with Magoun on the ascending effects of the reticular core, was now pursuing extracellular microelectrode techniques—exactly what we needed to have. Moruzzi cordially accepted us for the next academic year.

On our way to Pisa, we stopped at Madrid and made our sentimental journey to the Cajal Institute. We carried with us a bag of our own Golgi photographs and drawings. The Institute was empty, except for the diener, a cordial young man named Pedro Manzano who, it turned out, had grown up literally at the master's knee and was a pretty fair neurohistologist on his own. When we showed him what we had brought, he warmed even more, addressed us as “maestro” and immediately brought out sheathes of original drawings by Cajal. To cap the climax, we were allowed to study some of Cajal's Golgi stained material, using one of the master's microscopes. Most surprising to us was the beauty and vibrancy of the slide sections, some of them certainly 40 or 50 years old. It was an experience never to be forgotten. I might add that some 35 years later when Marian and I were in Madrid, and made another sentimental journey to what was left of the Cajal Institute, we were greeted by a dignified old man—Pedro Manzano—still shepherding the remainder of Cajal's magnificent legacy.

We arrived in Pisa in late August and found lodgings in the Hotel Victoria where we had the option of rooming in the “old wing” or the “new wing.” Because the former had been built in the 14th century and the latter in the early 16th, we opted for the latter. Our picture postal card view, of the “lung-Arno"—the sweeping curve of the Arno river—was certainly the crowning attraction of our little room. Pisa, a university town of some 80,000 people, was still recovering from the recent war. Feelings ran high against both Germany and the United States and most of the bridges across the Arno were graffiti-decorated with great signs demanding “a basso, bomba atomica” (down with the atomic bomb). Moruzzi's Institute was located about a half mile from the hotel, somewhat beyond the Scuole Normale where Galileo had worked more than 300 years earlier. The Institute was situated in a four-story palazzo with marble floors, great staircases, and an amphitheater. Our coworker and staff member, Amilcare Mollica, seemed to feel we were preferable to the previous Institute visitor, a young German investigator named von Baumgarten who, as a former Luftwaffe pilot, Mollica was convinced, had carried out strafing runs over Pisa during the war. Our mutual project was to work out patterns of convergent input upon brainstem reticular cells using extracellular microelectrode recording techniques. Starting as we did at the beginning of September and operating on three or four cats each week, it took until December before we managed to obtain useful data. In retrospect, it is hard to account for our problems because, by today's standards, the experimental approach was very simple.

It was a great day in September when Moruzzi, Il Professore, returned to the Institute. He was a large man and we all watched with interest from the upstair window as he slowly unfolded himself from his tiny Fiat, an unusually small car known locally as a "topellino" or “little mouse.” Actually we had rather restricted contact with him during the year, except in the late spring when we worked together on the preparation of our manuscript. One exception to this was when he descended from his upstairs living and working quarters to perform, with almost ritual gravity, the decerebration procedure that he had learned from Bremer some years earlier and that allowed recording experiments to proceed without further anesthesia. A long series of expired cats soon taught us to perform the decerebration quietly without professor's participation. The microelectrodes were flexible insulated wire of 12 or 37 micra, inserted by hand with ivory-tipped forceps. This laborious method was used instead of rigid microelectrodes because of our concern with respiratory and cardiovascular movements transmitted to the brainstem.

By spring time, it had become clear that each reticular neuron was the center of a widespread convergent pattern of inputs from ascending sensory systems, from brainstem and cerebellar neurons and in many cases from cerebral cortex, and that the “mix” of afferents on each cell was, so far as we could tell, idiosyncratic. The manuscript went through four or five drafts before we all reached agreement on its contents and it could be sent off to the Journal of Neurophysiology (Scheibel et al., 1955). Moruzzi's rigorous approach to data analysis proved a powerful learning experience. While at the Institute, we developed a rapid 2- to 3-hour histological method for establishing the position of the recording microelectrode tip. Because the usual procedure took several days and the new method gave consistently useful results, Moruzzi encouraged us to publish the method (Scheibel and Scheibel, 1956).

During the short winter break, we traveled north through Europe to visit several research centers. Most memorable was our several days spent with Oscar and Cecile Vogt at their institute in the Black Forest. Here, for the first time we saw what appeared to be neurohistological correlates of certain cognitive abilities. This became the germ for an entire program that I mounted in our own laboratory many years later. Before we left this picture-book setting, the Vogts paid us the ultimate compliment of asking us to stay, learn their methods, and assume direction of their institute when they retired. Although we felt we could not do this for many reasons, the warmth and generosity of their offer will always remain in my mind.

Our most powerful personal experience by far during our time in Pisa was meeting Alf and Inger Brodal from Oslo, who visited the Moruzzi Institute for a couple of weeks in the early spring. Alf, Inger, Mila, and I struck up an immediate friendship, a kind of elective affinity, which developed over many a lunch or dinner together, cooked in their little downstairs Institute apartment over a one-burner gas stove, and flowered during a short but memorable Roman holiday weekend. As a result, we joined Brodal the following August at the Neuroanatomy Institute in Oslo (after short visits to Denise Albe-Fessard in Paris and Turner MacLardy in London). Working in the office of Fred Walberg, Alf's young colleague, we tried to synthesize the Oslo school's data on inferior olive derived from Gudden and Glees methods with our own Golgi material (Scheibel et al., 1956). The results were not particularly significant, but the relationship was, and our personal and scientific friendship became lifelong.

By the time we returned to Memphis, Magoun had formally invited us to join him in California. As a result, we pushed along our research program, and I taught almost continually to make up for the time we had spent in Europe. During this short time, we tried to formulate our thinking on the role of oligodendroglia after demonstrating small numbers of axon terminals on the surfaces of many of these glial cells. These data were presented at what I believe was the first symposium devoted to neuroglia. It was chaired by William Windle at the NIH in the spring of 1955 (Scheibel and Scheibel, 1957). Transmission to oligodendroglia of samples of information inputs to neighboring neurons still makes good sense to me but I know of no further development of these data¹.

California

California really was the new world. We were surrounded by a group of enthusiastic, young neurophysiologists and neuroendocrinologists, all assembled in the new Department of Anatomy, all attracted by the combined magic of a dynamic new medical center and “Tid” Magoun. I was particularly happy to have a joint appointment in the Departments of Anatomy and Psychiatry, which allowed me to maintain at least some contact with my clinical specialty. Norman Brill, the new Chair of Psychiatry, and Magoun showed us our “digs,” the west wing of a World War II vintage bachelor officers quarters (boq) on the nearby Brentwood Veterans Administration Hospital grounds. The east wing was already occupied by the neurophysiologist Jim Olds who had recently described the positive and negative reward centers of the brain. The north wing was the domain of Sam Eiduson and his biochemistry group, involved with the relatively new amine, serotonin. With a large animal room in the center, our little converted barracks, Bldg. T 45, formed what was probably the first research institute at the center. Of course we were hot in summer and cold in winter, but we had space, and the opportunity for collegial interaction when we needed it. Crude and rickety as it was, I still look back to the almost 7 years of our occupancy of T 45 as a very special time.

It took time for us to assemble the material for a functioning electrophysiology laboratory, but Golgi neurohistology is less demanding of equipment and we were soon in operation. In this first couple of years, while trying to get used to the idiom and lifestyle of southern California, we began to establish the major features of reticular formation neurons. We were surprised at the axonal extent of large reticular cells. Some had bifurcating axons projected caudally into the spinal cord and rostrally into the diencephalon and even beyond, an enormously diverse topography on which to exert their effects. We were also surprised at the extreme degree of rostro-caudal compression shown by the dendrite systems of many reticular neurons. Their fancied resemblance to horizontally oriented stacks of poker chips led us to the idea of modularity. This may have been the origin of the module concept of organization of the nervous system, which is now quite familiar. These observations formed much of the basis for our presentation at the Henry Ford Symposium on Reticular Formation of the Brain that was held in Detroit in 1957 (Scheibel and Scheibel, 1958), Our talk followed an elegant presentation by Walle Nauta and Hans Kuypers (Nauta and Kuypers, 1958), which demonstrated the correlative power of their axon tracing techniques with ours, revealed neuropil patterning. We were very flattered, although not tempted, when right after the presentation, Ralph Gerard asked us to consider moving to the new institute he was developing at Michigan.

One of our first attempts at physiological analysis involved following the development of cortical and subcortical electrical rhythms in very young cats. We surgically implanted arrays of surface and depth electrodes in postnatal kittens and followed them through the next few weeks of their lives, combining multichannel electroencephalographic recording and behavioral observation. Tentative correlations were established between cortical activation patterns and discriminative responses to sensory stimuli with neurohistological patterns as revealed by Golgi impregnations. We were particularly intrigued by the very large amplitude delta waves from deep medial temporal sites that accompanied the first moment or two of suckling by the hungry animal. As satiety approached, the waves disappeared. Because we chose the poetic but otherwise inopportune name of “pleasure domes” for these waves, it was probably just as well that we published only in the bound proceedings of several meetings rather than in a peer-reviewed journal (Scheibel, 1962).

In exploring the activity of individual reticular neurons to repetitive stimulation in immobilized, locally anesthetised adult cats, we discovered how quickly such elements habituated to a familiar signal. It was clearly not a fatigue phenomenon because a slight change in the input completely restored the original intensity of response. Clearly, our cells loved the original and unexpected and were progressively “turned off” by the familiar and humdrum (Scheibel and Scheibel, 1965a). In doing this study, we found that we were recording from individual neurons for increasingly long periods of time (up to 9 hours) and, because of this, a new and unexpected property of reticular neurons was noted. Cells appeared to cycle through alternating periods of sensitivity and insensitivity to various sensory inputs. The most usual pattern we found in the relatively small number of cells that we could follow for very long periods was alternation between responsiveness to an exteroceptive stimulus from the body surface followed by responsiveness to an interoceptive stimulus such as respiratory movements or other slow endogenous rhythms. We followed a few of these cells through as many as three cycles of responsiveness, and it seemed fairly clear that the succeeding patterns were mutually exclusive. It was almost as if some (hierarchically higher?) pacemaker control system was manipulating the responsiveness of groups of reticular cells alternately to the outer and inner worlds. We wondered whether this might be a mechanism to prevent individual neurons from being drawn increasingly into the input-output transactions of single neural domains (Scheibel and Scheibel, 1965b). There were several fascinating theoretical aspects to this possibility that we wished to explore. Unfortunately, rapidly increasing health problems made further work impossible for Mila. This was the last study that we shared in the laboratory.

While involved with these single unit studies, I remained all-too-aware of the statistical insignificance of the individual neuron and thought a great deal about problems involved in sampling simultaneously from a larger cell population. With this in mind, I designed several microelectrode yokes for holding small clusters of microprobes, the individual elements within 400 to 500 micra of each other. The earlier designs moved the cluster as a unit. The final model allowed individual control of each electrode. Although it was possible to capture and record units with one or two of the electrodes, the tissue distortion produced by penetration of an adjacent probe sometimes caused loss of an already captured unit. Early results were moderately encouraging but our personal situation made further work in this direction impossible. Multiple simultaneous unit recording is only now becoming a reality to the neurophysiologist.

In a very different vein, I can remember having a number of discussions with a faculty colleague from neurology, Charles Markham, on the role of the reticular formation in controlling the vestibulo-ocular reflex arc. Charlie was interested in this system and went on subsequently to do outstanding work on the role of motion-induced eye movements in the selection of astronaut and cosmonaut candidates. Out of our discussions developed a research study, which included another colleague from psychiatry, Ronald Koegeler revealing the unusually powerful suppressive effects of basal ganglia stimulation on saccadic movements (Scheibel et al., 1961). At about the same time, another colleague from psychiatry, Fred Worden, was visiting the laboratory to learn neurohistology. Fred would come to the laboratory and park his new Bentley next to Charlie's vintage Rolls Royce and Ron's vintage Jaguar. I distinctly remember parking my Ford behind another laboratory building lest I destroy the effect!

Tid Magoun had struggled for 10 years to make his dream of a Brain Research Institute a reality. When it finally came to fruition in 1962, all of the outlying UCLA neuroresearch programs including ours were called in to take their places in the new laboratory space. By then, I did not want to move, having been spoiled by a couple of thousand square feet of research space and the relaxed comaraderie of our little troika with Jim and Sam. Nonetheless, the Veterans' Administration facilitated our departure by announcing plans for immediate destruction of the boq buildings. They were as good as their word and today the site of our old lab remains a parking lot.

With Mila's continued illness, a new life pattern developed that was to last until the end of her life 14 years later. Because I wished to spend as much of my time with her as possible, it became necessary to find a fulltime neurohistology technician who could provide us with the Golgi-stained material needed for further work. We were unusually fortunate in finding Miss Lore Liepmann who came out of semiretirement to work with us for some years until she left for permanent retirement in Sweden. Although I very much missed the thrill of shepherding each section through as I always had, Lore's contribution to our work was of incalculable value and I remain deeply in her debt. I learned to do virtually all of my research at home, going “downtown” only to give my lectures, check out the students, and receive more material for Lore. During the next decade and a half, we were also fortunate in having a group of gifted younger colleagues do their doctoral work in the laboratory. To mention only two, Larry Stensaas and Eugene Millhouse were both talented and a continual delight and they have remained my friends over the years. Larry did a seminal study on the development of the hippocampus (Stensaas, 1968), which is frequently quoted today, and Gene's Golgi analysis of the internal structure of hypothalamus (Millhouse, 1979) has also maintained a prominent place in the literature.

The following years, although physically and emotionally demanding, were productive of a number of insights. It had seemed wise to widen our neurohistological horizons so that other neuropil patterns in different parts of the nervous system might give us yardsticks against which we could compare the patterns characteristic of the reticular core. The spinal cord, although sometimes considered the “simplest” part of the Central Nervous System (CNS) immediately became a challenge and a delight. I will mention only two of the many observations that intrigued us.

Renshaw cells were a term given by John Eccles to a supposed group of short-axoned elements near the motoneuron pool. They were considered to be the necessary intercalated substrate for inhibition and by extension became the term applied to any short-axoned cell in the CNS whose role was believed to be inhibitory. Careful study of our Golgi material failed to reveal any short-axoned cells in the spinal grey matter (Scheibel and Scheibel, 1971a). We found many spinal interneurons, of course, from whose axons emerged collateral systems that played back over motoneurons. We were forced to conclude that these collateral extensions of typical longaxoned projecting interneurons were the only possible candidates for the Renshaw role (Scheibel and Scheibel, 1971a). Our interpretation was later born out by both anatomical and physiological studies in other laboratories. However, our finding so troubled Eccles that he refused to write or speak to us again, a really painful loss because I had had the chance to meet and speak to him only a few years earlier, on his return from Stockholm and his Nobel Award and we had corresponded since then.

While studying motoneuron dendrite systems in transverse and sagittal planes of section, it became clear that in the latter, dendrite systems tended to be organized in tight clusters we called bundles (Scheibel and Scheibel, 1970). It was well known that motoneuron somata arranged themselves in exclusive groupings, muscle by muscle. But once the dendrite stalks started streaming rostrally and caudally, it seemed almost as if they sought contact with dendrites from nuclei other than their own. Dendrite bundles were subsequently found in other sites including the cerebral cortex and brainstem. We literally stumbled across the apparent plasticity of these dendrite bundle complexes when we had the chance to compare samples of adult rat reticular core with those from neonatal animals. Since the time of Cajal, it had been well known that the rapid Golgi method is most effective in very young animal tissue and rapidly loses its sensitivity with the development of myelin. Accordingly, most of our work had been done with the brains of animals in the first 10 days to 2 weeks of life. While trying to perform the Golgi stain on coronal (cross) sections from young adults, we were pleased to find a small number of effective impregnations of the lower brainstem. We were surprised with the result. In the postnatal animal, reticular cell dendrites radiate out freely into the surrounding neuropil and are generally spine covered. In the mature animal, we found that the dendrites had lost their spines and were grouped into bundles similar to those we had seen in spinal cord. The dramatic loss of spines suggested a fundamental change in the wiring pattern of these dendrite, while the unexpected reorganization into bundle complexes suggested equally dramatic alterations in the mode of dendritic operation (Scheibel et al., 1973).

The functional role of these enigmatic structural complexes continues to elude us. Among several other possible interpretations that were made over the next few years, we suggested that they might conceivably provide a site—an intrafascicular micromilieu—for the laying down of central programs coding output patterns peculiar to the neural structure; in other words, a possible site for memory storage (Scheibel and Scheibel, 1975). Although supportive data for this supposition has not developed, there is a small but growing literature on dendrite bundles that keeps the issue alive—a structural paradigm in search of a function.

Our studies of the thalamus, which extended over a period of more than 5 years, presented some of the most enjoyable and the most challenging problems we were to face in examining the fine structure of the CNS. The range of neuropil patterns found in the many nuclei that make up the thalamic complex is remarkable as is the diversity of their input and output connections, the nature of their interactions with each other, and the details of their relations with cerebral cortex. The neuroanatomical building blocks in the field at that time were the structural descriptions of Cajal (Ramon y Cajal, 1911) and the connective studies of A. Earl Walker (Walker, 1938) with additional contributions from O'Leary on the lateral geniculate (O'Leary, 1940) and Herrick on the diencephalon of the tiger salamander (Herrick, 1948). The sheer beauty and diversity of the systems we saw resulted in a number of contributions of which two come particularly to mind.

The importance of the thalamic intralaminar (nonspecific) systems had been recognized for more than 20 years as central to thalamocortical substrates of consciousness and patterns of sleep-wakefulness. Our reconstructions based on thousands of Golgi-stained preparations were able to picture the actual course and relations of such fiber systems, both thalamocortical and corticothalamic. The latter, in particular, with their idiosyncratic and convergent terminal patterns suggested circuit architecture reminiscent of that in contemporary computer systems (Scheibel and Scheibel 1967a, 1971b). The role of the nucleus reticularis thalami (Cajal's “noyau grillage") had remained enigmatic for many years. Literally wrapped around the outer surfaces of the thalamus, separating it from the immediately adjacent internal capsule, it had been considered by many investigators (although not all) as the last link on the pathway from upper brainstem to cerebral cortex. Our Golgi studies showed that virtually all reticularis cell axons projected caudally onto thalamic and mesencephalic neurons and that all thalamocortical and corticothalamic axons traversing the nucleus reticularis made collateral connections with these cells (Scheibel and Scheibel, 1966, 1967a). A plausible interpretation for these connections involved a feedback control system, probably inhibitory, interposed between thalamus and cortex, thereby controlling the nature of thalamo-cortico-thalamic intercourse. Subsequent physiologic investigations documented the inhibitory effect of reticularis cell bursts (Schlag and Waszak, 1970), while immunohistochemical studies demonstrated the GABAergic nature of reticularis cells (Houser et al., 1980). It was subsequently shown that prefrontal cortex also had access to these gating cells (Yingling and Skinner, 1975) and so the potential for voluntary control was added, at least by inference, to the mechanisms of cortical input gating. This cluster of findings with their implied relation to selective attention, hypnosis, and placebo phenomena have given me a good deal of satisfaction over the years.

During this time, a young physician named A1 Globus joined the laboratory. He had been in medical practice for several years but decided the time had come to take a wanderjahr. Although he had had no research experience, I liked his sense of adventure and his obvious interest in neural substrate. A1 stayed with us for a couple of years and our mutual interest in axodendritic topography resulted in several reports identifying the sites of termination of a specific thalamocortical sensory influx (in this case the visual system) (Globus and Scheibel, 1967a) and also of corpus callosal fibers (Globus and Scheibel, 1967b). Synaptic coupling sites proved to be quite specific. Most surprising to us was the fact that, in the rabbit at least, primary sensory fibers entering cortex terminated principally on the apical shafts of fifth layer pyramids as they ascended through layer 4. Although we could not rule out some contacts on the layer 4 stellate cell population, they seemed not to be the primary postsynaptic receptive element as perceived wisdom dictated. Callosal fiber terminations, on the other hand seemed sharply limited to the oblique branches of pyramidal cell apical shafts. The studies were based on the placement of small lesions in the presynaptic path, followed by study of dendrite spine distortion or loss in the target synaptic zones. More elegant and revealing techniques are available today and should be used to reevaluate these findings that are of considerable importance in understanding dendritic computational mechanisms.

Another interesting laboratory colleague was Robert Lindsay, an early trainee in the new field of neurocomputation. The orientation of our work had always been in the classic qualitative and descriptive mode but I felt that time and new technology suggested the necessity of becoming more analytic and quantitative. To prepare for Bob's arrival, we bought a stateof-the-art Digital PDP 8 computer, a floor standing monolith with rows of flashing lights and a large tape deck mounted on its front surface. Bob rapidly “tamed” the new artifact and the eventual result was a couple of reports describing in semiquantitative terms some relationships between dendrite length and branching number (Lindsay and Scheibel, 1974). From my own naive point of view, it appeared that the mountain had labored and produced a mouse. In retrospect, I feel that if I could have provided conceptually sophisticated leadership, more might have come from this approach. With today's highly automated instrumentology, such studies are routine.

I must speak also of David Brunswick, never a member of our laboratory and yet very much a part of our lives at that time. David had taken his degree in physiology with Cannon in the early 1930s, then gone to Vienna for personal analysis with Freud. Returning to Los Angeles just before World War II, he rapidly became an accepted and practicing member in the local psychoanalytic community. Unlike most of his colleagues, he remained interested in possible neurophysiological substrates of the psychodynamic concepts he dealt with each day, and so he found his way to our laboratory on the Veterans' Administration grounds. David was a short-statured, almost child-like man with penetrating insights and a straightforward manner. I think he lived for the day when Mila's health would improve to the point that I could return full time to the laboratory and start some experiments with him on the role of hypothalamus in the id instinctual impulses. That time, unfortunately, never came. By the time I was able to return full time, David had passed away, but the memory of his gentle, enquiring nature and unfailing patience will live with me.

During the long period of Mila's illness, we were on occasion invited to participate in meetings. With perhaps two exceptions, we were unable to attend, but I was unwilling for our work to be omitted. Several alternatives were practiced. Most frequently, I sent our manuscript to the editor or meeting chair who was usually gracious enough to publish our contribution along with those that had been presented. On one occasion, I remember a manuscript written for a New York Academy of Sciences Meeting, which we entitled “The Anatomy of Constancy” (Scheibel and Scheibel, 1977). For various reasons a great deal of personal feeling became invested in this work, so much so in fact that we started the manúscript with a biblical quotation from the Book of Ruth:

“Whither thou goest, I will go;

 and where thou lodgest, I will lodge.”

Perhaps there were some presentiments of the end of our life together. I was, therefore, more than grateful when one of the editors, a colleague of ours, Bernice Wenzel, kindly volunteered to read the paper for us. On another occasion, I literally telephoned the full text of our paper in to one of the symposium editors in New York, reading the text and describing each slide in detail as it was to appear in the presentation. All of this was tape recorded at the other end of the line and copies of the slides were sent on. I understand that the tape and slide show were presented (despite some grumbling from one of the senior investigators at Columbia that it would never work) without a hitch and was applauded and discussed in its turn like any other “live-presented” contribution.

The final 2 years of Mila's life were particularly difficult ones with two episodes of surgery and periods of prolonged physical pain and increasing depression. Just 4 months before her own death, our long time friend and colleague, Jim Olds, died of a massive heart attack. His wife, Nicki, begged us to be with her at the ceremony at Cal Tech to help celebrate Jim's distinguished life and career. It was difficult to refuse her request and so, bundling Mila up, we joined Nicki on a rather dark and blowing November afternoon. I gave one of the tributes for our friend. Mila developed what appeared to be a viral pneumonia, shortly thereafter, with a pattern of hyperesthesia and pain almost like a thalamic pain, syndrome. She died shortly before midnight, on New Year's Eve, 1976.

Adjustment

It was undoubtedly fortunate for me that this was a busy time. In the laboratory, a graduate student, Tom Davies, was finishing a conjoint neuroanatomical and neurophysiological study on the ontogenetic development of somatosensory thalamus (Davies et al., 1976). A dynamic young physician from Mexico, Jesus Machado-Salas, was completing his thesis study on age-related changes in the brain of the mouse (Machado-Salas et al., 1977). And I was continuing our exploration of the aging and senile human cerebral cortex. In addition, my period of intensive teaching of functional neuroanatomy was about to begin. Daniel Pease, Chair of our Department of Anatomy, kindly suggested that he would find a teaching replacement for me and that I take the quarter off. However, I chose to carry on as best I could and in retrospect, it was the right thing. After profound loss, both body and mind suffer, but an unforgiving schedule may be the most forgiving in the long run.

In the early 1970s, the nature of brain aging, both normal and abnornal, had become a subject of growing interest. With the increase in life expectancy that became obvious in the second half of the 20th century and the swelling number of “senior citizens,” a whole range of behavioral and tissue changes were recognized and a new speciality, geriatric medicine, was in process of being born. When I was in medical school in the early 1940s, we were taught that Alzheimer's disease was a rare degenerative brain disease of “old women” and that we would be lucky to see two or three during our entire practice. Suddenly, Alzheimer's disease and other related degenerative syndromes were of major concern. Our old cerebral bete noir, senile arteriosclerosis, was losing importance and was being replaced by amyloid plaques and neurofibrillary tangles.

The chair of a planned symposium on the aging brain asked me to present a paper on human age-related cerebral cortical changes. When I told him that I had not done any work in this area, he suggested that with the techniques available in our laboratory, that deficit could quickly be remedied. Taking him at his word, I obtained tissue from the cerebral hemispheres of a group of old patients and studied them with several Golgi modifications (Scheibel et al., 1975) Some of the changes in neuronal and vascular morphology were striking, and this started a program which continued for several years. Some cortical material showed only modest loss of dendritic spines and occasional nodulation of dendrite shafts, while in others, there was obvious loss of dendrite branches, tortuosity of many of the remaining shafts, and progressive swelling and loss of the smooth triangular silhouette of pyramidal cells. In even more advanced disease, the cell bodies that remained were shrunken and distorted and often surrounded by glial cells. The capillary loops of cortical vasculature also looked distorted and nodulated. With the help of scanning electron microscopy, it later became clear that these vessels had lost their normal investment of fine axon fibers and terminals (the pericapillary plexus) and were infiltrated with masses of amyloid. In some places, these had apparently been disgorged, leaving gaping holes in the vessel wall (Scheibel et al., 1987). Inadequacies of the histories that accompanied some of the older tissue specimens and the largely nonquantitative nature of my approach resulted in an initial impression that pathological changes of this sort were an invariable concomitant of the aging process. It took several years and some quantitative studies such as those of Conner and Diamond in aging rat cortex (Conner et al., 1982) and those of Paul Coleman in human material (Buell and Coleman, 1979) to separate out phenomena of “normal” from “abnormal” aging.

One interesting variant of this pattern was picked up in the relatively small number of familial presenile Alzheimer's disease specimens that we examined. Although the dendrite systems of neocortex and archicortex (and in some cases, even cerebellum) were ravaged, there were numerous localized areas of explosive new growth, small clusters of newly developing, spine-covered dendrite tissue appearing almost like the “last gasp” of a dying dendritic system (Scheibel and Tomiyasu, 1978). I have never seen this phenomenon in any other type of tissue and can only imagine that it represents attempts at restitution by degenerating neurons.

Several of the graduate and postdoctoral students in the laboratory were involved in various stages of this work and I mention them with affection: Taihung (Peter) Duong, Ron Hammer, and Roland Jacobs as well as a group of talented undergraduates. However, none of our work on human tissue would have been possible without a reliable tissue source, and here I express my gratitude to a friend and colleague who, I believe, never stepped into our laboratory. Uwami Tomiyasu was pathologist at the Wadsworth and Brentwood Veterans' Administration hospital and had, over the years, built up and nurtured a brain bank, often over the protests of her administrators. Uwami was always there when we needed human specimens, whether it be epilepsy, aged brain, schizophrenic specimens, or normal controls. She is no longer with us, but maintains her place of honor in our memories and as a coauthor on many of our papers.

The venerable Golgi techniques proved their usefulness again in the study of several other clinical syndromes. The Department of Neurology and the Division of Neurological Surgery at UCLA were among the pioneers in developing surgical programs for the treatment of seizure disorders, particularly complex partial seizures (temporal lobe epilepsy). Following the program model initiated by Wilder Penfield at Montreal some years before, this provided an opportunity for both treatment and research. Our neurosurgeon at that time, Paul Crandall, was often able to make block resections of medial temporal lobe tissue, which provided precious opportunity to look for neurohistological substrates of the ictal process. In the limited number of specimens that we received, it was possible to identify a group of degenerative changes in neurons of prosubiculum and hippocampus (particularly CA 1), including loss of dendrite spines, nodulation and distortion of dendrite shafts, total loss of dendrite system, and disappearance of cells. Areas of gliosis were found and on occasion we noted fields of hippocampal dendrites “bent” toward gliotic areas, presumably because of torsion and shrinkage produced by the glial scars. An unexpected finding was the frequent presence of small aneurysmal outpouchings on the capillary plexus, a Golgi-based observation that we later confirmed with scanning electron microscopy (Scheibel, 1980). The amount of pathological change appeared related to the length of disease history, thereby suggesting a progressive course. The etiology and pathogenesis of mesiotemporal sclerosis remain enigmatic but disturbed neuroembryogenesis must still be considered along with a number of genetic, perinatal, and postnatal insults.

For a number of years I had served as a psychiatric consultant at Camarillo State Hospital, giving lectures to the resident physicians and seeing patients whom the staff were especially anxious to present. As in the case of most state institutions at that time, the patient population included a broad spread of psychiatric illness but schizophrenia, in its many manifestations, represented the largest fraction of the patient population. For much of the first half of the 20th century, schizophrenia was believed to be a “functional psychosis” based in the supposed emotional turmoil of early family life. With the introduction of chlorpromazine and the first generation of psychopharmacological agents in the mid 1950s, interest began to develop in a candidate's underlying organic mechanisms. Of these, the “dopamine hypothesis” was the model most frequently invoked. I had become intrigued by certain clinical similarities in the symptomatology of patients with temporal lobe epilepsy and those with schizophrenia. For this reason, I was more than interested when, in 1975, the retiring director of Camarillo, Philip May, tipped me off to the fact that the hospital was about to discard the collection of material from its brain bank. Some of the material was still in good condition and I was able to bring back to the laboratory perhaps a dozen “schizophrenic brains” and an equal number of specimens from patients with other syndromes, which would serve as our “non-schizophrenic controls.”

Golgi analysis of the schizophrenic material revealed unexpected findings in the hippocampus. The usually precise arch of the cornu ammonis with its regular files of hippocampal pyramidal cells was disturbed. Ordinarily, the pyramids and their apical shafts are aligned in soldier-like arrays. In these specimens, the cells and their shafts appeared spatially disorganized, pointing in all directions. This anomaly of organization was present in all 8 of the brain specimens that could be processed but absent in the 10 non-schizophrenic control brains. I was familiar with the fact that the literature already contained some reference to schizophrenia-related pathology including decreased brain size, enlarged ventricles, and gliosis and cell shrinkage in the basal forebrain. However, these hippocampal findings appeared to be the most specific yet described and I realized that the pathology might also provide clues to pathogenesis of the syndrome. Nonetheless, Mila's increasingly severe illness and the imminence of two surgical procedures took precedence and the work was put aside. The findings were finally organized for presentation a few years later and first aired in 1981 at the Society for Biological Psychiatry Meeting in Chicago (Scheibel and Kovelman, 1981). The amount of cellular disarray was immediately obvious but the results were admittedly descriptive and qualitative. I was joined in this endeavor by Joyce Kovelman, a graduate student who had recently entered the laboratory and chose to make this finding the subject of her doctoral thesis work. Joyce, a hard-working and talented student, agreed that we should develop another series of hippocampal specimens from schizophrenic brains and subject them to quantitative analysis, thereby providing a more rigorous statement of the amount of disarray affecting the hippocampal cell ensembles. This group of brain specimens was obtained from the Veterans' Administration Hospital brain bank. The histories of these patients suggested more fluctuating disease courses, unlike the profoundly ill, lifelong hospitalizations that had characterized the first group of patient material that I had received from Camarillo. Perhaps as a result, the extent of hippocampal pyramidal cell disarray seemed less severe, suggesting a spectrum of pathology reflecting the severity of the underlying disease. Nevertheless, the Nissl-stain based measurement paradigm developed by Joyce revealed significance differences between schizophrenic patients and non-schizophrenic controls particularly in the anterior third of the hippocampus or “pes” (Kovelman and Scheibel, 1984). Because of the size of the study and the difficulties involved in measurement and recording during those precomputer days, only left hippocampi were considered. Several years later tissue specimens from the right hippocampus were studied by another graduate student in the laboratory, Andrew Conrad, and similar results were obtained, making it unlikely that the schizophrenic “process” was unilateral (Conrad et al., 1991). We felt some concern that these findings might conceivably be related to the psychotropic drugs to which virtually all schizophrenic patients had been exposed since the mid 1950s. The Yakovlev collection housed at the Walter Reed Army Medical Center in Washington, D.C. provided an invaluable source of stained and mounted tissue from psychotic patients obtained before the drug era. Examination of this material also revealed cell disarray in some schizophrenic patients thereby mitigating this area of concern.

In terms of pathogenesis, several converging lines of reasoning pointed to a fault in neuroblast migration during the early- and mid-second trimester of pregnancy as causal to the hippocampal cell disarray. The process of migration appeared significantly dependent on the integrity of a group of neuronal cell adhesion molecules (NCAMs) whose importance had been initially explored by Gerald Edelman (Edelman and Chuong, 1982). The genetic mouse mutants, “reeler” and “staggerer,” served us as putative physical models for the disturbed migrational process, although not necessarily the etiology. At about this time, discussions with Sarnoff Mednick (personal communication and Mednick et al., 1987) and later reports from Finnish and English research groups underlined the import of maternal influenza virus infection during the early second trimester of pregnancy in subsequent development of schizophrenia in the offspring. In fact, Mednick's data indicated that mothers who had had influenza during their second trimester had a 300% greater chance of producing a schizophrenic child. We were especially struck by the fact that influenza is one of a very small number of orthomyxoviruses possessing the enzyme, capsular neuraminidase, which affects the binding properties of NCAMs. Thus putative links existed between influenza infection and disturbed neuroblast migration, and between the migrational difficulty and schizophrenia. Although there is no reason to believe that maternal influenza infection is the only significant etiologic factor in the development of schizophrenia, it highlights the importance of the period of fetal development in the pathogenesis of this psychotic disease.

Although never a major direction of laboratory effort, work with the scanning electron microscope holds a special place in my heart. Its remarkable ability to demonstrate three-dimensional structure at high magnifications, well beyond those available to the light microscope, made it in some ways another Golgi method, writ large! Several of the graduate students working with us at that time, notably Itzhak Fried and Linda Paul, joined in our studies of hippocampus and cerebellar cortex. However, I think I was most pleased with a short report we published on the apparent nonadhesive nature of axospinous dendritic synapses (Scheibel and Paul, 1985). We were able to demonstrate that after tearing and separating small blocks of brain tissue along natural cleavage planes, presynaptic axosomatic terminals always carried with them a fragment of postsynaptic membrane from the neuronal somal surface, leaving a small pit. However, those terminals pulled away from dendrite spines invariably separated “cleanly” without any evidence of membrane adhesion. We assumed that these observations argued for axo-somatic “hard wiring” and a more temporary and reversible type of synaptic articulation on dendrite spines. This result appeared then—and still appears—to be intuitively attractive in light of other studies that identify the spinous synapse as a “site of learning change.”

Early in 1979 I received an invitation from Professor Marian Diamond at the University of California, Berkeley, to give a seminar on consciousness and the reticular core to her neuroscience graduate students. Pleased by this invitation from a colleague I had never met, I made the first visit of my adult life to the fabled Bay Area. Many things combined to make it an unforgettable experience, not the least of which was Marian's dynamic personality and sensitivity. We immediately found a great deal to share, and over the next couple of years our relationship deepened, culminating in our marriage in 1982. I have been forever grateful for this wonderful gift of emotional and intellectual companionship that came to us both in our middle years. We have continued to work at our respective institutions, maintaining a “commuter marriage,” which, I understand, is becoming increasingly common among professional couples. As an extra plus, I have gained a family of four superb grown children, their own mates and a cadre of grandchildren. Clearly, Marian has been a most significant discovery in my life.

Neuropil and Cognition

Possible substrate relationships between neural structure and special cognitive “gift” had first been shown to me by Oscar and Cecile Vogt in their Black Forest laboratory many years before. The idea had remained with me, although the prospect of acquiring brain specimens from the especially gifted remained a daunting enterprise. However, as our laboratory became more adept with quantitative applications of the Golgi methods, an alternative idea presented itself. Why not use the behavioral and cognitive attributes of each individual in such a way that each brain became its own control. Several studies resulted from this strategy, based in the collaborative work of my graduate students, Itzhak Fried, Linda, Paul, Rod Simonds, and Bob Jacobs, undergraduates Jim Slotnick and Linda Kao, and our long-suffering statistical consultants, Alan Forsythe and Sondra Perdue.

Casual scanning of the Vogts' material, 30 years earlier, had suggested to me the presence of a more complex neuropil (the cells seemed farther apart), in sensory receptive layer 4 in the primary visual cortex of an artist with the lifelong gift of eidetic imagery (photographic visual memory). Marian's quantitative studies of the response of rat cortex to sensory enrichment had convincingly shown that enhanced processing loads led to dendritic growth (Diamond, 1988). Accordingly, using Golgi-stained human cerebral cortex, we compared two areas along the primary sensory strip (areas 3, 1, 2), the one receptive to hand and finger input, the other to input from the surface of the trunk. Basilar dendrite systems in the latter area were, as we hypothesized, significantly less complex than those in the former, presumably reflecting the more limited range of sensory input and processing associated with the trunk. Coincident examination of typical prefrontal and parietal association areas (areas 9, 40) revealed complex and idiosyncratic patterns whose significance we could only speculate upon (Scheibel et al., 1990).

In a related study, we compared the dendrite organization of supragranular pyramidal cells in the left and right opercular zones (Broca's area) in the inferior frontal gyrus with the orofacial area of the motor strip just behind (Scheibel et al., 1985). As we conceived it, the former provided the substrate for language formation; the latter controlled the motor substrate. We found that dendritic complexity of opercular tissue significantly exceeded that of the motor strip, a finding that seemed appropriate in terms of the presumably more subtle processing problems involved in word selection and organization. “Branchiness” of the dendrite patterns in tissue from the left Broca area exceeded that from the right as we expected with one exception, and this turned out to have been a left-handed individual. However, to our surprise, total dendritic length of the basilar skirts from cells in both left and right hemispheres was comparable. This stumped us until Itzhak had the good idea of counting the numbers of dendritic branches of each order (counting from proximal to distal). We then found that most of the dendrite length in the language dominant hemisphere was made up of higher order (more distal) dendrite branches. Lower order branches constituted the greater part of dendritic arbors on the nondominant side. We soon came to think of the adult dendrite arbor as a temporo-spatial record of dendritic development with these left-right differences in branch length representing differential growth sequences peculiar to the two hemispheres and to the areas involved. We deduced that greater length of lower order branches suggested that areas of right hemispheric cortex might “lead” the left during the first year of life and that as language processing began to develop during the second and third years and beyond, higher order branches might develop more extensively on the language-dominant left side.

Testing this challenging idea became the basis for Rod Simond's doctoral thesis as he studied these language-related areas in an age-graded group of human infant cortices from 3 months to 72 months of age (Simonds and Scheibel, 1989). The results clearly indicated an initial overall right hemisphere advantage in dendrite length until the end of the first year, followed by a more rapid growth, especially of higher order dendrite segments on the left side, presumably as language patterns developed. Careful evaluation of the data revealed another interesting dendritic characteristic. During the process of development, there might be retraction or absorption of some of the earlier dendritic growth (the more proximal segments) as later-appearing branch orders developed. The literature also suggested that in the absence of language development during the critical first 6–10 years of life, adequate language capability and left cerebral dominance might never appear. The interaction of cultural and social factors with the structure of neuropil and the reactive plasticity of the dendritic tree seemed indeed boundless.

Another body of data was provided by the comprehensive study of Wernicke's area by Bob Jacobs who considered a number of factors impinging on dendritic neuropil, including maturation and aging, gender, hemispheric difference, and environment (Jacobs and Scheibel, 1993; Jacobs et al., 1993). Bob did an elegant job. Most exciting here was the apparent relationship between education level and the extent of the dendritic tree. Subjects with a college and/or graduate level education had significantly more dendritic tissue than those with a high school education, who in turn exceeded those with less than high school education. We assumed that these results were not directly coupled to the level of education itself, but rather to the richness and variety of subsequent life experiences that extended periods of education allowed. It was also realized that an alternative explanation could be entertained, namely that the higher education levels attained by some might be the result of their inherently more complex dendritic systems rather than the cause. Experiments are more likely to throw light on correlation than on causality. However, several decades of animal-based research have stressed the significance of challenge and enrichment in shaping the cortical microenvironment, thereby lending credence to our assumption.

As I look back on these efforts of ours, and of similar efforts in other laboratories, to identify brain correlates of behavior, cognition, and special gift, it is obvious that we were addressing some of the central problems of neuroscience. These, along with consciousness, sleep and wakefulness, and learning and memory constitute a kind of roll call of honor for the faithful of the profession, the holy grails of ultimate attainment in the brain sciences. Considering that serious research goes back scarcely 150 years, our quest has not been without reward.

Other Aspects of Academia

The triad of research, teaching, and administration has long been the essential underpinning of the academic life. Of the three, I have been most delinquent in the category of administration. I think this reflects, in part, a retiring nature and a reticence on my part to “take charge,” along with a strong sense of devotion to the laboratory and my students. I cannot deny the warm feelings (and surprise) I experienced when in the early 1980s, our beloved medical school dean, Sherman Mellinkoff, asked me to serve with him as Associate Dean, following the sudden death of the former Associate Dean, the much admired Ted Rasmussen. Although I felt totally unprepared for a position like this and told Sherman so, I was also loathe (or too selfish) to leave our then-developing research program on the aging brain. Sherman was a gentle and empathic man and took my refusal graciously, but I have always felt some remorse that I refused him, even though I am still convinced it was the right decision. It was even more unexpected when shortly thereafter, I was asked to have my name put forward for Director of the National Institutes of Aging following the departure of Robert Butler. I appreciated the honor involved in the invitation but was not tempted. The prestige presumably connected with initiating programs at a national level, developing budgets, and testifying before congressional committees had far less appeal to me than the lure of the next series of brain sections and the secrets they might hold.

The one exception to this pattern developed when, in 1987, the new medical school dean, Kenneth Shine asked me to serve as Acting Director of the Brain Research Institute (BRI) at UCLA. As an early member and advocate of our Institute, I felt a strong sense of responsibility for the organization, as its former director, my long-time colleague, Carmine Clemente, stepped down. While my motivation might have been good, my timing was not, as the state promptly moved into a time of recession and shrinking budgets. After 3 years in the “acting” category, I suggested to Dean Shine that, while I did not particularly care what I was called, I felt that our Institute deserved a “real” director. He took the hint and instituted a search whereupon, again to my surprise, I was asked to continue in office as director. With minimal funding support we instituted a group of programs that might enrich the scope of institute activities while providing us with a higher profile. These included an active outreach teaching program by our students in the community schools (K through 12), the development of a series of interdisciplinary “affinity groups” to encourage transdiscipline interaction amongst our large membership, honorary lectureships (Magoun, French, Eiduson) to bring exciting speakers to UCLA, and monthly laboratory presentations ("Labs on View") to acquaint all of us with work going on within the institute. During this period, we completely reorganized the curriculum of the BRI's crown jewel, the Interdisciplinary Graduate Teaching Program (IDP) and the results were encouraging in terms of faculty enthusiasm and student morale. I was fortunate in receiving the wholehearted support of the institute membership as well as that of our small but devoted BRI staff, and could step down in 1995, after completing my full 5-year term, with real satisfaction. The chronic rumblings for “disestablishment” of the BRI were heard no more and the director who followed me, Alan Tobin, with increased financial support from Dean Levey, has added measurably to the impact of the Institute on all of our professional lives.

As a faculty member, teaching has always been a part of my life, starting with the University of Tennessee where the admission of a new medical school class each semester, guaranteed a neuroanatomy class to teach each half year. At UCLA, with a sparkling young group of neuroscientists to draw on, Magoun put together a basic neurology course taught by a cadre of experts, each a master in his or her own field. The content was up-to-the-minute and probably excellent; the result was disastrous. I was not surprised because I had experienced a similar type of instruction while a student at the College of Physicians and Surgeons, with the same unfortunate results. This teaching by “cameo appearance” as I thought of it, offered a series of vignettes without continuity, unless, of course, all of the instructors sat through all of each other’s lectures—an expenditure of time that few were willing to make. I finally achieved the luxury of chairing and teaching an entire course in the 1980s, first with the newly developed graduate level course in functional neuroanatomy and somewhat later with the undergraduate course in our new and growing neuroscience major. We taught on the quarter system and 10 intensive weeks of contact with motivated students, graduate or undergraduate, proved to be an unmitigated joy. Colleagues often wondered about the work involved in my giving all of the lectures and laboratories, aided only by one or two teaching assistants who had usually taken the course the previous year. I could assure them that it was far easier than trying to chair a course with a half a dozen or more other instructors, none quite clear what you wanted from them, or what the students had already heard.

In these circumstances, I found a deep source of enjoyment in my teaching. I think the main pleasure grew out of the challenge of trying to build with them a total image of their own nervous system in action. Snatches of neuroscience history, personal stories, “thought experiments,” case material and, of course, the laboratory were all used to make the subject matter alive and personal. The pleasure of watching many of them grow with the course was powerful and sustaining, helped along, I am sure, by the narcissistic gratification involved in leading and challenging them. It was not an idle choice, therefore when, toward the end of the 1990s, after almost 50 years of research, I decided to close my laboratory and devote myself to full-time teaching. Now, almost 5 years later, I still miss research at times and I have been known to show withdrawal symptoms when visiting some colleague's active laboratory. Nonetheless I feel I made the right choice and look forward, with the usual anticipation—and trepidation—to beginning the next class.

Although I must admit that the real challenge and thrill of teaching came to me somewhat later in life, I have always felt the excitement of discussion and argument among individuals from varying backgrounds tackling a problem of common interest. The old Spanish style home that we bought in 1959 had a separate three-car garage and guest room, all somewhat the worse for wear. We converted this into a rather casual meeting room that could hold 20 or more people. Starting shortly thereafter we began to have small faculty-student meetings here, discussing a paper or subject of interest. Things seemed to flow more easily in this off-campus (usually evening) setting. Visitors or foreign guests have been with us at times and the meetings have become something of a tradition. They also served in some sense as a model for the affinity groups that were started during my term as director of the institute.

Another bonus of academic life is the travel that becomes a natural part of it. Many are the attractions of national and international travel, the meetings and interaction with colleagues, and the exposure to new ideas being only some of the more obvious benefits. As already mentioned, after the first few years together, Mila and I were virtually unable to travel, or even to leave our home. The situation later with Marian was very different and some of our most rewarding memories are of trips we have taken together. Two that were particularly memorable were our 6 weeks in China in 1985 and, a few years later, our 4 weeks in Kenya. In China, we lectured rather widely in Shanghai and Beijing. Although we had been assigned a full-time interpreter and guide, the capable, young Anne Yeh, most of our classes or seminars refused her services. It seems that by that time (and this was virtually 20 years ago), the young university people were already well trained and fluent in conversational and scientific English and preferred to listen on their own. We were impressed by their invariable attentiveness and concern—reflecting, if not genuine interest in the subject, at least Chinese politeness and appreciation for scholarship. We were the first foreigners to address the students of the Chinese Naval Research Institute. I remember the picture book setting in an enormous amphitheater with row upon row of motionless cadets, all in their dress whites, almost as far as the eye could see. I cannot remember the subject of my lecture there, but I know I felt as if I were acting in a Busby Berkeley film extravaganza of the 1930s. We met with invariable hospitality and sensitivity to our needs. However, I do remember a more mixed reception, one morning at about 6:30 as we joined the citizens of Xian to do Tai Chi'ih in the street. Marian was an old hand at this and fit right in but I was clearly a novice and my version of Tai Chi'ih could more appropriately be called 'My Chi'ih'—and an obvious surprise to them.

Most of our time in Kenya was spent in Nairobi where we had the opportunity to lecture to medical students and young faculty people, as well as learn how giraffes keep their brains oxygenated. Our host, Professor Kimani, had done research on this subject and had been able to identify the importance of the highly muscular, contractile walls of the carotid arteries in forcing blood all the way up to the cranial cavity. The obligatory overland safari was an unmatched experience as was Marian's quick ascent of Kilimanjaro. However, no matter where you are, there are certain areas of invariant interest. In both Shanghai and Nairobi, when we had roundtable meetings with the students so that everyone could talk, the two most predictable questions were (1) how did we meet each other and (2) in the States, do young people engage in premarital sex.

I have already mentioned that I learned the rudiments of portrait painting while I was on active duty at Brooke General Hospital in San Antonio. Over the years, this has been a favorite diversion. I found that soft pastel was my medium of choice because one can work “fast” without sacrificing the infinite subtlety of facial structure and expression I particularly liked to suggest rather than delineate, leaving as much as possible for the viewer to reconstruct internally. I did notice, however, that during intense research periods of drawing neuropil patterns directly from microscope to paper, I completely lost the spontaneity of my pastel work and literally had to put it aside for months at a time. Clearly precision and impressionism were unable to exist simultaneously in my brain.

Another lifelong pleasure is the reading of history and cosmology. I see no particular dichotomy here because both are involved in trying to understand where we came from and how we got here, albeit with different time lines! However I do not believe I would take kindly to the craft of the professional historian. The archive-immersed life of a Gibbon or Ranke does not sound attractive. To make history and then write about it like Churchill is more appealing, although few of us have the opportunity to do that. But perhaps, in the long run, those of us who have had the privilege of doing scientific research are, in some ways, following that course after all. The history we attempt to create is the product of our own wonderment, and the history we write is the manuscript that becomes a part of the substance of our field.

As I look back over our field during this last half century, exciting and turbulent as it has been, the name of Francis O. Schmitt looms large. A first-rate investigator himself, Frank became, an outstanding entrepreneur and evangelist for the totality of the brain research disciplines. With his Neurosciences Research Program (NRP) starting in the early 1960s and the four great conferences on the neurosciences held in Boulder, Colorado in 1966, 1969, 1972, and 1977, Frank virtually created the concept and the reality of neuroscience as one overarching discipline. The magisterial volumes that resulted from these conferences remain the most comprehensive and satisfying statements of the state of the neural research arts in the third quarter of the 20th century. It was a privilege to be included in several of these volumes (Scheibel and Scheibel, 1967, 1970; Scheibel, 1979).

I suppose no exercise in retrospection is complete without some reflection on what might have been done differently. From this vantage point, one sees the missteps and can trace the sequelae, but even with that luxury, I do not think I would have made major changes. I feel fortunate that I found my way into academic life, fortunate that I was able to combine structural research with some clinical work, and fortunate to have lived my life with the two very special women, Mila and Marian, both of whom could share, albeit in very different ways, my professional life with me.

The joys involved in deciphering patterns in neuropil have been accompanied by those of watching bright young minds unfold. Students grace one's youth and enrich one's later years. Here too I have been lucky, and many of my students have remained warm friends over the years, wherever they may be. Above all, to be a teacher is to play a very special life role, whose challenges and rewards are beyond price. I am proud to be a teacher. But looking forward is more profitable than looking back.

Selected Bibliography

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Conrad AJ, Abebe T, Austin R, Forsythe S, Scheibel AB. Hippocampal cell disarray in schizophrenia as a bilateral phenomenon. Arch Gen Psychiatry 1991;48: 413–418.

Davies TL, Lindsay RD, Scheibel ME, Scheibel AB. Ontogenetic development of somatosensory thalamus. II Electrogenesis. Exp Neurol 1976;52:13–29.

Diamond MC. Enriching heredity. New York: The Free Press, 1988.

Edelman GM, Chuong CM. Embryonic to adult conversion of neural cell adhesion molecules in normal and staggerer mice. Proc Natl Acad Sci USA 1982;79:7036–7040.

Globus A, Scheibel AB. Synaptic loci on visual cortical neurons of the rabbit: The specific afferent radiation. Exp Neurol 1967;18:116–131.

Globus A, Scheibel AB. Synaptic loci on parietal cortical neurons: Termination of corpus callosum fibers. Science 1967;156:1127–1129.

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¹Recent communications by Bergles and colleagues (Nature 2004;405:187–191; Nature Neurosci:24–32) have described GABAergic and glutaminergic synapses on oligodendrocyte precursor cells in hippocampus that are reminiscent of our own observations of synaptic terminals on oligodendrocytes in newborn animals.

Gerald Westheimer

BORN:

Berlin, Germany

May 13, 1924

Naturalized Australian Citizen, 1944

EDUCATION:

Sydney Technical College (Optometry Diploma, 1943)

University of Sydney B.Sc. (Mathematics & Physiology, 1948)

Sydney Technical College, Fellowship Diploma, F.S.T.C. (1950)

The Ohio State University, Ph.D. (Physics: Physiological Optics, 1953)

APPOINTMENTS:

Faculty Member, Schools of Optometry, University of Houston, Ohio State University, University of California, Berkeley (1953–1968)

Professor of Physiology, University of California, Berkeley (1968–1989)

Professor of Neurobiology, University of California, Berkeley (1989–1994)

Professor of the Graduate School, Division of Neurobiology,

University of California, Berkeley (1994-)

Adjunct Professor of Neurobiology, Rockefeller University, New York (1994-)

HONORS AND AWARDS (SELECTED)

Fellow, Optical Society of America (1963)

Fellow, American Association for the Advancement of Science (1966)

Tillyer Medal, Optical Society of America (1978)

Proctor Medal, Association for Research in Vision and Ophthalmology (1979)

Fellow, Royal Society of London (1985)

International von Sallman Prize in Vision and Ophthalmology (1986)

Prentice Medal, American Academy of Optometry (1986)

Bicentennial Medal, Australian Optometric Association (1988)

Honorary D.Sc., University of N.S.W. (1988)

Honorary D.Sc., SUNY (1990)

Ferrier Lecturer, Royal Society (1992)

Fellow, American Academy of Arts and Science (1994)

After clinical practice as an optometrist in Sydney, Gerald Westheimer worked to attain a deeper understanding of human vision. He elucidated the neural control of eye movements and ocular accommodation by using the systems approach to map motor responses in the human and subsequently employed neurophysiological techniques to outline midbrain and brainstem circuits in the nonhuman primate. Measurement of the optical image of the eye led to the investigation of the retinal and cortical circuitry involved in the processing of spatial visual information, including the analysis of acuity, stereopsis, and contextual effects. In 1989 he set up and became the first head of the Division of Neurobiology at Berkeley.

Gerald Westheimer

Neuroscience as a career option or even as an undergraduate or graduate major was not available to people of my generation; most gravitated to it after studying medicine or occasionally biology, physics, or psychology. For me, the path was even more indirect.

Berlin

The critical juncture was a law enacted to take effect on April 7, 1933, a little more than a month before my ninth birthday. In it, the new German regime, no more than a few weeks old, mandated the removal from office of all academics and civil servants of Jewish descent, with almost no audible dissent from the rest of the university, legal, and professional communities. Having skipped a grade and been identified as promising, I had just been enrolled in the Goethe Gymnasium in the western part of Berlin, where our family—parents and a brother 2 years older—lived. Whatever schooling I might have, it was agreed, should prepare me to earn a living outside the confines of institutions. The subsequent emigration experience only served to reinforce this conviction.

Although my maternal grandfather, Sanitätsrat Dr. Moritz Cohn of Breslau, was a pediatrician, the family on both sides was almost exclusively business people. On my father's side, the family had been residents of a region near the Rhein in northern Baden for hundreds of years. On both sides they regarded themselves as Germans—all males had served in the Kaiser's Army during World War I—and at the same time consciously as Jews, fully aware of the limitations of their place in German society. Hence the growth of the Third Reich and its acceptance by the German people was a disappointment to them, but, deep down, not a total surprise.

I did not last long in the Goethe Gymnasium. My father's status as a veteran would have allowed me to stay but, even at this early stage of the Hitler regime, an atmosphere of anti-Semitism, albeit still genteel, pervaded the classroom teaching. Hence my parents decided to transfer my brother and me to the Mittelschule in the Grosse Hamburgerstrasse, a venerable Jewish institution. It required a half-hour train commute each way, but in those days, that was regarded as safe even for a 10-year old. Class size was large, up to 60 per form, teachers were barely competent, and there was little in the curriculum to enlarge the mind of the alert pupil, let alone challenge it. I still have my semiannual reports, which show undistinguished grades, not because of lack of ability, dedication, or diligence, but because tests were haphazard and students were essentially anonymous. Even in subjects in which I showed proficiency later, such as music and mathematics, the grades were mediocre.

I have no happy memories of my preteen years: The shadow of the Hitler regime loomed and the middle-class upbringing did not expose me to the glittering atmosphere that is often identified with Berlin. However, we had music lessons, participated in sports, and during vacations were dragged through museums. I would not be surprised if it were shown that in those days Berlin had more specialty museums than any other city in the world. At home, my academic bent, although not exactly fostered, was at least mildly encouraged, especially because my elder brother seemed at an early age to acquiesce to carry on the family business, which in fact he did into his 80s.

As long as I can remember I was a rapid and avid reader and seem to have developed, without any overt encouragement from parents, teachers, or other role models, a knack for effortlessly absorbing and sifting printed material. Thus, by the time of my bar-mitzvah I had figured out for myself the differing rational contents of science and religion—the latter loomed large in the home and school environment—and had my mind made up to become a scientist. And naturally the ultimate boundaries of the cosmos fascinated me. Two more factors entered to seal my future career as a scientist. Even then I seem to have had an attraction for the empirical aspects of acquiring scientific knowledge, although actual handicraft or working with gadgets or tools played absolutely no part in my upbringing. Curiosity about telescopes and optical astronomy, and, in an entirely different sphere, the need for optical correction of my incipient myopia, combined to direct my interest to vision. When I was 12 or 13 and had to write a school essay about a famous person, I chose Helmholtz, having checked out his Popular Scientific Lectures from the school library.

By about the same time, my parents had understood the political trend and decided to emigrate. The range of destinations had become limited. Presciently they did not consider other parts of Europe. The United States was then no longer an option, because the avenues of entry—"affidavits” by relatives guaranteeing support—had been preempted by other members of the family. Middle and South America and Australia were possibilities. A most compelling chronicle of the topics around the dinner table of a middle-class German Jewish family at the time is given in Victor Klemperer's diaries but with the essential difference that our family had always been observant Jews, in both meanings of observant: obeying religious rules and remaining aware of the ever-present possibility of a dissonance arising from being both German and Jewish. Klemperer's trenchant account of the matters of concern in 1938 still resonate in my mind: who emigrated where, to whom pets and house plants were passed on, what was said on terse postcards from ships or from Chile or perhaps the Dominican Republic, and what new regulations had been promulgated to make living conditions and emigration ever more difficult.

During 1937, my parents submitted an application for immigration to Australia and, in one of the pivotal days in my memory, in March 1938, the certificate arrived from Canberra, allowing us entry to Australia. There followed several frantic months, severing business and personal ties, liquidating assets, selecting what to pack and what had to be left behind, arranging passage, and trying to scrape together the £200 Australian currency that had to be shown on entry. When it was all over, there was the glorious moment in the morning of August 26, 1938 when we sailed into beautiful Sydney harbor on the R.M.M.S. Aorangi to start a new life.

Australia

In the 1930s, Australia had a population of about 7 million who regarded themselves unreservedly a part of the British Empire. It differed from England in that a lack of aristocracy and upper classes made it an egalitarian, live-and-let-live society. The 5000 refugees from Germany and Austria were accepted, although without any particularly warm welcome. But the distinction between Berlin and Sydney in 1938 could not be starker: The weather, scenery, and living conditions, instead of being dingy, repressive, and cold, were inviting and stress-free. Still, a wrenching change took place in our personal life: From being schoolboys, embedded in a structured school and family situation, my brother and I, aged 16 and 14, were now the main conduit to our new world, especially because we were beyond compulsory school age. We quickly learned English and found employment, providing an important fraction of the family income before our parents could eventually establish themselves. One should imagine the situation in which the adolescent sons are the ones to whom a family's interpretations of the surrounding language and culture devolved!

Gradually things settled and before long my violin lessons resumed. My father started anew in the leather business, but his health deteriorated and he succumbed to a heart attack in 1941 at age 57. My mother carried on as best as she could until my brother was discharged from the Australian army at war's end.

While working full time as an office assistant to supplement the family income, I enrolled in an evening course that, because I was left essentially to my own devices, allowed me to achieve high-school equivalency status at age 15. Full-time study at the University of Sydney, with its 3000 students in the faculties of Arts, Science, Medicine, Dentistry, Engineering, and Agriculture, was beyond reach then. But there was a less prestigious institution, the Sydney Technical College with evening courses in many subjects. Its most advanced offerings were 4- to 6-year part-time diploma courses for high-school graduates who had to have concurrent employment in the area of their studies. Subjects ranged from chemistry and various branches of engineering to architecture and optometry. Nothing could have been a better fit to my then vista and intellectual aspirations. Here was an area that closely matched my interest in optics and vision. It also satisfied the firm conviction in my world that one's occupation should allow an existence independent of government and institutions, formed by the German law of April 7, 1933 and confirmed by the difficulties of former academics and professionals to establish themselves as immigrants in Australia.

Thus, although still 15, I enrolled in the optometry diploma course at the Sydney Technical College and sought the required employment as an optometric assistant. Mr. E.J. Jackson, who had a working-class practice near Central Railway Station in Sydney, hired me, and the course of my career was set for what could have been the rest of my life but turned out to be the next 11 years. I easily took to the study and practice of optometry, completed the diploma course with honors and the college medal, and was offered a partnership in the practice. This had to wait for 2 years until I became legally of age and was eligible for registration as an optometrist in the State of New South Wales, a status I have meticulously maintained ever since. In due course I was elected a Fellow of the Institute of Optometrists (FIO) and became active in the Australian Optometric Association, being named state delegate to the national convention in 1951. I still have the warmest recollection of my years building a successful clinical practice of optometry in Sydney, with its beautiful scenery, sunny climate, and quality of life. Mr. Jackson was not only a generous employer and later partner but also a dedicated rationalist and reader of Marxist literature. His analysis of social and political affairs provided valuable insights that were not available from standard news sources.

Below the surface of this smooth career path, however, agitated another element of my mind, the one that had led me to read Helmholtz's popular scientific lectures as a schoolboy. My day job was dealing with optometric patients in a far corner of the earth, but I kept on reading voluminously and wondering about science. One quickly recognizes that clinical literature, although at its best fully valid, is different from science. I felt that a full understanding of the eye and the sense of vision needed a deeper approach and not one that could be achieved by merely enlarging one's clinical repertoire through, for example, studying ophthalmology. But how to go about that? Australia in the 1940s was intellectually a backwater when it came to anything beyond undergraduate or first professional training, be it in the arts, sciences, humanities, or health professions. No resource person was available for counseling or as a role model; my scientific career had to be my own creation.

I had made a start by adding to the optometry curriculum, as electives, the mathematics and physics courses taught to engineers at the college. Then, while learning to be a clinician, I had what was no less than an epiphany. On an occasional visit to the Sydney Public Library, with its magnificent reading room, I came across the paper by Hecht, Shlaer, and Pirenne (1942) examining the limitations placed on vision by the quantal nature of light. In the transition from preclinical science to actual clinical work one has to come to grips with the fuzziness of the findings on patients. The highlight of the paper by Hecht et al. to a budding clinician was not so much that just a few photons sufficed to set off a visual response in the dark-adapted human retina, as the claim that the variations of thresholds were due to inherent variability, not of the biological apparatus, but of the physical stimulus itself; the Poisson distribution that a very small number of quantal events obeys. A vista of reductionism opened, although at the time the word was not used, and my career goal was set. It was encapsulated in the title of a talk I gave to the Institute of Optometrists “Physics, Physiology and Vision,” and which later became the motto of the festschrift for my 65th birthday edited by Suzanne McKee and Ken Nakayama (1990).

What followed was the implementation of the program, as best as could be achieved in Sydney at the time and without disrupting, at the least for the next several years, the placid flow of developing and maintaining an optometric practice. I enrolled in the Faculty of Science of the University, studying part-time to graduate with a Bachelor's degree, majoring in mathematics and physiology/biochemistry. Then I completed the full sequence of diploma physics courses at the Technical College. There was the possibility of working toward a master's degree in physiology at Sydney University, but I was not accepted. On the other hand, one could submit a thesis to the Sydney Technical College for a higher diploma, the fellowship, and in due course I completed, without help from anyone, a 110-page thesis “Studies in the Optics of Contact Lenses,” which duly led to the award of the first higher academic qualification in Australian optometry. Rediscovering the Gaussian theory of expanding multiple surfaces by a matrix formulation and then applying that to the contact lens/eye combination was a source of great satisfaction.

Then what? I had exhausted the research possibilities open to me. One did not know that in just a few years Australia would house world-class neuroscience institutions led by Eccles in Canberra and Bishop in Sydney. Eccles was still in Dunedin, and Bishop was at the point of returning from his postdoctoral studies at University College, London. The very best graduates in mathematics, physics, and chemistry of Sydney University were sent off to England, usually Oxford or Cambridge, for graduate study, but there was no such tradition in biology. There was no one to turn to for advice, let alone to provide an introduction to a research institution around the world.

Unlike most Australians, I was looking to the United States rather than Great Britain. But the many letters of inquiry to graduate schools yielded nothing positive; American universities were awash with graduate students under the GI Bill and admission officers found little indication of outstanding promise in my case. But there was one exception: Professor Glenn A. Fry, director of the optometry school at the Ohio State University, responded offering me admission and a teaching assistantship valued at $1200 a year. Fry was on the map as a vision scientist, and I decided to accept. Consequently, I obtained a student visa to enter the United States, severed my connection with Mr. Jackson, booked a one-way flight to Columbus, Ohio, packed the violin, a few books and some clothes, and flew across the Pacific on a British Pacific Overseas Airlines DC-6 in September 1951. My fate turned out to be similar to many young Australian scholars, scientists, and artists for whom the challenges of taking on the wider world of their calling outweighed their nostalgia for the sunshine and beaches of their homeland and who returned only occasionally as visitors. For me at least, Australia has remained an anchor and a place of refuge from the terrors of central Europe in the 1930s and 1940s, and I have never relinquished the status of a naturalized Australian citizen.

Ohio

It took some adjustment to fit into the subdivision of the physics graduate program that was devoted to physiological optics and run single-handedly by Fry. The emphasis was on construction of mechanical equipment. More space and money was devoted to the workshop than to actual experiments, but Fry was interested in and exposed us to a wide range of topics. Ohio State was, for those days, a very large university; many of the younger professors were well-trained, alert to the latest developments, and upwardly mobile in their career track. This meant that it was not too long before they moved to the East or West Coast or perhaps to Michigan or Chicago. Three members of the psychology department, in particular, made a strong impression on my scientific development. Phil Ratoosh offered seminars on the research directions he had participated in at Columbia, where Clarence Graham continued the traditions and emphases of the Hecht school. He and his wife Mildred opened up in their home a cultural alternative, widening my vista beyond the limits of mid-century midwest state university life. Donald Meyer, a student of Harlow's at Wisconsin, taught a course in physiological psychology in which he placed inordinate stress (in early 1952) on the recent, yet not fully published findings, by Hodgkin and Huxley. By far the greatest intellectual influence was a graduate course taught by Paul Fitts, who had just joined the faculty after spending several years at the Wright-Patterson Air Force Base on human factors in the design and operation of aircraft. Within a couple of months in the fall of 1951, he introduced me to Wiener's cybernetics, Shannon's information theory, and the systems approach. Using differential equations to describe, analyze, and model human performance was grist to the mill for someone who had chosen to expand his study from optometry to mathematics, physics, and physiology!

My years as a graduate student at Ohio State University in the early 1950s were characterized by the convergence of several trends. The basis for this was a dissatisfaction with the softness of biological findings on the part of a clinician, who had therefore subjected himself to rigorous training in mathematics and physics and had subsequently struggled in vain to find a secure footing in the mathematical biology of Rashevsky and Luneburg. This was coupled with exposure to the uncomplicated, “can-do,” “hands-on,” farm-boy-who-became-pilot persona of the many fine scientists who populated midwestern universities. And finally, there was the impact of the post-World War II reductionist thrust of cybernetics, information theory, and the systems approach.

These influences found immediate and full expression in my thesis research, in which the eye movements of the normal human were subjected to what may be called the classical systems analysis. With the subject's head fixed, a light point was moved in the visual field with the instruction to keep looking at it. This was the input. The output was the eye position, recorded with millisecond time and half-degree position resolution. The input/output relations were then studied to steps, pulses, ramps and sinusoids, then the standard array of stimuli and allowed conclusions to be drawn about the neural control. The oculomotor apparatus utilizes what engineers call a sampled data strategy. Over a few tens of milliseconds the retinal image position and motion is being analyzed and then one of a small repertoire of response modes entrained; all this is followed by error feedback and correction. But, even at this early essay into a physiological control system, a couple of flaws in the approach became glaringly evident. The first step in systems analysis is to construct a model in which simple differential equations are fitted to the data; however, right here significant nonlinearities showed up. More important was a realization that even the very foundation of systems theory seemed inapplicable. A favorite analytical tool in this area is charting the amplitude and phase of responses to rhythmic stimuli of constant amplitude and frequency. In the first few seconds of such a record I saw that, whereas the response amplitude remained constant, the phase delay changed relatively quickly from a beginning value of 120 msec down to zero or quite often even to negative values (i.e., there was a response before the stimulus). The only interpretation was that human subjects, instead of responding in the manner of the physical systems that were our models, quickly learn to anticipate and to “voluntarily” introduce a negative delay so that the moving target always remained on the fovea.

The thesis work, for which the only outside help I received was in the construction of apparatus, was accepted and the Ph.D. in Physics: Physiological Optics duly awarded. Paul Fitts, who was not a demonstrative person, seemed to like it and made me prepare for him a couple of dozen copies to pass around in the human factors community. Two papers prepared for what I then regarded as the principal outlet in the field, the Journal of the Optical Society of America, were promptly returned by the editor as unsuitable but finally found a home in the Archives of Ophthalmology (Westheimer, 1954a,b). They shared a fate of quite a few of my subsequent papers in being ignored for several years before their impact on the subject became evident.

In retrospect, the two journeyman years spent as a graduate student transmuting myself from an armchair scientist to an experimentalist constituted an important developmental stage. What had heretofore been a purely theoretical and intellectual take on science had to confront and accommodate the imperatives of tackling nature via an empirical route. It was as significant a transformation as the one that I underwent earlier when my innately contemplative personality was faced with the task of adapting to the needs of handling patients in a clinical setting.

Academic Career in Optometry Schools

The newly minted optometrist-Ph.D. had to make a difficult decision: return to practice in Australia or try to make a career in academia? The prospect for the latter was not particularly propitious. Postdoctoral studies were not routine in those days. Physiological optics at Ohio State was a springboard for faculty positions in an optometry school or an eye department, but only a few of these had the scientific stature that fitted my, actually quite modest, aspirations. As it happens, a former fellow Ohio State graduate student, Charles Stewart, had just become dean of the newly founded optometry school at the University of Houston and persuaded me to join him. I thought I would give it try and deferred the decision whether to go back to Sydney. The year I spent in Houston was by no means wasted. Research was, of course, out of the question; there were no facilities (much less set-up money or grants) and the grueling teaching load did not leave much time. I had to prepare lectures in most of the preclinical sciences of the optometry curriculum, including optics, physiology of the eye, visual processing, color vision, eye movements, and binocular vision and, in addition, was responsible for the construction and design of apparatus for the teaching laboratory. An enormous amount of material needed to be sifted, understood, and made palatable to the small class of good-natured and at that time quite tolerant Texas optometry students. I am not sure that I would recommend this trial by fire to others, but for me it helped build an invaluable knowledge base for future research. Moreover, teaching undergraduate courses is exceedingly good training for clarity, concision, and relevance of presentation.

During that year in Houston, I recognized that this position was not the one for which I gave up optometric practice in Sydney, although I had advanced my visa status from student to “green card” resident alien, which I have maintained to this day. The question whether to return to Australia or whether to pursue an academic career in the United States was decided in the latter direction by an offer of a faculty slot at Ohio State. Although the teaching load was not much lighter, at least there was a tradition and some facilities for research. I was assistant professor from 1954 to 1957 and was promoted to associate professor with tenure in July 1957. In a very significant development of my career, the Office of Naval Research (ONR) (working on the basis “Don't call us, we'll call you!") approached me to submit a proposal and in due course awarded a contract for $10,000 for research in human accommodation, which was renewed in various forms for the next 12 years. This allowed some independence in research directions and also constituted a validation of a certain standing in American science. The Physiological Psychology branch of ONR, in those pre-National Institutes of Health (NIH) days, was the principal source of support of all the major laboratories in sensory processes.

From my earliest days, I was interested in optical aids to vision. Hence the teaching of ophthalmic optics was not only no chore but also the impetus to publish many small-scale studies over a 20-year span in optometric and optical journals These studies related to such areas as magnification, field of view, and aberrations of spectacle, telescopic and contact lenses, and microscopes. It prepared me for the future research in the optics of the eye and ocular accommodation and, quite directly, led to being recruited to Berkeley in 1960, where a vacancy occurred in the School of Optometry caused by the retirement of their instructor for ophthalmic optics.

More immediately, in the middle 1950s, I immersed myself in a couple of theoretical issues. Teaching the subject of eye movement made me aware of the lack in the literature of a rigorous treatment of the kinematics of the eyeball rotating in the orbit in the manner of a ball-and-socket joint. Rotations of rigid bodies are not vectors, and therefore I took up the topic by first studying the classical treatise on rotating tops by Felix Klein and Arnold Sommerfeld and then applying the theory to the eyeball by means of quaternions, a higher form of generalized complex numbers that allows the handling of rotations. The paper “Kinematics of the Eye” was accepted by the Journal of the Optical Society within 2 weeks without any revision, a situation almost unique in my career as an author of scientific papers (Westheimer, 1957b).

A second area that had also been left untreated in the literature, because it could not be handled without some mathematical preparation, was the generation of the optical image on the retina in a special situation called the Maxwellian view. In this mode of illumination a light source is imaged in the eye's pupil. Any target in the beam generates a diffraction pattern there, requiring analysis of retinal imagery in terms of coherent light, a topic that was to gain much prominence with the advent of lasers a few years later. The calculations were needed to specify the retinal image in an out-of-focus eye, which constituted the stimulus for accommodation responses. The theoretical work led directly to the realization that one can create retinal images that were independent of the refractive state, in effect bypassing the eye's optics. To put the thought into practice it was necessary to generate twin coherent beams, whose separation in the plane of the pupil determines the spacing of interference fringes in the image space of the eye. Not too many years later this could be easily accomplished with a HeNe laser. But when I tried to do this in 1957, I spent months getting it to work. Light from a very bright arc source had to be focused on a pinhole less than 0.1 mm in diameter and then passed through an interference filter. Gratings and variable magnification devices enabled the spatial frequency to be changed and modulation thresholds to be obtained on normal observers, including a measure of retinal resolution with 100% contrast. Thus, a true estimate of the resolving capacity of the retinal mosaic was arrived at. This disambiguation of optical and retinal factors of visual acuity had been a long-term goal in physiological optics; hence I proudly wrote this up for the Journal of Physiology, then the criterion outlet in neuroand sensory physiology, where it was soon accepted (Westheimer, 1960), not without very insightful comments and suggestions from the referees (who I later learned to have been Bernard Katz and Eric Denton). One of the most prescient of these was the request for me to explain to the readers what I meant by the phrase in the discussion that “the results might foreshadow a Fourier approach to spatial vision.” It made me think through the consequences of such an approach and explicitly reject it. Thus, when the Fourier theory of vision swept through the vision community a decade later I was immune to its temptations and could leapfrog to areas of spatial visual processing that it could not encompass.

Under the ONR contract I had studied fluctuations of accommodation and as a result I got together with Fergus Campbell and spent a sabbatical at the physiological laboratory at Cambridge University. Fergus, together with his then graduate student John Robson, had built an automatic infrared optometer, and we set about analyzing the oscillations that the instrument revealed. This involved many control experiments, such as opening the loop, examining odd and even errors, and comparison with pupil and finger tremor (Campbell, Robson, and Westheimer, 1959). The fluidity with which this lab would solve problems of instrumentation and procedure, utilizing off-the-shelf and war surplus components, was inspiring and a welcome counterweight to the elaborate and cumbersome metal constructions featured in Fry's laboratory. John Robson, barely out of his teens, quick-witted and intellectually arrogant, had a deep intuitive understanding of electrical circuitry. Together with Fergus, more experienced in medicine, ophthalmology, and experimental physiology, there was no technical problem that could not be solved in an afternoon. The outcome of this collaboration was a series of papers in which the human focusing responses were subjected to much the same systems analysis that I had used in eye movements, Stark and Sherman (1957) in the pupil, Schade (1956) in human spatial vision, and DeLange (1954) in flicker perception. It was the decade of systems theory, and because new technical resources for generating, modulating, and recording light beams were employed, major characteristics of human focusing responses, such as latency and speed, were revealed for the first time (Campbell and Westheimer, 1960), although some of the details would soon be overwhelmed by the nonlinearities brought to light by more extended experiments. Our interest, however, was chiefly on the light the findings could throw on the neural control apparatus. As in so many similar situations, a necessary preliminary step to charting the internal physiological apparatus is the exposition of the actual capability of the organism. And here, also, a full understanding of the central neural circuits for the eye's accommodation is still a work in progress, almost 50 years later.

Collaboration with Fergus Campbell was so successful that I asked him to work with me on the corollary of the retinal image experiments that had just been published. If in ordinary vision we cannot bypass the eye's optics, why not use the optical and electronic know-how between us to characterize the quality of the retinal image? The question was urgent because the literature was deeply divided on the issue. Direct image quality measurements in animal eyes gave results that were totally at variance with the single human study, by Flamant, in which the ophthalmoscopic image of a slit was analyzed by a rather cumbersome photographic technique. So Campbell and I, using narrow filament lamps, a photomultiplier and oscilloscope, obtained a good estimate of the eye's line-spread function (Westheimer and Campbell, 1962). It validated Flamant's results, accorded rather well with expectations from visual acuity and the retinal mosaic, and formed the basis of later work in Campbell's lab, which provided definite data on the optical image on the retina that held up for decades. In the early 1990s, I returned briefly to the optics of the eye in collaboration with Junzhong Liang, the most gifted of the new generation of researchers in ocular optics. We developed an ingenious method of conditioning the wavefront of light from a laser source entering the eye to generate patterns for measuring retinal resolution more sophisticated than interference fringes (Liang and Westheimer, 1995). Liang went on to found the new discipline of adaptive optics, which is about to replace all the traditional approaches to the optics of the retinal image (Westheimer, 2006).

Cambridge

Nothing I experienced in Australia, then a traditional British country, or in American universities, had prepared me for the cultural climate awaiting me when I arrived in Cambridge in early January 1958 and stayed in St. John's College. The buildings were ancient with high ceilings and thick walls, dreadfully cold in winter, and the bathrooms were across the courtyard; yet there were servants, waiters at meals, porters with top hats at the narrow entrance gates; fellows, usually bicycling everywhere, wore academic gowns and ate sumptuous meals at high table but only after a Latin grace was recited. Afterward there was port in the Combination Room where I could, and occasionally would, sit next to Paul Dirac, Fred Hoyle, or Harold Jeffreys, conversing on topics of mutual interest. In the physiological laboratory in Downing Street there was a traditional afternoon tea, separately for the academic staff and for the technicians, many of whom were excellent but who knew their place. Except for Fergus, a gregarious Scot, and Horace Barlow, whom I had known before and whose social grace is a natural attribute, I was totally ignored, people barely acknowledging a greeting on the corridor. This changed rather suddenly a few months into my stay. John Robson was the Michael Foster scholar and responsible for organizing the Michael Foster Club, a once-a-term function involving a more elaborate afternoon tea and a scientific seminar. John had forgotten to invite a speaker and in a last-minute decision asked me to do it. So I dug out the slides of my systems analytical treatment of eye movements and talked for 45 minutes. Somehow this resonated with the group, which included most of the well-known names in neurophysiology in Cambridge, many of whom had been active participants in war research utilizing this approach. There were numerous questions and a spirited discussion. My case was helped because in a naïve attempt at brevity I skipped over many slides with confirmatory evidence that I then proceeded to reveal in answer to specific queries. Campbell complimented me on what he thought was the clever subterfuge of keeping the best slides in reserve to drive home the major points in reply to the expected searching questions from the critical audience.

Within the hour my status in the physiological laboratory had changed from an outsider from America (it was fashionable then in Cambridge circles to be disdainful and patronizing to Americans) to a member of their circle. Someone had described the Journal of Physiology as the “Cambridge Physiological Laboratory and friends” and up until then and a few more years, nothing was regarded as firm knowledge unless and until it was published there. (There was the famous retort by William Rushton when confronted with a discrepancy in the peak absorption of a cone pigment, that the first publication was only in Nature and not yet in Journal of Physiology) My acceptance into the circle had several consequences. Whereas before the sole aim had been to satisfy my curiosity and try for a coherent understanding of a few phenomena that attracted my attention, I now began to subject myself more consciously to the rigid intellectual discipline I saw around me and to focus on areas where the expected scientific yield would have impact on the development of the subject.

The second consequence was that rather than being a remote acquaintance I developed personal friendship with many whose intellectual power I respected and with whom I shared a variety of cultural pursuits, music in particular. The Brindley's, Horace Barlow, and I often played quartets and many a Sunday afternoon was spent with William and Marjorie Rushton at Shawms, including the only time in my life that I played the Brahms Horn trio, with Marjorie and Adrian, one of their sons. It was an environment unlike any I had experienced before.

One of the fall-outs of this development was a lively intercontinental exchange. I spent many summer terms in Cambridge, and in turn hosted many English visitors in my lab, which soon moved from Columbus, Ohio to the University of California in Berkeley. One of the most cherished was Cyril Rashbass, with whom I studied the human eye vergence apparatus. The paper is one of the most satisfying of all those that came out of this period, featuring a new method of recording eye rotations free from translational artifacts, an analysis of open-loop vergence responses, and the demonstration of the inapplicability of standard engineering rules such as Bode's law of minimum phase (Rashbass and Westheimer, 1961). Cyril was one of the most gifted scientists I ever knew, quiet and somewhat shy, the son of an orthodox rabbi who made him study the Talmud and insisted on a career in medicine rather than mathematics. Cyril obeyed kosher dietary laws, yet smoked heavily although not on the Sabbath. Late on a Saturday afternoon he would go outside and look for the earliest possible manifestation of the requisite three visible stars that signaled permission to resume smoking. Although it was indirectly responsible for good visual performance through these exercises of attention and concentration in the aid of detection thresholds, this cigarette habit also, unfortunately, caused his early death of a heart attack.

During the 1960s, the optometry school in Berkeley was a veritable dependence of the English physiological establishment. I have mentioned Campbell and Rashbass already. They were followed, in due course, by William Rushton who utilized my expertise in retinal image quality to demonstrate that spatial summation of retinal signals could not be ascribed to passive optical image spread (Rushton and Westheimer, 1962): a validation, if ever there was one, of my motto “Physics, Physiology and Vision.” Giles Brindley had two sojourns in Berkeley. In the first he demonstrated unequivocally that there were no centrifugal fibers in the cat optic nerve, in the second I acted as an amanuensis in his electroretinogram research. There were many casual visitors, notable W.S. Stiles and on many occasions John Robson, but the most lasting impact on the local scene was made by Horace Barlow. During a year Barlow spent on a sabbatical in Berkeley, Gordon Walls, who had made an uneasy perch for himself in the optometry school, died suddenly at a relatively young age. Walls, whose “The Vertebrate Eye” remains a permanent classic in the literature, was a very knowledgeable and opinionated naturalist, a conversationalist who reveled in the intellectual yeastiness that these visitors introduced to the more formal and restrained atmosphere there. To everyone's surprise, Barlow expressed an interest in becoming Walls' successor as the resident scientist in the School of Optometry and took up the position in 1964, bringing along Bill Levick, who had been trained in retinal physiology by Peter Bishop in Sydney. Barlow had a different take from Rushton's on the origin of the pooling of retinal signals in the dark-adapted eye. The crucial test was the threshold elevation when the rods were bleached with a polka-dot pattern, and much depended on the retinal light distribution of disk-shaped targets, for which both parties had to turn to me. Thus, I was dragged into a series of dark-adaptation and increment threshold experiments to decide who was right. The back-and-forth lasted a couple of years and is entombed in several Journal of Physiology papers but for me it had a significant fall-out. The data-oriented attitude won rather than the theory-oriented attitude, into which the limited success of trying to shoehorn oculomotor responses to systems theory had molded me, and I withdrew from the battlefield. Instead I sank my teeth into an oddity that William Rushton and I had encountered while measuring increment thresholds in the dark-adapted retina and with which William naturally wanted nothing to do because it pointed to neural processing in the retina rather than passive summing of rod excitation.

Visual Neurophysiology in Berkeley

The trajectory that started with an early interest in optics and astronomy, led to the study and practice of optometry, continued on with the training to become a researcher, then extended to investigating the role of the eye's optics and intraocular and extraocular musculature in generating the image to the retina, now neared the point where it merged into neurobiology. In Berkeley, a very active group had assembled itself in the School of Optometry with many graduate and postdoctoral students, but it was hemmed in by the limitations of the space and teaching program of a small professional school. We made one attempt to break out. The recommendation of a faculty committee to replicate in the neural sciences the success 15 years earlier in establishing molecular biology as an independent academic discipline in Berkeley was unfortunately shelved. Relief, however, came in the form of a move to the Department of Physiology-Anatomy and more adequate space in the very large Life Sciences Building. A wider teaching program in the neurosciences was instituted and a couple of new faculty slots opened up. One of them was occupied by Michael Land, whose work on the optics of the scallop eye had made me secure for him a Miller Fellowship to come to Berkeley, where he began studies on the spider eye. These were also the days when one could count on that indispensable research aid: steady NIH funding. It provided the financial support for not only the eye-vergence research with Cyril Rashbass, but also for the rest of my research for more than 40 years. The university covered only 3/4 of one's annual salary in return for the teaching activities. Although the NIH indirect costs ("overhead") provided some compensation to the institution, the cost of all research, including even telephone calls and postage, came from funds that the principal investigator had to apply and account for, explain, and justify.

Given the new environment, my own research became more overtly physiological. I had spent the summer of 1957 in the nerve-muscle program organized by S. Kuffler, C. Ladd Prosser, and A.S.V. Burgen at Woods Hole and had become familiar with the neurophysiology practiced there on cold-blooded animals. But my interest was in the human visual system. As a student in Sydney I had thoroughly immersed myself in the one available compendium that attempted a complete coverage of the nervous system of higher animals, Fulton's Physiology of the Nervous System (1943), without finding in it promising research directions within the avenues available to me then. Things had changed in the meantime. Mammalian single-unit studies in the laboratories of Eccles, Kuffler, Mountcastle, Hubel and Wiesel, Bishop, and others brought insight into processing modules within the central nervous system. And at the front end, because stimulus artifacts from optical and optomotor sources could be convincingly ruled out, signals could be traced right through to the neural stages of vision.

The work in my laboratory now followed two separate tracks and in rooms on different floors of the Life Sciences Building. Downstairs we proceeded to outline the processing of spatial visual stimuli in the human by psychophysical experiments. At first the research was directed frankly at the retina to determine how the anatomical and physiological apparatus that had been discovered (by e.g., Hartline in Limulus and frog, Kuffler in the cat, and Dowling, Boycott, and Werblin in Necturus [see Dowling's chapter in Volume 4 of this series]) is being deployed in the human. (I was, and still remain, immensely impressed by the solid grounding given by the Necturus studies to our understanding of the retina, and was able to bring Frank Werblin to Berkeley, first as a postdoc in my lab and then as a faculty member.) It took the form of examining and outlining the neural circuits for the center-surround antagonism that had been in the way of William Rushton's models of photoreceptor signal pooling (Westheimer, 1965) but that have since shown to be an excellent bridge between processing deep in the retina and the eventual visual percept emerging from retinal and cortical circuits. It found overtones in color vision, as demonstrated in the thesis of Suzanne McKee (1970), in the diagnosis of retinal dysfunction as shown by the convincing work in Jay Enoch's lab over the years (Enoch, 1981), and in the differential diagnosis of amblyopia as proposed by Levi. The differentiation of its retinal from its cortical components continues to challenge current workers (Westheimer, 2004). The research merged into the more ambitious visual hyperacuity studies to be related later and the relationship with these collaborators has firmed into close friendship over the years.

Primate Oculomotor Studies

The 1960s were the times when single-unit neurophysiology held the greatest promise. Much had been learned already and many investigations were in progress all over the world. The most spectacular results came from tracing sensory signals because this approach could utilize the traditional physiological experimental procedure of keeping the organism in a neutral state and observing the responses to stimuli controlled by the experimenter.

The motor system posed a different set of problems. The knowledge base at the time had come down from Sherrington and was linked to single-cell physiology by the Eccles school, who had, however, soon found more fertile ground in synaptic physiology. The more global questions of motor control, of preprogramming of action pattern so convincingly described by W.R. Hess (1941), of extrapyramidal and cerebellar circuitry, remained wide open. Familiarity with the human oculomotor system made me aware that it featured routinized, ballistiform movement patterns (the saccades), involving sophisticated but innate switching circuits that keep 12 extraocular muscles working as a unit. Also, unlike skeletal muscles, extraocular muscles operate under constant load conditions and are not seriously affected by muscle-spindle feedback. And as an added bonus, I had a great deal of experience with the target movement stimuli needed to elicit the saccadic, smooth pursuit, and vergence response patterns.

However, unlike the majority of the contemporary studies on the sensory system, motor control research could not very well be conducted on an anesthetized organism. One was looking at the alert, behaving nonhuman primate preparation. This required an entirely different laboratory set-up and equipment. Facilities—space, animal rooms, veterinary care—could be found on the fifth floor in the vast Life Sciences Building, and NIH funding allowed the purchase and construction of the requisite equipment for surgery, head gear, and electrode-holding implants, monitoring of physiological functions, stimulus presentation, eye-movement and electrophysiological recording, and subsequent histological analysis. I was exceedingly fortunate in having associated with me in all this work, first as a graduate student and then as research associate, an extraordinarily capable medical graduate, Sidney M. Blair, who could meet every possible challenge in all areas of this research. In addition, a series of excellent and dedicated postdoctoral associates (Rolf Eckmiller, Barry Frost, Alex Skavensky, Rich Marocco, Ron Remmel, Essie Meisami, Meredith Wallace, Mary Gavin) helped keep up the momentum in this demanding research enterprise, which remained active between 1968 and 1981. Although I was intellectually engaged, most of the day-to-day work was conducted by this group and one or two technicians, while I divided my research time about equally between this laboratory and the psychophysical one on a different floor of the building.

The aim was to elicit oculomotor responses to visual and vestibular stimuli in the primate and relate them to single-unit activity in the brainstem with the hope of charting the underlying neural circuitry. After less than a year, the technical difficulties had been ironed out and recording began. Right away we found that cells in the third nerve nucleus discharge at constant rates that depend on eye position. This finding accorded well with the proposition I put forward 15 years earlier that a saccadic movement was the rapid change of the oculomotor apparatus from one set state to another. The neural correlate of the state was, obviously, the set of maintained impulse rates in the 12 muscles, all carefully calibrated to maintain the requisite steady eye position. (This formulation was subsequently modified to include transients in the impulse rate, to allow a faster repositioning.)

When it came to claiming credit for this finding, however, we were out of luck because this “position coding” of oculomotoneurons had just appeared in the literature in three different publications (Fuchs and Luschei, 1970; Robinson, 1970; Schiller, 1970). We had obviously started a year or two too late. The oculomotoneurons are what Sherrington called the final common path, the last neuron in the long interconnected series of pathways and they receive many thousand synaptic connections onto their extensive dendritic tree. So onward and inward was the motto: What signals might there be in near-by or related neural regions that have tight correlations with observed eye movements—the logically reverse process to finding firing correlates in higher sensory neurons to visual stimulation? One candidate problem, obviously, is the circuit that holds the maintained discharge at the designated rate, what became the search for the “neural integrator.” From the point of motor organization, the more interesting question was the origin of the signals for making a saccade, and the code containing instruction for its direction. Here one quickly ran into a morass. Recordings show several candidate classes of neurons, those that burst before or during saccades, those that stop during saccades, and a variety of related ones, but their codes, if any, remained elusive (Westheimer and Blair, 1972).

One question we tackled was whether there is a hierarchy of firing within the ensemble of the nuclei of the 12 extraocular muscles. It had been suggested, on neuro-ophthalmological grounds, that third-nerve activity was secondary to sixth-nerve activity. So we set about simultaneously recording from cell pairs in the alert behaving primate using separate electrodes, one cell in the third and the other in the sixth nerve nucleus, in what may readily have been the first use of this heroic procedure (Eckmiller, Blair, and Westheimer, 1974). It did not reveal that the sixth nerve cells fired earlier than those in the third nerve.

It may be mentioned parenthetically that the research was located in the strategic intersection of several disciplines. It is obviously motor physiology, and also part of the wider problem of oculomotor control and eye movement responses. But hints about normal functioning come from clinical observations of dysfunction and abnormal development. Neuroanatomists have always played a major role, witness Ann Graybiel's 1974 delineation by the marker horseradish peroxidase of several structures not previously suspected as part of the oculomotor complex. For awhile, also, there was much activity involving engineering and computational models. The inescapable kinematics of ball-and-socket joints has already been mentioned.

Considerable insight into motor organization was afforded by Hess's focal stimulation experiments of the 1930s, which demonstrated midbrain locations in which quite complicated and biologically relevant preprogrammed motor routines could be elicited. Sidney Blair and I made some efforts to map brainstem sites in which stimulation can trigger oculomotor responses. By this means we were able to describe in the monkey at least two syndromes whose counterpart can appear in clinical neuroophthalmological patients and whose neural substrate had therefore been located. One was saccadic inhibition (Westheimer and Blair, 1973a), in which for the duration of the stimulation all saccadic activity ceases; the other was the ocular tilt reaction (Westheimer and Blair, 1975), a unitary syndrome involving head and eye rotations.

The function of the cerebellum had long been the object of speculation. One conjecture, by H.H. Kornhuber (1971), assigned to it the role of a clock, in particular in counting down impulses to control the extent of saccades. The idea did not fit the picture that had by then emerged about the neural apparatus for generating saccades. Although its intimate internal circuits were receiving detailed attention (Eccles et al., 1967), the specific functions of the cerebellum remained uncharted. In discussing various ways of testing Kornhuber's proposition with Sidney Blair, he was quite willing to go the way of late 19th century experimental brain research and just ablate the whole of the cerebellum to determine whether this leads to an absence of saccades. No sooner said than done; when the monkey awoke from anesthesia next day, it had a full set of normal saccades. So much for Kornhuber. We saw, however, an entirely different syndrome: inability to make pursuit movements and, in addition, gaze-holding nystagmus, namely smooth centripetal drift toward the primary position followed by compensating outward saccades (Westheimer and Blair, 1973b). The pointer to a smooth eye movement component in maintaining eccentric fixation was unmistakable. Vergence movements were unaffected. Here, again, there were many clinical overtones, because this particular symptom complex is known in neuro-ophthalmology.

At the time, one of the most innovative contributions to the oculomotor physiology was published by Gonshor and Melville-Jones (1973) of McGill University. These workers demonstrated that the vestibulo-ocular reflex, long thought of as one of the most basic and neurologically simplest motor routines, evolutionarily conserved over hundreds of millennia, was subject to quite specific learning. The finding was very influential in that it pointed to the likelihood that the brainstem, pontine, and cerebellar neural circuits being studied were not only complex, interwoven, and just about impossible to decipher by any of the means available but were plastic to boot. It also put into better perspective the then popular attempts to describe the oculomotor system by engineering models.

As gripping as all this research was to Sidney Blair, with his background and board certification in neurology, and to me, so used in an earlier stage to look at patients' eye movements—daily we were reminded and encouraged by its clinical implications—the effort to maintain such an active primate lab became too much. The research being carried out in parallel on the other floor, to be described presently, was intellectually more attractive, and I began to turn all my attention to it. Dr. Blair rejoined the Navy to assume a sequence of important slots as Capt. S.M. Blair, MC, USN. The remaining primates were turned over to my colleague Russ DeValois in the psychology department.

Fine-Grain Visual Processing

If I had been forced to restrict my interest to a single topic in vision it would have been visual acuity. Resolution depends in the first instance on optical factors, but they had now been characterized in sufficient detail. The experiments bypassing the optics with Young's interference fringes had convinced me that the conventional wisdom about the match of the optical limit and the grain of the receptor mosaic held up. The focus, so to speak, now was on the central nervous system. The single-unit recordings from the primary visual cortex, insofar as they were available in the primate and could be extrapolated to the central fovea, however, did not reveal a grain fine enough to match the known resolving capacity. Because “wet” neurophysiology was not ready, guides to neural circuitry had to be provided by psychophysics.

The attention of the vision community in those days was riveted on sinusoidal gratings as stimuli, but these extend over long retinal distances and hence do not match the predominantly local neural processing in the retina and primary visual cortex. In addition, the application of systems theory in the 1950s had alerted me to the nonlinearities lurking on or just below the surface in biological phenomena. Where linearity holds, all complete basis functions are equivalent, but where it does not, the stimulus set must be chosen to fit the structure of the apparatus. The referees for the Journal of Physiology paper, in immunizing me to Fourier approaches to vision (although of course not to optics) gave me the advantage of being able to ignore the voluminous literature that for 20 years sponsored and for the following 20 years distanced itself from the “Fourier Theory of Vision” (Westheimer, 2001). Moreover, awareness of the pitfalls resulting from nonlinearities when using inappropriate basis sets allowed me to skip over all the claims for linear neural “filters” and computational models that employ them.

Driving my experimental program was the realization that the high foveal visual acuity, right at the edge of the maximal capacity of the eye's optics and retinal anatomy, places such high demands on neural processing that, when stressed, it would exhibit deficits whose nature might point to the strategies used in the nervous system to extract this fine information. The first study, showing that visual acuity deteriorated with shortening exposure time much more seriously than simple light detection (Baron and Westheimer, 1973), validated the suspicion of the importance of cortical neural factors. It also made me face up to the technical challenge of performing rigorous psychophysical experiments in this area. Randomizing stimulus presentations in many trials and recording responses would have to be automatized.

When this was accomplished, the next acuity experiment was performed with my former graduate student Suzanne McKee, who became the most significant research collaborator in this area before going over to Arthur Jampolsky's Smith-Kettlewell Eye Research Institute in San Francisco. Examining the effect of target motion across the retina, we found that quite prominent velocities and excursions leave acuity unaffected (Westheimer and McKee, 1975). The ability of cortical mechanism to resolve the orientation of a 1 arc minute gap in a letter now was shown to require more than 100 msec, but during this interval it was robust to location shifts of up to 50 times the size of the detail! The kind of mechanism that can accomplish this has not yet been laid out in neurocomputational detail, let alone been discovered by recordings from the cortex.

The advent of computers opened up an even larger and more challenging area of inquiry. Vernier and stereoscopic acuity had been known for a long time to be in the range below the width of a single foveal receptor. Hering (1899), realizing the difficulty of explaining this, had proposed that it was due to averaging of local signs along the length of the stimulus lines or edges. In a little-known paper, Ludvigh (1953) had undermined this idea by claiming that dots could be aligned as well as lines. Ludvigh, one of the ablest thinkers of his generation of vision researchers, did not, however, have any track record as an experimentalist and I was prepared to discount his claim, but not without subjecting it to a test. It turned out to be a difficult experiment to implement. Don Mitchell, Bill Baron, Ralph Freeman, and I found a space in the attic of the optometry building long enough to allow the positioning of two dots down to a precision of a few seconds of arc of visual angle. The procedure was tedious: Stimuli were positioned by hand with a micromanipulator using tables of random numbers, experimenters and observers communicated over the 30-meter distance by intercom, and data were graphed on Gaussian probability paper. The results, however, supported Ludvigh's claim and eliminated Hering's theory of averaging local signs.

Because the misalignment threshold in the vernier task is well below the resolution limit, it was necessary to dispel doubts that a law of physics was being transcended. Resolution, or separation of two feature elements, is indeed limited by the diffraction laws that any optical system, including the eye, must obey. But an object can be located with arbitrary precision, provided there is enough light (Westheimer, 1976). Suzanne McKee and I were able to demonstrate that the task devolved to identifying the centroid of a light patch on the retina, quite a feat of neural computation (Westheimer and McKee, 1977a). It is of the kind to which Georgopoulus pointed in the population vector summation model in the motor system. We showed that vernier acuity is just one of a whole class of relative localization abilities, where differences in location of two objects can be discriminated with high precision. Because the word visual acuity had been preempted, for at least 150 years, by its application to resolution, with its dependence on optical laws and retinal anatomy, I coined the term hyperacuity for this class of discriminations (Westheimer, 1975). I deliberately eschewed the word superresolution because it was being used in radar for quite a different process, viz., the identification of a target whose spatial-frequency components within the cut-off spatial frequency match those of a targets about whose total spatial frequency spectrum there is prior information.

A variety of findings—wide latitude for the shape but need for tight temporal synchrony of all components of the configuration, summation of some of the properties and masking of others by flanking stimuli in time and space—pointed to processing even more central than the primary visual cortex. Simple linear spatial filters could not be invoked to handle the range of target configurations and relative positions. Finally, aspects of learning and attention could not be ignored. The research that started with optical images and then led to retinal spatial interaction had unequivocally arrived in the central nervous system and the transition from optometrist to neuroscientist was complete.

In association with a steady sequence of graduate students and postdoctoral colleagues (Gert Hauske, Suzanne McKee, Keiko Shimamura, Tom Butler, Dennis Levi, Bertil Lindblom, David Badcock, Mike Fendick, Graeme Mitchison, Bob Bennett, Armand Abulencia, Manfred Fahle, Christian Wehrhahn, Mark Pettet, Wu Li, Eric Ley, Tina Beard, Scott Brincat, Angela Gee) I have investigated over the last 25 years many aspects of the neural processing that underlies the discrimination of such spatial attributes of visual features as location, orientation, and stereoscopic depth. Although the pattern components are sharply delineated and quickly identified by any observer, they are not easily characterized in the Fourier domain and hence not encompassed by the research routines of the many single-cell and psychophysical investigators who restricted themselves to the use of sinusoidal grating or Gabor targets. But even in electrophysiological explorations of the retina and cortex that were not so limited, elucidation of the neural substrate of spatial visual processing has evolved slowly, presumably because one is dealing with higher circuits involving representation of activity more widely distributed than can be captured by the analytical procedures of the day. Altogether, this research enterprise continues to strengthen my conviction that analysis of behavior has a primary role in a search for understanding neural functioning. In my investigations, we employ psychophysical procedures in human observers, which can yield results as sharp, repeatable and universal as anywhere else in biology. Tschermak (1947) used the term “exakter Subjektivismus” to address and counteract the impression that data based on human judgments necessarily lack general validity.

All along, binocular and stereoscopic vision fascinated me. As an optometry student I had made my own stereograms to use in orthoptic training of strabismics and vividly remember noting, about 1945, a phenomenon that later gained great prominence. In a monocular view of a tree one would see just a disordered array of foliage, but in stereoscopic viewing this would immediately arrange itself into separate, clearly articulated branches. Hence when random-dot stereograms became popular they contained no great surprise for me. In any case, the early claim that they contained no monocular clues was never fully accurate: They contained a great many monocular clues. The task, as was clearly defined by Marr and Poggio (1979), was the disambiguation and the suppression of conflicting pairings. Over most of my career I have intermittently returned to research in stereoscopic vision (Westheimer and Tanzman, 1956; Westheimer, 1979; Mitchison and Westheimer, 1984) and when selected as the Royal Society Ferrier Lecturer in 1992, I chose this as my topic (Westheimer, 1994). Over the ages, the two most controversial attributes of vision have been color and depth. The disputatious tone permeating color vision and its theories, starting with Goethe, I have always found unappealing, but depth perception with its roots in three-dimensional geometry had from the start exerted an intellectual attraction. Not that color vision does not harbor its own fascination for sophisticated geometry, witness Silberstein's (1943) elaboration of a Riemannian color space. However, during my most impressionable years as a beginning scientist, the literature was abuzz with what was widely claimed to be “the most important contribution to binocular vision since Helmholtz.” Luneburg, a mathematician, put forward in 1947 the proposition that perceptual visual space has the metric of a hyperbolic space of constant curvature. Because I did not understand what that meant, I had to go back to the mathematics books and learn about non-Euclidean geometry. After some time, much reading in differential geometry, and working through the experimental findings that the theory began to generate, I developed a skepticism not only about Luneburg's clever conjecture but about attempts in general to find anchor points for spatial vision in geometrical scholarship. The episode was paradigmatic of a tendency on my part to be intrigued by a mathematical model of visual perception when first encountered and then on further study to reject it as inadequate.

Serendipity played a part in alerting us to the plasticity that characterizes the functions we were studying. One of our good undergraduate student observers performed very poorly in a stereoscopic situation when transferred from a vernier to a stereoacuity acuity task. We were, of course, familiar with the fact that new observers, or seasoned observers starting a wholly different task, required a few hundred responses before settling into a steady response state, and had always made it a practice to discard the first couple of runs. So this particular observer was allowed to continue in the stereo task; it took 10 days of practice for him to reach a 10 arc seconds threshold. We were thus alerted to the role of perceptual learning (Fendick and Westheimer, 1983; Crist et al., 1995).

A second lesson was learned when Bertil Lindblom, an ophthalmologist from Goeteborg, came over to try to develop a clinical stereo test akin to the pseudo-isochromatic color vision plates. Preliminary results made it clear that an observer's stereo threshold—as also other spatial thresholds—depends critically on prior expectation. Thresholds rise directly with the degree of uncertainty (Lindblom and Westheimer, 1992). Both the perceptual learning and the uncertainty findings revealed that the cortical circuits involved have parameters that are not permanently fixed, even in the adult.

In the early 1990s I started active collaboration with the Neurobiology Laboratory at the Rockefeller University, which was at the time gradually being relinquished by Torsten Wiesel and taken over by his long-term associate Charles Gilbert. Charles saw in my psychophysical results not only evidence of cortical processing but specifically the operation of interaction of horizontal connections within the ensemble of neurons in the primary visual cortex. The response of individual neurons to even the optimal stimulus in its classical receptive field was seen by him to depend on context, learning, attention, and expectation. This cortical plasticity, for which there was no dearth of possible anatomical pathways, needed, however, to be demonstrated and moreover, if adequate comparisons were to be drawn to the human psychophysical findings, in the alert behaving primate. Charles, unusual for someone trained in medicine and neurophysiology, was quite prepared to accept that even Gestalt phenomena of good figures, grouping, continuous and contiguous arrangements, and so forth might have their neural counterpart in the primary visual cortex. A sequence of parallel studies, human psychophysics and primate single-unit recordings, was entrained, in which Mitesh Kapadia's enthusiasm and drive were particularly invaluable. And indeed, for suitably selected spatial configurations, the behavior of single neurons in the primary visual cortex of the primate matches those of a human observer in psychophysical tasks (Kapadia et al., 1995). This research is ongoing with Wu Li, who was trained by Prof. C.Y. Li in Shanghai, now playing a leading role.

Over the last dozen years, a steady visiting coworker has been Christian Wehrhahn, based in the Tuebingen Max-Planck Institute founded by the late Werner Reichardt. In one of Christian's enterprising collaborations, we teamed up with Barry Lee in Goettingen to conduct parallel studies in human hyperacuity and recordings from monkey retinal ganglion cells. These studies heavily implicated the magnocellular stream and revealed how additional cortical processing is needed to extract the relevant information from the retinal signals, which after all are the primary source (Lee et al., 1993).

Both from my musical activities and from the early observation showing accurate eye movement predictions for rhythmic stimuli, I had been curious about the fine grain in the perception of the sense of time. Suzanne McKee and I had shown that temporal asynchronies of just a few milliseconds could be correctly judged in the onset of adjacent visual stimuli (Westheimer and McKee, 1977b). A few years ago I took the question up anew, investigating the discrimination of the duration of intervals demarcated by visual, auditory, and tactile pulses. It seems that good time-interval discrimination is not achieved locally in the immediate cortical projection for each of the sensory modalities individually but by an apparatus that is common to all (Westheimer, 1999a). Unfortunately, I have to leave its further elucidation, along with the search for the neural substrate of motor anticipation, and of indeed motor programming in general, to the next generation of investigators.

Computers

An autobiographical sketch would not be complete without reference to a life-long fascination with computers. It was presaged by the interest engendered by material on numerical methods that were included in the lectures for the mathematics major in Sydney University—numerical integration and solution of differential equations, interpolation, etc. When measurements of the refractive state of the eye showed fluctuations, I wanted to analyze them and worked my way through the Wiener-Khinchine procedure of autocorrelation and Fourier transformation for the purposes of harmonic analysis. Ohio State had an IBM 650 computer and I proceeded to program and run the data through it. Thus, my first research using electronic computers was published in 1957 (Westheimer, 1957a). When I got to Cambridge in 1958, we generated a lot more data and fortunately were granted access to EDSAC, the computer for which Maurice Wilkes was responsible and which was in constant use by the molecular biologists analyzing electron diffraction patterns (leading to the identification of protein structure). Within the small and friendly community of computer mavens, colleagues helped each other by freely sharing programs. I remember Teddy Bullard and Peter Swinnerton-Dyer competing to have us use their harmonic analysis programs.

In Berkeley there was an IBM 704 card-programmed computer, and I had to learn FORTRAN to have it run the Fourier analysis needed for deconvolution of the measured line-spread function and the characterization of the contrast transfer function of the eye. Later we used it extensively to map image spread for all kinds of target patterns employed in the retinal interaction, acuity, and hyperacuity studies.

I was always keen to learn computer languages: FORTRAN, BASIC, FORTH, COBOL, PASCAL, and finally C, which I now have used almost exclusively for the last 20 years.

In 1970, on a visit to Mat Alpern in Ann Arbor, Bill Uttal showed me how he was testing visual perception by displaying patterns with a PDP-8 computer. I was sold on it instantly, and proceeded to request one in my next NIH grant renewal. Funding started on October 1, 1972 but in the mean time the PDP-11 had been released. There were long discussions in Berkeley with Horace Barlow and Bill Levick, who had been won over by the competing NOVA and wanted me to join that trend. But I was more impressed with the DEC system, which I had seen in action as early as 10 years before when the LINK was being developed and placed in neurophysiological laboratories.

When the PDP-11 finally arrived and was put into operation in May 1973 my life changed. I had taken on the charge of being my own systems manager and so had the responsibility for all aspects of understanding and maintaining it. The first task was to learn to program it, which had to be done in those days in assembly and sometimes even machine language. It gave me a unique insight of what is actually going on, program step by program step, when stimulus patterns are being generated and responses registered and sorted. Gaining familiarity with the computer bit by bit, so to speak, was an extremely time-consuming activity—there were almost no resource people to consult—but it has also given me unsurpassed versatility and assurance in the organization and control of experiments. For more than 30 years now I have felt secure in my grasp of stimulus generation, in terms of seconds of arc of visual angle and milliseconds. In time the PDP-11 was replaced by a LSI-11, then by a Microvax, and finally by a series of INTEL computers using first 286 and eventually Pentium processors.

My first home computer was a 1979 Northstar Horizon S-100 bus computer, using a Z80 processor, whose instruction set I also learned. But by the middle of the early 1980s the IBM machines had for all practical purposes replaced the much better S-100 bus architecture. Needless to say, I started e-mail in 1985 and my user name “gwest” reflected the then requirement to stay within 6 letters.

Institutions, Organizations, and People

Parental injunctions and early career planning notwithstanding, I have spent most of my life within universities, predominantly lecturing to undergraduate or professional students. In the optometry schools, there was a great deal of teaching, up to 10 lectures a week on occasions, as well as organizing laboratories and sometimes even clinical duties. Research had to be done in one's spare time and I developed the life-long habit of working in the laboratory on Saturdays. Only when I transferred to the Department of Physiology-Anatomy in Berkeley did the time and facilities make the position at least an approximately half-time research slot. During several time spans, however, I could devote full time to research: the academic year 1952 to 1953 as a predoctoral fellow at Ohio State, most of 1958 at Cambridge, England, and the academic year 1972 to 1973 when I received an appointment as Miller Research Professor. From then on the teaching load became progressively lighter as I had various sabbatical leaves and then took over administrative tasks. In 1994 I entered retirement status as professor in the graduate school with some duties in graduate teaching and the provision of some modest laboratory space. Altogether, the expansion of research funding and resources in the biomedical field in the United States during the second half of the 20th century made it progressively easier to be a life scientist. I was also fortunate in doing most of my work before the explosion of multiauthored publications and increased cost and complexity of instrumentation and procedures left those of us behind who look at science as a predominantly scholarly, intellectual activity and who enjoy the challenge of fast, even day-by-day, turn-around in the cycle of planning and performing experiments and interpreting their results.

It was only in the 1980s that I became involved in academic administration. Under Dan Koshland's leadership, a major initiative was started to reorganize the whole of the large biology community in Berkeley. After almost a decade of continuous meetings and conferences, we had something to show: two new laboratory buildings, a complete renovation of the old enormous Life Sciences Building, and a new departmental structure that allowed flexibility in accommodating changes in disciplinary boundaries. As a result, neurobiology became a division in the Cell and Molecular Biology “megadepartment” and we finally had neurobiology in the title of our appointments. After several years on various planning committees, I assumed the roles of both administrative head of one of the buildings, the Life Sciences Addition, housing the laboratories of 46 faculty members, and head of the new academic Division of Neurobiology, which I had organized. Because I was then in my 60s, with a good deal of experience in academic affairs, I was not overwhelmed by these tasks and took them in my stride. By the same token I had no regrets when passing them on to the next generation of administrators, Corey Goodman, Carla Shatz, and Geoff Owen.

For over 30 years I regularly commuted to Washington to serve on committees of the National Research Council and the National Institute of Health, as member and several times chairman of study sections, training committees, and then the Board of Scientific Counselors of the National Eye Institute. From the late 1960s to this day I have been associated with editing many scientific and professional journals, in particular Vision Research, Experimental Brain Research, Journal of Physiology, and during the last few years Proceedings of the Royal Society B. I have never minded the several hours every week that I have routinely spent preparing reports on grant and promotion proposals, refereeing manuscripts for publications, and writing letters of recommendation for what must have been a couple of hundred undergraduate, graduate, and postdoctoral students who have rotated through my laboratory.

I have always accepted that membership in scholarly and professional organizations is a part of belonging to the scientific community. The nearest thing to a vision society was the Optical Society of America and I became a member in 1948, when I was still a practicing optometrist in Sydney. To these were added various other organizations, including the Society for Neuroscience, when Ted Bullock recruited me the year after it was started.

Attending scientific meetings is an integral part of participating in the enterprise and in the early stages I did my full share. In the 1950s and 1960s I regularly attended the annual conventions of the American Academy of Optometry in early December, and the twice-yearly meetings of the Optical Society of America. They were modest affairs by contemporary standards with rarely a conflict due to parallel sessions. The vision community was relatively small and allowed good opportunities for personal interaction. The same applied to the less frequent international meetings. Between these events and the occasional visitors from abroad, it was possible to keep in touch with developments. In the last couple of decades, the number of organizations has grown enormously, and so has the size of their meetings and the number of presentations. I do not find these occasions particularly attractive, especially because my mind is not well matched to oral presentations and lectures. Over time I have developed the capacity of quickly capturing the essence of an experiment and the implication of its results. Hence the cost/benefit ratio is not in favor of the time spent in listening to a lecturer, compared to viewing an abstract or a publication. Rapidly walking along a row of posters and quickly taking in what is informative is not always appreciated by the eager exhibitors.

All this does not mean that I would shun getting personally acquainted with fellow scientists or hearing them give a lecture at least once; very much to the contrary. But on the whole, I subscribe to the description once presented to me by Stanley Stiles, one of the ablest and wisest vision researchers of the 20th century, of the practice of science as arriving at “the residue.” By this I took him to mean the distillate in the attempt at a rational description of natural phenomena, succinct, concentrated, and free of contradictions. On the other hand, the role that personality characteristics of scientists, beyond their abilities and opportunities, play in the creative nature of their contributions has long fascinated me. In visual science, the two polar opposites are Helmholtz and Hering.

Helmholtz single-handedly made more contributions to visual science than anybody before or since. Endowed with great mathematical ability, an orderly mind, and a calm and steady personality, he logically, linearly, and sequentially worked through the optical and anatomical stages to reach as full a description of the visual process as could be achieved at the time. When he reached the limit, he made unprovable propositions about cortical processing (the concept of unconscious inference) and proceeded to seek clues in the foundations of geometry. Being thoroughly embedded in 19th century thought, he regarded this as a natural progression. It was only a couple of generations later that the intuitional basis of mathematics and geometry was laid bare. Although Helmholtz helped secure a Berlin chair for Planck, one cannot help sympathizing with the dilemma he would have faced had he lived to be confronted with quantum mechanics and Goedel's theorem.

When it comes to inspired leaps of imagination, closing a gap not bridgeable by simple incremental steps, the outstanding figure is Ewald Hering, most notably when he examined a few psychophysical phenomena and enunciated the opponent theories of spatial and color vision. It took almost a century to uncover their neural substrate and integrate them into the body of visual science. More often, however, such conjectures remain open-ended, witness the compelling demonstrations of Gestalt groupings by Wertheimer of 1923. Despite assiduous study of the provenance of such formulations and the personal history of their proponents, the workings of these minds remain mysterious to me (Westheimer, 1999b).

In practice, of course, very many human traits are in play when doing science. Most of the ones on display during a lecture or on social occasions are not relevant. In assessing the personal attributes of a scientist, to me by far the most important trait is integrity. Carelessness, oversight leading to errors of omission, and failure to properly research the antecedents or to be sufficiently rigorous in analyzing the outcome of an experiment, these can perhaps be excused, although they can needlessly hinder progress. But I have no tolerance for the deliberate shaping of results in support of a preconception or the creation of the illusion of a phenomenon.

On the other side, there can be enormous rewards in personal contact with colleagues. Here are just a few of the many examples that I have encountered and that engendered admiration and the wish to be able to emulate: Francis Crick would grasp, in what seemed only a microsecond, all the ramifications of an experimental result related to him, a period that when he got into his 80s lengthened to perhaps a millisecond; Roger Penrose's mind similarly bores down instantly to the core of an issue—when shown my paper on the kinematics of the eye, he barely glanced at the expression in terms of quaternions, of which I was inordinately proud, but homed in on the fact that the eyeball moved as a ball in a socket and that Listing's law was, of course, a good possible mode of its operation; Glenn Fry, on the other hand, had such a remarkable geometrical intuition that it was obvious to him, without recourse to quaternions or other mathematical formulations, that the axis of the equivalent to two consecutive eye rotations does not lie in Listing's plane; Torsten Wiesel is unique in being a top scientist who always brings, unfailingly and quite naturally, a genuine empathy to interactions with his fellow scientists and with any one else, even the most junior; Jack Eccles, was a master at what would now be called multitasking—when I visited him in Canberra in the 1950s, he ran four laboratory set-ups concurrently and could explain in detail what was going on in each; Horace Barlow has a mind so well furnished and finely honed that he can contribute something interesting and insightful to any physiological or psychological topic; Dan Koshland was unmatched in his ability to bring divergent disciplinary agendas to a consensus in the interest of overall advance of the academic environment.

Overviewing my experiences in a variety of settings during a good fraction of the 20th century makes it obvious how much social and political conditions provided an inescapable framework beyond any individual's control. There is a great deal to be grateful for in a trajectory through the century's science that included an upbringing in Berlin, college and professional training during the darkest years of the century in sunny Australia, exposure to high-caliber intellectual atmosphere in Cambridge, and the opportunity to carry out scientific work with adequate NIH support in the inviting setting of the University of California in Berkeley. I remain enthusiastic about the future of the discipline. For me, the aim of illuminating the structure of the visual apparatus by catching it between the twin beams, one pivoted in the physical sciences, the other on a patient-centered clinical approach, yielded a satisfactory outcome when applied to the optics of the eye and the functioning of the retina. But the gap between our current knowledge of the operation of the cortical apparatus of vision and the ultimate performance of the human in visual perception and object recognition remains vast and not as simply bridged by optical physics and rigorous psychophysics as was the case for the more primitive visual tasks. This is the challenge of the road immediately ahead; I wished I could participate building it, much as it has been my privilege to help with its construction so far.

Selected Bibliography

Baron WS, Westheimer G. Visual acuity as a function of exposure duration. J Opt Soc Am 1973;63:212–219.

Campbell FW, Robson JG, Westheimer G. Fluctuations of accommodation under steady viewing conditions. J Physiol London 1959;145:579–594.

Campbell FW, Westheimer G. Dynamics of accommodation responses of the human eye. J Physiol London 1960;151:285–295.

Crist RE, Kapadia MK, Westheimer G, Gilbert CD. Perceptual learning of spatial localization: Specificity for orientation, position, and context. J Neurophysiol 1997;78:2889–2894.

DeLange H. Relationship between the critical flicker frequency and a set of lowfrequency characteristics of the eye. J Opt Soc Am 1954;44:380–389.

Eccles JC, Ito M, Szentagothai J. The cerebellum as a neuronal machine. New York: Springer-Verlag, 1967.

Eckmiller R, Blair SM, Westheimer G. Oculomotor neuronal correlations shown by simultaneous unit recordings in alert monkeys. Exp Brain Res 1974;21:241–250.

Enoch JM. Quantitative layer-by-layer perimetry. New York: Grune & Stratton, 1981.

Fendick M, Westheimer G. Effects of practice and the separation of test targets on foveal and peripheral stereoacuity. Vision Res 1983;23:145–150.

Fuchs AF, Luschei ES. Firing patterns of abducens neurons of alert monkeys in relationship to horizontal eye movements. J Neurophysiol 1970;33:382–392.

Fulton JF. Physiology of the nervous system. London: Oxford University Press, 1943.

Gonshor A, Jones GM. Changes of human vestibulo-ocular response induced by vision-reversal during head rotation. J Physiol 1973;234:102P–103P.

Graybiel AM, Hartwieg EA. Some afferent connections of the oculomotor complex in the cat: an experimental study with tracer techniques. Brain Res 1974;81:543–551.

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Hering E. über die Grenzen der Sehschärfe. Berichte der mathematisch-physischen Classe der königl Sächs Gesellschaft der Wissenschaften zu Leipzig [Naturwissenschaft Teil]1899;16–24.

Hess WR. Charakter der im Zwischenhirn ausgelösten Bewegungseffekte. Pflügers Arch d ges Physiologie 1941;244:767–786.

Kapadia MK, Ito M, Gilbert CD, Westheimer G. Improvement in visual sensitivity by changes in local context: parallel studies in human observers and in V1 of alert monkeys. Neuron 1995;15:843–856.

Kornhuber HH. Motor functions of the cerebellum and basal ganglia. Kybernetik 1971;8:157–162.

Lee BB, Wehrhahn C, Westheimer G, Kremers J. Macaque ganglion cell responses to stimuli that elicit hyperacuity in man: Detection of small displacements. J Neurosci 1993;13:1001–1009.

Liang J, Westheimer G. Method for measuring visual resolution at the retinal level. J Opt Soc Am A 1993;10:1691–1696.

Lindblom B, Westheimer G. Uncertainty effects in orientation discrimination of foveally seen lines in human observers. J Physiol 1992;454:1–8.

Ludvigh E. Direction sense of the eye. Am J Ophthalmol 1953;36:139–142.

Luneburg RK. Mathematical analysis of binocular vision. Princeton, NJ: Princeton University Press, 1947.

Marr D, Poggio T. A computational theory of stereo vision. Proc R Soc Lond B Biol Sci 1979;204:301–328.

McKee SP, Nakayama K, eds. Optics, physiology and vision: A festschrift honoring Gerald Westheimer on his 65th birthday. Oxford: Pergamon, 1990.

McKee SP, Westheimer G. Specificity of cone mechanisms in lateral interaction. J Physiol 1970;206:117–128.

Mitchison GJ, Westheimer G. The perception of depth in simple figures. Vision Res 1984;24:1063–1073.

Rashbass C, Westheimer G. Disjunctive eye movements. J Physiol London 1961;159:339–360.

Robinson DA. Oculomotor unit behavior in the monkey. J Neurophysiol 1970;33:393–404.

Rushton WAH, Westheimer G. Effect upon rod threshold of bleaching neighbouring rods. J Physiol London 1962;164:318–329.

Schade OH. Optical and photoelectric analog of the eye. J Opt Soc Am 1956;46:721–739.

Schiller PH. The discharge characteristics of single units in the oculomotor and abducens nuclei of unanesthetized monkey. Exp Brain Res 1970;10:347–362.

Silberstein L. Investigations on the intrinsic properties of the color domain. J Opt Soc Am 1943;33:1.

Stark L, Sherman PM. A servo-analytic study of consensual pupil reflex to light. J Neurophysiol 1957;20:17–26.

Tschermak A. Einführung in die Physiologische Optik. Wien: Springer-Verlag, 1947.

Westheimer G. Mechanism of saccadic eye movements. Arch Ophthalmol 1954a;52:710–724.

Westheimer G. Eye movement responses to horizontally moving stimuli. Arch Ophthalmol 1954b;52:932–941.

Westheimer G. Accommodation measurements in empty visual fields. J Opt Soc Am 1957a;47:714–718.

Westheimer G. Kinematics of the eye. J Opt Soc Am 1957b;47:967–974.

Westheimer G. Spatial interaction in the human retina during scotopic vision. J Physiol 1965;181:881–894.

Westheimer G. Editorial: Visual acuity and hyperacuity. Invest Ophthalmol 1975;14:570–572.

Westheimer G. Diffraction theory and visual hyperacuity. Am J Optom Physiol Opt 1976;53:362–364.

Westheimer G. Cooperative neural processes involved in stereoscopic acuity. Exp Brain Res 1979;36:585–597.

Westheimer G. The Ferrier Lecture, 1992. Seeing depth with two eyes: Stereopsis. Proc R Soc Lond B Biol Sci 1994;257:205–214.

Westheimer G. Discrimination of short time intervals by the human observer. Exp Brain Res 1999a;129:121–126.

Westheimer G. Gestalt theory reconfigured: Max Wertheimer's anticipation of recent developments in visual neuroscience. Perception 1999b;28:5–15.

Westheimer G. The Fourier theory of vision. Perception 2001;30:531–541.

Westheimer G. Center-surround antagonism in spatial vision: Retinal or cortical locus? Vision Res 2004;44:2457–2465.

Westheimer G. Specifying and controlling the optical Image on the retina. Prog Retinal Eye Res 2006;24:19–42.

Westheimer G, Blair SM. Concerning the supranuclear organization of eye movements. Bibl Ophthalmol 1972;82:28–35.

Westheimer G, Blair SM. Oculomotor defects in cerebellectomized monkeys. Invest Ophthalmol 1973a;12:618–621.

Westheimer G, Blair SM. Saccadic inhibition induced by brain-stem stimulation in the alert monkey. Invest Ophthalmol 1973b;12:77–78.

Westheimer G, Blair SM. The ocular tilt reaction—a brainstem oculomotor routine. Invest Ophthalmol 1975;14:833–839.

Westheimer G, Campbell FW. Light distribution in image formed by living human eye. J Opt Soc Am 1962;52:1040–1045.

Westheimer G, McKee SP. Visual acuity in the presence of retinal-image motion. J Opt Soc Am 1975;65:847–850.

Westheimer G, McKee SP. Integration regions for visual hyperacuity. Vision Res 1977a;17:89–93.

Westheimer G, McKee SP. Perception of temporal order in adjacent visual stimuli. Vision Res 1977b;17:887–892.