Neurobiology at Harvard

The scientists who introduced me to the biology of the nervous system in 1961 did not reappear in my life for another six years. For various reasons, I became increasingly uncertain about how to pursue my interest in the brain, if indeed I wanted to pursue at all it. In particular, my earlier conviction that psychiatry was a good choice began to wane as my knowledge of the field waxed during the next few years. The first disillusionment came in the summer after my first year in medical school, not long after the course that Kuffler and his recruits had given us. Although there was no rule against taking the summer break between first and second year as vacation, we were encouraged by the gestalt of med school—and a generous stipend—to spend the time working in one of the research labs at the school. Being zealots, many of us took advantage of the offer.

Our pharmacology course during the first year included several lectures on psychoactive drugs, and given my inclination toward psychiatry, I thought working with the professor who had presented this material made good sense. The professor, Dale Friend, was a respected clinical pharmacologist at the Peter Bent Brigham Hospital; I imagined I would learn a lot by working with him, and perhaps establish a useful liaison with someone in my intended specialty. Without making inquiries into what kind of a mentor he might be or who might have been better (I naively assumed that those who taught us were always the cream of the crop), I sought Friend out near the end of the term and he agreed to take me on as a summer student. However, shortly after I started working in his small lab in the hospital basement, he departed for an extended European vacation, and I was left to my own devices with only his lab technician as mentor. I came up with a cockamamie project that involved the measurement of norepinephrine (a neurotransmitter thought to be involved in depression) in the brains of rabbits given various doses of a popular antidepressant drug, and soldiered on. But the only significant result by the end of the summer was the demise of an unconscionable number of rabbits, and my sense that if this sort of work was typical of research in brain pharmacology, I wanted no part of it.

It was my first clinical rotation, however, that dispelled once and for all my earlier idea of pursuing psychiatry. Although we had some instruction in psychiatric diseases during the second year of medical school, our exposure to the psychiatry wards did not come until the third year. I was no stranger to psychiatric patients, having worked two summers in college as an orderly in a state mental hospital in Philadelphia, where I had grown up. It was interesting, if dispiriting, work that involved supervising very ill psychotic patients during the day, and making half-hourly bed checks and trying to stay awake on the night shift (which, as a summer employee, often fell to me). The male wards each had a padded room that was used to temporarily incarcerate patients who became unmanageable, and we orderlies were occasionally called on to wrestle a patient into a padded room and onto the floor so that a nurse could inject a massive dose of paraldehyde, a drug then in use that quickly put the patient into a stupor that lasted several hours. (The hospital also had a surgical suite for performing frontal lobotomies, and this approach to psychiatric treatment had only recently been abandoned.)

My third-year rotation in clinical psychiatry was at another state hospital, the Massachusetts Mental Health Center, housed in a ramshackle building a few blocks from the medical school. The range and severity of the disorders the patients suffered was not much different from what I had experienced as an orderly, but the treatment they were receiving was in some ways more discomforting than the padded room and paraldehyde method. Psychiatry at Harvard in 1963, particularly at the Mass Mental Health Center, was one of the last bastions of the Freudian analytical treatment of severely disturbed patients, and the preceptor during my rotation was a psychiatrist who believed strongly in its merits. Sitting through his analytically based interrogatories of psychotic patients eroded what little remaining faith I had that psychiatry was the field for me. The final blow came one Saturday afternoon when another student and I found a patient who had hung himself with his belt in one of the bathrooms. The usual resuscitative procedures were far too late to help the patient, but the psychiatry resident in charge clearly had less knowledge about how to proceed than we did, and dithered while we vainly undertook the steps for resuscitation that we had recently learned in other rotations. The message seemed clear: Psychiatrists were not real doctors, and being a "real doctor" loomed large for me, as it did for most of my classmates.

Anyone navigating the rigors of medical school gravitates toward one or more role models to provide inspiration. Having given up on psychiatry, I began to look elsewhere. Harvard abounded in such individuals, and one of the most charismatic in that era was Francis Moore, the chief of surgery at the Peter Bent Brigham Hospital, where I did my third-year rotation in surgery not long after my experience at the Mass Mental Health Center. Moore was then in his early fifties and already legendary. As an undergraduate at Harvard, he was president of both the Harvard Lampoon and the Hasty Pudding Club, and he had been appointed surgical chief at the Brigham at the age of 32. He was a member of the team that had performed the first successful organ transplant in 1954, and had written a widely respected book in 1959 called The Metabolic Care of the Surgical Patient that underscored his status as a physician-scientist of the first order. He had been motivated to write the book by the problems encountered with the burn patients he saw after the infamous Coconut Grove fire in 1942. Although the details in the book were largely incomprehensible to me when I read it as a student (and tried to use it later as a resident in surgery treating burn patients), holding retractors as a student assistant while Moore exercised his jocular authority and surgical skills turned me in a new direction. I decided then and there that I would train in general surgery. (Dramatic to the end, Moore committed suicide at the age of 88 by putting a gun in his mouth.)

After some further electives in surgery during my last year in medical school, I applied for a residency in general surgery at the Massachusetts General Hospital, considered the top program then, despite Moore's preeminence at the Brigham. I was accepted and started my surgical internship in summer 1964. It is hard to believe in today's atmosphere of managed care, oversight by insurance companies, and litigation over malpractice, that we "doctors in training" were largely unsupervised. Nevertheless, a strict hierarchy and rigid accountability existed within the cadre of surgical residents. In terms of workload and stress, that year was the most difficult of my life. The wards we were responsible for were always filled with patients who could not afford a private doctor, and, for better or for worse, they were entirely our responsibility ("better" was around-the-clock care by dedicated young doctors, "worse" was our lack of experience). Although a senior staff surgeon was nominally in charge, the attending, as he was called (no women were on the surgical staff), was in evidence only on morning rounds; he was rarely in the operating rooms, and then only on especially difficult cases at the invitation of the chief resident.

The chief resident I worked under during the first portion of my internship year was Judah Folkman. Much like Moore at the same age, Folkman was widely thought to be destined for great things, as turned out to be the case. At age 34, Folkman was named surgeon-in-chief at Boston's Children's Hospital, becoming, along with Moore, one of the youngest professors ever appointed at Harvard Medical School. He became justly famous in the early 1970s for pioneering a novel way of treating cancer by inhibiting blood vessel growth, and at 46 gave up this appointment as a professor of surgery to pursue basic research on angiogenesis full time. Folkman was perhaps the most impressive individual I have ever met. Physically slight, already balding, with a great nose inherited from his rabbi father, he dominated in any setting by intelligence, wit, and force of character. The residents universally looked up to him not simply because he was surgically skilled and supremely smart, but because he radiated a humorous self-confidence and integrity that made everyone under him better handle the daily strife and our inevitable mistakes. Folkman died prematurely in 2008, but inhibiting blood vessel growth remains a promising approach to some cancers and to other important diseases such as macular degeneration.

But working under Folkman that year had another effect on me. Competitive types continually measure themselves against the qualities and talents of their peers. As chief resident, Folkman was far advanced from an intern struggling to learn the rudiments of the trade. But he was only five years ahead of me, and I had to envision myself in his role in the near future. The comparison was discouraging. I didn't see him as necessarily smarter or feel that I could never reach his level of technical skill (although I had serious doubts on both counts). It was his obvious passion for the craft that dismayed me, a passion I had already begun to realize I lacked. I found reading the surgical journals as uninteresting as I had found reading Moore's book on postoperative care; and generating the zeal for operating that came naturally to Folkman was, for me, forced. The recognition that, as with psychiatry, a life in general surgery was probably not going to work for me came at 2 or 3 a.m. one night when Folkman was trying to make an apparatus to dialyze a patient dying from kidney failure using an old washing machine and other odds and ends he had collected from a hospital store room. Although the effort failed, I realized that I would not have made it, and that this disqualified me from trying to follow the footsteps of figures like Folkman and Moore.

And so I needed to invent another possible path to a professional future. The Vietnam War gave me some breathing space. By 1965, virtually all physicians in training were being drafted, and my notice arrived about halfway through my internship. Given my concern over the prospects of a career as a general surgeon, being drafted was not entirely unwelcome. There was another reason as well. Since the age of 12, I had suffered periods of depression. These bouts had tended to occur when my future direction seemed murky. A year of psychoanalysis during my last year of med school had not helped, although it contributed to my later decision that psychiatry, at least as it was then being practiced in Boston, was not something I wanted to pursue. Despite the modicum of professional training I had received by then, I thought of myself as neurotic instead of a person suffering from a clinical disorder, and that analysis might help; it didn't, and the diagnosis of depression did not seem to occur to the analyst I saw either. And so I ended my internship year not only without a clear plan, but clinically depressed. The bright side was that I would now have two years of enforced service to regain my balance and sort things out.

Despite the rapidly escalating war in Vietnam, the options for a young physician drafted in 1965 were surprisingly broad. I could join one of the armed services, which would have meant time in Vietnam and a domestic military base in some junior capacity; seek deferment for further specialty training and later service; apply for a research position at the National Institutes of Health; join the Indian Health Service; or apply to become a Peace Corps physician. This last option meant serving two years in the Public Health Service taking care of Peace Corps volunteers in one of many countries around the world. Given my uncertain frame of mind about what do to next, my lack of interest in research at that point, and my opposition (along with almost everyone else I knew) to the war, the Peace Corps seemed the best bet. And so after a few weeks of remedial training in tropical medicine at the Centers for Disease Control in Atlanta, I arrived in Venezuela in July 1965, without any idea of what my professional or personal future would be.

The Peace Corps turned out to be a good choice. The volunteers that I

and another young doctor had to look after were an inspiring bunch who demonstrated all the good things about Americans and American democracy of that period. Because I spoke Spanish as the result of living in Mexico for four years as a kid and a further summer working in a rural Mexican clinic as a college student, I could travel easily and interact with local doctors. And Venezuela in the 1960s was a beautiful and relatively progressive country. From the medical perspective, the job was easy: I served as general practitioner to about 400 sometimes difficult-to-reach but generally interesting and healthy young adults. My life in South America was in every way a radical change, and for the first time since college, I had time to think about whatever I pleased instead of what I had to do next to meet the demands of medical training.

I read widely, including a lot of books on science that I had not been exposed to as an undergraduate majoring in philosophy, or as a medical student and intern with little extra time. One of the books I picked up while rummaging around the American Bookstore in Caracas was The Machinery of the Brain, by Dean Wooldridge, someone I had never heard of. He was an aeronautical engineer who, together with his Caltech classmate Simon Ramo, had left the aerospace group at Hughes Aircraft in 1953 to found the Ramo-Wooldridge Corporation, which later became the very successful defense-related company TRW. Having become wealthy, Wooldridge resigned from TRW in 1962 to pursue his passion for basic science, particularly biology. The Machinery of the Brain, published in 1963, was his first effort. By his own admission on the back cover of the book, Wooldridge's intention was simply to review the discoveries and ideas about the brain that he found interesting. Although I was passingly familiar with much of the content, his lucid synthesis of what was essentially the information I had learned about the brain as a med student got me thinking about issues that I had been keenly interested in when first exposed but had lost touch with as I morphed into a prospective surgeon. Unlike authors whose success in some unrelated field encourages them to pontificate about a new theory they imagine will explain the mysteries of the brain, Wooldridge's book was modest and provocative—and remains so as I look at it now—and it got me thinking about the nervous system once again.

Because I had two years to mull things over before I was scheduled to resume my post in general surgery at Mass General, I didn't need to rush to sort out my thoughts about a career that might combine an interest in the brain with my training as a physician. I even wrote a novel, on the premise that perhaps I had missed a literary calling (the few hundred pages of sophomoric prose I managed to crank out made clear that I had not). Finally, I concluded that the most logical course under the circumstances was neurosurgery. In addition to the internship year I had already completed, becoming a neurosurgeon required the further year of general surgery that awaited me on my return to Boston, so I was already well along this path. I thought that neurosurgery would combine my earlier and now reviving interest in the nervous system, which I had pushed aside as a result of my disillusion with psychiatry.

Soon after returning to Boston in summer 1967, I asked William Sweet, the head of neurosurgery at Mass General, if I might join his program when I completed my second year of general surgery. He agreed, and I was to start formal training in neurosurgery the next year. Despite the logic of this plan, within a few months of my return from the Peace Corps, I began to have doubts about what had seemed, in principle, an optimal marriage of interests and training up to that point. One of my rotations that year was as the general surgical resident assigned to neurosurgery, and I had looked forward to that stint. But disillusionment was not long in coming. Sweet, it turned out, was a caricature of the popular image of a brain surgeon and not the model I needed at that point to spur me on. He had a high-pitched voice and was something of a martinet, making him an easy target of mockery by the residents, one of whom was especially good at mimicking his prissy persona. Sweet was no Moore or Folkman, and his colleagues on the neurosurgery faculty at the time were not much more inspiring. When I experienced it first hand, their daily work was not all that interesting. In contrast to my abstract enthusiasm for exploring the brain in this way, the actual operations were long and tedious, and the outcomes (especially in patients with brain malignancies) were all too often a foregone and unhappy conclusion. Some procedures—such as evacuating a hematoma, clipping a ruptured blood vessel, or removing a benign tumor—were curative but didn't do much to stoke my interest in understanding the brain in some significant way. Even the psychosurgery then being carried on at Mass General was unappealing, because of both its oddball practitioners and the flimsy scientific grounds on which such work was being justified.

As I worried increasingly about the prospect of neurosurgery, my thoughts kept turning back to the neurobiologists Kuffler had brought to Harvard in the late 1950s and the impression they had made on me as a first-year student. In winter 1967, I found myself back at Harvard Medical School in the office of David Potter, who had taught us about action potentials and synaptic transmission six years earlier. I remembered Potter as the most approachable of the group and sought him out for advice about whether research in neuroscience might be a reasonable option. He listened with apparent enthusiasm as I summarized my concerns with neurosurgery and my interest in perhaps giving research in neuroscience a try. On the face of it, my arguments were feeble: The sum total of my research experience was the disastrous summer spent in Friend's pharmacology lab, and my desire to try research had been reached largely by excluding other options. Despite the manifest weakness of my case, Potter agreed to think about my situation, and we agreed to meet again. In the meantime, I asked Sweet if I might take my first year in the neurosurgery program as a research fellow, and, primarily because of scheduling issues with other residents in the program, he agreed.

When I returned to Potter's office a couple of weeks later, he had indeed given the matter some thought. He considered my intention to try research plausible enough and suggested that I contact John Nicholls (Figure 2.1) to ask if he could take me on as a fellow. Kuffler had just recruited Nicholls to Harvard but he was still working at Yale as an assistant professor. (Kuffler's original group was then in the process of expanding and to form a full-fledged department.) I was disappointed because I had no idea who Nicholls was and had hoped to work with Potter or perhaps even Hubel and Wiesel, whose stars were rising even when I was a student. I was even more dismayed when Potter told me that Nicholls was working on the nervous system of the medicinal leech. I had no idea what any of the neurobiology faculty was doing then or why, but it was difficult to imagine how the leech could be pertinent to my ill-formed ambition to become a neuroscientist who might ultimately say something important or at least relevant to the human brain.

Figure 2.1 John Nicholls circa 1975. (Courtesy of Jack McMahan)

Figure 2.1 John Nicholls circa 1975. (Courtesy of Jack McMahan)

In fact, Potter's suggestion was a good one. I was somewhat reassured when Potter told me that Nicholls had been a graduate student with Bernard Katz in the late 1950s after he had completed his medical training in London, that he had been a fellow in Kuffler's lab thereafter, and that his work on the leech was widely regarded as an outstanding example of what was then a new approach to understanding neural function—studying the nervous systems of relatively simple invertebrates. Potter went on to say that because Nicholls would be starting up a new lab at Harvard, he would probably welcome a fellow, even one whose experience in neuroscience was nil. As a result of this conversation I wrote to Nicholls, who invited me to visit him at Yale to meet and talk things over.

And so on a bleak Saturday in February 1968, Shannon Ravenel, whom I was going to marry later that spring, and I drove down to New Haven. I had met Shannon while still in med school, and we had an on-again, off-again relationship that had, happily for me, been on-again since I returned from Venezuela. Yale Medical School was unimpressive (I had never actually been there, even though it was only a few blocks from the residential college where I had lived as an undergraduate). Nicholls's lab was equally nondescript, and it was quickly evident that he had a complex personality that might not be such a good fit with my own. He asked us to dinner at his modest apartment, where his two unruly children cavorted about in their underpants, and where what appeared to be a dysfunctional relationship with his wife was palpable. Driving back to Boston that night, Shannon pointedly asked me if I really wanted to make this change in light of all the evidence that I would be sailing into unknown and possibly stormy waters. Even though my confidence in answering was minimal, several reasons argued for seeing it through: Potter's word that working with Nicholls was a good bet, the lack of obvious options if I wanted to try research, and a determination on my part to do something that might reignite a passion for understanding the brain. And I could always go back to the neurosurgery program at Mass General if the research year failed; that was Sweet's expectation, even if I had my doubts.

Another factor in going forward was Denis Baylor, a research fellow whom I had briefly met in Nicholls's lab. Baylor had gone to medical school at Yale; like me, had decided to try his hand at neuroscience research; and had ended up spending three years with Nicholls as his sole postdoctoral collaborator (not an unusual arrangement in those days). When we were alone, he told me in no uncertain terms that Nicholls had been a terrific mentor and friend. Baylor, who later went on to work with Alan Hodgkin at Cambridge and had a stellar career investigating the properties of photoreceptors in the retina, was clearly sensible, and his encouragement counted for a lot. So a few days after getting back to Boston, I called Nicholls to say that I was willing if he was, and he agreed that I could take Baylor's place when he arrived at Harvard later that summer. Shannon and I married in May, I finished my second year of residency in June, and after spending that summer in Vietnam under the auspices of a Boston-based antiwar group selecting war-injured children to come to the United States for treatment, at age 30 I began life as a neuroscientist.

Although the Department of Neurobiology at Harvard was the best place I could possibly have tested the merits of this new direction, the transition was not easy. For the previous four years, I had been a practicing doctor, and whether in Boston, Venezuela, or Vietnam, I had all the responsibilities and respect that being a physician entails. Suddenly I was a superannuated student on the bottom rung of the ladder; even the two beginning graduate students in the new department knew more science than I did, and they seemed a lot smarter to boot. The stress was of a very different kind than I had experienced during the year I had worked as a surgical intern, but the first year I spent in Nicholls's lab was in some ways nearly as trying, with one fundamental difference: Despite my ignorance and well-justified sense of inferiority, I finally loved what I was doing. For the first time in years, I worked hard not because I had to, but because I wanted to.

The approaches to the brain and neural function that Kuffler and his young faculty were spearheading when I was a student in 1961 had flowered by the time I returned as a fellow in 1968. During the first half the twentieth century, the major goals in neuroscience had been reasonably clear: to determine how action potentials work, and to understand how information is conveyed from one nerve cell to another at synapses. Because it was obvious that all brain functions depend on these fundamental processes and their cellular and molecular underpinnings, it didn't make sense to grapple with more esoteric issues until these central challenges had been met (although, of course, other research was going concurrently, primarily with the goal of better understanding the organization of the brain). By the early 1960s, however, Hodgkin and Huxley had deciphered the mechanism of the action potential, and Katz and his collaborators had convincingly demonstrated the basic mechanism underlying chemical transmission at synapses. The question that confronted the next generation of neuroscientists—Nicholls and the rest of the faculty—was what to do next.

In determining the possible directions of neuroscience, Kuffler and his eclectic style of research was a powerful force. It helped that he had collaborated with Hodgkin, Huxley, and Katz in the 1940s, and that he was, in his own different way, an intellectual giant. One would never have guessed this, however, from his inability to give a coherent lecture, his penchant for bad puns, and his democratic approach to everyone in the department, whom he insisted call him "Steve" ( Figure 2.2). His only affectation, a minor one to be sure, was always wearing a white lab coat.

Figure 2.2 Steve Kuffler in the department lunchroom, circa 1970. (Courtesy of Jack McMahan)

Figure 2.2 Steve Kuffler in the department lunchroom, circa 1970. (Courtesy of Jack McMahan)

Kuffler's study of the retinal cell responses at Hopkins, which was the impetus for Hubel and Wiesel's work on vision, had already supplied one general answer to the question of what to do next. By the time I arrived back at Harvard as a fellow, Hubel and Wiesel were already well on the way to the dominant position in brain physiology that they would hold, for very good reasons, for the next several decades. Everyone working in neurobiology in the late 1960s assumed that it was just a matter of time until Hubel and Wiesel, and the cadre of followers they were beginning to spawn would provide a deep understanding of vision and perception.

Another aspect of Kuffler's work had stimulated a different direction that seemed equally promising, and this had determined the work that Nicholls was doing when I joined his lab. Despite the growing success of the experiments that Hubel and Wiesel (and others) were carrying out in the brains of cats (and later in monkeys), a concern in the 1960s was that the brain might be too complex to readily give up the secrets embedded in the details of its circuitry. Kuffler always had a knack for picking relatively simple systems such as the retina, the neuromuscular junction, or the sensory receptors found in muscles as a way to unravel some problem in neuroscience and extract answers of general significance. His approach was not unique—Hodgkin and Huxley had used the squid giant axon to understand action potentials for similar reasons, and Katz had focused on the frog neuromuscular junction as a model system in which to understand synaptic transmission. But Kuffler was especially insistent about the value of using a variety of simple preparations to advance the cause, and one of these preparations was the nervous system of the medicinal leech ( Figure 2.3). Following his graduate work with Katz, Nicholls had joined Kuffler's lab as a fellow in 1962, and they had worked together to understand the function of the other major class of cells in the nervous systems of all animals, the non-neuronal cells called glia. Glial cells outnumber neurons in the brain by three or four to one, and their role was largely a mystery; therefore, it made sense to look at what they were doing and their relation, if any, to the functions of nerve cells. For various technical reasons, Kuffler had decided that the leech was the best animal in which to carry out such work. By the time Nicholls left Harvard to join the faculty at Yale, the work on glia had largely finished, but he continued using the leech as a simple system in which to explore neuronal circuitry in relation to behavior.

The opinion held by Nicholls and many other neuroscientists when I joined his lab in the fall of 1968 (the only other lab member at that point was Ann Stuart, a graduate student earning her Ph.D.) was that a logical next step in moving beyond the established understanding of neural signaling would be to focus on invertebrate nervous systems as models for fathoming the basic principles of neural organization and function. The nervous systems of the leech and some other invertebrates were attractive in terms of neuronal numbers (hundreds or thousands compared to the 100 billion or so nerve cells in the human brain), large enough to enable the identification of the same nerve cell from animal to animal using only a low-power microscope, and easily recorded from with intracellular microelectrodes (see Chapter 1). The prospect of relating the function of identified nerve cells to some bit of behavior seemed both attractive and straightforward. Nicholls, Baylor, and Stuart had been plugging away with this goal when I visited Nicholls at Yale, and I threw myself into it as a novice neuroscientist at Harvard.

Figure 2.3 The medicinal leech and its central nerve cord (the chain of ganglia shown at the bottom right), the preparation that Kuffler and Nicholls used to study the role of glial cells in the nervous system. (After Purves, Augustine, et al., 2008)

Figure 2.3 The medicinal leech and its central nerve cord (the chain of ganglia shown at the bottom right), the preparation that Kuffler and Nicholls used to study the role of glial cells in the nervous system. (After Purves, Augustine, et al., 2008)

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