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Absorbing the rationale for exploring the nervous system in this way, and learning the required methods and their scientific basis as a beginner with no background in electronics, mathematics, or anything else that was particularly relevant, led to many low moments. But the work was conceptually and technically fascinating, and I was buoyed by the fact that a lot of obviously smart people thought this was a good way to explore how vastly more complex brains do their job. In addition to Nicholls, the members of the department then operating under the assumption that a route to further success in neuroscience lay in mining answers that could be provided by simple preparations were Ed Kravitz, working on neurotransmitters in lobster ganglia ( Figure 2.4A); Potter and Furshpan working on the synaptic function of small numbers of isolated nerve cells in tissue culture; Zach Hall working on the molecular components of synapses; and Kuffler and his group working on the nervous systems of leeches, mudpuppies, crayfish, and frogs with a variety of related interests and aims.

Figure 2.4 Some other "simple" central nervous systems being studied in the late 1960s under the assumption that invertebrate preparations would be a good way of understanding the operating principles of more complex nervous systems. A) The "brain" and stomatogastric ganglion of the lobster. B) The abdominal ganglion of the sea slug. The perceived advantage of these preparations compared to mammalian brains was the small number of cells, many of which could be individually identified and studied by intracellular recording. (After Purves, Augustine, et al., 2008)

Figure 2.4 Some other "simple" central nervous systems being studied in the late 1960s under the assumption that invertebrate preparations would be a good way of understanding the operating principles of more complex nervous systems. A) The "brain" and stomatogastric ganglion of the lobster. B) The abdominal ganglion of the sea slug. The perceived advantage of these preparations compared to mammalian brains was the small number of cells, many of which could be individually identified and studied by intracellular recording. (After Purves, Augustine, et al., 2008)

The only people in the department actually working on mammalian brains were Hubel and Wiesel. Although they had begun as Kuffler's protégés in the late 1950s, by 1968, they had established a largely separate unit within the department, which they ran according to their own lights. Hubel and Wiesel were attentive to and interested in what others in the department were up to, but they seemed to see their own goals as different (and, one sensed, more important) than those represented by the work that the rest of Kuffler's faculty was doing. The lab assigned to Nicholls when he arrived was in the same limb of the U-shaped department that housed Hubel and Wiesel's separate empire (in reality, just a few contiguous lab rooms, but with space for their own secretary and a small room for a technician who did photography and histology). They also had a little lunchroom, and Nicholls, Stuart, and I routinely ate lunch with Hubel and Wiesel and the four or five people in their lab. So I came to know more about them and their work than the others in the department. Although the respect everyone had for Kuffler kept a lid on things, strains were apparent. The tension seemed to arise not just from personal idiosyncrasies, but from the philosophical differences between Hubel and Wiesel's direct approach to brain function and the different approach of the majority who were working out cellular circuits and mechanisms in simpler systems. It didn't help that Hubel and Wiesel's scientific success was rapidly outstripping that of the other members of the department.

The enthusiasm for simple invertebrate systems as a way to understand aspects of neural function eventually paid off, but not in the ways that were envisioned in the 1960s. The dominant idea then—that relating the properties of individual neurons to neural circuits and behavior would yield insights into the functional principles of complex brains—died a slow death during the following 20 years. There were several reasons, but a primary cause was the rapid rise of molecular biology that followed the discovery of the structure of DNA in the early 1950s. It was apparent by the mid-1970s that the tools of molecular biology provided a powerful way to study neural function. James Watson, in his typically provocative way, proclaimed publicly that molecular biology would solve the remaining problems in neuroscience within 25 years. Although Watson's claim was nonsense, the entry into neurobiology in the late 1960s and 1970s of superb molecular biologists such as Sydney Brenner, Seymour Benzer, Marshall Nirenberg, Gunther Stent, Julius Adler, Cyrus

Levinthaland others (Francis Crick ultimately joined the crowd) rapidly changed the scene with respect to simple nervous systems. With surprising speed, the neurogenetics and behavior of rapidly reproducing invertebrates, such as the roundworm Cenorhabitis elegans and the fruitfly Drosophila melanogaster, supplanted leeches, lobsters, and sea slugs as the invertebrates of choice, with molecular genetics considered the best way to ultimately understand their nervous systems. Even the success of Eric Kandel, who started working on the sea slug nervous system ( Figure 2.4B) in the 1960s for the reasons then in fashion, was ultimately based on how the modulation of the genes by experience can lead to synaptic changes that encode information. Kandel, who won a Nobel Prize in 2000 for this work, was the most energetic cheerleader for the simple central nervous system approach when I arrived in Nicholls's lab. The first lunchtime seminar I presented in the Department of Neurobiology in 1968 was a critique of one of Kandel's early papers. Nicholls saw Kandel as a competitor whose work did not meet the standards of scientific rigor that he had absorbed as a student of Katz and Kuffler. Even though I had been at it only a few months, Nicholls's bias had already rubbed off on me. Nonetheless, I quickly gathered that there was no consensus among my new colleagues about how to go about understanding the brain and the rest of the nervous system.

As Baylor had promised, Nicholls was indeed a good mentor. After two years of working hard to understand how sensory and motor neurons in the leech's nervous system were related, I had written two papers of very modest interest that were published in the Journal of Physiology, the journal of record in those days (an output of one detailed paper a year was typical then, although it wouldn't get anyone a job today). But despite my appreciation of his teaching, Nicholls and I did not get along particularly well. In addition to what we were doing on a daily basis, I wanted to discuss the broader issues that had always interested me about brains and their functions, and Nicholls didn't have much stomach for that sort of thing. He told me that as a graduate student, he had been terrified of Katz and the prospect of his failing in his eyes; perhaps as a result, he seemed unwilling to think in grander terms that Katz would presumably have thought overblown or silly. Our personalities and perspectives were very different in other ways as well. One day Hubel and Wiesel called us into their lab to show us the response properties of a particularly interesting neuron that they were recording from in the visual cortex of one of their cats. There was not much doubt by then that what Hubel and Wiesel were doing would influence thinking about the brain for a long time to come, and some humility in the face of this presumption was certainly warranted. But I was taken aback when Nicholls remarked after we went back to the lab that some of us in science inevitably had to be the drones and not the queen bee. Although empirically true, to hold this view while still in one's thirties (Nicholls was then 36) seemed to me a bad idea.

By mutual consent, Nicholls and I agreed that I would spend the third year of my fellowship in Kuffler's lab (I had already told Sweet that I would not be returning to the neurosurgical program). During my last months with Nicholls, I had been working with Kuffler's senior collaborator at the time, Jack McMahan. We had been looking at the anatomy of leech neurons revealed by the injection of a fluorescent dye that Kravitz had developed as a sort of sideline. This was an exciting new method that for the first time enabled neuroscientists to see all the axonal and dendritic branches of an identified nerve cell whose electrical properties had been studied by recording through the electrode that injected the dye. Jack, who is a terrific neuroanatomist, was about my age, although he was years ahead of me as a neuroscientist and about to be named to the faculty. We got along famously and had a wonderful time that year, during which he taught me how to do electron microscopy. Unlike Nicholls, who was always reticent to simply natter on about neuroscience, Jack and I argued incessantly about what might be done and how to do it.

During that year, Katz visited Kuffler's lab, as he regularly did. The friendship and mutual respect between the two formed in Australia had resulted in a small but steady flow of young neuroscientists between Boston and London. It was clear that working in Katz's orbit would be a fine next step for me. Although I had learned a lot of neuroscience in my three years as a fellow, I had started from scratch. It seemed foolhardy not to seek more training before going off on my own, and no one seemed to disagree. Moreover, I had decided that working on invertebrate nervous systems was not the road to the future I wanted to follow; working as a fellow on a different topic would therefore be important. And so I asked Nicholls and Kuffler if they would support my case to Katz, which they did. Harvard offered a generous traveling fellowship that supported two years of study abroad, and in the summer of 1971, Shannon and I set off for London with our one-year-old daughter. What I would pursue in Katz's small Department of Biophysics at University College had not been specified, but I was at least sure by then that I had found the right profession.

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