Figure 11 The faculty Steve Kuffler recruited when he came to

Harvard in 1959. Clockwise from the upper left: Ed Furshpan, Steve Kuffler, David Hubel, Torsten Wiesel, Ed Kravitz, and David Potter. This picture was taken in 1966, about the time the pharmacology group became a department in its own right under Kuffler's leadership. (Courtesy of Jack McMahan)

For me, and for most of my fellow first-year medical students, this instruction was being written on a blank slate. I had graduated the previous June from Yale as a premed student majoring in philosophy, and my background in hard science was minimal. Then, as now, premeds were required to take courses in only general chemistry, organic chemistry, biology, and physics. The premed course in biology at Yale that I took in 1957 was antediluvian, consisting of a first semester of botany in which we pondered the differences between palmate and pinnate leaves, and a more useful but nonetheless mundane second semester on animal physiology. We learned little about modern genetics, although James Watson and Francis Crick had discovered the structure of DNA several years earlier and the revolution in molecular biology was underway. John Trinkaus, the young Yale embryologist who taught us, ensured his popularity with the all-male class by well practiced off-color jokes that would today be grounds for dismissal.

Since the age of 14 or 15, I was determined to be a doctor. I decided in college that psychiatry was a specialty that would combine medicine with my interest in philosophy of the mind (the idea that the nuts and bolts of the brain biology might be involved in all this did not loom large in my thinking). In my senior year at Yale, I had been one of a dozen members of the Scholars of the House program that permitted us to forego formal course requirements and spend our time writing a full-blown thesis on a subject of our choosing (or the equivalent—two members of the group were aspiring novelists, and one was a poet). I am somewhat embarrassed to say that my thesis was on Freud as an existentialist. Although I enjoyed the perks of the program, the main lesson I learned from writing this philosophical treatise was that thinking about mental functions without the tools needed to rise above the level of speculation was frustrating and likely to be a waste of time. Therefore, in early spring 1961, I was especially attuned to what I might get out of our first-year medical school course on the nervous system. I assumed it would be the beginning of a new effort to learn about the brain in a more serious way than I had managed as an undergraduate, and so it was.

Even the least interested among us paid close attention to the distillation by Kuffler's young faculty of the best thinking about the nervous system that had emerged during the preceding few decades. The major topics they covered were the cellular structure of the nervous system, the electrochemical mechanisms nerve cells use to convey information over long distances, the means by which nerve cells communicate this information to other neurons at synapses, the biochemistry of the neurotransmitters underlying this communication, and, finally, the overall organization of the brain and what little was known about its functional properties. A truism often heard in science education is that much of what one learns will change radically in the near future. In fact, the fundamentals of neuroscience that we were taught in spring 1961 would, with a few important updates, serve reasonably well today.

The part of the course that was easiest to absorb concerned the cellular structure of the brain and the rest of the nervous system. A long-standing debate in the late nineteenth century focused on whether the cells that comprise the nervous system were separate entities or formed a syncytium in which, unlike the cells in other organs, protoplasmic strands directly connected these elements to form a continuous network. In light of the apparently special operation of the brain, the idea of a protoplasmic network was more sensible then than it seems now. The microscopes of that era were not good enough to resolve this issue by direct observation, and the discreteness of neurons (neurons and nerve cells are synonyms) was not definitively established until the advent of electron microscopy in neuroscience in the early 1950s.

The warring parties in this debate were Spanish neuroanatomist Santiago Ramon y Cajal, who favored the ultimately correct idea that individual cells signaled to one another by special means at synapses, and the equally accomplished Italian physician and scientist Camillo Golgi, who argued that a network made more sense. Ironically, Cajal won the day by using a staining technique that Golgi had invented, showing that the neurons absorbed the stain as individual elements (Figure 1.2A). Their joint contributions to understanding neuronal structure were enormous, and they shared the Nobel Prize for Physiology or Medicine in 1906. This work led to an increasingly deep understanding of the diversity and detail of nerve cell structure established by the legion of neuroanatomists that followed.

In addition to the individuality of nerve cells, a second key feature of neuronal anatomy is structural polarization (Figure 1.2B). Neurons generally have a single process extending from the cell body, called the axon, that conveys information to other nerve cells (or to non-neural target cells such as muscle fibers and gland cells), and a second set of more complex branches called dendrites, which receive information from the axonal endings of other nerve cells. Together with newly acquired electron microscopical evidence about neuronal structure ( Figure 1.2C), this comprised a fundamental part of what we learned in 1961.

Figure 1.2 The basic features of nerve cells. A) The typical appearance of a nerve cell revealed by Golgi's silver stain—the method Cajal used to demonstrate neuronal individuality. B) Diagrammatic representation of the same class of neurons as in (A), showing the relationship of the cell body, dendrites, and the axon (the asterisk indicates that the axon travels much farther than shown). C) Electron micrographs from the work of Sanford Palay, another teacher who had been recruited to the Department of Anatomy at Harvard Medical School in 1961. The micrographs show the same elements as (B), but at the much higher magnification possible with this method. The panel on the left shows dendrites (purple), the central panel shows two-cell bodies and their nuclei, and the right panel shows part of an axon (blue). ( The Fine Structure of the Nervous System: Neurons and Their Supporting Cells, 3e, by Alan Peters, Sanford L. Palay, Henry Webster; © Oxford University Press, 1991. Reprinted by permission of Oxford University Press, Inc.)

The second body of information we learned was how nerve cells transmit electrical signals and communicate with one another. For much of the first half of the twentieth century, neuroscientists sought to understand how neurons convey a signal over axonal processes that, in humans, can extend up to a meter, and how the information carried by the axon is passed on to the nerve cells (or other cell types) it contacts. By 1960, both of these processes were pretty well understood. Potter and Furshpan, Kuffler's young recruits from their postdoctoral training in London, shared the duty of teaching us how axons conduct an electrical signal—the action potential, as it had long been called ( Figure 1.3). Although efforts to understand the action potential can be traced back to Luigi Galvani and Alessandro Volta's studies of animal electricity in the late eighteenth century, British physiologists Alan Hodgkin and Andrew Huxley had only recently provided a definitive understanding in work that they had published in 1952. Galvani discovered that an electrical charge applied to nerves caused muscles to twitch, although he misunderstood the underlying events; it was Volta who showed that electricity produced by the battery he invented triggered this effect. By the mid-nineteenth century, German physician and physiologist Emil du Bois-Reymond and others had shown that an electrical disturbance was progressively conducted along the length of axons; by the beginning to the twentieth century, it was apparent that this process depended on the sodium and potassium ions in the fluid that normally bathes the inside and outside of neurons and all other cells. Despite these advances, the way action potentials are normally generated remained unclear; by the 1930s, it was obvious that the most salient problem in neuroscience at the time was to understand the action potential mechanism and how this electrical signal is conducted along axons. After all, this signaling process is the basis of all brain functions.

Hodgkin had begun working on the action potential problem in 1937 as a fellow at Rockefeller University and the Marine Biological Laboratory in Woods Hole on Cape Cod. Back at Cambridge in 1938, he and Huxley, who was one of his students, began to collaborate. Their joint effort was interrupted by the war, but by the late 1940s, Hodgkin and Huxley had shown, on the basis of a beautiful set of observations using the giant axon of the squid, that the mechanism of the action potential was a voltage-dependent opening of ion channels, or "pores," in the nerve cell membrane that enabled sodium ions to rush into an axon, causing the spike in the membrane voltage illustrated in Figure 1.3 (the technical advantages of this very large axon explains why they used squid, as well as the reason for working at Woods Hole and, subsequently, at the Plymouth Marine Laboratory in the United Kingdom). They found that the voltage reduction across the nerve cell membrane that caused the inrush of sodium underlying the spike was the advancing action potential itself. By successively depolarizing each little segment of an axon, the electrical disturbance (the spike) is conducted progressively from one end of the axon to the other. A good way to visualize this process is how the burning point travels along the length a fuse, as seen in old western movies. The analogy is that the heat at the burning point ignites the powder in the next segment of the fuse, enabling conduction along its length. Hodgkin and Huxley's discovery of the action potential mechanism was quickly recognized as a major advance; ten years after the work had been published, the Nobel committee awarded them the 1963 prize in Physiology or Medicine.

Figure 1.3 The electrical signal (the action potential or spike) that is conducted along nerve cell axons, transferring information from one place to another in the nervous system. A) Diagram of a cross-section of the spinal cord showing the stimulation of a spinal motor neuron (red) whose axon extends to a muscle. The electrical disturbance conducted along the axon is recorded with another electrode. B) The brief disturbance elicited in this way can be monitored on an oscilloscope, a sensitive voltmeter that can measure changes across a nerve cell membrane over time. The action potential lasts only a millisecond or two at the point of recording, traveling down the axon to the muscle at a rate of about 50 meters per second. If, as in this case, the action potential is being recorded with an electrode placed inside the axon, it is apparent that the phenomenon entails a brief change in the membrane potential that first depolarizes the axon (the upward part of the trace), and then quickly repolarizes the nerve cell to its resting level of membrane voltage (the downward part of the trace that returns to the baseline). (After Purves, Augustine, et al., 2008)

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This much deeper understanding of the mechanism of the action potential in the late 1940s and early 1950s made an equally important question more pressing: When the signal reaches the end of an axon, how is the information then conveyed to the target cell or cells? For example, how does the information carried by the axon of the motor neuron in Figure 1.3A cause the muscle fibers it contacts to contract? Teaching us the answer to this question about neural signaling also fell to Potter and Furshpan, and their zeal was missionary. Although the class included about 110 of us, they called each of us by name within a week. They had just finished fellowships working together in Katz's lab, and it was Katz who supplied the answer to this question about neural signaling. Trained in medicine in Leipzig in the early 1930s, Katz, who was Jewish, had emigrated to England in 1935. Archibald Hill, then head of the Department of Biophysics at University College London and a preeminent figure in the field of energy and metabolism, particularly as these issues pertained to muscles, took Katz under his wing. Katz had worked on related problems as a medical student; the two had corresponded, so it was natural for Hill to take him on as a graduate student, even though the political importance of his sponsorship left Katz deeply indebted (a bronze bust of "A.V.," as Hill was known to his faculty, had a prominent place in Katz's office in the department he eventually inherited from Hill).

His work on muscle energetics with Hill led Katz to a growing interest in the signaling between nerve and muscle. When he finished his doctoral work in 1938, Katz went to Australia as a Carnegie Fellow to work more directly on this aspect of signaling with John Eccles, the leading neurophysiologist then working on synaptic transmission. While in Australia, Katz became a British citizen, served in the Royal Air Force as a radar officer, married, and eventually returned to University College London as Hill's assistant director in 1946. Back in England, he briefly collaborated with Hodgkin and Huxley on understanding the action potential and coauthored a paper with them that reported one of the major steps in this work in 1948. Katz had joined the effort at the end of Hodgkin and Huxley's remarkable collaboration, and had the foresight to see that he would be better off working on a related but different problem: how action potentials convey their effects to target cells by means of synapses. As fellows in Katz's lab, Furshpan and Potter had been involved in one aspect of this work just before Kuffler recruited them to Harvard in 1959.

The concept of synaptic transmission had emerged from Cajal's demonstration that nerve cells are individual entities related by contiguity instead of continuity. British physiologist Charles Sherrington coined the term synapse in 1897 (the Greek word synapsis means "to clasp"), which was soon adopted, although not until the 1950s were synapses seen directly by means of electron microscopy. The information that Potter and Furshpan conveyed to us in their lectures was essentially what Katz had discovered during the first decade or so of his work on the nerve-muscle junction. The steps in this process are illustrated in Figure 1.4.

Figure 1.4 Synapses and synaptic transmission. A) The neuromuscular junction, the prototypical synapse studied by Katz and his collaborators as a means of unraveling the basic mechanisms underlying the process of chemical synaptic transmission. B) Diagram of a generic chemical synapse, illustrating the steps in the release of a synaptic transmitter agent from synaptic vesicles, which is stimulated by the arrival of an action potential at the axon terminal. The binding of the transmitter molecules to receptors embedded in the membrane of the postsynaptic cell enables the signal to carry forward by its effect on the membrane of the target cell, either exciting it to generate another action potential or inhibiting it from doing so. (After Purves, Augustine, et al., 2008)

Katz's work on synapses had effectively begun during his fellowship with Eccles in Sydney in the late 1930s. Eccles, an Australian, had trained at Oxford as a Rhodes Scholar under Sherrington, and had earned his doctoral degree there in 1929. When Katz arrived in Australia in 1938, Eccles had been working on synaptic transmission, having been interested in this problem since his time with Sherrington. Another recent arrival in Sydney was Kuffler, who was at that point just another bright young Jewish emigré. He had come in 1937 after completing medical training in Hungary, and had been working in the pathology department of the Medical School in Sydney. Kuffler met Eccles by chance on the tennis court. During their conversations, he expressed openness to doing something more interesting than his work in pathology, and Eccles eventually invited him to join his lab as a fellow. Katz and Kuffler quickly became friends and, with Eccles' blessing, began working on how action potentials activated muscle fibers ( Figure 1.5).

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