ECCLES, JOHN CAREW

(b. Melbourne, Australia, 27 January 1903;

d. Contra, Switzerland, 2 May 1997), spinal cord, cerebellum, neurophysiology, synapse.

John (“Jack”) Eccles was a pioneer of the physiology of the nerve cell, a leader in the rise of modern neuro-science in the middle of the twentieth century. He led the way in characterizing the mechanisms of the contacts (synapses) between nerve cells in the central nervous system. He was the first to identify a central neurotransmitter, the action of a central inhibitory neuron, and central circuits formed by synaptic contacts and synaptic actions.

Early Life and Career . Eccles was born and raised in Australia. His parents were both schoolteachers and Catholics, a family background that shaped his future career. He received his undergraduate and medical training at the University of Melbourne, graduating in 1925 with first-class honors. He won a Rhodes Scholarship for study at Oxford University, where he joined the group of outstanding young investigators, which included Derek Denny-Brown, John Farquhar Fulton, R. S. Creed, and E. G. T. Liddell, producing a series of studies under Charles Sherrington on spinal cord reflexes. This resulted in the landmark book Reflex Activity of the Spinal Cord (1932) by Creed and others. The book was believed to have played a significant role in the awarding of the Nobel Prize to Sherrington (together with E. G. Adrian of Cambridge) that year.

Eccles completed a BS at Oxford in 1927 and a DPhil in 1929, and then became a tutor at Magdalen College and a university demonstrator in 1934. Sherrington took him on as his research assistant for Sherrington’s last experiments on excitation and inhibition of spinal cord reflexes. Eccles then developed his own studies of synaptic transmission in sympathetic ganglia, in which he interpreted his findings in terms of electrical transmission between the stimulated nerves and the postsynaptic cells. This brought him into conflict with the emerging pharmacological evidence by Henry H. Dale, Wilhelm Feldberg, Lindor Brown, and others for the release and action of chemical transmitters at the synaptic junctions between nerve cell fiber terminals and their target glands and muscles. Thus was engendered the “soup versus sparks” debates, which often involved pitched battles between the participants at one meeting after the other throughout the 1930s. Bernard Katz, who came to England in the mid-1930s as a refugee from Germany, described his amazement at how violently the younger Eccles and the older Dale would attack each other during these meetings, and his further amazement at how they would then retire to sherry and a convivial dinner together.

Return to the Antipodes . Sherrington retired in 1935 (at the age of seventy-five, having been granted a personal extension). Although Eccles was an obvious candidate to succeed him, his youth, brashness, and pugnacity were not a good fit with Oxford traditions and John Mellanby was appointed instead. In 1937 Eccles left to return to Australia (a common career trajectory after training in England) to head a small medical research unit in the Kanematsu Institute of Pathology in Sydney. It was near oblivion for him, with no university connection, no access to students, and an unsympathetic administration. Soon the onset of the war in Europe in September 1939 diverted most of his attention to the war effort. By good fortune, he was joined by both Katz and another refugee, Stephen Kuffler. There is an often reproduced photograph of the three young neuroscience greats strolling together down a street in Sydney (a painting of the photograph hangs in the physiological laboratory in Oxford). In 1939 Eccles reported electrophysiological recordings from the neuromuscular junction with evidence of chemical transmission, simultaneously with similar reports by T. P. Feng (Feng De-Pei) in China and H. Gopfert and H. Schaefer in Germany. Although this was a great breakthrough in the analysis of the physiology of the synapse, it also disproved his own electrical hypothesis, at least for peripheral synaptic transmission.

With prospects for building his research efforts dim at the institute, in 1944 Eccles accepted the professorship of physiology at the University of Otago, in Dunedin, New Zealand. Despite the remote location, it gave him the opportunity to return to an academic setting for his research, though with a heavy teaching load. He describes how in his first year he gave all the physiology lectures, totaling some 500 contact hours. On the positive side, it gave him discipline in using his time and a broad grasp of physiological principles.

Eccles was still depressed over the failure of his theoretical predictions in the 1930s, until meeting the philosopher Karl Popper in New Zealand just after the war. Popper was developing his philosophy of science, with the dictum that science can never prove a hypothesis correct, it can only falsify it, the goal of the scientist being to erect hypotheses that can be tested and disproven. According to this view, Eccles had been advancing science by proving himself wrong. The two became lifelong friends. The new concept of doing science rescued Eccles from his depression. “I was urged by Popper to formulate the hypotheses of electrical excitation and inhibition in models that invited experimental testing and falsification” (Eccles, 1977)—to which Eccles added a corollary: only Eccles would be allowed to disprove Eccles’s hypotheses!

Despite the isolation of Dunedin, after the war he assembled a group of outstanding young students and colleagues from New Zealand and abroad, including the electrophysiologist Archibald (“Archie”) McIntyre and the American biophysicist Wilfrid Rall. For several years he pursued his hypothesis of electrical transmission in the spinal cord. This required convoluted reasoning to account for current flows that could cause postsynaptic inhibition. In his remote location, one less motivated might have lost out in the postwar era of gearing up for modern cellular research and drifted out of the mainstream.

However, around 1950 McIntyre returned from the Rockefeller Institute with the circuit for the new state-ofthe-art amplifier built by Jan Friedrich Toennies, an outstanding German-trained engineer (who before the war had trained Alan Hodgkin in cathode followers for his squid axon studies). Dexter Easton came with the news that J. Walter Woodbury and Harry Patton in Seattle were beginning to make intracellular recordings in the spinal cord. This galvanized Eccles to a single-minded focus on this goal, with an intensity that could not be matched by the Seattle group.

It was a singular moment for Eccles, “a crisis in my life.” Spurred by fear of the competition, he resolved to get there first. He needed hands to do it. Eccles asked John (“Jack”) Coombs, a physicist, to find help with the electronics for doing the microelectrode work. Coombs decided it was interesting and would do it himself, constructing the needed cathode follower amplifier with high input impedance to reduce input capacitance and neutralize pipette capacitance by negative feedback.

Laurence Brock had just completed his medical course; he was good with his hands, and he pulled the micropipettes. This was done on a “microforge,” requiring extreme concentration to pull the pipettes to a fine tip, and luck to get them fully filled with the electrode solution. Rall had started earlier work with Eccles, but decided he would do his own project for his PhD thesis. Archie MacIntyre was a mild-mannered person at an early stage in his career. Eccles at the time was using the classical mechano-electric Lucas pendulum breaks for stimulators, recording the data on glass negatives that were developed as they went along. When he realized he needed McIntyre’s state-of-the-art equipment, he simply took it over. All efforts were bent on beating the Americans.

Eccles plunged into making intracellular recordings from the motor neurons in the spinal cord in response to an electrical shock to the motor neuron axons in the ventral roots. This approach enabled him to identify a motor neuron by the action potential in its axon invading backwardly (antidromically). He could then analyze the response of the cell to injected current and to synaptic activation over the normal (orthodromic) route by a shock delivered to sensory axons in the dorsal roots. The recordings immediately showed that stimulation of the sensory nerves from an agonist muscle set up depolarizing, excita-tory postsynaptic potentials in a motoneuron, whereas from an antagonist muscle, hyperpolarizing inhibitory postsynaptic potentials were set up. These responses showed clearly the properties of chemical rather than electrical transmission. The electrical hypothesis was triumphantly demolished by its own Popperian architect.

These results were published in the Journal of Physiology beginning in 1951. In that year Eccles accepted the opportunity to move back to Australia, to be professor of physiology in the newly established Australian National University (ANU) in Canberra. It took fifteen months for the new laboratories to be ready, an interim that might have been fatal to most research workers at that critical juncture. However, Eccles typically used it to full advantage. He spent five months traveling in early 1952, first to a Cold Spring Harbor symposium on the neuron, where he learned about the Hodgkin-Huxley action potential model and the Katz neuromuscular junction work, then back to England to summarize the new results in the Waynflete Lectures, delivered at Magdalen College in Oxford in 1952 and published in his The Neurophysiological Basis of Mind: The Principles of Neurophysiology in 1953.

Neurophysiology . In many ways, this work and the book launched the modern cellular physiology of the central nervous system. It established the basic functions of chemical excitatory and inhibitory synapses, just before they were visualized morphologically for the first time in the electron microscope. They were furthermore developed firmly within the context of the emerging modern concepts of the properties of cell membranes, thanks to his rapid assimilation of the work of Alan L. Hodgkin and Andrew F. Huxley in developing their model of the action potential in the squid axon, and of Katz and Paul Fatt in their model of the neuromuscular junction. It immediately laid out the future of cellular and circuit neuroscience, at a time when neurophysiology ruled studies of the nervous system, before the advent of the biochemical and pharmacological approaches that we take for granted today.

Starting in the new laboratories in early 1953, Eccles, with Fatt and Kyozo Koketsu, identified the circuit mediating recurrent inhibition, from the collateral branches of the motor neuron axon to an inerneuron and back onto the same and neighboring motor neurons. The inhibition of a motoneuron by an interneuron had previously been predicted from recordings around 1940 by a young investigator at Harvard University, Birdsey Renshaw, who subsequently died at an early age of polio in 1947. Eccles termed these “Renshaw cells” in his honor, and they became the paradigmatic form of self and lateral feedback inhibition, with examples being found subsequently in many different regions of the nervous system. Paradoxically, in those regions specific functions for the inhibition could be proposed, whereas the functions in the spinal cord remained elusive. A new synthesis of these results with intracellular recordings in other nerve cells was summarized in his widely read book The Physiology of the Nerve Cell in 1957.

These findings on central synaptic transmission in the spinal cord were paralleled by the reports of Katz and his collaborators Fatt and José del Castillo revealing the mechanisms of chemical transmission at the neuromuscular junction. The air was suddenly cleared;

chemical transmission appeared to be the way neurons communicate by means of synapses. This soon received strong support from the revelations of the electron microscope of the fine structure of the chemical synapse by Sanford Palay and George Palade in the United States and Eduardo de Robertis and H. S. Bennett in Argentina. However, within a few years electrical synapses were described by Ed Furshpan and David Potter, and their basis in gap junctions was shown, to give the present understanding of both chemical and electrical transmission in the central nervous system.

During the 1950s Eccles engaged in several unduly harsh efforts to apply the Popper doctrine to falsifying the findings of colleagues. One was David P. C. Lloyd, a former student at Oxford, over details of synaptic connectivity in the spinal cord. Another was his former student Rall, who brought forward evidence from Eccles ’s own recordings for dendritic dominance of synaptic integration. Eccles would brook no opposition, claiming another explanation based on a postulated persistent current. Rall refuted this explanation, and Eccles eventually abandoned it. But as late as 1960 he was still defending the idea that dendrites had mostly nutritive roles, being too distant to affect synaptic integration, which he believed was focused at the cell body where his recordings were made. His opposition greatly impeded recognition of the significance of Rall’s work and the value of theory in neuroscience, in which Rall first adapted basic cable theory followed by his new methods of compartmental analysis to show that most synaptic integration takes place in the dendrites. However, as was typical of Eccles, harkening back to his interactions with Dale, when Rall and his colleagues came forward with evidence for novel interactions between dendrites, it was Eccles who organized and invited Rall to co-chair with him a meeting in 1968 where these new findings were presented. The reason for his harsh attacks may be traced back to his training in England, where such exchanges, as described above, could take place between colleagues within the clubby atmosphere of the Physiological Society. However, in the outside world, they were interpreted as doing unnecessary harm.

During the 1950s Eccles’s laboratory in Canberra was a magnet for a new generation of cellular neurophysiologists from around the world. More than 100 of his approximately 200 students and collaborators came from that time. The several experimental rigs were in use around the clock, experiments often lasting through the night and sometimes through the next day (as in other electrophysiological laboratories of that era). For social variety there were the famous parties at Eccles’s home, where he and his wife Irene Francis would entertain the group with square dancing, party games, and sports.

In the 1960s Eccles broadened his interests from the spinal cord to other brain regions, assisted by several outstanding students. A leading strategy was to test the generality of the Renshaw cell inhibitory feedback pathway. To this end he carried out a series of experiments, with Per Andersen from Norway, extending the model to inhibitory circuits in the thalamus and hippocampus. The productivity of that collaboration can be judged by the twenty-four papers produced in their two years together. With Masao Ito and others, Eccles carried out a series of intracellular experiments on neuronal interactions in the cerebellum. This produced evidence for the basket cell as an inhibitory interneuron, one of the first extensions of the Renshaw cell concept (along with the granule cell of the olfactory bulb) to the brain. This resulted in the book The Cerebellum as a Neuronal Machine(1966), written with Ito and the neuroanatomist John Szentagothai. These investigations increasingly used pharmacological tools to characterize the nature of chemical in these different areas, which were summarized in another widely read book, The Physiology of Synapses(1964). From a current perspective it is noteworthy that all of this work was in anesthetized animals, predating the introduction of the brain slice preparation in 1971.

Late Career . As Eccles approached retirement age in the 1960s, his wish to remain active at the ANU went unheeded, so he left in 1966 to carry on his studies at a new private Institute of Biomedical Research set up by the American Medical Association in Chicago. Rodolfo Llinas, among other young investigators, joined him there. When this institute collapsed, he went to the State University of New York at Buffalo, together with his second wife Helena, also a neurophysiologist. There he continued to pursue his work on the cerebellum with a new generation of young neurophysiologists, including visiting former colleagues such as Don Faber, Henri Korn, Robert Schmidt, and Yamakazu Oshima. He also began to be interested in the interactions between the cerebellum and the neocortex, intrigued by the fact that 88 percent of the human cerebellum is oriented exclusively to the contralateral cerebrum. However, the grant to support this work ended in 1975, leading to his retirement in that year at the age of seventy-two.

He moved to a mountain village in Switzerland, which might seem remote, but not for Eccles. His retirement did not mean the end of his career in neuroscience, but rather a refocusing of his interests. An omnivorous reader and indefatigable traveler, he followed closely the current research, particularly on the cerebral cortex. The role of Ca2+ in synaptic integration in cortical neurons engaged his interest and prompted a series of articles well into the 1980s.

Retirement also meant the opportunity to pursue his lifelong absorption in the relation of brain circuits to cognition, philosophy, and religion. This had started with the last chapter in The Neurophysiological Basis of Mind in 1953, a rather startling—and some felt irrelevant— distraction from the solid science in the book, but this was his life view from the start. As a Catholic, he attacked the problem of the mind and the brain with the same vigor that he used in his scientific endeavors. He was inspired in this by his Oxford years with Sherrington, who set forth his own philosophical views on Cartesian dualism in Man on His Nature in 1940. Eccles published many articles and several books on resolving the mind-body problem (106 of his 588 publications according to Andersen and Lundberg, 1997), his most extensive attempt in a dialogue between himself, a dualist, with his old friend Popper, an agnostic, laid out in the book The Self and Its Brain: An Argument for Interactionism in 1977. It continued his attempt to probe the neural basis of consciousness, which has lately become a fashionable topic in cognitive neuroscience. So he can be called a pioneer in this field as well.

Many honors were bestowed on Eccles during his career. Among them, he was a member of the Royal Society, and Nobel laureate in 1963 with Hodgkin and Huxley, recognized for his discoveries of the ionic basis of the function of nerve cells in the central nervous system.

In summing up his career, several themes are of interest to early twenty-first century scientists. One is his odyssey, as he described it himself, across the oceans, from Australia to Britain, back to Australia, to New Zealand, back to Australia, and to the United States and finally Switzerland; a scientist goes where the opportunities are greatest to realize one’s career goals. Another is his life as an educator: he was willing in Dunedin to assume overwhelming teaching responsibilities that not only served his institution but grounded him in the fundamentals of his field. He was also an educator through his research: his 200 students and collaborators populated academia and industry with the new science. Scientists are supposed to write original research articles, not books, yet his books were instrumental in shaping modern neuroscience.

To those who knew him, his was a personality truly larger than life. He had a vigorous physique, with prodigious stamina at the experimental rig, at his desk, or traveling the world with his message. The voice was penetrating, with a broad Australian accent, overwhelming in debate and naturally dominating in conversation. He had a wide mouth, ready instantly to break out into a broad grin or hearty laugh to express a life-embracing sense of humor. There was total engagement in whatever issue was being discussed, with an encyclopedic grasp of the literature. He was courteous and generous to his friends and colleagues. Finally, he was a scientist who reserved a place in his life for his spiritual side. To those who knew him, he was the embodiment of a great era in the creation of modern neuroscience.

BIBLIOGRAPHY

A full account of all aspects of Eccles’s life and works may be found in the numerous articles in a memorial issue: Stuart, D.G., ed. “The Contributions of John Carew Eccles to Contemporary Neuroscience.” Progress in Neurobiology 78, no. 3–5 (2006): 135–326.

WORKS BY ECCLES

The Neurophysiological Basis of Mind: The Principles of Neurophysiology. Oxford: Clarendon Press, 1953.

The Physiology of the Nerve Cell. Baltimore, MD: Johns Hopkins Press, 1957.

The Physiology of Synapses. New York: Academic Press, 1964.

With Masao Ito and John Szentagothai. The Cerebellum as a Neuronal Machine. Berlin and New York: Springer-Verlag, 1966.

With Karl Popper. The Self and Its Brain: An Argument for Interactionism. New York: Springer International, 1977. The most complete account of his philosophy and spiritual beliefs.

“My Scientific Odyssey.” Annual Review of Physiology 39 (1997): 1–18.

OTHER SOURCES

Andersen, Per, and Anders Lundberg. “John C. Eccles (1903–1997).” Trends in Neuroscience20 (1997): 324–325.

Burke, R. E. “John Eccles’ Pioneering Role in Understanding Central Synaptic Transmission.” Progress in Neurobiology78 (2006): 173–188.

Stuart, Douglas G., and Patricia A. Pierce. “The Academic Lineage of Sir John Carew Eccles (1903–1997).” Progress in Neurobiology 78 (2006): 136–155.

Gordon M. Shepherd