John Carew Eccles 1903-1997

Written by David R. Curtis and Per Andersen.

• Introduction
• Early years and family background
• Oxford
• Sydney
• Dunedin
• Canberra
• Chicago and Buffalo
• Switzerland
• The mind-brain problems: Philosophical considerations
• Personality
• Family
• Australian Academy of Science
• Education
• Positions held
• Honours and awards
• About this memoir
  • Acknowledgements
  • References
  • Bibliography

Introduction

Sir John Eccles, internationally recognized for his remarkable and outstanding impact on the neurosciences for more than six decades, died on 2 May 1997 at the age of 94. He carried out his research in Oxford, Sydney, Dunedin, Canberra, Chicago and Buffalo from 1927 until 1975 (441). His numerous scientific papers and books, arising from detailed and pioneering experimental studies of synaptic mechanisms and the organization of neurones in the mammalian central nervous system, continue to have a major influence on brain research. Furthermore, his writings on the mind-brain interaction generated wide interest and debate. Eccles also made his mark as an administrator, particularly at the Australian National University and the Australian Academy of Science, of which he was a Foundation Fellow and the second President.

Early years and family background

John Carew Eccles was born on 27 January 1903 at Northcote, a suburb of Melbourne. Both his father, William James Eccles, and his mother, Mary (née Carew) were born in Victoria and were school teachers. The Eccles family came from Lancashire in England, his paternal grandfather Henry Basil Eccles having migrated to Victoria in 1849 and his grandmother Mary Jane Ingram from Limerick in Ireland in the same year. His maternal grandfather John Carew migrated to Victoria from Tipperary in Ireland in 1852, his grandmother Harriet Elizabeth Merry from Berkshire in England in 1858. Eccles's sister, Rosamond, to whom he was closely attached, was born in 1904.

At the age of 12, Eccles began his secondary schooling at Warrnambool High School. After four years, prior to entering the University of Melbourne, he studied science and mathematics for another year at Melbourne High School. He headed the school at the final State-wide examination, shared the State geometry prize and gained a Senior Scholarship to the University. Although deeply interested in mathematics, Eccles chose medicine and commenced his five-year course early in 1920 at the age of 17. He lived at home and attended tutorials at Newman College. His continuing academic successes attracted the attention of a number of professors, including W.A. Osborne (Physiology). As a medical student he was active in university societies and sport, gaining a full blue in athletics for his Australian universities record in pole vaulting.

Eccles also developed his interests in the arts. His reading of Darwin's Origin of Species in the first-year zoology course led to wide reading of classical and contemporary works in philosophy dealing with the mind-brain problem. Unable to obtain a satisfactory explanation of the interaction between the mind and the brain and realizing that so little was known about the brain itself, he decided as a medical student to become a neuroscientist (see 425). After reading CS Sherrington's 1906 book, The Integrative Action of the Nervous System, Eccles resolved to achieve a Rhodes Scholarship to work with him at Oxford University. He later described Sherrington as 'the one man in the world whom I wished to have as my master' (441).

Eccles completed his medical course in February 1925, gaining First Class Honours and First Place, the exhibition in eight of ten subjects and several clinical prizes, and graduated with the degrees of Bachelor of Medicine and Bachelor of Surgery. He had already been awarded the Rhodes Scholarship for Victoria in November 1924. After six months as a Resident Medical Officer at St Vincent's Hospital, he left Melbourne at the end of August 1925 and arrived in Oxford early in October.

Oxford

Eccles had been accepted by Magdalen College, of which Sir Charles Sherrington was a Fellow. A letter of introduction from Sherrington's friend Professor Osborne initiated Eccles's close and deeply influential friendship with Sir Charles, which continued until the latter's death (441,468, 505). Initially, he spent two years studying for the Final Honours School in Physiology and Biochemistry, and over this period at Magdalen he read widely in the neurophysiological, biochemical, philosophical and theological literature. In mid-1927 he was awarded First Class Honours, the Christopher Welch Scholarship and a Gotch Prize. He commenced his DPhil under the supervision of Sherrington in the autumn of 1927 and moved to Exeter College, having been appointed a Junior Research Fellow for five years.

Eccles has vividly described 'life in Sherrington's laboratory' over the period 1925-1935 which was enriched by numerous visitors from Europe and North America (441, Chap.5 of 468, and 505). At this time there was much speculation regarding the nature of the transmission process at central synapses. Strong evidence for chemical transmission at peripheral excitatory and inhibitory synapses had been provided, particularly by the findings of O Loewi and of HH Dale and his colleagues. Nevertheless, central synaptic transmission was widely considered to be similar to the electrical propagation of impulses along nerve fibres, although Sherrington (1925) had suggested that the inhibition of spinal reflexes might be mediated by a chemical agent.

Eccles's introduction to research was with EGT Liddell and D Denny-Brown in a study of the effects of electrical stimulation of the cerebellar cortex on spinal reflexes in the cat (3). Later in 1927 he joined RS Creed in a study of inhibition in the spinal cord (1), and in 1928 investigated crossed extensor reflexes with RA Granit. Reflex responses were measured as muscle contractions by means of an optical isometric myograph, the design of which was improved after Eccles discovered that friction in the bearing distorted the records (4).

In mid-1928 Eccles joined Sherrington in a series of experiments. The first led to the discovery of two distinct populations, based on diameter, of motor fibres in peripheral muscle nerves (7). It was not until later that L Leksell (1945) showed these to be the axons of alpha- and gamma-motoneurones, the latter innervating muscle spindle stretch receptor organs. Sherrington and Eccles (see 14) also examined the time course of the 'central excitatory state' (c.e.s.) which Sherrington had proposed underlay the excitation of motoneurones by afferent volleys to the spinal cord, and also of the active 'central inhibitory state' (c.i.s.) associated with the inhibition of flexor reflexes by volleys in contralateral muscle nerves (17). The latter observations provided no support for the then current theory that the inhibition of reflexes resulted from interference with the access of excitatory impulses to the cord.

These experiments finished early in 1931, and were the last in which Sherrington, then aged 74, took an active part. In 1932 the influential monograph Reflex Activity of the Spinal Cord was published by Creed, Denny-Brown, Eccles, Liddell and Sherrington (21) giving an account of studies carried out in the Sherrington 'School' in Oxford over the previous decade. That year Sherrington and ED Adrian from Cambridge shared the Nobel Prize for Physiology or Medicine for 'their discoveries regarding the functions of the neurone'.

Sherrington's Nobel Lecture, entitled 'Inhibition as a coordinative factor', had a major influence on the future research activities of John Eccles, then aged 29. His own 1963 Nobel Lecture (267) was entitled 'The ionic mechanism of postsynaptic inhibition'.

In 1931 Eccles was appointed to the Staines Medical Fellowship at Exeter College. A study with GL Brown of the acetylcholine-mediated vagal inhibition of the heart apparently reinforced his belief that only an electrical process could account for the much shorter delays and duration of transmission at central synapses. In 1932, Eccles, JZ Young and Granit showed, for the first time, that action potentials were conducted in both directions along earthworm giant nerve fibres (20), an observation which, when later extended by others to the giant axon of the squid, was of fundamental significance to the understanding of impulse conduction along axons.

Eccles returned to the study of synaptic transmission in 1935, selecting the superior cervical sympathetic ganglion as a simpler system than the spinal cord. Although he accepted that acetylcholine (ACh) released by presynaptic impulses was the chemical mediator for slow excitation, the failure of the ACh esterase inhibitor physostigmine to prolong the fast component of ganglionic responses strengthened his doubts that the fast excitatory process could be chemical. Accordingly, he introduced the concept of a rapid 'detonator' response by which the action currents of presynaptic impulses directly excited cells at synaptic regions, causing ganglion cells to discharge (41, 506). This proposal was extended to synaptic excitation of striated muscle, of smooth muscle and in the spinal cord (50). The ensuing controversy between Eccles and adherents of chemical synaptic transmission considerably enlivened many meetings of the Physiological Society (429, 506, see Dale 1954).

Eccles continued demonstrating, tutoring, lecturing and supervising undergraduate and DPhil students, and in 1934 achieved a permanent position in Oxford as a Tutorial Fellow at Magdalen College and as a University Demonstrator. In 1935, however, Sherrington retired and was replaced by J Mellanby. Eccles was disappointed about the new directions research in Oxford would take, and was also concerned about the increasing political uncertainty in Europe. Accordingly, he applied successfully for the Directorship of the Kanematsu Memorial Institute of Pathology at Sydney Hospital, then the largest general hospital in Sydney. He resigned his Oxford appointments and arrived in Sydney with his family in August 1937.

Sydney

The Kanematsu Institute (see Courtice 1985) opened in April 1933, initially as a department of diagnostic pathology for the Sydney Hospital. The part-time Director, Dr WK Inglis, had persuaded the Hospital Board that research should be an integral function of the Institute, and funds were sought from the Nuffield Foundation and the government of New South Wales. The position of Director was advertised in August 1935, and the appointee was expected to devote most of his time to some field of medical research, whilst exercising general supervision of the routine work of the Institute. The Hospital Board, however, retained administrative control of the Institute.

Eccles proposed to continue his research on the central and peripheral nervous systems and, by the end of 1937, he had established research facilities on the top floor of the building with the assistance of a grant from the Australian National Health and Medical Research Council (NHMRC). Throughout his period in Sydney he was very concerned about his academic isolation from physiologists at the Medical School of the University. Although he had been elected a Foundation Fellow of the Royal Australasian College of Physicians in 1938 in recognition of his scientific achievements, Eccles and his colleagues never had any formal association with the University. In 1938, 1939, and jointly with B Katz in 1940, however, he gave a series of lectures to the third-year medical students at the University. Thereafter, and until 1943, lectures, demonstrations and discussions took place for interested students at the Institute.

In 1938 Eccles and WJ O'Connor for the first time recorded end-plate potentials electrically from the surface of striated muscle strips. The belief that these were preceded by muscle action potentials, coupled with the effects of physostigmine and the ACh receptor antagonist curare, led Eccles to deny a role for ACh as the neuromuscular transmitter and to claim support for his detonator theory (59). The subsequent detailed study of neuromuscular transmission with B Katz and SW Kuffler, however, led to Eccles's apparent acceptance that ACh was responsible for end-plate potentials set up by motor nerve impulses (68). An investigation of transmission in the cat stellate ganglion appeared to confirm his earlier proposal of dual fast and slow excitatory processes in ganglia, only the latter being mediated by ACh (69,71).

In accord with a Hospital Board desire for clinically relevant research, Eccles also investigated the atrophy of striated muscle which follows disuse or tenotomy (74). The outbreak of war in Europe in 1939 led to some reduction of the Institute's research, and its continuation was severely curtailed from late 1941 by the war in the Pacific region. Eccles, who had been elected FRS in March 1941, became involved in a number of committees and research projects dealing with the problems of vision (70), hearing, noise and communication in aircraft and tanks. He also actively participated with an Army unit responsible for the supply of blood and serum for the armed forces.

In the meantime, however, Eccles's relations with the Hospital Board became less than harmonious. He believed that the Board and the Hospital's honorary medical staff lacked an understanding of the basic neurophysiological research being carried out and of its long-term relevance to clinical medicine. Early in 1943, without consulting Eccles, the Board proposed to add two floors to the Institute building to accommodate resident medical staff. Since this would prevent any future expansion of the research laboratories, Eccles resigned in October 1943 and accepted appointment to the Chair of Physiology in the Medical School of the University of Otago, New Zealand.

Dunedin

Eccles arrived in Dunedin with his family in January 1944. The university, the first in New Zealand, was founded by the Presbyterian Church in 1869 when Dunedin was New Zealand's principal city. The Medical School, the only one in the country, was established in 1876. The Professor of Physiology was also responsible for teaching biochemistry, and Eccles appointed N Edson as Senior Lecturer in Biochemistry. The teaching load was heavy, and considerable changes were made to provide students, over two pre-clinical years, with a scientific basis for the practice of medicine similar to the Final Honours School in Oxford. Eccles also introduced in 1945 a BMedSci degree whereby at the end of the second year a number of the best students spent twelve months on a research project before returning to their medical studies.

A research laboratory was set up with financial support from the Medical Research Council of New Zealand, and Eccles commenced experimentation late in 1944. He recorded ventral root responses to dorsal root stimulation (76) and, with J.L.Malcolm, potentials and 'reflexes' from dorsal roots (77) which had been described earlier by Barron and Matthews (1938). All results were considered to be consistent with an electrical hypothesis of synaptic and neuromuscular transmission that Eccles published in Nature in December 1945 (75), and presented in February 1946 at the New York Academy of Sciences during his first visit to the United States.

Eccles's formal enunciation of his electrical hypothesis was primarily the consequence of his meeting in May 1945 with KR Popper (see Miller 1997). Popper had been a member of the staff of Canterbury University College in Christchurch, New Zealand, since 1937. At the invitation of Eccles and Edson, he spent a week in Dunedin lecturing on, and discussing his views about, the philosophy of science. Eccles was deeply impressed by Popper's main tenet, that scientific hypotheses should be both clearly formulated and testable by experiment, and that the strength of a hypothesis depended on the failure of rigorous investigation to falsify it rather than on evidence which apparently supported it. This meeting, and subsequent meetings in Christchurch, not only led to Eccles's continuing friendship with Popper (see 450, 515, 516), but additionally had a marked impact upon his future research (see 359). To quote Miller, when referring to Popper's lecture course in Dunedin: 'It had the notable effect also of converting a naive believer in induction (as Eccles described himself [see 515]) into one of the most vigorous of all scientific advocates of the method of conjectures and refutations'.

At the time, Eccles considered chemical transmission to play a subordinate or negligible role in sympathetic ganglia, at the neuromuscular junction and in the spinal cord, despite the strong evidence, particularly from the investigations of Dale and his colleagues, that ACh mediated both ganglionic and neuromuscular transmission. Eccles's experimental evidence that ACh was unlikely to be a transmitter in the spinal cord (80) reinforced his opinion that central synaptic transmission was an electrical process. Accordingly, influenced and encouraged by Popper, he stated his hypothesis of electrical excitatory transmission at central and ganglionic synapses, and the neuromuscular junction, in precise terms, and proposed a number of crucial physiological and pharmacological tests (75).

In essence, Eccles replaced his earlier 'detonator' theory with the proposition that presynaptic action currents initiated depolarizing local responses at specialized regions of the postsynaptic membrane. Above a critical level of depolarisation action potentials would be generated. The synaptic delay and the time course of the synaptic potential were accounted for in terms of the time course of the presynaptic action currents and the electrical properties of the postsynaptic membrane. The terminal regions of presynaptic fibres were also proposed to be similarly specialized, so explaining dorsal root potentials (DRPs) and reflexes (DRRs). He also provided explanations for some of the difficulties his hypothesis faced.

Early in 1946 Eccles and C.McC.Brooks tested this hypothesis by recording the electrical events associated with monosynaptic excitation of cat spinal motoneurones. Enamel-insulated metal electrodes were used to record extracellular synaptic and action potentials (focal potentials) generated by presynaptic impulses. The results were interpreted as 'agreeing closely with the predictions of the electrical hypothesis of synaptic transmission' (82, 86). The following year, Brooks and Eccles published in Nature (81) an electrical hypothesis of central inhibition, developed to account for the 'direct' inhibition of spinal reflexes by impulses from antagonistic muscles. Earlier, both B.Renshaw and DPC Lloyd at the Rockefeller Institute had suggested that direct inhibition had the same central latency as that of the monosynaptic excitation of motoneurones.

Eccles's electrical hypothesis proposed that the inhibitory pathway included a short-axon interneurone (Golgi cell) that synapsed upon motoneurones but did not discharge an impulse when excited by inhibitory afferent volleys. Synaptic potentials caused currents to flow through Golgi cell axon terminals and to passively depress motoneurone excitability. This hypothesis was tested by recording synaptic potentials near motoneurones and ventral root reflexes. The results, together with the interaction between synaptic inhibition (88) and antidromic invasion of motoneurones (89), were regarded as being consistent with the Golgi cell hypothesis.

In 1949 Eccles reviewed and restated his electrical hypotheses of synaptic excitation and inhibition in the spinal cord in a slightly modified form (92). His study with W.V.Macfarlane in 1948 of the effects of a number of ACh esterase inhibitors on the end-plate potentials of frog muscle (90), together with the results of Kuffler and others, had by then convinced him that transmission at the neuromuscular junction was a chemical process mediated by ACh. He was uncertain, however, about the application of the electrical hypothesis to transmission in ganglia, and confined his restatement to monosynaptic excitation and direct inhibition in the spinal cord. He saw no need to postulate specialization of the postsynaptic membrane at excitatory synapses, and outlined the situation if Golgi cells discharged an impulse. This revised electrical hypothesis, however, could not account for the prolonged inhibition of motoneurones by impulses in cutaneous afferent fibres (92).

With colleagues including Malcolm, Brooks, CBB Downman, TH Barakan, AK McIntyre, LG Brock, W Rall, K Bradley and DM Easton, Eccles undertook a number of studies of spinal cord excitation and inhibition. These investigations set the stage for the later breakthrough intracellular experiments. He and his colleagues investigated motoneurone orthodromic and antidromic action and after-potentials (95), and synaptic potentials generated during and following repetitive excitation of low-threshold afferent fibres (103). The effects on spinal monosynaptic transmission of dorsal root section peripheral to the ganglia (115) and during chromatolysis after ventral root section (110) were also studied. The electrical thresholds, conduction velocities and central actions of impulses in Groups I, II and III muscle afferent fibres were characterized (101), and Group I fibres from thigh muscles were found to include two sub-types (Ia and Ib) (118). Both direct and poly-synaptic inhibition were found to be reduced by intravenous sub-convulsive doses of strychnine (119), an antagonism later to be of critical significance to the identification of glycine as a spinal inhibitory transmitter.

The outstanding achievement of Eccles's eight years in Dunedin, however, was undoubtedly the pioneering success he and his colleagues Brock and JS Coombs had in using microelectrodes to record intracellularly from cat spinal motoneurones in vivo. He was aware of the advances just achieved by the introduction of intracellular recording from squid giant axons and isolated muscle fibres, and wanted to use this technique in the central nervous system. Furthermore, his experimental skills and broad anatomical and physiological knowledge of the spinal cord were essential. So was his experience with recording extracellular potentials in the cat spinal cord in vivo using insulated metal electrodes. Brock developed techniques for making and filling glass microelectrodes, and Coombs, a physicist aptly described by Eccles as a 'shy genius', designed a versatile and readily operated electronic stimulating and recording unit, later widely known as the 'ESRU', together with amplifiers and a cathode-follower input stage essential for recording with high resistance electrodes.

Success came in June 1951 with the recording of resting, action and depolarizing excitatory synaptic potentials from motoneurones. The recording on 20August 1951 of membrane hyperpolarizations having time courses similar to that of direct inhibition was sensational (see 429), as the potential had the opposite polarity to that predicted by the Golgi cell hypothesis (105). Eccles immediately considered his hypothesis to have been falsified, and accepted that spinal synaptic inhibition and excitation were both chemical in nature, and mediated by two specific chemical transmitters. This rejection of electrical transmission (425, 429) was a most dramatic conversion by one of the strongest critics of chemical transmission in the mammalian central nervous system. Dale, a long-standing friend of Eccles, was later to write (1954): 'A remarkable conversion indeed. One is reminded almost inevitably of Saul on his way to Damascus when sudden light shone and the scales fell from his eyes.'

Eccles was committed to travel abroad from Dunedin in November 1951, and also expected to be without research facilities for at least a year. In 1950, concerned that the heavy teaching load in Dunedin limited his competitive edge in the rapidly advancing field of neurophysiology, he had accepted an invitation to the Chair of Physiology in the John Curtin School of Medical Research (JCSMR) in Canberra. Since no laboratories were then available in Canberra, arrangements were made for him to continue working in Dunedin after January 1951, and he took up his appointment in December that year. Meanwhile, in June 1950, the President and Fellows of Magdalen College had invited him to deliver the 1952 Waynflete Lectures. Leaving Dunedin in November 1951, Eccles flew via North America to visit colleagues and give lectures before arriving in Oxford in January 1952.

The eight Waynflete Lectures, delivered at weekly intervals, attracted large audiences. The first five dealt with basic membrane and synaptic neurophysiology, and the final three were concerned with plasticity, memory, conditioned reflexes, the cerebral cortex and the mind-brain problem. His dualistic approach to the latter, a neurophysiological hypothesis of will, first published in Nature in July 1951 (99) and elaborated further in the final Waynflete Lecture, created intense discussion. The lectures were published in 1953 as a monograph, The Neurophysiological Basis of Mind: The Principles of Neurophysiology (111), which had a considerable influence on the development of neuroscience.

In late February, Eccles visited Sherrington at a nursing home in Eastbourne. Following Sherrington's death on 4March he returned to Dunedin via the United States where he contributed to a Cold Spring Harbor Symposium on the neurone, at which there was much discussion and controversy related to intracellular recording (441). In September 1952 he and his family moved to Canberra.

Canberra

The Australian National University (ANU) and the JCSMR were established in August 1946 (Fenner 1971, Foster and Varghese 1996). Initially the Department of Physiology was located in a temporary one-storey building completed in March 1953. Eccles then began a remarkable and intense period of research activity that continued for over thirteen years. During this time, 74 investigators from 20 different countries worked in the Department (441). Of these, 41 from 14 countries collaborated and published with Eccles. He later wrote about this period: 'Without doubt it was the high point of my research career' (441), and in 1989 described it as 'my 14 golden years, scientifically speaking' (Letter to RA Hohnen, ANU Registrar during Eccles's period in Canberra). Early in 1957 the Department of Physiology moved into the permanent building of the JCSMR. The additional space, which included six large research laboratories, enabled expansion of the research staff and increased interest in neuropharmacology and neurochemistry.

With Coombs, who had accompanied him from Dunedin, and P.Fatt, Eccles began his research in Canberra with a biophysical study of the motoneurone membrane, and of synaptic excitation and inhibition in the cat lumbar spinal cord, using single and double-barrel glass intracellular electrodes (127-131). Inhibitory postsynaptic potentials (IPSPs), initially recorded as hyperpolarizations, were observed to gradually diminish and reverse to depolarizing potentials. The recognition that this was the consequence of the leakage of ions from microelectrodes containing potassium chloride led to the use of electrical currents to inject anions and cations of different hydrated ion diameter into motoneurones. Together with the first measurement of the reversal potential for IPSPs in the mammalian central nervous system, these findings suggested that an increased permeability to potassium and chloride ions occurred at the inhibitory synapses of the direct and recurrent pathways in the spinal cord (128). In contrast, excitatory postsynaptic potentials (EPSPs) were generated by a non-selective increase in the permeability to all species of ion (129), as had been demonstrated earlier for muscle end-plate potentials by Fatt and Katz (1951). Later studies by Eccles also indicated the involvement of both chloride and potassium ions in generating spinal (252) and hippocampal IPSPs (445, see 465).

Eccles, with Coombs and D.R.Curtis, analysed the antidromic, orthodromic and directly evoked action potentials of motoneurones in terms of the morphology of these cells (149, 150). Direct measurement of the specific membrane resistance and capacitance (164) enabled the time course of synaptic currents underlying EPSPs and IPSPs to be calculated (165). The rapid decline of these currents was ascribed to the diffusion of transmitter from the synaptic cleft, consistent with a theoretical analysis that Eccles published in 1957 with J.C.Jaeger (154).

Early in 1953 Eccles and Fatt (see 425) made two very significant discoveries. The first, with K.Koketsu, showed that the spinal recurrent inhibitory pathway was disynaptic. Impulses in motor axon collaterals excited, at nicotinic cholinergic synapses, interneurones which were appropriately named 'Renshaw' cells in memory of B.Renshaw who first recorded their high-frequency discharge in response to ventral root stimulation (Renshaw 1946). In turn Renshaw cells monosynaptically hyperpolarized motoneurones (123). This, the first direct evidence that ACh was a central transmitter (see 134), exemplified what Eccles called Dale's 'principle' (540), namely that the same transmitter is released at all synapses made by one neurone (Dale 1935). Renshaw cells were the first central inhibitory interneurones to be identified physiologically and pharmacologically. Later, Eccles and his colleagues recorded intracellularly from Renshaw cells, and examined their connectivity in order to elucidate the functional significance of this inhibitory mechanism (204, 205).

In 1953, direct spinal inhibition was still thought to be monosynaptic since its central latency appeared to be similar to that of the monosynaptic excitation of motoneurones. Although Brock, Coombs and Eccles had earlier found that the central latency of direct IPSPs exceeded that of monosynaptic EPSPs by as much as 1ms, this difference was ascribed to a longer intraspinal pathway of the 'inhibitory' fibres. Eccles and Fatt, with S Landgren, however, showed that direct inhibition was disynaptic (133), the inhibitory interneurones being located in the spinal intermediate nucleus. The disynaptic nature of direct inhibition was later confirmed in 1960 by Eccles, with T Araki and M Ito. Direct and recurrent inhibitions had been shown to be blocked by strychnine and Eccles, with VB Brooks and Curtis, found that tetanus toxin had a similar effect (138).

These 1953-55 investigations led Eccles to postulate that a central neurone had either an excitatory or an inhibitory action on other neurones (120, 133, 441). This proposition included inhibition of inhibitory neurones as the basis for disinhibition (see 343). Synapses of all primary afferent dorsal root fibres were excitatory, any subsequent inhibitory action was mediated by excitation of interposed inhibitory interneurones. In later investigations Eccles and his colleagues identified and established the role of other inhibitory interneurones in the spinal cord, dorsal column nuclei, the thalamus, hippocampus and cerebellum (see 343).

Eccles was invited to present the Twenty-Ninth Course of Herter Lectures at the Johns Hopkins School of Medicine, Baltimore, in October 1955. The four lectures, largely based on research carried out in Canberra, were revised for publication in 1957 as a monograph, The Physiology of Nerve Cells (137), one of the most influential books in neurobiology.

With his daughter R.M.Eccles and A.Lundberg, Eccles initiated in 1956 a series of papers on the neuronal organization within the lumbar spinal cord using intracellular recording of postsynaptic potentials, a technique that was more discriminative than the recording of neuronal discharges (208). The monosynaptic connections between Groups Ia, Ib and II afferent fibres from muscle and different types of alpha motoneurone (142, 144, 148), intermediate nucleus interneurones (191) and gamma motoneurones (187) were examined, the latter study also involving A.Iggo. He also examined the properties of chromatolysed motoneurones with B.Libet and R.R.Young (159), and the effects on monosynaptic EPSPs of peripheral section of afferent fibres with K. and R.Miledi (163). In collaboration with O.Oscarsson, Eccles also studied the cells of origin of the ventral (196) and the dorsal (197) spinocerebellar tracts, a prelude to his later investigations of the cerebellar cortex.

In 1956-1957 Eccles, with R.M.Eccles and Lundberg, discovered that significant differences existed in both the axonal conduction velocity and the after-hyperpolarization (AHP) of motoneurones innervating slow- and fast-contracting muscles. The maximum firing frequency of a motoneurone was controlled by the duration of its AHP, and matched the contraction response of its motor unit (157). Subsequently, in 1958 with A.J.Buller and R.M.Eccles, neural influences from the spinal cord were found to affect the post-natal differentiation of slow but not fast muscles in the cat hind limb (182). The crossing and subsequent regeneration of nerves to fast and slow muscles changed their contraction properties, suggesting that specific substances secreted at motoneurone axon terminals both caused and maintained differences in the contractile properties of fast and slow muscles (183).

Because of his continuing interest in plasticity (see 158), Eccles searched with R.M.Eccles and F.Magni for changes in the monosynaptic connections of cat hind limb motoneurones after various regenerations of muscle afferent nerves in kittens (190). There was, however, relatively poor synaptic plasticity of spinal cord connections in mature cats (217).

In 1960 Eccles began a comprehensive study of the mechanism and organization of what came to be called 'presynaptic' inhibition in the spinal cord. K.Frank and M.G.F. Fuortes (1957) had reported that stimulation of a flexor muscle nerve depressed monosynaptic EPSPs of extensor muscle motoneurones without recordable changes in membrane potential or excitability. The prolonged inhibitory process could be due to either a presynaptic reduction of transmitter release, or a membrane conductance increase at distal dendritic sites (Frank 1959). Eccles was in a unique position to explore the nature and significance of this type of inhibition. He had, in 1948, with C.McC.Brooks and Malcolm, observed that presynaptic spikes and excitatory synaptic potentials recorded near spinal motoneurones were reduced by a prior inhibitory input. This reduction, considered at the time to be of little physiological significance, was attributed to depolarization of excitatory presynaptic fibres (88), later to be referred to as primary afferent depolarization, PAD. Additionally, with in 1958, Eccles had recorded dorsal root potentials (DRPs) intracellularly from intraspinal afferent fibres, and also prolonged EPSPs from dorsal horn interneurones possibly involved in the generation of DRPs (179).

Over the period 1961-1965, 29 full papers dealing with various aspects of presynaptic inhibition, 21 of which Eccles co-authored, were published in refereed journals from his department, and also 13 review articles and one book (245) in which presynaptic inhibition was featured. Eccles's collaborators in studies of this inhibition in the lumbar and cervical spinal cord and dorsal column nuclei were RM Eccles, Magni, Willis, WM Kozak, RF Schmidt, PG Kostyuk, P Andersen, TA Sears, T Oshima and T Yokota. The investigations were carried out on barbituate anaesthetised cats, often cooled to accentuate the inhibition and PAD. In addition to recording DRPs, DRRs and extra- and intra-cellular potentials from intraspinal primary afferent fibres and neurones, changes in the excitability of intraspinal afferent fibres indicating PAD were determined using the extracellular microstimulating technique developed by PD Wall (1958).

Prolonged depression of monosynaptic EPSPs (and of reflexes, 212) of extensor muscle motoneurones was produced by impulses in flexor muscle Group I afferent fibres without changes in motoneurone membrane potential, excitability or EPSP time course as would be expected from a membrane conductance increase. These results suggested that the depression of monosynaptic EPSPs and reflexes was entirely a presynaptic inhibitory phenomenon (193), and PAD became synonymous with presynaptic inhibition (203).

Presynaptic inhibition, hitherto not considered a significant factor influencing spinal reflex activity, provided a negative feed-back control of sensory information into the cord and supraspinal centres. Eccles's extensive investigations (see Schmidt 1971) dealt with the organization and mechanism of PAD in the spinal cord (202, 207, 210, 211, 212, 215, 231, 232) and dorsal column nuclei (248, 268, 269). Electrical stimulation of the sensorimotor cerebral cortex also produced PAD and reduced excitatory transmission from spinal (246) and cuneate (248) afferent fibres.

PAD was considered to be generated by an increase in the ion conductance of primary afferent fibre terminals, both this increase and the depolarisation reducing the amplitude of terminal action potentials and thus affecting transmitter release (228). Eccles had proposed in 1961 that PAD may be generated by the prolonged action of a chemical transmitter at synaptic contacts on terminal boutons of afferent fibres (195). Morphological evidence for such axo-axonic synapses upon boutons in the cat spinal cord was first reported by E.G.Gray (1962). The observation with Schmidt and Willis in 1961 that picrotoxin but not strychnine reduced both PAD and the presynaptic inhibition of spinal monosynaptic reflexes led to the proposal that 4-aminobutyric acid (GABA) was the depolarizing transmitter at these axo-axonic synapses (237).

With an early exception (3), Eccles had mainly examined synaptic mechanisms in, and the organization of, the spinal cord. From late 1961, however, he concentrated upon supraspinal regions, including the somatosensory system, the hippocampus and the cerebellum. This change in direction reflected his interests in cognitive functions, and was coupled with collaboration with a number of colleagues from abroad with similar interests, including Andersen, CMc Brooks, Schmidt, Sears, Oshima, Yokota, Y Løyning, PE Voorhoeve, R Llinás, K Sasaki, P Strata, DM Armstrong, RJ Harvey and PBC Matthews. Although the effects of stimulating the cerebral cortex on transmission in the spinal cord (246), dorsal column nuclei (248) and ventrobasal thalamus (271) were examined, Eccles never studied neurones and their interconnectivity in the neo-cortex itself.

After a study of synaptic transmission and inhibitory processes in the dorsal column nuclei (269), Eccles turned to the ventrobasal complex of the thalamus (271, 272) where two interesting observations were made: a prominent recurrent postsynaptic inhibition and large post-inhibitory 'rebound' depolarizing responses with superimposed bursts of action potentials. The pivotal role of this response, labelled by Eccles 'post-anodal exaltation' (see 222), in the rhythmic and synchronized activity of thalamic cells and of various types of cortical neurone was later confirmed by others.

Taking advantage of the laminar arrangement of hippocampal synapses, Eccles's group found in 1962 that the large and prolonged chloride-dependent IPSPs recorded from pyramidal cells were generated at the soma, suggesting that basket cells, with synaptic terminals clustered around the somata of pyramidal cells, were inhibitory interneurones (253,254). This discovery served as a guide for identifying other central inhibitory neurones and synapses (see 284). The subsequent finding that cerebellar basket cells inhibited Purkinje cells through synapses located on the soma (270) led to a hypothesis that postsynaptic inhibition is largely mediated by somatic synapses (230). Later, however, cerebellar stellate cells, which synapse upon medium-size Purkinje dendrites, were also found to be inhibitory (288). Inhibition of hippocampal pyramidal cells, cerebellar Purkinje cells and ventrobasal thalamo-cortical relay cells were all found to be insensitive to strychnine (239).

Eccles's last period of experimental neuroscience, concerned with the synaptic organization and mode of operation of the cerebellum, began in Canberra in 1963 and continued in Chicago and Buffalo until his retirement from direct involvement in laboratory experimentation in 1975. In large measure due to him and his colleagues Janos Szentágothai in Budapest and Masao Ito in Tokyo, a comprehensive view of the cellular organization of the mammalian cerebellar cortex became available in the late 1960s, summarized in the influential monograph, The Cerebellum as a Neuronal Machine (317), published in 1967. It will be convenient here to give an account of Eccles's cerebellar research carried out in Canberra, Chicago and Buffalo.

In a remarkable series of letters to Nature, and subsequent detailed publications, Eccles and his collaborators described the essential properties of all major types of cerebellar neurone. Each cell type was categorized and its synaptic effect on target cells determined. Somewhat surprisingly, only the granule cells were excitatory while all other neurones were inhibitory. While Ito and his colleagues had shown that Purkinje cells monosynaptically inhibited neurones in the intracerebellar and vestibular nuclei, Eccles found that basket, stellate and Golgi cells were also inhibitory. In a series of papers inaugurating the new journal, Experimental Brain Research, for which Eccles was a founding co-editor, he observed that all of these different inhibitory interneurones had similar functional properties and could only be distinguished by their location in the cerebellar cortex (288-290).

The large inhibitory postsynaptic potentials of Purkinje cells were attributed to the activity of basket cells, terminating on Purkinje cell somata (233, 270), similar to the situation in the hippocampus. Comparing basket and Golgi cell inhibition, the latter was more focussed (0.2mm on either side of the cerebellar folia) and faster than basket cell inhibition which could spread as far as 1mm to either side (292, 312). Basket and Golgi interneurones had roughly the same threshold to parallel fibre activation. Golgi cell inhibition, however, had the lowest threshold to mossy fibre stimulation, largely due to the effective mossy fibre/Golgi cell synapses. Powerful climbing fibre excitation of Purkinje cells was elicited by stimulation of the contralateral inferior olive (255). Eccles stressed the one-to-one connectivity between one climbing fibre and a given Purkinje cell (291). Climbing fibre responses could be evoked by peripheral nerve stimulation and also occurred spontaneously.

Eccles discovered a major organizational principle by activating a thin strip of parallel fibres (288). With an ingenious de-afferented preparation, an excited strip of Purkinje cells was flanked on either side by a band of inhibition mediated by basket and stellate cells. The discovery of this arrangement became a hallmark of cerebellar cortical activation. Transmission through the mossy fibre-granule cell glomeruli was also analysed (311). Mossy fibre stimulation efficiently activated granule cells which in turn excited Purkinje cells and the three types of inhibitory neurones mentioned above (290, 316). The activity of granule cells was strongly depressed by parallel fibre activation, most likely through parallel fibre activation of Golgi cells which in turn had an inhibitory effect on granule cells. This first comprehensive analysis disclosed the mode of operation of the main cellular elements of the cerebellar cortex (311, 317, 318).

An important part of Eccles's cerebellar studies was to dissect the extra- and intra-cellular potentials recorded in the cerebellar cortex in response to activation of known afferent pathways, including the topography of the activation pattern. Using his wide experience from spinal cord work, Eccles activated specific afferent fibres from muscle, joint and skin, charting surface and depth potentials, and determined whether the afferent signals were mediated by climbing or mossy fibre inputs (335). The afferent inputs to the cerebellum showed a notable somatotopical organization, although much more widely distributed than in the somatosensory thalamo-cortical system (390). The connectivity showed a remarkable mosaic pattern and a large variation in the response sizes from different afferent nerves. A cluster of papers discuss how natural activation, like taps to the foot, produced purely excitatory responses from many mossy fibres, very similar to those elicited by electrical stimulation of the nerves (386, 387). The Purkinje cells, surprisingly, were most readily excited by impulses in cutaneous fibres, and particularly in low threshold fibres. The responses to mechanical stimulation of the skin produced by climbing fibre inputs were analysed by depressing the mossy fibre contribution with pentothal anaesthesia (384, 385). Eccles also studied the activation of intracerebellar and associated nuclei by afferent impulses in peripheral nerves. Again, impulses in cutaneous nerves of all four limbs were particularly effective (374, 382, 384, 401, 403).

Eccles was awarded a Royal Medal in 1962, and the award in 1963 of the Nobel Prize in Physiology or Medicine, shared with AL Hodgkin and AF Huxley, recognized his fundamental contributions to the ionic mechanisms of synaptic transmission in the brain. His 1964 monograph The Physiology of Synapses (245) surveyed research carried out since 1951, in his and other laboratories, on excitatory and inhibitory synapses. In the preface he acknowledged the influence on his writings of three great scientists: Ramon y Cajal, Sherrington and Dale.

Faced with retirement as Head of the Department of Physiology in 1968 at the age of 65, Eccles became concerned that the research facilities, personnel and financial support that would then be available would severely limit continuation of his research. In the absence of assured funding to support collaborators, he did not regard as acceptable a three-year appointment as a University Fellow together with his own equipment in a new laboratory in the John Curtin School. Consequently, in 1966, he resigned from the Chair of Physiology, which he had occupied since 1951, to take up an appointment as a member of the Institute of Biomedical Research, recently established by the American Medical Association in Chicago. An important factor in Eccles's decision to leave Australia was his feeling of intellectual isolation, especially in relation to his increasing interests in philosophy and the mind-brain interaction.

Chicago and Buffalo

Eccles described his period in Chicago (1966-1968) as 'the briefest, the least successful, and the most unhappy (stage) of my research career' (441, p.15). Although he established a research laboratory and continued his study of the cerebellar cortex, his understanding that adequate financial support would continue after the age of 68 failed to materialize, and problems within his group apparently created considerable dissension. Accordingly, he accepted an invitation from the State University of New York at Buffalo to establish a research unit as a Distinguished Professor of Physiology and Biophysics. His laboratories were located in temporary buildings some distance from the main university, and he described his research facilities as the best he had ever had although on a smaller scale than in Canberra (441).

In the United States, from 1966 until he retired at the end of 1975, Eccles had 20 collaborators from 11 countries including the USA, and co-authored 43 papers reporting experimental results with the following (in alphabetical order) G.I.Allen, D.S.Faber, S.T.Kitai, H.Korn, J.T.Murphy, R.A.Nicoll, L.Provini, T.Rantucci, I.Rosén, F.J.Rubia, N.H.Sabah, P.Scheid, D.W.F.Schwarz, T.Shimono, H., N.Tsukahara and T.J.Willey, and also Strata, Schmidt and Oshima who had worked with him in Canberra. Their cerebellar research has been described above, and was an important component of the very large amount of new and detailed information, including the discovery of several governing principles and cellular mechanisms, that Eccles contributed to the understanding of the cerebellum and its associated structures.

In Buffalo Eccles revisited hippocampal inhibition, the subject of his three last experimental papers. He and his colleagues reported that barbiturates prolonged postsynaptic potentials (427). He also studied the anionic permeability underlying hippocampal IPSPs, by polarization of the membrane and anion injection. The permeant anions were identical to those reported in motoneurones (444). The observations hinted at the dichotomy of hippocampal IPSPs, an early GABA-A part and a later GABA-B part, as later demonstrated by one of Eccles's coworkers on this paper, R. A. Nicoll. The Eccles group found no evidence for an outwardly directed chloride pump and concluded that an inward chloride current is the likely source for the hippocampal IPSPs (445). This was the last experimental paper from John Eccles's hand.

Switzerland

In 1975, Eccles voluntarily retired and moved to Contra in the Swiss canton Ticino, in what he described as 'idyllic mountain surroundings' (441), to dedicate himself to work on the mind-brain problem. From here he travelled extensively, attending scientific meetings, lecturing in continental Europe, the UK, Japan and North America, and playing a prominent role in the International Physicians for the Prevention of Nuclear War organization. He had visiting appointments at the University of Basle, the Max-Planck Institute for Biophysical Chemistry in Göttingen and the Max-Planck Institute for Brain Research in Frankfurt. With his books, journals and reprint collection he was able to continue his academic life, completing scientific papers and writing numerous influential reviews and books, alone and in collaboration. A particularly important concept introduced in 1978 by Eccles and PL McGeer was the recognition of two general types of the postsynaptic action of transmitters: 'ionotropic', in which the transmitter increases postsynaptic membrane conductance by directly opening ion gates, and 'metabotropic', in which the transmitter acts indirectly through intracellular metabolic reactions (465, 475).

The mind-brain problem, however, was the topic which by far occupied most of Eccles's time in the period between 1975 and his death. He wrote extensively on the subject, sought new views and explanations, and discussed the issue at numerous conferences and meetings. His final book, How the Self Controls its Brain, was published in 1994 (567).

The mind-brain problem: Philosophical considerations

Eccles recounted how, when 18 years old, he was struck by an awesome feeling of uniqueness (450, p.357). He marvelled at his own brain and its capacity for thoughts and emotions, and started a life-long search for the explanation of human achievements. Without further details, he gave this special experience as the cause for 'spending his life in the neural sciences with some continuing involvement in philosophy'. Throughout his adult life he was a declared dualist, and searched relentlessly for mechanisms by which the mind controls the body. In fact, no fewer than 18per cent of his 568 publications dealt with this issue.

Although not explicitly stated, his family's religious belief must have been important. A second reason was his own scientific curiosity and wide reading. A third, strong influence came from his mentor Sir Charles Sherrington, in particular his book Man on his Nature (1940). A final driving force may have been his scepticism towards materialism. In a letter enclosed with complimentary copies of his last book (567), Eccles wrote about scientific materialism: 'A most important program for this book is to challenge this materialism and to reinstate the spiritual self as the controller of the brain.'

Although Eccles was 'a believer in God and the supernatural' (450, p.VIII), his approach to the mind-brain problem was neither purely religious nor philosophical, but largely neurobiological with a Cartesian influence. In this respect, MacKay (1987) remarks: 'Though they [Eccles and Popper] differ in important respects from that of Descartes, they agree with him that "the brain must be open to non-physical influences if mental activity is to be effective" '. In a letter to us, BIB Lindahl (1999) concurs: 'One could say that he was a follower of Descartes. Like Descartes, Eccles's point of departure in the mind-brain field was partly religious, partly scientific, but in practice Eccles's approach was, as I see it, primarily scientific.'

Eccles first discussed mind-brain interactions in relation to voluntary actions and used the term will for the mental force he saw as the initiator (111). Later, he used mind and, later again, the term self-conscious mind. In his book The Human Psyche (482, p.2) he defined the term self-conscious mind: 'it implies knowing that one knows'. He continues: 'One can also use the term self-awareness instead of self-consciousness, but I prefer self-consciousness because it related directly to the self-conscious mind'.

Eccles searched for answers to a set of essential questions:

• how can Man's enormous capacity for thinking, memory, and emotional feeling and expression be explained?
• how can the 'Will' have such a strong and precise effect on our skeletal muscles during voluntary movement?
• since our intentions ('Will') appear so strong, can they lead to a change of brain substrates, both structurally and functionally?
• can a mind-brain interaction be localized to certain, selected parts of the brain, or even to specific cells or synapses?
• which physiological, chemical and physical processes are associated with the mind-brain interaction?

His intention was to develop testable propositions in relation to these questions. In The Self and Its Brain (450, p.355) he summarized his views on the mind-brain interaction: 'It is a very strong dualism and raises the most severe scientific problems in relationship to the interface between the world of matter-energy, in the special instance of the liaison area of the brain, and the world of states of consciousness that is referred to as the self-conscious mind. Briefly, the hypothesis states that the self-conscious mind is an independent entity that actively engages in the reading out from a multitude of active centres in the modules of the liaison areas of the dominant cerebral hemisphere.'

Eccles maintained that conscious experience is provided by the self-conscious mind by itself, and not by the neural machinery of the brain with its excitatory and inhibitory synaptic interactions (450, p.362). He further proposed that the mind-brain liaison has traffic in both directions, from the brain to the mind in perception and from mind to brain in willed action (111, p.281). His term liaison brain included all those areas of the cerebral cortex that are potentially capable of being in direct liaison with the self-conscious mind, and he located this liaison brain in the cerebral cortex of the dominant hemisphere, but only in those areas which have linguistic and ideational performance. Further, he felt that a small part, maybe less than a tenth of the cortex, in the right state of activity would be enough to give an effective mind-brain liaison (111, p.283). To illustrate the mind-brain interaction in the liaison areas, Eccles used an analogy: 'a multiple scanning and probing device that reads out from and selects from the immense and diverse patterns of activity in the cerebral cortex and integrates these selected components, so organizing them into the unity of conscious experience' (450, p.363). The language Eccles used here is similar to that used by a neuroscientist to explain neuronal interaction in an activated cortical area. He stated, however, that the self-conscious mind is not identical to some physical part of the cerebral cortex like cells or synapses.

He proposed that 'the self-conscious mind exercises a superior interpretative and controlling role upon the neural events by virtue of a two-way interaction across the interface between World1 and World2' (450, p.355), using Popper's nomenclature: World 1, the world of physical objects, and World2, the world of subjective experiences. As to possible mechanisms, he proposed: 'An attempt is made to show how the operative features of modules of the cerebral cortex can result in properties of such subtlety that they could be recipients of the weak action that are postulated to be exerted by the self-conscious mind across the interface. These actions are evident by voluntary movements as described in chapter E3 and also by the recall of memories on demand by the cognitive processes, as described in Chapter E8.' (450, p.356)

In the second-last chapter of How the Self Controls its Brain (567), and in (556), Eccles and Friedrich Beck postulated that the self-conscious mind interacts with the brain on aggregations of cortical pyramidal cell dendrites, forming structures named dendrons, and further that the self-conscious mind acts by reciprocally linking each unit of mental experience, labelled a psychon, to its specific dendron. The action of psychons was considered to involve an enhancement of the release probability of transmitter vesicles at excitatory dendritic synapses, an interaction they regarded as consistent with the laws of quantum physics.

Eccles was strongly influenced by Popper's philosophy, stemming from their contact in New Zealand in 1945. In the chemical/electrical controversy about synaptic transmission, Eccles took Popper's advice, wrote several reviews summarizing the evidence and concluded that the process was electrical (75,92). Ironically, he subsequently, in 1951, came to the opposite conclusion based upon his own intracellular recordings from spinal motoneurones. Conversely, Eccles also deeply influenced Popper. In a Festschrift article to Eccles, Popper described their first encounter as creating immediate and reciprocal sympathy, and how their common interest in the mind-brain problem made them write a book together (450), about which Popper testified: 'It became an important event in both our lives' (Creutzfeldt et al. 1984). In fact, it was Eccles who made Popper change his initial formulation to the terms World1, 2 and 3 (450, p.38). Their co-authored book The Self and its Brain (450) is by far the most cited of all Eccles's philosophical contributions.

Eccles's views on the mind-brain relationship have not been accepted by a large section of the neuroscientific community. Many opponents regarded his formulation of hypotheses as too imprecise or as untestable, and some colleagues interpreted some of the underlying experiemental observations differently from Eccles. His claim that perception is an effect of the conscious mind leaves most neuroscientists with the impression that 'the conscious mind' describes a neural entity: many do not accept that there is a distinction between the conscious mind and the activity of neurones on which it plays. There are, however, arguments in favour of Eccles's belief that mental states can influence the activity of neurones. Whatever the judgement of posterity between these two positions, Eccles deserves much credit for bringing into the open the relation between mind and brain, and for putting forward hypotheses about it which he hoped and believed would be testable.

In spite of the criticisms of his mind-brain views, there can be no doubt that he used his vast knowledge and imagination to foster real understanding. In grappling with the mind-brain problems he showed the same broad knowledge displayed in his experimental activities. He covered aspects as wide apart as conscious perception, voluntary movement, language centres, effects of brain lesions and memory functions. From this wide perspective he extracted principles of importance for his philosophical ideas. In these efforts he combined his vast knowledge with skills as a writer and lecturer.

Personality

As an individual, John Eccles combined a remarkable talent with the strong motivation and stamina necessary for an outstanding scientific career. His energy was nearly overwhelming, as was his appetite for new knowledge, particularly of the brain and its mode of operation. He was actively involved in laboratory-based research from 1927 until 1975, and was closely associated with numerous scientific collaborators and with neuroscientists in other laboratories world-wide. Eccles was indeed fortunate in being able to develop his experimental expertise during the last years of the Sherrington 'School' in Oxford, using electrophysiological stimulating and recording equipment that would now be regarded as relatively crude, and to have the opportunity to hone his skills during the next forty years of increasing technical sophistication resulting from the introduction of thermionic 'valves', cathode ray tubes, glass microelectrodes, transistors, integrated circuits and computers. In Sydney he attracted investigators of the stature of Katz and Kuffler, and later he established contact with Popper in New Zealand. Furthermore, after the pioneering achievement of recording intracellularly from motoneurones in vivo, the unrivalled opportunities and facilities provided in Canberra, including academic positions for many distinguished investigators, enabled him to exploit his new-found support of central chemical neurotransmission at both a synaptic and an organizational level, the latter interest continuing in the United States.

The following remarks apply particularly to Eccles's time in Canberra, with which we are both most familiar (D.R.C., 1954-1966; P.A., 1961-1963), and to our later encounters at meetings abroad. Colleagues from the Buffalo period confirm that the same congenial atmosphere also characterized Eccles's laboratory there. Much of his success depended on an exceptional ability to create productive research teams that were usually a blend of experienced investigators and new recruits. Often he undertook projects of interest to new arrivals in the laboratory, while some of his visitors worked on their own projects. Eccles was a prolific writer, his bibliography listing 568 items, including nineteen books of which he was the sole author of twelve. His name on a publication invariably indicated his personal participation in all aspects of the investigation. His infectious enthusiasm over a new or unexpected finding, his extensive knowledge of virtually all experimental neurophysiology, which he gladly shared, and, above all, his ideas for further experimentation were both instructive and formative for his younger colleagues. With the passage of time, the term 'Prof', used by his younger colleagues to combine respect with admiration and friendship, was replaced by 'Jack'.

As a team leader Eccles was demanding, every member of the team being expected to contribute fully in a co-operative fashion. His ambition was that his groups should make solid and substantial progress. He did, however, welcome opposition provided that the evidence for an alternative view was sound or at least reasoned. Most major investigations involved at least two long experiments each week, beginning very early in the morning and often lasting for 16-20 hours, occasionally longer and extending well into the following day. He regularly participated in the animal preparation, and took considerable pride in his anatomical knowledge and surgical expertise. He also ensured that the technical equipment available for experimentation was the best available, and insisted on having first-class electronic and mechanical workshop personnel and facilities within his own department.

A particular event appreciated by his collaborators in Canberra was a late 'tea-break' in his study, usually around 11pm. This provided an opportunity for relaxed discussion, in which he provided glimpses of his scientific life including his travels to conferences abroad, his mentors, other scientists and previous colleagues. Eccles's comments were always honest, albeit at times quite terse. Those who had made significant discoveries or other progress were, however, unreservedly praised, including his strongest competitors. Interwoven in these reminiscences was advice, including the need to remember the importance of experimental design: 'Put yourself in control of the experiment, do not let the findings run away with you!' His own experiments were always carefully planned and executed, but there was always sufficient flexibility to exploit an unexpected finding.

The mixture of scientific ambition and stimulation from Eccles as leader, coupled with the satisfaction of making interesting and significant new contributions, provided his collaborators with an experience never to be forgotten. Most established life-long friendships with Eccles and each other, as did their families, and many have made their own impact on neuroscience. To commemorate Eccles's Nobel award, 48 of his colleagues contributed brief papers to a book, Studies in Physiology, presented to John C. Eccles (Curtis and McIntyre 1965). In 1983, over 200 colleagues met in the Max-Planck Institute for Biophysical Chemistry in Göttingen to celebrate Eccles's 80th birthday, of whom 52 contributed to the commemorative volume, Sensory-Motor Integration in the Nervous System (Creutzfeldt et al. 1984). In May 1993 a similarly large number of his former colleagues and associates contributed to a Scientific Symposium held at the Max-Planck Institute of Brain Research in Frankfurt to honour Eccles's 90th birthday. Eccles gained considerable personal satisfaction from the award of a knighthood in 1958 when he was President of the Australian Academy of Science, and later, in 1990, from being appointed a Companion in the Order of Australia.

Family

John Eccles married Irene Francis Miller, whom he had met in Melbourne, on 3July 1928 in Oxford. They had five daughters and four sons, of whom their eldest daughter, Rosamond Margaret, became a neurophysiologist. She spent three years in Cambridge from 1951 as an ANU PhD scholar and subsequently was a very productive member of her father's department in Canberra from 1955 until her resignation in 1966.

In Sydney the family lived in Mosman, a short ferry trip across the harbour from the Circular Quay terminal which was close to the Sydney Hospital. Following the move to Dunedin, they also lived relatively close to the university. The acquisition in Canberra of almost a hectare of land enabled Eccles to establish an orchard and vegetable garden that were the envy of his colleagues, apart from the area of lawn which required frequent mowing. In Canberra, as earlier in Sydney and in Dunedin, he and his wife were gracious hosts, particularly at weekend tennis parties on the family court and at regular country dancing sessions for members of his staff, research students, visitors and their families. Eccles was an enthusiastic participant in both forms of exercise.

When Eccles decided to move to Chicago in 1966, his wife preferred to remain in Australia close to her family, and their marriage was dissolved in 1968. In April of that year he married Helena , a neurophysiologist who collaborated closely with him from 1966 until he ceased experimentation in 1975, after which they moved to Switzerland. Here, in a majestic mountainous landscape, Eccles concentrated on the mind-brain problem. In spite of his considerable age, he continued writing on this and related themes (for example 452, 456, 464, 467, 482, 492, 509, 515, 528, 529, 531, 535, 548, 549, 555, 556, 567). A long series of books, articles, reviews, comments, book reviews, and obituaries flowed from his hands, all hand-written, until well beyond his 90th year. In all of this activity, he was efficiently and caringly assisted by his wife Helena. Eccles's activities, however, were severely curtailed by ill health from 1994, and he died on 2May 1997 in the Hospital La Carita in Locarno. He was buried on 3May 1997, following his own wish, in Contra.

Australian Academy of Science

From 1951, Eccles was one of 23 distinguished Australian scientists, including 14 Fellows of the Royal Society of London, whose successful petitioning of the Queen led to the granting of the Charter of the Australian Academy of Science on 16February 1954 (441, see Fenner 1995). He was a member of the Provisional Council in 1953, and of the first Council of the Academy from 1954 until 1957 under the Presidency of the physicist M.L.Oliphant, and was himself President from 1957 until 1961. During his Presidency the Academy's distinctive 'dome' building (Becker House, now the Shine Dome) was constructed and opened in May 1959. Major activities of the Academy in which he was involved as President included the beginnings of the Anglo-Australian Telescope Project, the establishment of a Fauna and Flora Committee to advise on major research projects in the biological sciences, a report proposing preservation of the Kosciuszko summit area as a primitive reserve, recommendations to the Prime Minister concerning science and technology, and recommendations to the Government of a policy on oceanography. In 1963 he delivered the Academy's Matthew Flinders Lecture, established to be given as a mark of distinction by scientists of the highest standing (235).

Education

University of Melbourne, MB, BS (1925); Oxford University, BA (1927), MA, DPhil (1929).

Positions held

• 1925-1928 Rhodes Scholar, Oxford.
• 1927-1929 Christopher Welch Scholar, Oxford.
• 1927-1932 Junior Research Fellow, Exeter College, Oxford.
• 1932-1934 Staines Medical Fellow, Exeter College, Oxford.
• 1934-1937 Tutorial Fellow, Magdalen College, Oxford; University Lecturer in Physiology, Oxford.
• 1937-1943 Director, Kanematsu Memorial Institute of Pathology, Sydney Hospital, Sydney.
• 1944-1951 Professor of Physiology, University of Otago Medical School, Dunedin, New Zealand.
• 1951-1966 Professor of Physiology, John Curtin School of Medical Research, Australian National University, Canberra.
• 1966-1968 Member, Institute for Biomedical Research, American Medical Association, Chicago, Illinois, USA.
• 1968-1975 Distinguished Professor of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York, USA.
• 1975-1997 Distinguished Professor Emeritus, State University of New York at Buffalo, New York, USA.

Honours and awards

Decorations

• 1958 Knight Bachelor. 1987 Order of the Rising Sun, Gold and Silver Stars (Japan). 1990 Companion in the Order of Australia.

Membership of learned academies and professional bodies

• 1928 Member, The Physiological Society, U.K.
• 1938 Foundation Fellow, Royal Australasian College of Physicians.
• 1941 Fellow, The Royal Society, London.
• 1950 Fellow, Royal Society of New Zealand.
• 1952 Honorary Member, The American Physiological Society.
• 1954 Foundation Fellow, Australian Academy of Science; President, 1957-1961.
• 1957 Honorary Member, Neurosurgical Society of Australasia.
• 1958 Honorary Member, Australian Association of Neurologists.
• 1959 Foreign Honorary Member, American Academy of Arts and Sciences.
• 1960 Foundation Member, Australian Physiological Society.
• 1961 Member, Pontifical Academy of Science.
• Member, Deutsche Akademie der Naturforscher Leopoldina.
• 1963 Foreign Honorary Member, Accademia Nazionale dei Lincei.
• 1964 Honorary Member, American Philosophical Society.
• Honorary Member, American Neurological Society.
• Honorary Member, Australian Physiological Society.
• Honorary Member, Société Française de Neurologie.
• 1965 Member, World Academy of Arts and Sciences.
• Honorary Member, New York Academy of Sciences.
• 1966 Foreign Associate, U.S. National Academy of Sciences.
• 1967 Honorary Member, Academia Medica Lombarda.
• Honorary Fellow, American College of Physicians.
• 1968 Honorary Fellow, Indian Academy of Sciences.
• Honorary Member, Czechoslovak Medical Society J.E. Purkyně
• 1969 Associate Member, Académie Royale de Belgique.
• 1971 Honorary Member, The Physiological Society, U.K.
• 1976 Honorary Member, European Brain and Behaviour Society.
• 1977 Honorary Member, European Neuroscience Association.
• 1982 Honorary Member, Society for Neuroscience.
• 1983 Honorary Member, Japanese Physiological Society.
• 1984 Honorary Member, Indian Physiological Society.
• Honorary Member, Australian Neuroscience Society.
• 1985 Member, Bavarian Academy of Sciences.
• 1986 Member, Academia Europoea.

Honorary degrees

• Doctor of Science: Cambridge, Tasmania, British Columbia, Marquette, Loyola, Oxford, Fribourg and Yeshiva Universities, Gustavus Adolphus College.
• Doctor of Medicine: Charles, Torino, Madrid, Ulm, Basel, Georgetown and Tsukuba Universities.
• Doctor of Laws: Melbourne University

Awards

• 1925 Rhodes Scholarship, Victoria.
• 1927 Gotch Memorial Prize, Oxford.
• 1932 Rolleston Prize, Oxford.
• 1961 Baly Medal, Royal College of Physicians.
• 1962 Royal Medal, Royal Society of London. Cook Medal, Royal Society of New South Wales.
• 1963 Cothenius Medal, Deutsche Akademie der Naturforscher Leopoldina.
• Nobel Prize in Physiology or Medicine.
• Australian of the Year.
• 1991 Cortina-Ulisse Literary Prize.
• 1993 Gold Medal of the Charles University, Prague, Czech Republic (first since 1348).

International lectureships

• 1952 Waynflete Lecturer, Magdalen College.
• 1955 Herter Lecturer, Johns Hopkins University.
• 1959 Ferrier Lecturer, The Royal Society. (delivered June 1960).
• Squibb Centenary Lecturer.
• 1963 Flinders Lecturer, Australian Academy of Science.
• Rennie Lecturer, Royal Australasian College of Physicians.
• 1965 Eddington Memorial Lecturer, University of Cambridge.
• Boyer Lectures, Australian Broadcasting Corporation.
• William G. Lennox Memorial Lecturer.
• 1966 Sherrington Lecturer, University of Liverpool.
• 1968 Alexander Forbes Lecturer, Grass Foundation.
• 1968 Dunning Trust Lecturer, Queen's University, Kingston,Ontario.
• 1969 Foerster Lecturer, University of California at Berkeley.
• 1972 Patten Memorial Lecturer, Indiana University.
• 1973 Compton Lecturer, Washington University, St.Louis.
• 1973 Phi Beta Kappa Lecturer, U.S.A.
• 1976 Pahlavi Lecturer, Iran.
• 1977 Phi Beta Kappa Lecturer, U.S.A.
• Botazzi Lecturer, Società Italiana di Fisiologia.
• 1978 Gifford Lecturer, University of Edinburgh.
• 1979 Gifford Lecturer, University of Edinburgh.
• 1980 Lecturer of 'Werner Heisenberg Vorlesungen', Carl Friedrich von Siemens Stiftung, Munich.
• 1981 Carroll Lecturer, Georgetown University.
• Lecturer, '100-Jahr-Feier Walter Rudolph Hess', Zurich.
• 1990 Idrios Lecture, Oxford.

Other marks of recognition

• 1960 Member, Research Advisory Committee, CSIRO.
• 1961 Honorary Fellow, Exeter College, Oxford.
• 1961 Kempner Visiting Professor, University of Texas Medical School.
• 1964 Honorary Fellow, Magdalen College, Oxford.
• 1966 Visiting Professor, University of California, Davis.
• 1967 Distinguished Visiting Professor, University of British Columbia.
• 1978 Visiting Professor, Department of Biology, New York University.
• 1979 Green Visiting Professor, University of Texas Medical Branch at Galveston.
• 1991 Eccles Fellowships established by Australian NHMRC.
• 1992 Eccles Lectureship established in Canberra.
• 1995 Eccles PhD Scholarships established in JCSMR.
• 1997 ANU Medical Library in the JCSMR named the Eccles Medical Sciences Library.
• 1998 The John Eccles Neuroscience Laboratory opened in JCSMR.
• 1999 Postgraduate courses at Ettore Majorana Foundation and the Centre for Scientific Culture, Erice, Sicily, Italy, named Sir John Eccles School of Neurophysiology and Neurology.