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Home , 1952 in science, Alan Hodgkin, Andrew Huxley

Professor Sir OM KBE MA ScD FRS 1914-1998

A Ian Hodgkin was distinguished for his Disease is named. His father, a friend of contributions to the understanding of Keith Lucas, originator of the All-or-None nerve conduction, the Law, died in 1918 on a excitation of muscle, mission to investigate and phototransduction conditions among in the retina. With his refugees in Armenia. colleagues Bernard Alan Hodgkin's Katz and Andrew autobiography tells us Huxley, he established that being sent away to the ionic basis of the the Downs School, , Colwall, near Malvern, in r e v o I u t i o n i s i n g 4his ninth year was not a and happy experience, and laying the foundations subsequent entry to for subsequent work, Gresham's School, Holt, now burgeoning more in Norfolk, found him in than ever, on ion the bottom class. But he channels. In 1963, at worked his way up to win the age of 49, he won Brya Organs portrait of Sir Alm Hodgkin OM as a Scholarship to Trinity the for Chancenor of the University of Le tr. College, , in and Photogmph courtesy of the Botany, Zoology, and Medicine with Andrew Chemistry. His future Huxley and John Director of Studies, the Eccles. He was a Fellow of the Royal zoologist Carl Pantin, persuaded him to use Society at the age of 40, and held its the time between school and university to Foulerton Research Chair from 1952 to learn as much mathematics, physics, and 1969. In 1970 he succeeded F J W German as possible. Though he was largely Roughton to the John Humphrey Plummer self-taught in mathematics and physics, his Chair of in the University of technical innovation in methods of Cambridge. He was President of the Royal electrophysiological recording and his Society from 1970 to 1975, its Croonian elegance and quickness with mathematical Lecturer in 1957, and winner of its Royal arguments must owe something to Pantin's Medal in 1958 and its in 1965. advice. These qualities were to become He was Master of Trinity College from 1978 hallmarks of his future scientific papers, to 1984, President of the Marine Biological which were rigorous in their theoretical Association from 1966 to 1976, and basis, as was the clarity - simplicity even ­ Chancellor of the University of Leicester and directness in the writing. German was from 1971 to 1984. He served on the learned during an extended visit to , Committee of The Physiological Society from where experience of Nazism removed the 1949 to 1953 and again as Foreign absolutist pacifism of his Quaker Secretary from 1961 to 1967. He gave the background. Annual Review Lecture in the Society's Centenary year (1976) and became an At Cambridge, Alan Hodgkin became quickly Honorary Member in 1979. He was made introduced into the Natural Science Club, a KBE in 1972, and a Member of the Order of 'somewhat elitist group' that included among Merit in 1973, an Order in which he joined his its members many scientists who would gain cousin by marriage, Dorothy Crowfoot distinction. He was also later introduced by Hodgkin, and was later to be joined by his Victor Rothschild and the physiologist Grey collaborator and life-long friend Andrew Walter into the Apostles - the Cambridge Huxley, the three making up an eighth of the Conversazione Society - a group of far total membership. greater exclusivity. It was evidently a bit of a toss-up whether he read physiology or Alan Hodgkin was born on 5 zoology in his third year at Part II. Perhaps near Banbury, Oxfordshire, the oldest of sneaking into a Physiological Society three brothers. His family was Quaker, meeting in May 1934 helped, where he whose strong traditions in medicine included heard a 'splendid debate on humoral 'Uncle Hodgkin' after whom Hodgkin's transmission with Henry Dale, G L Brown and Feldberg on one side and Jack Eccles This work was not without danger, since the on the other'. But physiology also won out circuitry was likely to flash over at altitude partly as a result of F J W Roughton's during the 15,000 V ps pulse required to get advice: 'if you want to find out anything really a decent range. Further the adapted aircraft new you must join us in Physiology'. This were not always identified as friendly. Such advice sounds rather arrogantly phrased an error resulted in the death in 1942 of AE today. But find out new things he did. Downing (who with G W Edwards from GEC and Alan Hodgkin made up the team Even as an undergraduate, Alan Hodgkin undertaking flight trials) and his pilot when had started experiments studying nerve an adapted Beaufighter was shot down by conduction. These experiments, showing Spitfires, ordered to intercept an unidentified that excitability is raised ahead of the aircraft. The work was of great importance propagating impulse, began to establish the to the survival of our country during a period local circuit theory of nervous conduction. of great peril, directly enabling the His expertise in nerve however led to the destruction of many enemy aircraft. nightmare of finding his Part II Tripos papers lacking any questions on this subject. The end of the war permitted the return to Evidently the examiners thought their Cambridge and to basic science. This was inclusion would be unfair to other not necessarily the easiest transition to candidates. A thesis on nerve conduction make. Alan Hodgkin's autobiography led to election as a Fellow of Trinity College records a letter from Marni Hodgkin to her in 1936 and, through AV Hill's introduction of parents describing her husband as 'like a his work to Gasser, to the invitation to spend dolphin that has suddenly been released into a year at the Rockefeller Institute in New the open sea. He plunges and gambols and York. This year (1937-38) was of great cavorts in pure research after so long'. This importance. Gasser's laboratory 'helped next decade from 1945 would revolutionise turn (him) from an amateur into a neuroscience. professional scientist'. A visit to K S Cole in Woods Hole introduced him to the With W A H Rushton, was giant and would later introduce him to developed for application to nervous the . And he met the family of conduction. With the Peyton Rous whose daughter, Marion de hypothesis, now testable, was firmly Kay - Marni - was to become his wife in established by showing that the action 1944. potential changed in size and rate of depolarisation as predicted when Na was Work on squid axon started in just replaced in the extracellular fluid. Goldman's before the outbreak of war. With Andrew constant field theory was also put into its Huxley, he succeeded in making the first useable, and still widely used form. With intracellular recording of an action potential. , the ionic movements that This recording overthrew the received occurredduring an actiop potential (only opinion that resting selectivity to 10,000 K ions lost per mm ) were measured ions was simply lost during an action for the first time. potential, since the voltage overshot zero by several tens of mV. The result was written Above all, the voltage clamp was exploited up as a note in , but exploitation of the with stunning success with both Katz and sodium hypothesis which began to emerge Huxley. The experimental results that gave had to be abandoned until the latter part of the 1952 papers were collected in little more the next decade. than a month in the summer of 1949. The rapidity was permitted because the During the war Alan Hodgkin worked briefly hypothesis had been thought about pretty in medical physics, with Bryan Matthews, hard. The initial idea was that Na would and later in the group developing airborne enter through a carrier-mediated short wavelength (centimetre) radar. His mechanism. This carrier would be work was directed primarily towards effective negatively charged so that it would sit at the means of aircraft interception (AI) and outside of the membrane at negative naturally involved flight trials of equipment. membrane potentials. Depolarisation would O

be needed to let the carrier transport Na' in; Nastuk developed the discovery of Ling and the transfer would be inactivated at longer Gerrard that fine glass microelectrodes could times by a reaction between the carrier and be inserted through the membrane of a cell, some axoplasmic constituept. This carrier such as a skeletal muscle fibre. They hit on was also thought to bind Ca at the outgide, the idea of filling pipettes with 3M KCI and which immobilised it. The effects of Ca on introduced a cathode follower with a driven excitability would later be established in shield, both developments that allowed collaboration with Bernard Frankenhaeuser. action potentials to be recorded without distortion. In this technical innovation, as in The carrier the development of voltage clamping idea did not apparatus, he and his colleagues were last long. supported by his instrument maker R H Coo. The Current would paper describing the work on muscle, unlike the be caused by great majority of his others, was published in movement of the Journal of Comparative and Cellular the carrier, yet Physiology, owing to a 15-month wait this current experienced with the Journal of Physiology. would have to So much that followed be small used this method. It was immediately picked c o m p a r e d up by Silvio Weidmann to record from with ionic cardiac muscle, and Alan Hodgkin extended current. Thus cable theory to deal with conduction through the unitary intercalated disks. Currently, is event would a particularly elegant combination of the Alm Hodgn &AndrewHuxley iPlymouth.Itis have to be the voltage clamp of Hodgkin, Huxley and Katz believed that the photograph was taen m 1939 opening of an and the micropipette of Nastuk and Hodgkin. at the time of the first intracellular recoding frcm I the giant squid axon active patch' through which Work now turned to studies with Richard many Na ions could move. This concept Keynes and later with Peter Caldwell and was already close to that of an Trevor Shaw of active transport of ions by and the 'gating currents' that were predicted squid axon developing principles of sodium would later be discovered by Armstrong and pump action in maintaining the ionic Bezanilla in the United States and by Keynes gradients whose storage of energy is and Rojas in the UK. Later measurements essential for excitability. With Peter Baker with of unidirectional fluxes and Trevor Shaw, the perfused giant axon and of their ratio would establish potassium was developed and was used to show that permeability sites as pores,,and indeed as action potentials did not require metabolic pores occupied by several K ions at a time. energy for their generation or for their recovery. Effects of changes ofthe intracellular The wonderfully elegant mathematical milieu on excitability were investigated with descriptions of the permeability changes to Knox Chandler and Hans Meves. All of Na and K3 - the, -jodgkin-Huxley these experiments put the final objections to formulation, m h for Na, n for K - have the sodium hypothesis to rout, and Alan survived amazingly intact. It scarcely came Hodgkin considered this development of the as a surprise when potassium ion channels perfused axon in 1962 to be a decisive factor were later shown to be tetramers of pore- in the awad of the Nobel Prize the following forming subunits. Further, recent evidence year. Ca permeability of was from W Catterall's laboratory (and others) established with Baker and Ridgway. Ca+ suggests that in Na -channels, only three of was shown to enter partly through Na the voltage-sensing S4 domains (S4 ) chqnnels and partly through voltage-gated regulate activation, while the fourth (S4...) Ca channels, whose presence in axon was regulates nactivation. This is remarkal Yy thereby demonstrated for the first time. The close to m h. Famously, the calculation of sodium-calcium exchange of axon was the propagating action potential was made discovered with Mordie Blaustein, Peter by Andrew Huxley using a hand cranked Baker and Rick Steinhardt. calculator, owing to the lack of availability of the Cambridge University Computer. During The microelectrode technique was this period too, Alan Hodgkin and W J beautifully exploited with Paul Horowicz in

1t studies of dissected single skeletal muscle McNaughton, P M O'Bryan and K-W Yau. fibres - a fiendishly difficult dissection. His last paper in this series - a detailed These studies showed how both K and CI kinetic analysis of the interplay between permeated the resting membrane of skeletal cGMP and the inhibitory effects of Ca in muscle and how K permeability was higher salamander rods - was published in 1988 when the driving force on K was inward - the with Brian Nunn, whose death two months now classical (V-E ) dependence of inward after its completion caused deep regret. rectifiers. The probable T-tubular location of inward rectifiers was established through Alan Hodgkin's primary contributions were beautiful experiments involving rapid K as a remarkable experimentalist able to find concentration changes. Studies of elegant ways of testing clear hypotheses. excitation-contraction coupling began with However he was also a very effective, measurements of potassium contractures assiduous scientific administrator. His and were continued with voltage clamp tenure of the Presidency of the Royal studies with W K Chandler and R H Adrian. Society occurred at a difficult time. The With these colleagues he also established report in 1971 by his long-time friend Lord the ionic basis of the action potential of Rothschild - heading the Downing Street skeletal muscle and the beginnings of 'think-tank' - into the funding of scientific diversity of potassium permeability research caused considerable concern for mechanisms. His last experiments on the future of basic science. The Green muscle were conducted with Shigehiro Paper, The Organisation and Management Nakajima, a rigorous extension of cable of Government Research and Development, theory and careful measurement of proposed a scheme of customer sarcoplasmic resistivity. (government department) and contractor (the scientist) and the substantial transfer of Work on squid axon was arduous. At funds from the Research Councils to other Plymouth, squid were captured by trawler government departments, such as Health, during the day, and dissected and worked on Industry, Environment, and Energy. Hodgkin during the evening and night. The was particularly concerned for the future of combination of absence from home - the the Natural Environment Research Council, spouses of those working on squid were then still in relative infancy. He did much to known as 'squidows' - analysis by day and maintain science funding through high level experiment by night was exhausting. negotations, on one occasion not letting Hodgkin recalled himself and pretty severe influenza deflect him. In the Frankenhaueser being mistaken for end the transfers were not as large as refugees by a Plymouth shopkeeper, who originally proposed. His preoccupation with was worried enough at their exhausted state this issue can be seen in his Anniversary to contact the Director of the MBA and Addresses to the Royal Society of 1972 and request they be properly fed. In 1962 1975. Thinking the most innovative science Hodgkin had collaborated with M G F as 'not well suited to the specific contract', in Fuortes in studies of Limulus eye, explaining 1972 he defended basic science with a how the gain -of the eye was altered through quotation from Francis Bacon: 'The real and its synaptic connections. In addition an legitimate Goal of the Sciences is the extended visit to Cambridge by Denis Baylor, endowment of human life with new who brought the technique of intracellular Inventions and Riches.' recording from retina, permitted Alan Hodgkin to turn his attention to this system. 'Thus had anyone meditated on balistic Nonetheless the change of field must have machines and Battering Rams, as they were made demands, because it occurred at a used by the Ancients, whatever application time when he had become President of the he might have exerted, and though he might Royal Society, a position that carried its own have consumed a whole life in the pursuit yet responsibilities. In the period from 1970 to he would never have hit upon the Invention 1988 Alan Hodgkin brought the same of Flaming Engines, acting by means of reforming rigour and insight to Gunpowder; nor would any person who had phototransduction that he had brought to made woolen Manufactories and Cotton the bear on nerve conduction. As well as Denis subject of his observation and reflection, Baylor, his colleagues at this time included have ever discovered thereby the nature of Trevor Lamb, Peter Detwiler, Peter the Silkworm and Silk.' He also initiated a development fund to physicist J J Thompson's opening a secure the then somewhat shaky finances of conversation with W B Yeats with the the Royal Society, which had recently moved sentence 'Been writing much poetry lately, to new premises in Carlton House Terrace. Mr Keats?'. (At least the area of endeavour Since the economic conditions in the UK was right.) Or that his vote of thanks to J C could not be viewed optimistically at the Eccles for his lecture at the Dale Centenary time, this was a particularly difficult period to Symposium should consist of the one initiate such a policy. Yet the security was delightfully ambiguous sentence: 'I have just achieved. He also created a scientific one thing to say - you're all right, Jack'. Or dialogue with China, leading a delegation indeed that he would share the audience's and going ahead with the visit in spite of last amusement at finding himself giving his minute withdrawal of Chinese permission, at Nobel Prize lecture in Stockholm in 1963 a time when the Cultural Revolution was a with a 'Reserved' sign stuck electrostatically very recent event. As Master of Trinity he (appropriately) to the seat of his trousers. He 'helped a little' with the development of would later recall the incident with the Trinity Science Park in Cambridge. I suspect aphorism "Nothing is more sure-fire than the he did not find his duties as Chancellor of the bishop on the banana peel". University of Leicester always the easiest. He found the platitudes expected by some in Alan Hodgkin was widely travelled, had a the Chancellor's address difficult if not strong sense of wonder at the natural world probably downright dishonest and he did not and was deeply cultured. He was, in the indulge in them. Behind the scenes he words of a message from Chilean scientists would be full of wise advice, and would take to the Society at the time of his death, 'a pleasure in the University's strengths in scientist for all seasons'. Certainly he was a biology and physics. man against whom other scientists come, by some, to be measured. His long marriage to Alan Hodgkin was an outstanding teacher. Marni, the daughter herself of a Nobel His lectures on nerve conduction in laureate, brought four children and was Cambridge were remakable for their clarity, remarkably supportive during the long In the 1960s, at the time when he had just autumns of squid seasons, during his won the Nobel Prize, he still taught in third- Presidency of the Royal Society and his year practical classes - the only Professor Mastership of Trinity. And also during his so to teach us. He would help make long struggle with arthritis. Two things in life experiments work and would take great were of the greatest importance to him, and pains to explain the principles. Explaining he put them in proper order in a letter written cable theory and running out of space, he at the time of his 70th birthday: 'For 90% of would drop to his knees in the chalkdust to the time science can be an intensely make use of the last bit of the blackboard. frustrating business, but the occasional Although he was remarkably well networked breaks have brought me more happiness through family and through friendship to an than anything else outside love and intellectual elite, there was a lack of any marriage'. sense of position. He did not wish (as some do) to seem a great man, yet he undoubtedly Peter Stanfield was so. And the more so for his unfailing University of Leicester modesty and courtesy, especially towards undergraduates, and within The Physiological Society to younger scientists. SirAlan Hodgkin was: Elsewhere he could be more exacting. Elected Ordinary Member 1938 Elected Honorary Member 1979 He had a debunking sense of humour and Member of The Physiological Society often wore a look of incompletely Committee 1949-1953 suppressed amusement at some foible. Foreign Secretary 1961-1967 Evidently the trick of not quite suppressing laughter was learned during Quaker meetings in childhood. It is typical that he would recall in his autobiography the