Andrew Fielding Huxley College (1925–30) and Westminster Schools Command and Later for the Admiralty (1917–2012) (1930–5), Where He Was Inspired by J
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J Physiol 590.15 (2012) pp 3415–3420 3415 IN MEMORIAM Andrew Fielding Huxley College (1925–30) and Westminster Schools Command and later for the Admiralty (1917–2012) (1930–5), where he was inspired by J. F. for the rest of the war, developing radar Rudwick’s teaching to turn from Classics control of antiaircraft guns and naval Christopher L.-H. Huang to physical sciences. He chose to apply to gunnery. This was after a brief interlude Physiological Laboratory, University of Trinity College, Cambridge, through his working as an experimental subject for Cambridge, Downing Street, Cambridge family’s friendship with George Trevelyan, Robert McCance and Elsie Widdowson, CB2 3EG, UK where he won a major Entrance Scholarship who had been making physiological analyses Email: [email protected] (1935). His interests eventually turned to of calorific values of food before the war, Physiology through his contact with Delisle and were then conducting studies on food If I have seen further, it is by standing Burns, and then with E. D. Adrian, Jack rationing. The wartime research sharpened on the shoulders of giants.(Isaac Roughton, William Rushton, Alan Hodgkin his already considerable mathematical and Newton, in a letter to Robert Hooke and Glenn Millikan amongst others. To this engineering skills: this interest and aptitude (1676). From The correspondence of end his studies proceeded along a medical in engineering dated from his receiving, as Isaac Newton,vol.1,1661–1675,ed. direction pursuing Anatomy in 1937–8 and a gift from his parents as a young boy, Turnbull, HW, 1959, p. 416.) Physiology in Part II of the Natural Sciences a lathe which he continued to use in the Tripos in Cambridge in 1938–39. course of his subsequent scientific work and His first introduction to physiological which remains in his garage in his home Andrew Fielding Huxley, OM 1983; Kt experimental work began when he joined in Grantchester, where he continued to live 1974; FRS 1955; PRS 1980–1985, MA, Hon. Alan Hodgkin, who had previously tutored following retirement. This had led him to ScD Cantab. Physiologist and Biophysicist. him in Trinity, at the Plymouth Marine design and build microscopes and other Born Hampstead, London, 22 November Biological Laboratory in 1939. They scientific instruments. These skills proved 1917. Demonstrator, 1946–50, Assistant succeeded in making electrophysiological invaluable in his subsequent scientific work, Director of Research, 1951–59, and Reader recordings from the inside of the squid enabling him to design much of his in Experimental Biophysics, 1959–60, giant axon, whose structure was first experimental equipment. In the course of Physiological Laboratory, Cambridge; demonstrated by Young (1936), of the time his career, he developed an interference Director of Studies, Trinity College, course of its action potential, demonstrating microscope for studying striation patterns Cambridge, 1952–60; Jodrell Professor its overshoot for the first time (Hodgkin in isolated muscle fibres, a microtome 1960–69, Royal Society Research Professor, & Huxley, 1939, 1945). For the first year for making electron microscope sections, 1969–83, University College London. of the Second World War, Huxley was and a micromanipulator, testimony to the Master, 1984–90, Fellow, 1941–60 and since a clinical student in London. However, importance of technical skills and to the 1990, Trinity College, Cambridge (Hon. when medical teaching was stopped by air good mechanical workshop facilities then Fellow, 1967–90). Died 30 May 2012, aged attacks, he turned to operational research in available to physiologists (Huxley, 1954, 94. gunnery, first for the British Anti-Aircraft 1957a; Huxley & Niedergerke, 1958). Sir Andrew Huxley, shown in his laboratory in Fig. 1, was a giant among modern physiologists, pioneering the fields of nerve conduction, and skeletal muscle activation and tension generation. He The Journal of Physiology worked with exceptional and elegant originality and had a characteristically quantitative approach to physiological analysis within a physically rigorous framework, an approach now beginning to permeate from physiology and biophysics into their cognate biological and biomedical sciences. He was born in Hampstead, London, to the writer Leonard Huxley and Rosalind Bruce in 1917, within an illustrious family. His grandfather Thomas Huxley was a distinguished 19th-century biologist and early proponent of evolutionary theory. Julian Huxley, a pioneer in animal behaviour, and Aldous Huxley, the author of Brave New World among other works, Figure 1. Sir Andrew Huxley photographed in his laboratory were half-brothers from his father’s first Taken in 1997 by Martin Rosenberg (Physiological Society Archive, Contemporary Medical marriage. He was educated at University Archive Centre, Wellcome Institute for the History of Medicine, London). C 2012 The Author. The Journal of Physiology C 2012 The Physiological Society DOI: 10.1113/jphysiol.2012.238923 3416 In memoriam J Physiol 590.15 Andrew resumed his collaboration with membrane depolarization produced either to membrane potential restoration to its Alan Hodgkin between 1946 and 1951, by applied stimulation or pre-existing original level. This ends the action potential, pursuing their study on squid nerve activation of adjacent membrane would but a further time interval, the refractory axons, with the able assistance of produce a rapid, steeply voltage-dependent period, is required for the Na+ permeability Hodgkin’s technician, Ron Cook, in the activation of the Na+ conductance. The to recover its capacity for further excitation handling, transport and maintenance of resulting depolarization produced by the (for historical accounts see Hodgkin, 1976; the squid. They used the voltage-clamp resulting net inward Na+ movement down Huxley, 2002; Waxman & Vandenberg, technique first invented by K. S. Cole its concentration gradient then further 2012; Schwiening, 2012). (review: Cole, 1968). This permitted increases Na+ permeability, initiating an His award of the 1963 Nobel Prize, with Sir detailed study of permeability changes accelerating positive feedback process. This Alan Hodgkin in recognition of their ionic through the separation and measurements terminates only as the membrane potential hypothesis, and Sir John Eccles for his work of ionic currents crossing the membrane approaches the Nernst potential ENa,set on synaptic signalling, recognized these when the potential across it was stepped by the higher extracellular compared to contributions as providing the conceptual from a chosen resting level to a known intracellular Na+ concentrations, when the foundation for the study of excitable cell test value (‘voltage clamping’) defined by net inward driving force on Na+ becomes signalling. They also prompted a cascade the experimenter, rather than permitting zero, and with the slower development of of important discoveries with implications this voltage to vary through the complex a similarly voltage-dependent inactivation. ranging from the fundamentals of channel time course of a conducted action potential. A similar, but more gradual activation function to their translation into the basic It was thus possible to explore the of K+ permeability permitting outward mechanisms of disease. The 1991 Nobel voltage-sensitive properties of sodium and movement of K+ along an opposite Prize was to be subsequently awarded to potassium currents and their time courses, concentration gradient also contributes Erwin Neher and Bert Sakmann for the separated from the initial capacitative charging current contributions, through different, controlled test voltages (Hodgkin et al. 1952). The behaviour of the under- lying sodium and potassium conductances could then be computed with the aid of their known intracellular and extracellular concentrations that furnished the driving forces for such currents (Hodgkin & Huxley, 1952a,b). These resembled first order transitions incorporating steeply voltage-dependent forward and backward rate constants, whose variables were raised to their third (m3) and fourth (n4)powers, respectively. The Na+ conductance showed an additional, first order inactivation (h) variable that was to prove of fundamental importance in understanding post-excitation refractoriness (Hodgkin & Huxley, 1952c). The final step in the analysis of the data obtained under voltage clamp conditions owed much to Huxley’s mathematical ability, scientific imagination and end- urance in then computing how the in vivo conducted action potential might behave (Hodgkin & Huxley, 1952d). This gave excellent agreement between the pre- dicted and observed time courses as well as solutions for conduction velocities of the propagated action potential at 18.5◦C(Fig.2a–d). Lastly, this computation also quantitatively predicted the exchange + + Figure 2. Computed (a and b) and experimentally recorded (c and d) propagated of Na and K through the action action potentials in squid giant axon at 18.5◦C, plotted on fast and slow time scales, potential time course (Fig. 2e). These results and underlying conductance changes thus established and quantified the ionic Calculated conduction velocity was 18.8 m s−1; that actually observed was 21.2 m s−1. e,time + hypothesis implicating movements of Na courses of propagated action potential and underlying ionic conductance changes computed in the production and overshoot property from voltage-clamp data. The constants used corresponded to an 18.5◦C temperature. − of the in vivo action potential. An initial