1

Andrew Fielding Huxley

1917-2012

Sir Andrew Huxley (1917-2012) pioneered the physiology and biophysics of nerve conduction, skeletal muscle

activation and tension generation. His ground-breaking work on nerve excitability of nerve in collaboration with

Alan Hodgkin in the Cambridge Physiological Laboratory and the Plymouth Marine Biological Laboratory provided

the basis for our understanding of how voltage-gated ion channels generate propagating action potentials and

led to award of the 1963 Nobel Prize for Physiology and Medicine with Alan Hodgkin and Jack Eccles. Huxley

then went on to perform seminal work of similar importance on muscle activation and contraction whilst at

University College London. This led to the sliding filament theory and cross-bridge hypothesis of muscle

contraction, completing a momentous quest within physiology, in his view, “the mechanical engineering of living

things”.

Huxley was born in London within an illustrious family. His father Leonard was a writer and his grandfather

Thomas an early proponent of evolutionary theory. His half-brother Julian pioneered in animal behaviour and

Aldous, another half-brother, was a distinguished writer, authoring, among other books, Brave New World.

He was educated at University College (1925-30) and Westminster Schools (1930-5), winning a major

Entrance Scholarship in 1935 to Trinity College, Cambridge. His interests turned to physiology, for which his

studies pursued a medical direction including anatomy in 1937-8 and Part II Physiology in the Natural Sciences

Tripos (1938-9). He also showed exceptional engineering talent, which was to be his close companion for the

rest of his career, wherein he often invented equipment integral to his experiments. He thus invented a

micromanipulator, an interference microscope for studying striation patterns in muscle, and a microtome for

making electron microscope sections (Huxley, 1954, 1957a; Huxley & Niedergerke, 1958).

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His first encounter with physiological research was in 1939 with Alan Hodgkin on the properties of the

propagated impulse in giant axons of squid. It was known that this was an all-or-none event resulting in an

advancing membrane potential change along the fibre cable structure thereby stimulating adjacent, initially

quiescent membrane. Bernstein (1902) had attributed the resting negativity of the fibre interior to a selective

permeability of the membrane to potassium relative to sodium, and the greater intracellular relative to

extracellular potassium concentration. The action potential might then result from a generalized increase in

membrane permeability to all ions in response to alteration of the internal potential beyond a threshold level,

collapsing this potential to zero. An increased membrane permeability had indeed been demonstrated by

membrane impedance measurements by a high-frequency alternating current (AC) bridge (Cole & Curtis, 1939).

However, Hodgkin and Huxley’s (1939, 1945) intracellular recordings of the action potential demonstrated that

the membrane potential becomes substantially positive (Fig. 1). This observation was to lead eventually to the

current view that this reflects an increased permeability specific for sodium ions, which would diffuse inwards

carrying a positive charge. However, work in this direction was interrupted by Hitler’s invasion of Poland and the

subsequent outbreak of war. It was only to resume seven years later, when Huxley returned from work first for

the British Anti-Aircraft Command and later for the Admiralty, developing radar control in antiaircraft guns and

naval gunnery.

Figure 1

Intracellular recording of the squid giant axon action potential.

A, photomicrograph of an electrode within a squid giant axon (diameter ~500 μm), showing two views of the same axon

which allowed simultaneous viewing of the electrode from both front and side made visible from a system of mirrors

devised by Huxley. This ensured that the electrode would not damage the nerve membrane as it was threaded down the

axon (Hodgkin & Huxley, 1945). B, the first intracellular recording of an action potential and its overshoot. The sine wave

time marker has a frequency of 500 Hz (Hodgkin & Huxley, 1939; by permission from Macmillan Publishers Ltd: Nature

C1939).

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Andrew thus resumed his collaboration with Alan Hodgkin in 1946. By 1947, voltage clamp equipment invented

by Cole (Cole & Curtis, 1939; for a review see Cole, 1968) had successfully demonstrated continuous current–

voltage relationships in squid nerve membrane that nevertheless included a region of negative slope compatible

with the regenerative, all-or-none, property shown by the action potential. This was made possible through

control of the voltage through imposed steps from a chosen, resting level to known test values (‘voltage

clamping’) defined by the experimenter, as opposed to its variation through the complex time course of a

conducted action potential. It was then also possible to explore the time courses of sodium and potassium

currents traversing the membrane, and determine the underlying permeability changes, separated from the initial

capacitative charging current contributions, through different, controlled, test voltages (Fig. 2; Hodgkin et al.

1952). A consecutive sequence of four experimental papers described the current–voltage relationships in squid

giant axon membranes (Hodgkin et al. 1952), characterized their currents attributable to movements of sodium

and potassium ions (Hodgkin & Huxley, 1952a), and the effect upon these of varying the times and durations of

depolarizing and repolarizing steps (Hodgkin & Huxley, 1952b), and ended with studies on the ‘inactivation’ of

the sodium permeability following its initial activation produced by depolarization (Hodgkin & Huxley, 1952c).

Figure 2

A family of currents acquired using large depolarizing steps under voltage clamp control

Early records of this kind plotted both current traces with inward currents represented as positive and voltages with

depolarizations given relative to the holding potential and the outside voltage plotted relative to the inside. The –91 mV

step represents a depolarization of the inside of the nerve fibre to +15 mV (Hodgkin et al. 1952).

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The final, theoretical paper then synthesized these results into a ‘Quantitative description of membrane current

and its application to conduction and excitation in nerve’ (Hodgkin & Huxley, 1952d), describing amongst the

most elegant applications of computational methods in the biological sciences. The sodium and potassium

conductances were described in terms of first order transitions with steeply voltage-dependent forward and

backward rate constants, with variables raised to their third (m3) and fourth (n4) powers, respectively, with the

sodium conductance additionally incorporating an inactivation (h) variable. The resulting reconstruction of the in

vivo conducted action potential closely agreed with the observed time courses and conduction velocities (Fig.

3a-d) (Hodgkin & Huxley, 1952d). It was also possible to reconstruct the detailed Na+ and K+ movements

through the action potential time course (Fig. 4). Thus was established the ionic hypothesis implicating

movements of sodium ions in the production and overshoot property of the in vivo action potential. An initial

stimulation or pre-existing activation of adjacent membrane would produce a rapid, steeply voltage-dependent

activation of the sodium conductance. This would result in a further depolarization, in turn further increasing

sodium permeability, initiating a positive feedback process terminated only as the membrane voltage approaches

the sodium Nernst potential, and with a slower potassium permeability activation driving a repolarizing outward

current. The latter would also contribute to membrane potential restoration to its resting level into a period of

refractoriness over which the sodium permeability and therefore the membrane regains its capacity for

activation (Historical accounts: Hodgkin, 1976; Huxley, 2002; Waxman & Vandenberg, 2012; Schwiening,

2012).

Figure 3

Computed (a and b) and experimentally recorded (c and d) action potentials propagated in squid giant axon at

18.5°C, plotted on fast and slow time scales.

Calculated conduction velocity was 18.8 m s-1; that actually observed was 21.2 m s-1 (Hodgkin & Huxley, 1952d).

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Figure 4

Time courses of propagated action potential and underlying ionic conductance changes computed from voltage

clamp data.

The constants used corresponded to a 18.5°C temperature. Conduction velocity, 18.8 m s-1 (Hodgkin & Huxley, 1952d).

Over this time, Huxley also collaborated with Robert Stampfli on the function of the myelin sheath in vertebrate

nerve fibres in restricting inward and outward local current passage to the nodes of Ranvier, resulting in an

enhanced, salutatory, conduction of their nerve impulses between nodes (Lillie, 1925). This reflected the

reduced stimulation thresholds and greater sensitivity to anodal polarization and to local anaesthetics at nodal

than along internodal regions (Tasaki, 1953). Huxley and Stämpfli (1949) refined those earlier techniques,

pulling an isolated frog myelinated fibre through a short glass capillary traversing a partition separating two

Ringer-solution-filled compartments (Fig. 5A). The capillary diameter was small enough to impart the fluid-filled

space around the nerve an appreciable, 0.5 MΩ, resistance. Longitudinal current flow between neighbouring

nodes would then generate a measurable voltage across the two sides of the partition. The resulting records of

longitudinal current showed (Fig. 5B) that currents were similar in magnitude and timing at all points outside any

one internode but their peaks were displaced stepwise in time by ~0.1 ms as successive nodes were traversed.

The current flowing radially into or out of the fibre could be determined by subtracting successive pairs of

records from one another (Fig. 5C). This demonstrated only slight current leaks over the internodes but a brief

pulse of outward current followed by a much larger pulse of inward current restricted to each node.

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Figure 5

Method used by Huxley and Stämpfli (1949) to investigate saltatory conduction.

A, the isolated frog nerve fibre was pulled through a 40 µm diameter aperture in an insulating partition. Current flowing

along the axis cyclinder out of one node and into the other indicated by the arrows causes a voltage drop outside the myelin

sheath. The 0.5 MΩ resistance of the fluid in the gap between the two pools permits measurement of the potential

difference between them. The internodal distance in a frog’s myelinated nerve fibre is about 2 mm. B, longitudinal currents

flowing at different positions along the fibre with the right hand diagram showing the position where each record was taken.

Distance between nodes ~2 mm. C, transverse currents at different positions along the fibre with each trace showing the

difference between successive longitudinal currents. Vertical mark above each trace shows the time at which membrane

potential change reached its peak at that position along the fibre. Outward current plotted upwards (Huxley & Stämpfli,

1949).

The 1963 Nobel Prize to Hodgkin and Huxley for their ionic hypothesis and Sir John Eccles for his work on

synaptic signalling thus recognized key contributions that provided the conceptual foundation for studies of

excitable cell signalling. They had a similar significance for neurophysiology and biophysics as the structure of

DNA reported by Watson and Crick had for biochemistry. The findings in nerve prompted a cascade of important

discoveries whose implications range from the fundamentals of channel function, through their application to

excitable tissues generally, to their translation to understanding the basic mechanisms of disease. Firstly, of

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those concerning sodium channel properties and function itself, the voltage dependence of the sodium

conductance and its rate constants led Hodgkin and Huxley to predict that channel opening and closing would

involve net transfers of intramembrane charge in response to alterations in the transmembrane electric field.

Such gating currents were to be demonstrated twenty years later, providing a direct biophysical handle for

studying the mechanisms of the molecular configurational changes underlying channel activation (Armstrong &

Bezanilla, 1973; Keynes & Rojas, 1974). The 1991 Nobel Prize was then to be awarded to Erwin Neher and Bert

Sakmann for their introduction of the patch clamp technique. This made direct measurements of currents

traversing single sodium channels, thereby directly demonstrating the unit channel events through single ionic

channels underlying the observed conductances (Sakmann & Neher, 1983, 1984; Hamill et al. 1981; Raju, 2000;

Nilius, 2003). Finally, in more recent years, the field of biochemistry was to describe the structure of the sodium

channel and characterize its gating transitions (Yarov-Yarovy et al. 2011; Payandeh et al. 2012).

Secondly, both the voltage clamp techniques and their associated mathematical formulations were applicable to

analysis of function in other excitable tissues, including mammalian nerve (Huxley & Stampfli, 1949;

Frankenhaeuser & Huxley, 1964), skeletal (Adrian et al. 1970) and cardiac muscle (Noble, 1962, 1984), and in

neuronal encoding processes exemplified by repetitively firing gastropod nerve (Connor & Stevens, 1971a-c).

Thirdly, the electrical circuit theory formulations used in the ionic hypothesis prompted subsequent more realistic

mathematical simulations that could reconstruct not only electrophysiological, but also volume regulatory

effects, of not only electrogenic, but also of electroneutral and osmotic fluxes and metabolic change (Fraser &

Huang, 2004; Fraser et al. 2005; Usher-Smith et al. 2006).

Finally, the fundamental ideas indicated paths through which work seeking translational implications for clinical

medicine would follow. Within nerve function these concerned our fundamental understanding of local

anaesthesia and pain, as well as of the importance of the Schwann cell sheath on conduction velocity in

demyelinating conditions. Skeletal muscle proved a fertile ground for the application of both the Hodgkin-Huxley

analysis and cable theory in an analysis of the repetitive firing in the neurological condition of myotonia congenita

(Adrian & Bryant, 1974). Arrhythmic and abnormal excitation conditions in cardiac muscle have proven an

important area for the application of basic biophysical ideas (Lei et al. 2008). These included recent studies of

genetically modified murine cardiac models for sodium channelopathies (Papadatos et al. 2002; Sabir et al.

2008; Killeen et al. 2008). These demonstrated how altered sodium channel activation and recovery properties

would result in sino-atrial pacemaker (Lei et al. 2005), atrial and ventricular arrhythmic disorders, in murine

models for the human arrhythmogenic conditions including the Brugada and Long QT3 syndromes (Martin et al.

2011, 2012; Matthews et al. 2012).

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Huxley moved from Cambridge to University College London in 1960, turning his interests to skeletal muscle,

starting with the recognition that the excitation beginning in its surface membrane need to be transduced into a

contractile activation of myofilaments in the fibre interior. AV Hill (1948; for a full historical account see Hill,

1965) had demonstrated that the timescale of such excitation was difficult to explain in terms of diffusion into

the interior of an activating substance liberated at the surface membrane. However, preliminary light microscope

evidence suggested a “Krause’s membrane” that might form a continuous structure across the fibre at the Z-line.

Huxley and Taylor (1958) depolarized very small patches of the surface membrane of isolated muscle fibres by

placing the end of a ~1 μm diameter micropipette in contact with the surface and applying a negative electric

potential to the fluid contained within the pipette. They demonstrated a highly localised contraction, visible

under interference microscopy, only when the pipette apposed an I band, and never when the pipette was

opposite an A band (Fig. 6). A loose-patch adaptation of this localized micropipette technique was to prove

useful to characterize channel distributions over the membrane area (Almers et al. 1983). Electron microscopic

studies correlated this with an occurrence of a transverse tubular membrane system continuous with the surface

membrane and open to the extracellular space (Huxley & Taylor, 1958; Huxley, 1982). The latter structure,

including its fragility following osmotically induced volume change (Gage & Eisenberg, 1969; Fraser et al. 1998),

was to be the subject of subsequent study by, among others, Clara Franzini-Armstrong, Robert Eisenberg and

Lee Peachey, who had begun scientific work with Huxley. These prompted the application of electrical cable

representations of that tubular geometry to Hodgkin & Huxley’s original analysis, in a reconstruction of its role in

active conduction of excitation into the fibre interior and the activation of contraction (Adrian & Peachey, 1973;

Huang & Peachey, 1992). This, in turn, led to the current view suggesting a rapid propagation of the action

potential along the membrane surface to the ends of the fibre. The lower frequency components of this action

potential then activate the tubules by initiating a further centripetal wave of excitable activity (Sheikh et al.

2001; Pedersen et al. 2011). Finally, clarifications of the subsequent excitation–contraction coupling

mechanisms at the molecular level, involving dihydropyridine receptor-mediated voltage sensing allosterically

coupled to ryanodine receptor-mediated release of intracellularly stored calcium, similarly involved voltage clamp

techniques (Huang, 1988, 1993; Huang et al. 2011; Huang & Peachey, 1989, 1992).

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Figure 6

Local activation experiments in amphibian skeletal muscle.

Panels 1-4 show the edge of an isolated frog muscle fibre with apposed pipette. This is photographed under polarized light

with A bands appearing dark. Comparison of the results of stimulation at an A (panels 1 and 2) and an I band (panels 3 and

4) before (panel 1 and 3) and during (panels 2 and 4) stimulation demonstrates contraction only with the pipette opposite

an I band (panel 4). Successive cine frames (at 16 frames s–1; panels 5-8) show the shortening where the local

depolarization is applied between panels 5 and 6 (Huxley & Taylor, 1958).

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Huxley’s interest then turned to muscle contraction itself. It had previously been assumed that muscle

contraction involved coiling and contraction of long protein molecules akin to the shortening of a helical spring.

Andrew Huxley & Rolf Niedergerke, and Hugh Huxley & Jean Hanson, independently suggested the sliding

filament theory (Huxley & Niedergerke, 1954; Huxley & Hanson, 1954), prompted by findings that sarcomeric A

band lengths remained constant in both stretched and actively or passively shortening muscle. Huxley then

produced elegant evidence that contraction thus resulted from a relative sliding of thin filaments between thick

filaments probably driven by cross bridge interactions between them (Gordon et al. 1966). This compared

isometric tension and filament overlap itself held at a range of fixed lengths by optical servomechanisms in single

amphibian muscle fibres. The resulting length–tension diagram (Fig. 7A) closely correlated with predictions from

electronmicroscopy determinations (Fig. 7B) of 2.05 µm long actin, including a 0.05 µm Z-line, and 1.6 µm long

myosin, filaments whose 0.15 to 0.2 µm middle regions were bare of cross bridges. Thus, (1) sarcomere lengths

>3.65 µm would not permit cross bridge formation directly explaining the accompanying loss of tension

development (Fig. 7C). In contrast, between 3.65 µm and (2) 2.2 to 2.25 µm, cross bridge number would

linearly increase with decreasing sarcomere length. This correlated with the corresponding linear increase in

isometric tension. However, further shortening between (2) and (3) would leave constant cross bridge numbers,

predicting the tension plateau between 2.05 and 2.2 µm. Tension fell with further shortening beyond (3)

attributable to actin filament overlap. (4) Below ~2.0 µm a clash between actin filaments between halves of the

sarcomere would predict the fall in tension. (5) At 1.65 µm, myosin filaments would hit the Z line, predicting a

distinct kink in the curve beyond which tension falls much more sharply to zero tension at ~1.3 µm before (6).

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Figure 7

Analysis of the length–tension relationship of skeletal muscle in terms of a cross bridge hypothesis.

A, the isometric tension of isolated frog muscle fibre at different sarcomere lengths. The numbers 1 to 6 refer to the

myofilament positions shown in C. B, electronmicroscopic measurements of myofilament dimensions in frog muscle. C,

myofilament arrangements at different lengths. Letters a, b, c and z refer to dimensions given in panel A (Gordon et al.

1966).

Huxley’s final interest concerned the cross bridge interactions mediating the cross bridge sliding itself

accompanied by ATP breakdown (Huxley, 1957b). Cytsolic Ca2+ elevation then initiates cyclic reactions between

projections on the myosin filaments and active sites on the actin filaments in the form of cross bridge formation

and configurational change that drives a filament sliding and ATP breakdown. Huxley’s 1974 model (Huxley &

Simmons, 1971; Huxley, 1974) explained the resulting tension transients in terms of elastic and step-wise

shortening elements driven by an actin-myosin binding through a sequence of attachment sites each reflecting

increasing strengths of interaction (1 to 3 in Fig. 8), Myosin detachment, permitting re-initiation of a further

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cross bridge cycle with a fresh actin binding site, would then take place in position 3 accompanied by ATP

hydrolysis. This final direction of work involved amongst others, Lincoln Ford, Yale Goldman, Hugo Gonzalez-

Serratos, Lucy Brown, Vincenzo Lombardi and Gabriella Piazzesi.

Figure 8

The Huxley-Simmons (1971) model for cross bridge interaction.

This incorporates elastic and step-wise shortening elements and three possible myosin head positions 1, 2 and 3 of

successively greater strengths of binding to actin. The myosin head can dissociate in position 1 without, but in position 3

only with ATP utilization (Huxley, 1974).

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Sir Andrew was elected to the Royal Society in 1955 and was its President between 1980 and 1985. He

became Jodrell Professor of Physiology in 1960, then Royal Society Research Professor in University College

London in 1969. He was Master of Trinity College, Cambridge between 1984 and 1990, knighted in 1974 and

appointed Order of Merit in 1983. He was elected Ordinary and Honorary Member of the Physiological Society

in 1942 and 1979, served in its Committee (1957-61; 1970-4) and served on the Editorial Board of The

Journal of Physiology (1950-57). He was joint president of the International Union of Physiological Societies in

1986 to 1993. He worked at Woods Hole, Massachusetts, in 1953 as a Lalor Scholar, and gave the Herter

Lectures at Johns Hopkins Medical School (1959) and the Jesup Lectures at Columbia University (1964). In

1947 Andrew Huxley married Jocelyn Richenda Gammell Pease, daughter of the geneticist M. S. Pease, and the

Hon. H. B. Pease (née Wedgwood), who predeceased him in 2003. They had five daughters and a son.

Acknowledgements

I would like to record my deep gratitude to Andrew Huxley for his encouragement of work I pursued on surface

and tubular action potential conduction in skeletal muscle, channelopathic models for arrhythmogenesis in

cardiac muscle, and with Lee Peachey and the late Richard Adrian on excitation-contraction coupling, during

which Lee Peachey stayed with Huxley in the Trinity College Master’s Lodge. I thank Carol Huxley for important

biographical details, Jeremy Skepper and Alan Catell for archival information, particularly concerning

instrumentation invented by Huxley. I apologize in advance to those whose contributions and roles in Sir

Andrew’s life I may have inadvertently omitted or slighted.

Christopher L-H Huang

Professor of Cell Physiology, University of Cambridge

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