(b. Banbury, Oxfordshire, England, 5 February 1914; d. Cambridge, England, 20 December 1998),
physiology, the ionic mechanisms of action potentials.
Hodgkin’s most important work, for which he shared the 1963 Nobel Prize in Physiology or Medicine, was on the ionic mechanisms of the action potential. This research and the development of an equation set that fits its electrical characteristics was a keystone of twentieth-century neuroscience and provides the foundation for our current understanding of neuronal conductance. In addition to his research achievements, Hodgkin served the scientific community as a director of research at Trinity College (Cambridge University), president of the Royal Society in London, and finally as master of Trinity College.
Family, Scientific Training, and Initial Discoveries . Born in 1914 to George and Mary Hodgkin, both Quakers, Alan was the oldest of three boys: Alan, Robin, and Keith. His early interest in science was sparked by his Aunt Katie (Catharine; née Wilson). Interestingly, she was related to Alan not only through her marriage to Edward Hodgkin, the elder brother of Alan’s father, but also as sister of Alan’s maternal grandfather. She encouraged Alan to keep precise records of his ornithological observations—a passion he pursued throughout his youth.
Hodgkin was initially ambivalent about his course of studies. His interests were divided between biology and history, a passion he shared with his grandfather George Hodgkin and his uncle Robin Hodgkin, both historians. His enthusiasm for outdoor explorations eventually tipped him toward natural history, and he decided upon a course of study that pursued this interest. He was accepted at Trinity College in 1932 as a student in botany, zoology, and chemistry.
Hodgkin was surrounded in both his family and professional lives by a cadre of eminent scientists. His cousin, Dorothy Crowfoot Hodgkin, received the 1964 Nobel Prize in Chemistry for “her determinations by x-ray techniques of the structures of important biochemical substances.” His wife’s father, Peyton Rous, shared the 1966 Nobel Prize in Physiology or Medicine for “his discovery of tumour-inducing viruses.” During his first few months at Cambridge, Hodgkin joined the Natural Science Club, a “small elitist organization” (Hodgkin, 1992, p. 51), whose members during Hodgkin’s attendance included Edward Bullard, John Pringle, Dick Synge, Maurice Wilkins, and Andrew Huxley—all of whom eventually became fellows of the Royal Society and four of whom won Nobel Prizes. Hodgkin also worked under E. D. (Edgar) Adrian in the physiological laboratory and came into contact with A. V. (Archibald) Hill, both of whom won Nobel Prizes for Physiology or Medicine.
In 1936 Hodgkin became a junior research fellow at Trinity College and spent several months repeating some of his own promising but rudimentary experiments. His results were published in the Journal of Physiology. A year later he was invited to the Rockefeller Institute by Herbert Gasser, then the institute’s director, who later (1944) shared the Nobel Prize in Physiology or Medicine with Joseph Erlanger. This experience proved crucial toward Hodgkin’s development of a systematic approach to physiology. By his own account, it transformed him from an “amateur into a professional scientist” (Hodgkin, 1992,’p. 95).
While at the Rockefeller Institute, Hodgkin communicated with K. S. (Kacy) Cole, who invited Hodgkin to the Woods Hole Oceanographic Institution in Massachusetts. While there, Cole and Hodgkin conducted a series of experiments to measure resistance-length curves in nervous tissue, hoping that this research would allow them to calculate the resistance of the membrane at rest (Hodgkin & Cole, 1939). However, these experiments did not provide any quantitative data about the resting membrane potential. At the time, Cole and Hodgkin hypothesized that membrane potential could be measured by inserting a miniature electrode into the cell and measuring the potential both at rest and during the action potential. Both continued to carry out these experiments during the following year, with different collaborators.
In the summer of 1939 Hodgkin paired with Andrew Fielding Huxley to test the membrane theory proposed by physiologist Julius Bernstein. According to Bernstein, selective permeability to certain ions was the result of membrane breakdown. On this theory, current flow from a neighboring region makes the inside of the cell less negative, the membrane breaks down, and the resting potential falls, thus generating an action potential. If correct, the action potential should match the potential energy of the cell at rest. Huxley was able to overcome the technical difficulties that ensued from the initial attempts to place an electrode in a neuron, which allowed him and Huxley to record the resting membrane potential. This experimental breakthrough opened the door to studying the action potential. Their experiments yielded the unexpected result of an “overshoot” in the action potential. It was significantly larger than the resting potential: (roughly) +50 millivolts (mV) as compared to -50mV. (Their recorded action potential is displayed in Figure 1.) This finding, along with Howard Curtis and K. S. Cole’s (1940), served as disconfirming evidence for Bernstein’s idea that the action potential arose merely as the result of a breakdown in the membrane, producing a leak from inside to outside. Instead, they hypothesized that the action potential resulted from a process involving large proteins oriented along the axon. What their hypothesis still required, however, was a mechanism that induced the reversal in the electromagnetic polarity of the membrane.
Hodgkin’s initial research on neuronal conductance was halted in late 1939, due to the imminence of World War II. He served for a brief period in an unpaid position with the Royal Aircraft Establishment at Farnborough, but the bulk of his wartime research went toward developing an airborne radar detection system for nocturnal interception. Though Hodgkin and Huxley met occasionally throughout the war years, they did not renew their collaborative efforts researching neurophysiology until 1945.
Subsequent Work on the Action Potential . To appreciate Hodgkin’s contribution to scientists’ understanding of the action potential, it is useful to consider the basics of the current account. (The following information is rudimentary and can be found in any introductory biology textbook.) The cellular membrane of a neuron is a lipid bi-layer whose resting potential is maintained by a differential charge. This charge results from a differential distribution of ions inside and outside the cell. Potassium (K+)
and organic anions (amino acids, A-) are found in higher concentration inside the resting cell, while sodium (Na+) and chlorine (Cl-) are more abundant in extracellular space. Sodium-potassium pumps, the most prominent transport mechanism in neurons, actively transport Na+ out and K+ into the neuron at a rate of three Na+ ions for every two K+ ions. Highly concentrated inside the cell, K+ is driven outward along its concentration gradient, leaving a negative charge inside. Additionally, the negatively charged amino acids are too large to pass through open membrane channels. There is also a greater concentration of Na+ cations in extracellular space. Overall, the
Total entry of sodium = 4.33 pmole/cm2; total exit of potassium = 4.26 pmole/cm2.
membrane of a resting neuron is maintained at about -70 mV (with some variation across cell types).
The activity of selectively permeable ion channels permits some ions to flow across the cell membrane. Voltage-gated sodium channels closed at resting membrane potential are opened by a local depolarization, allowing the passage of Na+ ions into the cell. Na+ ions, higher in concentration outside the cell, flow inward through the open channels both along their concentration gradient and due to electrostatic pressure. Sodium influx generates a localized increase in positive charge inside the cell, causing additional localized depolarizations at surrounding regions. The result is a sharp change in localized membrane potential, briefly turning from negative to positive. If a critical threshold is reached (when Na+ inward current is greater than the outward potassium current), depolarization of the membrane becomes irreversible and the cell generates an action potential. Sodium activation is a positive feedback system, propagating the potential down the length of the cell’s membrane. This biochemical cascade typically begins at the axon hillock, a structural protrusion at the junction of the cell soma and axon, dense with voltage-gated ion channels predominantly selective for Na+.
Efflux of K+ ions through voltage-gated K+ channels that open at the peak of the action potential—equivalent to the Na+ equilibrium potential, around +55mV in most types of neurons—stops depolarization. Additionally, within 1 millisecond after reaching the threshold of action potential generation, Na+ channels begin to close, ceasing Na+ influx. The electrical potential reverses as a result of the outward movement of K+, initiating repolarization. The potassium current takes longer than the sodium current to reach its maximum, and the cell membrane, as a result of sustained K+ efflux in the absence of Na+ influx, becomes more negative than the resting membrane potential. During this refractory period the cell cannot be brought to threshold to produce an action potential. By the time K+ channels close, the membrane potential has “overshot” its resting potential and has become hyperpolarized due to the accumulation of K+ outside the membrane. Resting membrane potential is quickly reestablished by the diffusion of K+ throughout the extracellular fluid and the active transport of Na+ ions out of and K+ ions into the cell by the sodium-potassium pumps.
Hodgkin’s Contribution . Initially, Hodgkin worked from Bernstein’s account of membrane permeability. Additionally, there was evidence against the sodium theory of the action potential. Curtis and Cole (1940) reported the reversible abolition of the resting potential by increasing the external potassium concentration, equal to the internal concentration. They later (1942) reported a discrepancy between the predicted and observed internal sodium concentrations and found that resting potential was unaffected by the removal of all ions. Based on work by Ernest Overton (1902), who had theorized that the action potential might be the product of sodium and potassium exchange, Hodgkin and Huxley in 1947 provided evidence that potassium leakage occurs during an action potential. After considering several alternatives, Hodgkin proposed an ionic transport mechanism of a lipid-soluble molecule with a large dipole moment—a negatively charged carrier molecule that “ferried” ions across the membrane.
Evidence against Cole and Curtis’s (1942) findings was initially provided by Bernard Katz (1947), as well as by Hodgkin’s subsequent work after reading Katz’s manuscript. Hodgkin placed a nerve fiber in an external sodium-deficient solution to observe the effect on action potential and simultaneously recorded the longitudinal resistance of both the external and internal fluid. He found that reduced external concentration of sodium reduced the action potential by a proportional amount. He repeated these experiments in the spring of 1947 and showed that external solutions of choline chloride yielded an unexcitable nerve fiber.
In the summer of 1948, Hodgkin left for the laboratory of the Marine Biological Association, Plymouth, to be joined by Huxley and Katz that autumn. In a series of experiments that followed, Hodgkin became convinced of the sodium hypothesis. The evidence included the observations that the action potential is both reversibly and rapidly abolished by an external sodium-free solution, and increased by a sodium-rich solution. This increase was proportional to the increase in sodium density, as predicted by the Nernst equation. Finally, the maximum rise in action potential was strongly dependant on the sodium concentration, consistent with Overton’s hypothesis.
What was needed was a theory that could predict the potential difference across the membrane, while accounting for features such as the increased sodium permeability over other ions when at rest and its reversal during the action potential. In October 1947, Cole had written to Hodgkin about using a “central outside region with a guard region on each side and [the] use of a feedback circuit to control either the current flow in the central region or the potential difference in that region to the desired value” (Correspondence, 1947, as it appears in Chance & Design, 1992, p. 282). This “voltage clamp,” as it has come to be termed, for the first time allowed for control over the membrane potential independent of the influence by ionic current. Cole’s results seemed to comport with Hodgkin’s earlier findings that a membrane suddenly depolarized by 50 mV produced an initial spike in the capacity current, followed by a brief inward current and, finally, an outward current. Though introduced to the technique in March, Hodgkin (working with Huxley) was not able to put it to use until mid-August 1948.
Realizing that two electrodes were necessary in order to measure both voltage and current, Hodgkin and Huxley modified Cole’s (and Marmount’s) technique to yield both the clamp and a device to measure current. Varying the external ionic concentration and holding the voltage at a predetermined specified step, Hodgkin and Huxley were able to separate the current and determine the relation between ionic permeability and membrane potential. These experiments generated most of the data they analyzed over the next two years and subsequently published in five articles in the Journal of Physiology in 1952. These results led them to abandon the carrier mechanism hypothesis of the action potential in favor of a voltage-dependent gating system—the basis of scientists’ current understanding.
Hodgkin and Huxley analyzed the action potential into three phases: rising, falling, and refractory. They characterized the early inward current as due to external Na+ ions moving into the axon, a process that could be reversed if the internal potential were raised beyond the sodium equilibrium or if the external solution were sodium deficient to the point of equilibrium. They characterized the outward current as due to K+ ion efflux, which was confirmed experimentally by R. D. (Richard) Keynes in 1948 using radioactive tracers to study the leakage of potassium and further confirmed by Hodgkin and Huxley’s calculations and indirect measurements (see Figure 2).
Hodgkin, Huxley, and Katz (1952) provided an outline of their methodology and a baseline measure of the relations between current and voltage as a function of time. They sought to measure the resistance of the membrane, the inverse value of which is permeability or conductance. Their methods included using the voltage clamp to step the determined membrane potential to displaced levels. They found that depolarizations of less than 15 mV produced only outward currents, while depolarizations between 15–110mV produced an initial inward current that disappeared at about 110mV and was followed by a sustained outward current. They found a continuous relationship between ionic current and membrane potential.
Hodgkin and Huxley published four other articles in 1952 (a–d). These results revealed the effects of changing the extracellular sodium concentration and resolved the ionic current into sodium and potassium currents. Their experiments included not only varying the voltage of the clamp but also varying the external sodium concentration. This tested for effects on inward and outward current with respect to voltage and time, and permitted them to divide the recorded current into components carried by sodium and potassium, respectively.
The membrane of the squid giant axon, when depolarized by 10mV, produced an initial inward current that was of the right magnitude and location to be capable of “charging the membrane capacity during the rising phase of an action potential” (Hodgkin & Huxley, 1952a, p. 449). This was the phase of the action potential that appeared to be carried by Na+ ions. When the external sodium concentration was reduced sufficiently, the inward current disappeared, being replaced by “an early hump in the outward current” (1952a, p. 450). This outward current was only slightly altered by the change in external solution. When sodium ions were present, the action potential produced a peak potential above which the ionic current was inward and below which the current flowed outward. This peak varied with external sodium concentration.
These results supported the view that depolarization leads to a rapid increase in permeability, allowing Na+ ions to flow in either direction toward equilibrium. A delayed outward current, observed during prolonged depolarization, was only marginally affected by replacing Na+ ions with choline ions. It was here that Hodgkin and Huxley speculated that the reason was that this late current was produced by K+ ions. Thus, for the first time, it became possible to resolve the inward and outward currents into two distinct currents. Sodium was found to rise rapidly toward a maximum and then decline along an approximately exponential curve. Potassium conductance was found to rise more slowly, along an S-shaped curve, and this increase in permeability was maintained for an appreciably longer period of time (see Figure 2). The effect of stepping from resting level to a new level was a sharp rise in inward current across the membrane, caused by a depolarization of 15mV or greater (up to 100 mV), initiating the cascade of events that constitute the action potential.
Hodgkin and Huxley acknowledged that various molecular mechanisms were consistent with their data. Thus, their 1952 papers aimed at the more modest goal of describing a series of equations that represented the movement of ions across the neural membrane. These equations could be used to determine ionic movement over time, subthreshold phenomena, changes in impedance, and several measurable properties of the action potential, including form, duration, and amplitude. The equation can be presented in several different formulations, but the standard one given by Hodgkin and Huxley (1952d) is:
I = CM dV/dt + GK n4 (V-VK) + GNa m3 h (V-VNa) + G1 (V- V1)
The total current crossing the membrane is represented by I and is the sum of four components: the capacity current (CM dV/dt), the potassium current (GK n4 (V-VK)), the sodium current (GNa m3 h (V-VNa)), and the leakage current (G1 (V- V1)). The capacitance, CM, is characterized as the ability of the membrane to hold a differential charge across the membrane. G is the maximum conductance value for the indicated ionic current. VK, VNa, and V1 are the displaced values from equilibrium for each ion, and “V” is the displacement value of the membrane (Vm) from resting (Vrest). After dividing the ionic current into two distinct phases, the rising phase controlled by sodium and the falling phase controlled mainly by potassium, each phase was measured and then described, making it possible to predict the properties of the action potential given sufficient conditions to solve the equation.
After the Nobel Prize . Although Hodgkin and Huxley never worked in the same lab after 1952, they continued to consult about their respective research interests. Hodgkin viewed Huxley as a person of “penetrating intelligence” and continued to cherish his friendship. Hodgkin acknowledged that it continued to impact him greatly, even after their scientific interests began to diverge (Hodgkin, 1992).
Subsequent to receiving the Nobel Prize in 1963, Hodgkin shifted away from strictly research toward administration, although he continued to pursue research part time until the end of his life. He continued to investigate ionic mechanisms, including research on sodium-potassium pumps, muscle fibers, and salamander rod cells. He continued to work at Plymouth on squid neurons nearly every autumn until 1970.
In 1969 Hodgkin became a university research chair at Cambridge, obtaining the John Humphrey Plummer Professorship of Biophysics. He became president of the Royal Society in 1970. In 1972 he was knighted, and he received the Order of Merit in the following year. He became master of Trinity College at Cambridge in 1978, the year Trinity first admitted women undergraduates. He held that post until 1984.
Encouraged early in his studies to work on his own, Hodgkin came to view self-directed research as essential and “perhaps the most important thing [learned] at school” (Hodgkin, 1992, p. 30). He never worked toward a PhD degree and never had a formal research supervisor (Hodgkin, 1992). Most of the equipment that he used to address his research questions he either built or borrowed (Detwiler, 1999). These facts reflect his modesty, also found in his writings.
Upon leaving the Trinity College Master’s Lodge in 1984, Hodgkin moved with his wife Marion into the British countryside. He continued to pursue the outdoor activities he loved in his youth. He was an avid fisherman and was remembered by family and professional colleagues as a man of “quiet disposition, a good sense of humor, and lively eyes that could express a full range of emotions” (Detwiler, 1999, p. 753). In 1989 he underwent a spinal operation that left him unable to walk and with progressive medical issues. He passed away on 20 December 1998. Alan Hodgkin was survived by his wife and four children, Sarah (S.M.), Deborah (E.D.), Jonathan (J.A.), and Rachel (R.V.).
WORKS BY HODGKIN
With Kenneth S. Cole. “Membrane and Protoplasm Resistance in the Squid Giant Axon.” Journal of General Physiology 22 (1939): 671–687.
With Andrew F. Huxley. “Potassium Leakage from an Active Nerve Fibre.” Journal of Physiology 106 (1947): 341–367.
———. “Currents Carried by Sodium and Potassium Ions through the Membrane of the Giant Axon of Loligo.” Journal of Physiology 116, no. 4 (1952a): 449–472.
———. “The Components of Membrane Conductance in the Giant Axon of Loligo.” Journal of Physiology116, no. 4 (1952b): 473–496.
———. “The Dual Effect of Membrane Potential on Sodium Conductance in the Giant Axon of Loligo.” Journal of Physiology116, no. 4 (1952c): 497—506.
———. “A Quantitative Description of Membrane Current and Its Application to Conduction and Excitation in Nerve.” Journal of Physiology 117, no. 4 (1952d): 500–544.
With Andrew F. Huxley and Bernard Katz. “Measurement of Current-Voltage Relations in the Membrane of the Giant Axon of Loligo.” Journal of Physiology116, no. 4 (1952): 424–448.
Curtis, Howard J., and Kenneth S. Cole. “Membrane Action Potentials from the Squid Giant Axon.” Journal of Cellular and Comparative Physiology 15 (1940): 145–157.
———. “Membrane Resting and Action Potentials from the Squid Giant Axon.” Journal of Cellular and Comparative Physiology 19 (1942): 135–144.
Detwiler, Peter B. “Retrospective: Sir Alan Hodgkin (1914–1998).” Science 284 (1999): 753.
Huxley, Andrew F. “Sir Alan Loyd Hodgkin, O.M., K.B.E. 5 February 1914–20 December 1998.” Biographical Memoirs of Fellows of the Royal Society 46 (2000): 219–241.
———. “From Overshoot to Voltage Clamp.” Trends in Neuroscience 25 (2002): 553–558.
Katz, Bernard. “The Effect of Electrolyte Deficiency on the Rate of Conduction in a Single Nerve Fibre.” Journal of Physiology 106 (1947): 411–417.
Lamb, Trevor. “Obituary: Alan Hodgkin (1914–98).” Nature 397 (1999): 112. Available from http://www.nature.com/nature/journal.
Overton, Ernest. “Beiträge zur allgemeinen Muskel- und Nervenphysiologie.” Pflügers Archiv: European Journal of Physiology 92 (1902): 346–386.
Piccolino, Marco. “Fifty Years of the Hodgkin-Huxley Era.” Trends in Neuroscience 25 (2002): 552–553.
Sean P. Keating