Hodgkin-Huxley and the ionic theory of nerve action
Robert G. FRANK, Jr.
The publication in 1949, by the young Cambridge physiologists Alan Hodgkin and Andrew Huxley, of the ‘sodium hypothesis’ of the action potential in nerve and muscle was a pivotal event in 20th-century fundamental neuroscience. In this paper I use interviews with participants (especially Hodgkin) and unpublished correspondence (especially of Hodgkin, Bernard Katz, and the American K.C. Cole), as well as published autobiographies and the scientific papers, to reconstruct the experimental work and theorizing c. 1936-1949 that led to the sodium hypothesis.
My central figure is Hodgkin, and I emphasize especially the crucial role played by the introduction of invertebrate single-axon preparations, such as crab nerve and the squid giant axon in 1936. The SGA made possible the discovery by Cole in 1938 at Woods Hole, recording from external electrodes, that the passage of the nerve impulse coincided with a decrease in membrane impedance. Cole’s visiting collaborator there, Hodgkin, took the SGA preparation back to England. At the Plymouth marine laboratory in 1939, using an elegant experimental apparatus designed in large part by his Trinity College friend, Huxley, they were able to insert an internal electrode into the SGA. Hodgkin and Huxley were surprised to find that the newly discovered decrease in membrane resistance, in both lobster and squid axons during activity, not only caused the membrane potential to rise from -55 mV to 0 (as predicted by longstanding theory), but also to ‘overshoot’, becoming positive some 40-50 mV—a puzzling anomaly. As Hodgkin and Huxley returned c. 1944 to physiology after war research, they focused on possible ion flows or membrane changes that might explain such an anomaly. They were aided materially by accurate assays of Na+ and K+ concentrations in squid axoplasm done by Burr Steinbach at Woods Hole in 1943. However, it was a key hint by Katz in late 1946, that a single crab fiber became unexcitable in isotonic dextrose, which led Hodgkin definitively to a sodium hypothesis. In the ‘squid summers’ of 1947 and 1948 at Plymouth, working with both Katz and Huxley, he got crucial evidence that the action potential is caused by precisely timed and voltage-dependent flows, first of Na+ inwards, and then of K+ outwards. This ionic hypothesis was rapidly accepted and became the theoretical and experimental model on which many important new explanations of nerve activity were based.
Session I. Instrumentation and Laboratory Sciences
12th Annual Meeting of the International Society for the
History of the Neurosciences (ISHN)