The Independence Principle - A Neglected Feature of the Hodgkin Huxley Legacy

The legacy of Hodgkin and Huxley rests on their squid giant axon studies, which were summarised in an empirical model of impressive predictive power that successfully quantified the permeability changes of excitable membranes and accurately reconstructed the action potential. Hodgkin and Huxley applied the independence principle to their experimental data in order to reveal potential mechanism(s) of trans-membrane ion movements. This was motivated by their lack of information on the manner in which ions crossed the membrane and which they considered simply a ‘permeability pathway’ of unknown structure. The inconclusive nature of those studies prompted Hodgkin to seek the expertise of Richard Keynes who was skilled in the radiotracer method that quantified uni-directional trans-membrane ion movements, a more accurate and less invasive technique than the electrophysiological methods employed in the Hodgkin and Huxley studies. Hodgkin and Keynes experimental data did not support independence principle predictions and led them to develop a model based on the presence of long pores in the membrane through which ions moved sequentially – ‘ion channels’, whose existence were confirmed decades later with the advent of molecular biology and refined X-ray crystallography techniques.