Book review by Dr Angus Brown
University of Nottingham, UK

This book joins a long list of those dedicated to illuminating the work of Hodgkin and Huxley, contained in the five classic papers published in The Journal of Physiology in 1952 (Hodgkin and Huxley, 1952a, b, c, d; Hodgkin et al., 1952). The need for such books emphasises two important aspects of the Hodgkin and Huxley work, its central role in physiology and its seemingly impenetrable complexity. The first academic to meaningfully address the work was J Walter Woodbury in the Department of Physiology and Biophysics at the University of Washington, Seattle, in the late 1950s. Woodbury, a physicist by training, realised the rich rewards offered by the work and ran a course where students were instructed in non-linear partial differential equations as well as the underlying physiological mechanisms. Based on this lecture series he was asked to contribute relevant chapters to the 18th edition of the textbook Medical Physiology & Biophysics edited by Ruch & Fulton in 1960. The rigour with which Woodbury approached the subject would horrify contemporary students, and one need only consult his section on “Potentials in a volume conductor” to realise how far standards and expectations have drifted since the 1960s. Woodbury was asked by the Nobel committee to nominate worthy candidates for the Physiology and Medicine Prize: his nomination secured the Prize for Hodgkin and Huxley in 1963. The 19th edition of the book was published in 1965 (Maynard, 2014) and Bertil Hille assumed duties for the excitable membrane chapters in 20th and 21st editions. The role of Hille in publicising the Hodgkin and Huxley work cannot be overstated, his own book Ionic Channel of Excitable Membranes published in 1984, with further editions in 1991 and 2001, reaching a vast and receptive audience ready to utilise the recently developed patch clamp and cloning techniques to study structure and function of ion channels. Every modern neuroscience textbook contains at least one chapter on the membrane potential and the action potential, which begs the question, what does this new book add?

Students approaching in-depth study of a research topic are routinely advised to consult original sources and in the introduction to this book seven convincing reasons are provided as to the wisdom of this advice. But what if the original sources are based on outmoded conventions and refer to redundant equipment and terminology? This book offers a very pragmatic solution by providing appropriate up-to-date explanations, interpretations and redrawn graphs based on information in the original papers. The format of the book is novel as the original Hodgkin and Huxley papers are printed on the left side of the page with updates and explanations on the right. This format runs the risk of blank pages where no explanation is necessary or text spilling over to the subsequent page, interrupting the narrative flow. The need for such updates stems from the conventions for reporting current and voltage used by Hodgkin and Huxley, which are different from those in use today. The movement of +ve charge into axons was depicted as an upward deflection, with the resulting membrane depolarisation a downward deflection. However, upward pointing action potentials were deemed more pleasing to view thus the voltage scale was depicted as –ve volts. This was compounded by reporting resting membrane potential as 0 mV, where adherence to the contemporary convention would depict it as +ve volts. For students familiar with modern textbooks, consulting the original papers is an exercise in confusion, frustration and inevitably capitulation. However, browsing through only a couple of pages of this current book reassures the reader they are in safe hands. Indeed, one gets the impression that if the authors were to uncover Hodgkin and Huxley’s old equipment in a dusty cupboard, they would have it up and running by the end of the day. Further validation comes in the form of an enthusiastic recommendation from Beril Hille, and the recent award of The Physiological Society’s Hodgkin-Huxley-Katz Price Lecture to one of the authors, Indira Raman.

Full appreciation of the Hodgkin and Huxley work requires understanding of the historical context, which is provided in the introduction, with a fascinating fuller account available (McComas, 2011). Thus, one must understand what Hodgkin and Huxley set out to do, the techniques and model available them and the work of their contemporaries. Although the five papers in the canon are considered complete, it would have made sense to include the Hodgkin and Katz 1949 paper as a logical introduction (Hodgkin and Katz, 1949). Indeed, had it not been for Huxley being unavailable due to wedding commitments in the summer of 1947, Katz would not have been invited to participate in the experiments and the canon would consist of six Hodgkin and Huxley authored papers. The five papers comprise 126 pages, but contain a multitude of redundant information, and heretical as it sounds, about one third of the content could be happily ignored with no loss of impact or meaning. This refers principally to equipment and terminology that is obsolete and unknown to contemporary students, i.e. inductance, series resistance, guard systems, polarisation, cathode follower etc. The independence principle experiments, although important in suggesting that INa and IK were separate entities, was not an integral component of the model, and the incorrect conclusions drawn from these experiments took several years to be corrected (Hodgkin and Keynes, 1955). In addition, the lack of a system for cooling the seawater bathing the experimental squid axons ensured the experiments in the Hodgkin and Katz 1949 paper were carried out at room temperature. The later introduction of a cooling coil, which was used in experiments described in the five classic papers, meant the seawater was at an appropriate temperature, but required reconciling with the room temperature data, thus there are eight figures at room temperature that could be deleted. Indeed, of the seventeen figures in the 1st paper (Hodgkin et al., 1952) only five are essential to the model. Thus, the inclusive nature of this book, where every aspect of the original papers is updated, means considerable labour has been expended for information that will be of interest to a very few readers. Another important point to make is that students don’t need to understand everything in the papers to appreciate Hodgkin and Huxley’s work.

The book is aimed at graduate students, an appropriate target audience. Having undertaken a similar venture recently (Brown, 2020), I appreciate the enormous amount of work that goes into producing a book of this sort, where every word and graph must be minutely weighed for clarity and meaning and can happily report that this book is a very welcome addition to the Hodgkin and Huxley oeuvre. In covering such a vast subject there are inevitable omissions and a few minor grumbles, but I regularly dip into the book for pure pleasure, and it does not disappoint. Highly recommended.

A few observations

p.70 Update composition of salt solutions to mM rather than g/kg H2O.

p.78 Confusing Nernst predictions. What should be straightforward Nernstian calculations include an additional step to account for reporting the resting membrane potential as 0 mV.

p.86 Given that only half of the page is used, some detail of the calculus required for isolation of IK could have been included (Cronin, 1987).

p.93 Good graphical explanation of chord and slope conductance.

p.142 Polarisation of the voltage clamp– Hodgkin and Huxley mention a polarisation effect of unknown origin in their estimates of EK. We now know this is due to accumulation of K+ in the limited space between the axolemma and a surrounding tight membrane, where the longer the duration of the pulse, the more K+ accumulation and the more depolarised EK became. This only came to light with later experiments (Frankenhaeuser and Hodgkin, 1956).

p.199 The best explanation I have come across for gating particles.

p.230 The authors offer no explanation for the phrases “under a travelling anode… under a travelling cathode”, which have puzzled me for the last 35 years.

p.255 Excellent graphical illustrations and of membrane current to explain

p.259 threshold and anode break excitation, respectively.

p.279 Excellent appendices on derivation of equations used to fit data

References

Brown AM (2020). A Companion Guide to the Hodgkin- Huxley Papers. The Physiological Society, London, UK.

Cronin J (1987). Mathematical Aspects of Hodgkin-Huxley Neural Theory. Cambridge University Press, Cambridge.

Frankenhaeuser B and Hodgkin AL (1956). The aftereffects of impulses in the giant nerve fibres of Loligo. The Journal of Physiology 131, 341–376.

Hodgkin AL and Huxley AF (1952a). Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. The Journal of Physiology 116, 449-472.

Hodgkin AL and Huxley AF (1952b). The components of membrane conductance in the giant axon of Loligo. The Journal of Physiology 116, 473-496.

Hodgkin AL and Huxley AF (1952c). The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. The Journal of Physiology 116, 497-506.

Hodgkin AL and Huxley AF (1952d). A quantitative description of membrane current and its application to conduction and excitation in nerve. The Journal of Physiology 117, 500-544.

Hodgkin AL, et al (1952). Measurement of current-voltage relations in the membrane of the giant axon of Loligo. The Journal of Physiology 116, 424-448.

Hodgkin AL and Katz,B (1949). The effect of sodium ions on the electrical activity of the giant axon of the squid. The Journal of Physiology 108, 37-77.

Hodgkin AL and Keynes, R.D. (1955). The potassium permeability of a giant nerve fibre. The Journal of Physiology 128, 61-88.

Maynard RL (2014). Great Textbooks of Physiology, Part 1: Ruch and Patton’s Physiology and Biophysics, 19^th edition, 1965. Physiology News 94, 9. McComas AJ (2011). Galvani’s Spark. Oxford University Press, Oxford.