by Frank I. Katch
INDEX	Santorio experiments breakthrough in energy metabolism

A brilliant student at Trinity and Kings Colleges, Cambridge, England, A.V. Hill attracted the notice of two eminent physiologists. W. M. Fletcher and (Sir) F. G. Hopkins (Nobel Prize in Physiology or Medicine, 1929) convinced Hill to pursue advanced studies in physiology rather than mathematics. Hill's early experiments researched the effects of electrical stimulation on nerve function, the mechanical efficiency of muscle, energy processes in muscle during recovery, the interaction between oxygen and hemoglobin, and quantitative aspects of drug kinetics on muscle. Hill used his background in mathematics to explain the results. Later, Hill devised mathematical models describing heat production in muscle, and applied kinetic analysis to explain the time course of oxygen uptake during both exercise and recovery. Hill combined aspects of physics and biology, a discipline which he championed as biophysics (Hill, 1931).

During World War I, Hill directed a laboratory and published technical reports on anti-aircraft defense (Katz, 1986). After the war, Hill achieved international acclaim for research in muscle physiology. In 1920, he left Cambridge to Chair the Physiology Department at Manchester University. In newly refurbished laboratories, Hill expanded his work on muscle physiology in animals which resulted in a book on muscular activity (Hill, 1926). Hill shared the Nobel Prize in Physiology or Medicine in 1922 with German chemist Otto Meyerhof for discoveries about the chemical and mechanical events in muscle contraction.

The Figure shows Hill's famous Thermopile apparatus to measure heat production in sartorius muscle. Until the invention of this equipment, it was impossible to accurately measure a muscle's heat production. In the muscle twitch of a frog's sartorius at 20 degrees C, the rise in temperature did not exceed 0.003 degrees C, and lasted only a few hundredths of a second. Thus, this instrument paved the way for Hill and co-workers to carry out their historic experiments. As a point of information, a thermopile can be thought of as a kind of battery made of alternating pieces of two different metals; heat applied to the couples produced an electric current (based on the strength of the muscle action and measured by a galvanometer) (Stevenson, 1953). The thermopile precisely measured the heat liberated from the muscle based on the change in temperature. Hill made insightful comments about his early experiments during his acceptance of the Nobel Prize in 1922 (Stevenson, 1953):

One of my earliest observations on the subject was that the galvanometer deflection persists much longer in a live muscle than in a control experiment....This phenomenon can be due only to a delayed production of heat, and I found that this "recovery" heat as we called it is appreciable only in oxygen, being abolished by keeping the muscle in nitrogen, or by previous exercise violent enough to use up the oxygen dissolved in the muscle....A rough estimate of the magnitude of the recovery heat production made it approximately equal to the total initial heat. This estimate appeared to answer unequivocally a question long debated, on the fate of lactic acid in the recovery process. Fletcher and Hopkins had found (in 1907) that lactic acid is removed in the presence of oxygen, though the same muscle at the end of the recovery process can liberate during exercise or rigor the same amount of lactic acid as before. Was lactic acid removed by oxidation, or by restoration to the precursor from which it came? Previous experiments of my own had shown that the production of one gram of lactic acid in rigor leads to the liberation of about 500 calories .... Peters had proved that the production of 1 gram of lactic acid in exercise... leads to the liberation of about the same quantity of heat. Hence, if the recovery heat were equal to the initial heat, the oxidative removal of one gram of lactic acid would lead to the production of about 500 calories, which is less than 1/7th of the heat of oxidation of the acid. The conclusion ... seemed to me to be inevitable that the lactic acid is not removed by oxidation. The most important point brought out by ... analysis of the initial heat-production is that relating to the influence, or rather to the absence of influence, of oxygen .... No difference whatever can be detected between the curves obtained (a) from a muscle in pure oxygen and (b) from one which as been deprived of oxygen in the most rigorous manner for several hours. The conclusion is important and supplements the observations previously described on the recovery heat-production. Oxygen is not used in the primary breakdown at all: it is used simply in the recovery process.

While Hill's research is best known in physiology and exercise physiology, he was also acclaimed by nutritionists. Lusk's (1925) Lectures on Nutrition (based on a series of lectures given at the Mayo Foundation and five universities) contains chapters by Hill on muscular activity and carbohydrate metabolism. (Other prominent scientists, F. G. Benedict, E. F. DuBois, E. V. McCollum, H. M. Evans, and G. Lusk, lectured about nutrition-related topics). The opening paragraph of Hill's lecture connects muscle physiology with nutrition:

It has long been discussed whether the breakdown of carbohydrate, rather than of other substances, is primarily responsible for the provision of energy in muscular contraction. It is known and accepted that work may be done, in the general melting-pot of the body, by the use of any kind of foodstuff. We are now concerned, however, specifically with the primary process of muscular contraction. In the complete chain of processes involved in long-continued exercise, this primary process may be disguised, or even apparently obliterated, by simultaneous transformations that take place between the different food constituents. Considering the internal combustion engine, it is obvious that petrol and benzole may be used indiscriminately for providing power and driving the machinery. In the same way, however, as we ask whether carbohydrate is the specific fuel of muscle, or whether fat may be used in an identical manner, so we might query whether petrol or coal can be used in an internal combustion engine. The obvious answer is that coal must be prepared beforehand by distillation, before it can be used in the engine, while petrol can be used directly; and that in the preparation of coal to form benzole for use in the engine, a considerable proportion of the energy of the coal is wasted, as regards its work-producing power. Putting our problem in terms of the modern theory of muscular activity and assuming that the initial process in contraction--that which causes the mechanical response--is an entirely non-oxidative one, consisting of the formation of lactic acid from glycogen, we are asking now whether the recovery process by which the lactic acid is restored to its precursor can go on at the expense of any oxidation, or only of that of carbohydrate. May the recovery mechanism, so to speak, be driven by any kind of combustion, as a steam engine may be, or is it necessary specifically to combust carbohydrate?

An avid sportsman, Hill became interested in recovery from exercise after himself experiencing fatigue during track meets. He coined the term "oxygen debt" based on experiments in the early 1920s (Hill et al., 1924a-c; Hill & Lupton, 1923). He maintained that the amount of oxygen consumed above resting in recovery represented the oxidation of approximately one-fifth of the lactic acid produced during exercise and provided the necessary energy to resynthesize the remaining lactic acid to glycogen.

Hill's more important scientific achievements included: discovery and measurement of heat production associated with the nerve impulse; improved analysis of heat development accompanying active shortening in muscle; application of thermoelectric methods to measure vapor pressure above minute fluid volumes; analysis of physical and chemical changes associated with nerve excitation; and excitation laws for animal tissue (Katz, 1986). An outspoken critic of Hitler's wartime persecution policies against Jewish and dissident scientists, Hill helped found the Academic Assistance Council (later called the Society for the Protection of Science and Learning) to assist refugee scientists. Hill wrote popular articles about science (Hill, 1926), a practice he continued in addition to a productive scientific career for 15 years after retiring from University College London in December, 1951 (Hill, 1960, 1965).

© Frank I. Katch, William D. McArdle, Victor L. Katch. 1997.

References

Hill, A.V. (1931). Adventures in biophysics. University of Pennsylvania Press, Philadelphia.

Katz, B. (1986). Archibald Vivian Hill. Dictionary of National Biography, Oxford University Press, Oxford, p. 406.

Hill, A.V. (1926). Muscular activity, Herter Lectures. Sixteenth Course. Williams & Wilkins Company, Baltimore.

Stevenson, L.G. (1953). Nobel Prize Winners in Medicine and Physiology. 1901-1950. Henry Schuman, New York.

Lusk, G. (1925). Lectures on nutrition. 1924-1925. W. B. Saunders Company, Philadelphia.

Hill, A.V., Long, C.N.H., and Lupton, H. (1924a). Muscular exercise, lactic acid and the supply and utilization of oxygen. Pt. 1-III. Proceedings of the Royal Society B, 96, 438.

Hill, A.V., Long, C.N.H., and Lupton, H. (1924b). Muscular exercise, lactic acid and the supply and utilization of oxygen. Pt. 1V-VI. Proceedings of the Royal Society B, 97, 84.

Hill, A.V., Long, C.N.H., and Lupton, H. (1924c). Muscular exercise, lactic acid and the supply and utilization of oxygen. Pt. VII-IX. Proceedings of the Royal Society B, 97, 155.

Hill, A.V., and Lupton, H. (1923). Muscular exercise, lactic acid, and the supply and utilization of oxygen. Quarterly Journal of Medicine, 16, 135.

Hill, A.V. (1926). The scientific study of athletics. Scientific American, 224 (April).

Hill, A.V. (1928). Myothermic apparatus. Proceedings of the Royal Society B. 103, 117. 

Hill, A.V. (1960). The ethical dilemma of science, and other writings, Rockefeller Institute Press, New York.

Hill, A.V. (1965). Trails and trials in physiology. a bibliography, 1909-1964; with reviews of certain topics and methods and a reconnaissance for further research. Arnold, London.

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