Wednesday, August 13, 2008

Nobel Laureate: Archibald Hill

 

The Nobel Prize in Physiology or Medicine 1922.
"for his discovery relating to the production of heat in the muscle"

Archibald Vivian Hill (1886 - 1977) received the Nobel Prize in Physiology or Medicine for his work on heat production in muscle. He related the heat produced when glycogen was broken down to lactate to the heat generated in frog muscle. Hill was one of the first scientists to relate chemical thermodynamics to biological work.

Hill shared his Nobel Prize with Otto Fritz Meyerhof.

The presentation speech was delivered by Professor J.E. Johansson, Chairman of the Nobel Committee for Physiology or Medicine of the Royal Caroline Institute on December 10, 1923(Note that the 1922 prize was awarded at the same time as the 1923 prize.)

THEME:
Nobel Laureates
Your Majesty, Your Royal Highnesses, Ladies and Gentlemen,

The object of physiology is to endeavour to recognize in the vital processes well-known physical and chemical processes. Accordingly it has to give answers to such questions as these: what is it that takes place in a muscle that contracts, in a gland that emits a secretion, in a nerve when it transmits an impulse? In former times these processes were explained as being the work of what were called «life spirits» - beings who in their mode of existence possessed an unmistakable resemblance to the person who spoke of them. If the muscles of a recently killed animal were seen to twitch when cut or pierced, this was explained by saying that the life spirits had been irritated. From this way of looking at things there still remains the expression «irritation», which we use to denote the starting - or, as we also put it, the liberation - of an active process in an organ. It is a long time, however, since we learnt to regard living organs, muscles, nerves, etc., as mechanisms; and the expression «muscular machine» will probably not strike any educated person in our days as being strange or offensive.

In order to render clear the working of a mechanism it is customary to give a «simplified model» of it. A schematic drawing or an imaginary model may perform the same service, and is at any rate cheaper. The first model that was made of muscular mechanism had the steam-engine as its prototype. Very soon, however, it was perceived that the adoption of an engine of this type presupposes the existence of substances in the muscular fibres capable of sustaining temperatures far exceeding 100°C. The efficiency of muscular work can in fact amount to 20-30%; and such values cannot be obtained by a heat-engine unless the temperature in certain parts of the engine is raised to a considerable height. Hence the muscular machine cannot be referred to that group of motors that transform heat into mechanical work and that are based on the equalization of different temperatures. Theoretically, however, differences in osmotic pressure, surface tension, electrical potential, and so on, offer the same possibility of developing work; and consequently any chemical process whatever that takes place «spontaneously» and that gives rise to such differences in «potential», might be employed in a model of a muscular machine. Thus there is no lack of material for the construction of such a model. The difficulty is to select. In this case there was also a further difficulty, namely that of being able to emancipate oneself, in the design of such a model, from the old and discarded model of a heat-engine. One need not be a physiologist to recognize that muscular activity is essentially bound up with the development of heat, or even with combustion. Now as it is impossible to regard the muscle as a heat-engine, how is it possible to fit these phenomena into the course of action?

This problem has been successfully solved by the two investigators to each of whom the Professorial Staff of the Caroline Institute has this year resolved to award half of the Nobel Prize for 1922 in Physiology or Medicine, namely Professors Archibald Vivian Hill of London and Otto Meyerhof of Kiel. These two men have each worked independently and to a large extent with different methods. Hill has analysed, by means of an extremely elegant thermoelectrical method, the time relations of the heat production of the muscle; and Meyerhof has investigated by chemical methods the oxygen consumption by the muscle and the conversion of carbohydrates and lactic acid in the muscle. Both have made use of the same kind of experimental material, namely the surviving muscle excised from a frog - in fact, the classical frog muscle preparation.

Such a preparation remains alive for several hours, or even days. A suitable stimulus liberates a contraction or develops a state of tension, both of short duration. The twitch takes only one or two tenths of a second. If the stimulus be repeated, the muscle makes a new twitch, apparently resembling the preceding one; and if the muscle is attached to a suitable connecting lever, the several twitches give the same effect as the strokes of a piston in a steam-engine. What was more natural than to regard the muscular twitch as the expression of a circular process in the muscular elements? This process makes itself known in another way also, namely in the form of a development of heat in the muscle preparation. The amount of heat is very insignificant. It is measured in millionths of the usual unit of heat and is recorded in a thermoelectrical way in the form of readings on a galvanometer. Armed with technical resources for observing both the mechanical process and the development of heat in the twitch of an isolated muscle, investigators tried to penetrate more deeply into the muscular process proper. Our countryman Blix showed that everything that impedes the contraction of a muscle during the twitch - that is to say, impedes the diminution of surface of the muscular elements - increases the formation of heat, and from this concluded that the process sought is localized to the surface of certain structural elements which, owing to changed conditions in surface tension, acquire a tendency to pass from an ellipsoidical to a more spherical form. If the load of the muscle gives way to the tension thus created, external work is done. Hence the muscle is mainly to be regarded as a machine that converts chemical energy into tension energy.

In the first experiments that Hill carried out on this subject in 1910 he made use of a thermo-galvanometer designed by Blix. Here he noticed that the reading not only gives the total amount of heat developed, but also is to some extent affected by the period of time taken in the development of heat. He was able to distinguish between an «initial» and a «delayed» development of heat. A subsequent work contained the starting-point for a new method of investigation, which made it possible to trace the development of heat in muscular movements in their various stages. This technique may be described as having been completely developed by 1920; but some of the results that I shall mention had been obtained as early as 1913, that is to say before the outbreak of the World War.

The development of heat in the contraction of the muscle - which to preceding investigators appeared to be «one and indivisible», that is to say, was lumped together as a single phenomenon - can be divided by Hill's method into several periods, the last of which comes long after the end of the mechanical process, that of the twitch. To this must be added the fact that this delayed development of heat entirely fails to appear if the supply of oxygen to the muscle be cut off, while the development of heat during the actual twitch - tension and relaxation - is completely independent of the presence of oxygen. The process of combustion, which it had been customary to connect immediately with the contraction of the muscle, does not actually take place until afterwards. In the experimental arrangements with which we are now dealing (isometrical work) the development of heat during the actual twitch also includes the amount of energy which under other circumstances appears as external work.

Hill's discovery has had a veritably revolutionizing effect as regards the conception of the muscular process. The ordinary view of this process as divided into two phases, tension and relaxation, can, it is true, be retained with regard to the mechanical process, but with regard to the chemical process another division must be adopted - the working phase proper, independent of the supply of oxygen and corresponding to the whole of the mechanical process, and following it an oxidative phase of recovery. If previously in their speculations as to the muscular process physiologists had mainly shown an interest in the actual twitch, investigations now became directed towards the muscle in rest and especially the muscle after preceding exhaustion. Chemical considerations now attracted attention as well as the physical ones.

The earliest known chemical process in the muscle is the formation of lactic acid. This is mentioned as early as 1859 by Du Bois-Reymond. He had found that an excised muscle becomes acid on repeated stimulation even when the rigor mortis sets in. He supposed the cause of this to be the formation of lactic acid - owing, it is stated, to a communication from Berzelius, who had found great quantities of that acid in the flesh of a deer that had been killed in the chase. Since that time lactic acid has played a very important part in discussions as to rigor mortis and the fatigue of the muscle. Some years before Hill began his investigations, two of his countrymen, Fletcher and Hopkins, had shown that the excised muscle not only forms but also converts lactic acid, this depending on whether the muscle is shut off from oxygen or whether oxygen is supplied to it. Some observations also suggested that when the lactic acid disappears from the muscle, only part of it is burnt up, while the rest is re-transformed into the mother substance of lactic acid. In consequence of this there was reason to surmise that the part played by lactic acid in the muscles is not completely represented by such expressions as «by-product of the metabolism», «fatigue substance», «cause of rigor mortis», etc. In this connection Hill proposed that lactic acid should be included as a part of the actual muscle machine.

The formation of lactic acid in the muscle, according to Fletcher and Hopkins, and this development of heat in the muscle during its working phase, according to Hill, exhibit the striking accordance that they take place independent of the oxygen supply. According to Blix, the twitch came about due to the fact that along the surface of certain structural elements there suddenly appears some substance, the nature of which is not stated. If we suppose this substance to be lactic acid - formed either directly or with some intermediate stage from the muscles' well-known store of glycogen - we have a model which combines in itself the most valuable contributions of the investigations of the last few decades on this question. We make the stage of recovery, accompanied by the supply of oxygen, follow the working phase together with Hill's delayed development of heat and Fletcher's conversion of lactic acid. The fact is that lactic acid, when it has done its work, must be got rid of somehow in order that the machine may be kept going.

By a well-known calculation Hill tried to find support for the recently quoted supposition of Fletcher and Hopkins with regar d to a reversion, in conjunction with the lactic acid combustion, of lactic acid to glycogen during the phase of recovery. It is easy to see that the correctness of this supposition forms a condition that the model cited should be acceptable from the point of view of energetics. But objections were made against the analyses and arguments of Fletcher and Hopkins. Moreover, there were adduced, from what were considered to be extremely competent quarters, direct observations which seemed to show that the lactic acid formed in the working phase was completely used in the process of recovery - a piece of wastefulness on the part of Nature which could only be explained by means of auxiliary hypotheses in the presence of which it would have been the simplest thing to let the whole of the attractive model take part in the combustion.

It is at this stage in the development of the question that Meyerhof's contribution comes in. In his investigations concerning the respiration of the tissues (1918) he came to devote his attention to the things that take place in the surviving muscle, and in this connection also to the objections that had been raised against the conclusions of Fletcher and Hopkins and their interpretation of the «lactic acid maximum» of the muscle. He showed that these objections do not really affect the result of the recently cited calculations of Hill. Most important of all, however, was his parallel determination of the lactic acid metabolism and the oxygen consumption during the recovery of the muscle, which yielded the result that the oxygen consumption does not correspond to more than 1/3 - 1/4 of the simultaneous lactic acid metabolism. Evidently the greater part of the lactic acid disappears in some other way than through combustion. In another parallel determination - the development of heat and the oxygen consumption - the development of heat exhibited a deficit in comparison with what could be calculated from the simultaneously observed oxygen consumption. From this the conclusion may be drawn that the combustion of lactic acid in the muscle is combined with some other process, an endothermic one, in the course of which part of the heat developed in the combustion is used up. Meyerhof also made a parallel determination of the carbohydrates and lactic acid in the resting and in the working muscle, also in the recovery period after fatigue; he found: when lactic acid is stored in the muscle, an equivalent quantity of carbohydrates, chiefly glycogen, disappears, while when lactic acid disappears, the quantity of carbohydrates in the muscle is increased by an amount equivalent to the difference between the total amount of lactic acid that has disappeared and the quantity oxidized corresponding to the oxygen consumption.

Hence the processes which we have to take into account in the muscles are: (1) the formation of lactic acid from carbohydrates; (2) the combustion of lactic acid to carbonic acid and water; and (3) the reversion of lactic acid to carbohydrates. But these processes are not confined to the uninjured muscle. Meyerhof has also traced them in finely chopped muscle substance kept moist in a suitable liquid, and in that case found them take place 10-29 times more rapidly than in the well-known muscle preparation. In such a dilution it is also possible to study the effect of different factors such as the concentration of hydrogen ions, the presence of phosphates, etc.; and in particular it has been possible to make clear to what extent the various processes are connected with one another or can be varied in relation to one another. A matter of extremely great interest is the establishment of the fact that the combustion of lactic acid in the muscle cannot take place without a simultaneous formation of lactic acid from carbohydrates, and that the combustion of lactic acid is connected with the formation of carbohydrates in such a way that out of four molecules of lactic acid one is oxidized, while the three others are reverted to carbohydrates. lt is not inconceivable that the reversion does not always extend so far as to produce carbohydrates; but the ideal course of the process may be regarded as precisely defined by Meyerhof, and it has been represented by him in the form of a scheme of chemical reaction. In this scheme, too, can well be fitted the lactacidogen discovered by Embden as a connecting link between glycogen and lactic acid.

The chemical processes just cited have to be fitted into the model of the muscle machine. Ignoring other considerations than those of energy, we can express the course of action in the following way: the change in the muscle which forms the basis of the mechanical process (the external work) presupposes a certain quantity of lactic acid, which comes from the muscle's store of glycogen. When this lactic acid has done its work, 1/4 is burnt into carbonic acid and water, while 3/4 return to the store of glycogen. The upper limit of the efficiency of the machine, calculated according to this scheme, will be 50%, which fully corresponds to the real state of things.

The combustion of lactic acid demands oxygen. The muscle preparation, however, can work even if the supply of oxygen is cut off. The lactic acid formed at every twitch spreads in the muscle out from the places where it is formed until the muscle substance finally becomes so impregnated with lactic acid that it is not relaxed between the twitches, and the impulses applied do not give rise to any further formation of lactic acid. The muscle is exhausted or, as one might also put it, poisoned with lactic acid. In the body the muscle is transfused with blood, which supplies oxygen in far greater abundance than that which the excised muscle preparation can obtain from its environment. Owing to its store of alkali, moreover, the blood itself provides room for a certain quantity of lactic acid from working muscles - a quantity of lactic acid that the blood can afterwards get rid of during a subsequent interval in the work. The possibility of thus distributing the combustion of lactic acid during a period that is longer than the work itself, provides us with an explanation of the immense amount of work achieved, especially in the sporting competitions of our day. Even with a volume per minute corresponding to the extreme working capacity of the heart there is not obtained in these cases a supply of oxygen corresponding to the formation of lactic acid in the muscles; and consequently the individual exposes himself to an accumulation of lactic acid in the blood and in all the tissues or the body - an accumulation that must be characterized as poisoning. When we are dealing with competitions for children and young people who are not yet grown up, there is good reason to think about this detail with regard to the muscle machine.

Professors Hill and Meyerhof. Your brilliant discoveries concerning the vital phenomena of muscles supplement each other in a most happy manner. It has given a special satisfaction to be able to reward these two series of discoveries at the same time, since it gives a clear expression of one of the ideas upon which the will of Alfred Nobel was founded, that is, the conception that the greatest cultural advances are independent of the splitting-up of mankind into contending nations. I also feel confident that you will be glad to know that the proposition which has led to this award of the Nobel Prize originated from a German scientist who, in spite of all difficulties and disasters, has clearly recognized the main object of Alfred Nobel.

In conferring upon both of you the sincere congratulations of the Caroline Institute, I have the honour of asking you to receive from His Majesty the King the Nobel Prize for 1922 in Physiology or Medicine.


3 comments:

  1. more importantly, who won? I know I got it right.

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  2. Although his work on muscle contraction was of course the work that won him the Nobel Prize, it is perhaps worth noting also that Hill's name will also be remembered for a long time for the Hill plot and the Hill coefficient for assessing binding cooperativity.

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