Otto Fritz Meyerhof
1884 - 1951
|
|
Otto Fritz Meyerhof 1884 - 1951 |
"for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle"
Presentation Speech by Professor J. E. Johansson, Chairman of the Nobel Committee for Physiology or Medicine of the Royal Caroline Institute
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.
From Les Prix Nobel 1922.
A series of yearbooks is published on behalf of the bodies responsible for
awarding the Nobel Prizes. Published since 1901.
Contents: The Nobel institutions, prize-winners and citations, the Nobel ceremonies
and presentation speeches, as well as speeches by the laureates at the banquet.
Includes also, biographical notes and portraits of the laureates and the Nobel
lectures.
Edited by Tore Frängsmyr, Prof. of History of Science at Uppsala University,
Sweden. Printed by Norstedts Tryckeri AB
Back (English)
Zuruck (Deutsch)