Presentation Speech by Professor J.E. Johansson, Chairman of the Nobel Committee for Physiology or Medicine of the Royal Caroline Institute, on December 10, 1920
Your Majesty, Your Royal Highnesses, Ladies
As the first application of a quantitative approach to the field of Physiology, one quotes the calculation on which Harvey based his theory of the circulation of the blood. In his well-known paper of 1628, Harvey compared the heart's output and rate of beating on the one hand with the total amount of blood contained in the human body on the other. Then he showed that the supply of blood available to the body at any given moment passes through the heart in less than a minute. According to a view which dates from antiquity, the blood sent by the heart to the different parts of the body is assimilated, and simultaneously replaced by a transformation of food in the intestines. It was clearly absurd to suppose that sufficient blood could be formed to maintain the flow of blood expelled from the heart, whose calculation had been established by Harvey. There was nothing left except to admit the idea of circulation. It is evidently necessary that the volume of blood which the heart drives to the various parts of the body through the arteries is transferred to the veins and returned from them to the heart. Harvey was not allowed to see the link between arteries and veins. He had not got the technical means for this at his disposal. As is well known, Malpighi discovered the final link in the circulation in 1661, four years after Harvey's death. With the aid of a simple microscope which magnified by a factor of 180, he observed how the blood flows through fine vessels from the arteries to the veins. These vessels, called capillaries, which have a diametre of some thousandths of a millimetre, form, as we now know, networks whose form and density vary in different tissues. The blood, as it passes through this network, fulfils the task with which it has been credited since time immemorial, namely that of supporting the functions vital to life. Across the capillary walls, which are extremely thin, the blood releases or absorbs the substances which are respectively used up and formed in the surrounding tissues, and in this way provides for the transport of substances through the body, which are necessary to maintain the vital functions. I am going to quote some figures to give an idea of the transfer of materials involved: in a man at rest, about 300 cubic centimetres of oxygen are carried per minute from the lungs to the tissues, while about 250 cubic centimetres of carbon dioxide are transferred at the same time in the opposite direction. During heavy muscular work these quantities can be increased tenfold. This increase corresponds with the renewal of material brought by the blood, mostly during the period of activity, from the various stores which the body possesses. The volume of blood contained by the body amounts to about 4 litres. However, it is not this amount of blood, which one might call the standing volume, that is of special interest in this particular context of ideas. We are more interested in the blood flow, whose rate is usually indicated in terms of something conventionally called the minute-volume, i.e. the quantity of blood which passes through the cross-section of the circuit in one minute: we can imagine the section taken through the aorta, for example, where it leaves the heart, or indeed through all the capillaries throughout the body. The minute-volume, or what one might call the effective blood-volume, reaches about 3 litres at rest, and can rise to 30 litres during work.
What I have just said brings out the interest, from the physiological viewpoint, which pertains to the mechanisms controlling the capillary blood flow, as well as to the processes which regulate the transport of matter through the capillary walls. In this branch of physiology, August Krogh, Professor of the University of Copenhagen, has made a discovery which the Staff of Professors of the Caroline Institute had judged of such importance that it has awarded him this year the Nobel Prize intended to reward discoveries in the field of physiology or medicine.
The work with which Krogh achieved his present standing in the world of science a little less than 10 years ago, dealt with pulmonary gas exchange, and took as its starting-point the question of whether this phenomenon should be considered a diffusion or a secretion of gas. This question had attracted special interest because of the brilliant work on the chemistry of respiration by Krogh's teacher, the Danish scientist Christian Bohr.
We know that the lungs consist of a great number of little alveoli whose walls are interwoven with capillaries. Between the air in the pulmonary alveoli and the blood in the capillaries is a wall some thousandths of a millimetre thick. Across this wall an exchange of oxygen and carbon dioxide takes place between the blood and the pulmonary air. The most natural explanation of this gas exchange is to suppose that gas molecules enter, or, as the expression goes, are dissolved in the wall, and pass through it from a region of greater to one of lower pressure, just as happens in the well-known phenomenon of physics called diffusion. According to this supposition the wall itself would be quite passive. On the other hand it does form part of the living organism and could well be the site of special functions - functions which might possibly be likened to those of a gland. So it is a question here, as in so many other cases, of choosing between the application of a simple proposition from physics and a concept tinged, so to speak, with vitalism.
In this discussion, Krogh represented the theory of diffusion. His contributions are distinguished by an experimental critique of high standard. I will confine myself to mentioning his method of determining blood gas tensions. Like his predecessors, he analysed the contents of a gas chamber which had been allowed to reach a state of equilibrium with the blood stream; but he reduced this gas chamber to a little bubble of air, whereas his predecessors used to work with such capacious containers that in many cases it was in fact impossible to equalize pressures with the blood stream. In support of the supposition that there was a secretion of gas in the lung, observations had been quoted which seemed to indicate that the absorption of oxygen could produce an oxygen tension in the arterial blood which was higher than that of the air in the lungs. Such differences in tension no longer occur, as Krogh has demonstrated, if the sources of error, which he has pointed out, are avoided. Other methods were resorted to in an attempt to demonstrate new aspects of the phenomenon under discussion. However, the situation did not change. Krogh pointed out further sources of error, after whose elimination the experiments provided evidence in favour of the theory of diffusion. Finally, using a very elegant method, Krogh succeeded in proving that the quantities of gas, which, under the given physical conditions, must necessarily be taken to diffuse across the walls of the pulmonary alveoli, correspond exactly to the exchange of gas which does in fact take place, even when the requirements are exceptional. From then on, the theory of secretion could be considered to have had its day. It is true that certain distinguished scientists still defend it, enamoured, one would say, of the possibility of applying the entelechy of Aristotle to modern physiology.
But it is not this work, despite its great merit, which the Nobel Prize is intended to reward. Settling a question in dispute, whose relations and implications are known in advance, should hardly be considered as a discovery. This work by Krogh which I have mentioned forms some sort of introduction to other investigations having as their aim the determination of the process by which the oxygen requirement of the tissues is satisfied. In the account which I have just given, I have tried to give an idea of the nature of gas transport in the body. By virtue of this fortunate characteristic of the heart which enables it to provide a minute-volume which is both flexible and adapted to requirements, it is possible, as we have just seen, for a relatively small store of blood to transport very considerable amounts of gas in a short space of time. The figures I quoted in support are largely taken from Krogh's publications. In his most recent work, he has centred his investigations on the so-called internal respiration, especially on the mechanism underlying the transport of oxygen from the capillaries into the tissue elements. In so doing, he entered a hitherto relatively little explored territory, which, however, offered scope for experiments fruitful in new concepts.
As regards the exchange which takes place between capillary blood and the surrounding tissues, we have no good grounds for assuming any process other than diffusion. But, as regards what there may be in the way of physical factors controlling it, it is not very easy to get a survey of them. We can determine the oxygen tension of the blood arriving in the arteries, and of the blood flowing away through the veins. So we believe ourselves justified in thinking that we know the capillary oxygen tension with a fair degree of certainty, and we can also calculate the extent to which the supply of oxygen brought by the arteries will have been used up. The rate of diffusion is determined by the difference between the tension in the blood and that in the surrounding tissue. But what is the oxygen tension of the tissue outside the capillaries, or rather, what is the tension at different points in the space between them? Attempts to determine it directly run into difficulties of a technical kind. Krogh is the first person to have elucidated this question in a mathematically comprehensible way. Using an extremely ingenious method of investigation, he determined the diffusion constant of gases in different organic tissues, especially in muscle. In this tissue, the capillaries have a lay-out whose geometry is so simple and regular that the dimensions of the capillary network can be incorporated into a calculation without any difficulty. In this way he found a method of calculating the difference between the oxygen tension of capillary blood and that to be found anywhere in the intervening tissues. This calculation showed that the oxygen tension of muscle tissue, even during heavy work, was only very little less than that of the capillaries. The result Krogh obtained is surprising in the sense that it had been thought reasonable until then to assume a more or less minimal tension in resting muscle, which would have led to establishment of even lower values during work, when consumption is greater. On the other hand, it must be recognized that a high oxygen tension in muscle tissue during work should favour the rapid consumption of material under these conditions. But all the contradictions disappear, as Krogh made clear, if, in the calculation mentioned above, the distance between blood-filled capillaries is varied in relation to the oxygen consumption, or, in other words, if it is accepted that the capillaries in muscle tissue are all filled with blood only when the tissue is at its most active. It occurred then to Krogh that only a certain number of capillaries contain blood at any one time during the resting-state, and that this number increases when a greater flow of blood has to be allowed through, i.e. a larger minute-volume. This supposition is a plausible one. If the number of capillaries carrying blood was fixed, an increase in the minute-volume would entail a corresponding acceleration of the linear rate of flow. What the diffusion process would gain from the greater flow of blood, would be lost, at least partly, through the increase in speed, and through the reduction in the time available for blood and capillary wall to come into contact during each circuit. On the other hand, a rise in the number of capillaries carrying blood would obviously mean an increase in the surface available for diffusion, and would enable actual use to be made of the greater minute-volume supplied by the heart.
But confirmation for the hypothesis was still lacking. Krogh resorted to the same procedure which Malpighi once employed, namely examining various organs under the microscope while keeping their blood supply intact. The frog's tongue in particular proved an excellent subject for experiments. While examining it, he was able to observe how a certain number of previously invisible capillaries would rise up in the visual field and transport blood in response to different stimuli, and later contract and disappear. A mechanical excitation by means of the fine point of a needle causes the capillaries in the immediate neighbourhoods to open. In resting muscle, scattered capillaries only are to be found, separated by large intervals. If the muscle is set to work, the picture changes immediately. The muscle is found to be interlaced with a compact capillary network, which is well shown in the injected preparations of the anatomists. Shortly after the muscle has returned to the resting condition, all these capillaries have disappeared again. In this way Krogh found confirmation for his hypothesis. What one might call the effective capillary network of a tissue has a density which varies considerably in different physiological conditions and it only corresponds in special cases to the picture produced by the anatomists in successfully injected preparations.
As a result of a very varied series of experiments, Krogh realized that the capillaries are not made to open up by an increase in blood pressure in the afferent artery. So it becomes necessary to consider them as being in a state of «tonus» (steady contraction), whose relaxation is brought about periodically, and through the action of certain stimuli. So the capillary volume is not determined solely by the blood pressure in the afferent artery, as is generally imagined. This would require neighbouring capillaries to dilate or constrict simultaneously. The capillary wall clearly possesses the property of contractility, i.e. there is a mechanism which causes the wall, at different moments, to vary its resistance to the internal pressure of neighbouring capillaries.
We have a similar mechanism in the vaso-motor system, which has been known for nearly three quarters of a century as a result of virtually innumerable investigations, since the discovery by Henle of the smooth muscle of vessels, the discovery of vaso-constrictor and vaso-dilator nerves by Claude Bernard, and the explanation provided by Ludwig of the influence these structures have on the blood flow. This mechanism, since the point where it acts is provided by the circular muscles of the medium-sized arteries and arterioles, should, as Krogh observed, more properly be named arterio-motor. Krogh's investigations showed the existence of yet another system regulating the blood flow, the capillaro-motor mechanism. These two mechanisms differ not only with regard to anatomical considerations, but also, as Krogh proved, in their relation to the nervous system and in their reaction to some poisons such as adrenaline, urethane and cocaine. The most important difference, however, between these two mechanisms lies in their different roles where physiology is concerned. The arterio-motor mechanism distributes the minute-volume supplied by the heart to the various organs of the body, while the capillaro-motor apparatus controls the surface separating blood and tissue in these organs, i.e. the surface which all the materials brought up to supply the tissues must cross.
Here a question claims our attention. In the long period of time which elapsed after Malpighi saw blood flowing in the capillaries, did no one observe their contractility? But indeed yes. Several scientists saw the capillaries change in response to various stimuli. But none of them thought of investigating whether these phenomena could be related to a new mechanism, differing both in the way it was arranged and the way it functioned from the known vasomotor-regulating mechanism. This makes one think of the evolution of conceptions which ended in the discovery of the circulation of blood. Before Harvey, many doctors, over several centuries, had the opportunity of confirming how, after the tourniquet has been applied just before a bleeding is to take place, the veins swell up on the side of the tourniquet furthest from the heart. But none of them could understand that such confirmation is incompatible with the hypothesis which requires that the blood in the veins should come from the heart. Césalpini, to whom the discovery of the circulation of the blood is attributed by his compatriots, got as far as believing that the blood in the veins flows to the heart during sleep. A Swedish historian, Per Hedenius, who described the discovery of the circulation of the blood, says of him that he was almost on the point of winning the laurels which posterity was to award to Harvey, but that he fell short of the achievement. We may say that he lacked the quantitative approach which Harvey made use of. In the same way, we can understand that the mere observation of capillary contraction would hardly be enough to suggest a mechanism of the kind discovered by Krogh. To arrive at this, it was necessary in the same way to take a quantitative approach to the transport of materials in the blood stream.
Professor Krogh. It has fallen to you to make an important discovery in the field of physiology. The Staff of Professors of the Caroline Institute, which claims the honour and the pleasure of being among the first to afford you public proof of its appreciation, invites you to accept the Alfred Nobel Prize from the hands of our King.
From Nobel Lectures, Physiology or Medicine 1901-1921, Elsevier Publishing Company, Amsterdam, 1967
Copyright © The Nobel Foundation 1920
"for the discovery of the role played by the sinus and aortic mechanisms in the regulation of respiration"
"for his discovery relating to the production of heat in the muscle"
"for their discoveries concerning heart catheterization and pathological changes in the circulatory system"