The further stage of development to which I have referred as characterizing more recent physiology concerns the attention now directed on the co-ordination, or, as it is often termed, regulation of life-processes. The development of physical chemistry and accurate methods of physical measurement, and of analysis of blood and other liquids, have made it possible to see far more clearly certain outstanding facts with regard to the exact co-ordination of familiar physiological processes, and the essential importance of this co-ordination. To some of these facts attention was first clearly directed by the experiments and writings of Claude Bernard; and since then their importance has come to stand out more and more prominently in every department of physiology.
In experiments on the oxidation of sugar in the living body Bernard started with the expectation that when sugar and the other carbohydrates which are converted into sugar by the digestive ferments are withheld from an animal, the sugar which he had found to be present in the blood would disappear. He found, however, that this was not the case: the sugar was still present in the blood after prolonged starvation. Moreover, if very large amounts of sugar were given, there was only a slight increase in the percentage present in the blood, since rise in this percentage was prevented owing to the disappearance of the sugar, or its copious excretion by the kidneys. He was thus led, on the one hand to the search for and discovery of glycogen as an immediate source of and repository for sugar in the body, and on the other hand to the conception that the blood, and particularly its plasma, is a general internal medium which is kept remarkably constant in composition and amount, owing to the co-ordinated regulating influence upon it of various organs, such as the kidneys, liver, lungs, etc. On a wide survey of what was then known of animal physiology he even went so far as to conclude that “all the vital mechanisms, varied as they are, have only one object, that of preserving constant the conditions of life in the internal environment.”
The conception embodied in these words has proved an extraordinarily useful one in guiding physiological work into fruitful channels, and in uniting together what would otherwise be no better than a chaotic collection of isolated observations. Side by side with increased knowledge of the co-ordination of physiological activities in maintaining the “conditions of life” there has grown up a correspondingly increased knowledge of the physiological importance of these conditions being maintained accurately. The whole matter is so important as to require illustration in some detail.
As one example we may take the physiology of excretion of urine. The rate of excretion, and amount excreted, of each urinary constituent depends quite evidently on the extent to which that constituent is in excess of or falls below a normal proportion in the blood. Let us consider, as a case in point, the excretion of water. When excess of pure water is drunk voluntarily it is rapidly absorbed from the intestines, but almost as rapidly excreted by the kidneys, so that at no time is there more than a very minute excess in the proportion or amount of water in the blood, and very little excess in the tissues as a whole.1 The presence of this minute excess is evidently sufficient to evoke a very great increase in the excretion of water. Thus the rate of excretion of water may be temporarily increased ten times or more above normal, though the increase in the proportion of water in the blood-plasma is so small as to be only measurable with the greatest difficulty. Moreover, the increase in the rate of excretion of dissolved constituents is extremely small, the excreted urine becoming dilute in proportion to its increased volume. What is excreted in excess is practically speaking water alone, other substances, such as chlorides, which are present in abundance ordinarily, being only present in a dilution which may be only a minute fraction of their concentration in the blood-plasma. In extreme cases not even a demonstrable trace may be present in the urine, as when, owing to excessive loss of salt by sweating, the concentration of salt in the blood has been slightly reduced.
The excretion of water is far less rapid if a solution containing about one per cent. of sodium chloride is drunk in excess, instead of pure water. The principles of physical chemistry render this fact quite intelligible provided that we assume Bernard's general principle and interpret it as meaning, when applied to the water of the internal medium, that the diffusion pressure of this water is constantly being kept as nearly normal as possible in the blood-plasma.2 Since this pressure is about the same in blood-plasma and one per cent. sodium chloride solution, we can understand why the response of the kidneys is so much less active. We can also understand why very copious and dilute urine with a high diffusion pressure of water is excreted when there is a tendency for the diffusion pressure of water in the blood to be raised above normal, while only scanty and concentrated urine is excreted when there is an opposite tendency. Whichever of the normal constituents of urine is considered, we find the same sort of relation between the variations in their concentrations in the urine and in the blood. The kidneys are evidently engaged constantly in excreting water and other crystalloid constituents which are present in abnormal concentration, and at the same time in actively retaining within the blood constituents which are not present in excess. The blood, for instance, is normally very slightly alkaline, but the kidney responds to the minutest change of the blood towards the acid or alkaline side by a relatively enormous increase in excretion of acid or alkali, thus keeping the blood normal in reaction, though acid substances, or occasionally alkaline substances, are constantly being discharged into it.
The advances of physical chemistry and its applications to the liquids present in the body have made it possible to see more and more clearly how closely Bernard's principle agrees with the facts relating to renal activity. This principle summarizes the known facts, and suggests directions in which to carry investigation further. Without it we should be lost in a maze of unrelated observations. It has, moreover, shown us how far-reaching, effective, and exact is the co-ordination of physiological activity as revealed by exact analysis of the blood-plasma under varying external conditions.
For another illustration of Bernard's principle we may go to the physiology of respiration. The act of breathing may be regarded as nothing but a mechanical process leading to a further mechanical process by which oxygen passes into the blood, and carbon dioxide passes out of it. For recent physiology, however, the act of breathing has come to signify a very precisely co-ordinated process, comparable in every way to the precisely co-ordinated action of the kidneys; and the regulation of breathing is now simply a part of that regulation of the internal medium which Bernard drew attention to.3
That the breathing is so co-ordinated as to maintain within the lungs during rest a definite concentration of carbon dioxide can be demonstrated easily in short experiments by analyses of samples of air from the lung alveoli as obtained at the end of a deep expiration. However irregular the rhythm of breathing may be, and however much its rate may alter, provided that its depth is allowed to adjust itself naturally, this concentration remains steady but for a very slight diminution on inspiration, and increase on expiration. We can, for instance, increase the rate of breathing threefold, or diminish it to a third, without disturbing the concentration of carbon dioxide, since the depth naturally adjusts itself in such a way as to keep the concentration steady. At ordinary atmospheric pressure and for men this concentration is usually about 5.6 per cent. of carbon dioxide in the lung air, but varies appreciably in different individuals. If two or three per cent. of carbon dioxide is already present in the inspired air, the depth of breathing becomes naturally so much increased that the lung air contains only very slightly more carbon dioxide than before. Thus with an increase of three per cent. in the carbon dioxide of the inspired air there is only an increase of about 0.2 per cent. in the air within the lungs. Similarly, when, during even very moderate muscular exertion, the production of carbon dioxide within the body is increased five times or more, there is only a very small increase in the percentage of carbon dioxide in the lung air, since the ventilation of the lungs is increased during the exertion to nearly five times. By observations on the breathing at different atmospheric pressures we can easily show that it is not the percentage of carbon dioxide, but its partial pressure or diffusion pressure that is exactly regulated.
The diffusion pressure of carbon dioxide in the gaseous medium with which the blood is in contact during its passage through the lungs is thus kept nearly, but not quite, constant; and since other evidence shows that diffusion between the blood and this gaseous medium is perfectly free and complete, the diffusion pressure of free carbon dioxide in the arterial blood leaving the lungs and heart is also nearly constant. But, other things being equal, the alkalinity of the blood diminishes or increases as the pressure of free carbon dioxide in it increases or diminishes; and by the application of extremely delicate methods of measurement by Hasselbalch and others it has been shown that what is kept nearly constant by the breathing at different times and under various physiological conditions is not the mere percentage of carbon dioxide, but the reaction, or hydrogen ion pressure, of the arterial blood. We find, for instance, that the carbon dioxide pressure to which the lung air is approximately regulated varies distinctly at different times in the same individual; but the hydrogen ion pressure remains the same. When, however, acid or alkaline substances are added rapidly to the blood, the regulation becomes imperfect owing to imperfect exchange of ions between the blood and the protoplasm of the tissues.
The fact that the reaction of the blood is regulated by the breathing connects the breathing with the action of the kidneys in regulating the blood reaction. The reaction depends partly on the alkaline salts present in the blood, and partly on the concentration of free carbon dioxide in it; and unless the kidneys could be relied on to keep approximately steady the alkalinity dependent on the salts, the reaction would not be steady with a steady concentration of carbon dioxide, as is approximately the case. Thus there is close co-ordination between the activities of respiration and of the kidneys, with, as a result, amazingly exact constancy in the hydrogen ion pressure of the arterial blood under normal conditions.
The breathing not only removes carbon dioxide from the lungs, but supplies the blood with oxygen; and if the breathing is sufficient to keep the carbon dioxide pressure approximately steady in the lung air, it will also be sufficient, as a rule, to keep the arterial blood normally saturated with oxygen, assuming that, as is normally the case, diffusion is perfectly free between the lung air and blood. If, however, owing to a low oxygen percentage in the air inspired, or owing to very low atmospheric pressure such as exists at considerable altitudes, the arterial blood is not normally saturated with oxygen, the breathing is stimulated by the want of oxygen. The increase of breathing can only be small, since increased breathing lowers the carbon dioxide pressure in the lung air, and this, in its turn, tends to diminish the breathing by increasing the alkalinity of the blood. Thus two opposing influences are in play; but in the course of time the kidneys, reacting normally to the slightly increased alkalinity of the blood, make considerably increased breathing possible without more than a trifling residual increase in the normal alkalinity of the blood. This is one important factor in acclimatization to high altitudes, which will be discussed further in Lecture V.
The respiratory movements are controlled by the central nervous system, and it has now become quite clear that the stimuli which ordinarily determine the whole of this nervous control, including that exercised through the vagus nerves, are carried by the arterial blood passing to the central nervous system. Two of these stimuli—diminished alkalinity and diminished concentration of free oxygen—have already been referred to. Various other changes of an abnormal character in the blood are known to affect the nervous control; and, reasoning from analogy, we may be certain that the nervous system would not respond normally to the usual respiratory stimuli unless the composition of the arterial blood remained normal apart altogether from variations in the ordinary respiratory stimuli. Into the regulation, therefore, of the responses of the nervous system to the respiratory stimuli there thus enter all sorts of other conditions which experimental investigation is gradually revealing, and the regulation of which must in reality be essential to the normal responses of the nervous system to ordinary respiratory stimuli.
The activity of the nervous system in so controlling respiratory movements as to maintain in certain definite respects constancy in the character of the internal medium leads naturally to a more general consideration of nervous activity. In accordance with Bernard's conception, the whole of that activity is so co-ordinated as to contribute towards maintaining the constancy of the internal medium. We have only to glance through what has been revealed by experiment as to the activities of the nervous system in order to see how fully this conception is borne out. It is, for instance, through the nervous activity that the circulation through the skin, the secretion of sweat, and the production of heat are so controlled as to maintain almost constant the internal blood temperature. It is also largely through nervous activity that a sufficient arterial blood pressure is maintained to render possible a proper distribution of blood and hence a proper maintenance of the composition of the internal medium in different parts of the body. Were it not for constant adjustment of the circulation in accordance with varying local activity the composition of the internal medium would vary beyond the limits which are consistent with normal maintenance of such local activity. This follows from the mere fact that all continued local activity is bound up with the consumption of oxygen, to mention only one substance which is consumed or produced in excess. If the local circulation failed to meet the consumption of oxygen the activity would soon be brought to an end.
Looking at the activity of the nervous system from the standpoint of conscious as well as unconscious activity, Bernard's principle still holds good: for conscious as well as unconscious activities may be regarded as so co-ordinated as to maintain the internal medium in a normal state or provide for its reproduction. In so acting as to avoid hunger or thirst, excessive heat or cold, or injuries of any kind, we are contributing, albeit unconsciously, to keeping the internal medium normal, and if we did not do so life would soon come to an end.
When individual nervous reactions are investigated in detail, as has been done in many cases by Sherrington, the co-ordinated, or, as he expresses it, “integrated,” character of these reactions stands out prominently. Here, as elsewhere in recent physiology, the fact of co-ordination has been the keynote of recent work.
Let us now, however, examine Bernard's conclusion somewhat more closely. When we do so we find that it is primarily the arterial blood, and only indirectly the blood as a whole, that is regulated so evenly. In different parts of the body the venous blood varies in composition and temperature, and must do so, considering the varying exchanges of material and of heat which are known to occur between the blood and various organs. So far, however, as our present knowledge goes, the composition of the blood is kept nearly constant in each individual organ. This is brought about with the help of local regulation of the circulation. During extra muscular work, or extra secretory work, for instance, the local circulation is so increased as to neutralize the local changes in blood-composition which would otherwise occur, so that in each individual part the composition of the blood remains normal.
The fact that the arterial blood remains so constant in its main features is nevertheless significant as tending to limit the variations in the blood passing through different organs. For instance, the constancy in temperature of the arterial blood tends to prevent the temperature in different internal organs from varying at all considerably. It has also been found that through the agency of various “buffering” substances present in the blood and tissues, and of local variations in the rate of circulation, the gas pressures and hydrogen ion pressures in the blood of different parts of the body tend to be prevented from deviating to more than a limited amount from what they are normally. Thus various factors act together in maintaining a normal composition.
The buffering has been not uncommonly confused with the direct and active regulation which is every-where evident. Owing to the presence of buffering substances we can add a quite considerable amount of acid or alkali to blood without producing more than a small disturbance in its reaction, whereas if the blood were simply water or an ordinary salt solution the disturbance would be a far greater one. Similarly, owing to the very peculiar behaviour of the oxyhaemoglobin in the red corpuscles, we can, within certain limits, withdraw or add a considerable amount of oxygen without more than a limited disturbance in the oxygen pressure of the blood-plasma. These, however, are very different matters from direct active physiological regulation through the action of the lungs and kidneys, and it is nothing but sheer ignorance of, or disregard of, observation that has led to the confusion. Were it not for the active regulation the constancy of the conditions in the arterial blood would disappear rapidly, in spite of all the buffering.
Let us now glance at the physiological importance of the regulation of the arterial blood. We can judge of this from the effects of deviations from this constancy, whether produced experimentally or in disease. The amount of knowledge so gained in recent times is very large. As a simple and easily intelligible case we may take a deficiency in the concentration of oxygen in the plasma of the arterial blood. This is easily and quite commonly brought about in disease or under certain abnormal conditions, and can also be studied experimentally in a simple and uncomplicated manner. When the pressure of oxygen in the inspired air is rapidly reduced by about a third, either by reducing the total atmospheric pressure or by reducing the oxygen percentage of the air, the oxygen pressure in the arterial blood is reduced. There is also a reduction in the total oxygen present in the loosely combined form in oxyhaemoglobin, though this latter reduction is only slight, since the haemoglobin can still saturate itself in the lungs to not far from the normal extent with oxygen. The immediate effect on the breathing is only slight, for the reason already explained; but if the exposure is continued for long enough a train of marked pathological symptoms is produced—the symptoms known to mountaineers as “mountain sickness” and consisting of headache, nausea, vomiting, pain referred to the heart, and marked depression. In the absence of other illness these symptoms are usually recovered from in the course of two or three days, when sufficient acclimatization has had time to take place; and they do not occur at all if the reduction in oxygen pressure has been so gradual that acclimatization can occur during the reduction. They may occasionally, however, become progressively more serious till life itself is endangered if the reduction has been rapid; and with greater reductions and longer exposures the probability of ultimate danger to life becomes increasingly greater.
It should be noted that the arterial blood still contains far more oxygen than corresponds to what the tissues take from it on an average in its passage through the capillaries. What is deficient is not, or need not be, the total amount of oxygen carried by the blood to the tissues, but the pressure of the free oxygen. We can also infer from the symptoms that in man, at least, this deficiency affects most easily the brain. It does so by reducing the partial pressure or diffusion pressure of oxygen in or round nerve-cells or their arborizations; and owing to their consumption of oxygen this partial pressure must be normally lower than in the arterial blood. We can infer, however, that it cannot be greatly lower; otherwise a slight diminution in the total amount of oxygen carried by the arterial blood could hardly have so serious an effect. Similarly, we can infer that the normal hydrogen ion pressure in or around the nerve-cells which are sensitive to the normal stimulus for respiration is normally only a little higher than in the arterial blood. The more or less urgent symptoms produced by failure in the regulation are nervous symptoms, and it is in reality the oxygen pressure and hydrogen ion pressure in or around nerve-cells in the brain that is being directly regulated by respiration. If the oxygen pressure of the arterial blood is much reduced, the effects, which culminate in complete loss of consciousness and paralysis, become more and more serious and dangerous. It has also become more and more evident that during the exposure progressively increasing damage of some kind is produced in the living tissues of the brain, so that after the normal arterial oxygen pressure is restored they only recover slowly or else do not recover at all. Their intimate structure, whatever its nature, has been so altered as to be incapable of acting normally. Gross structural change, visible to the eye, may also be produced.
By variations in the rate of circulation the damaging effects which would otherwise be produced by abnormally low oxygen pressure in the arterial blood are, in the case of many tissues, avoided. This variation is brought about partly by central action of the nervous system, as was shown by Bernard and others, but to a far greater extent also by the local opening up of large numbers of capillaries which were previously closed, as has recently been shown by Krogh. It seems, however, that in the case of the central nervous system the normal oxygen pressure is so high that this means of regulation becomes more or less ineffective when the oxygen pressure of the arterial blood is materially lowered.
It was shown by Paul Bert that an oxygen pressure above normal may be as damaging in its effects on life as an abnormally low oxygen pressure. Here again, however, the tissues seem to be largely protected by variations in the rate of circulation, and from experimental data there is every reason for believing that the central nervous system is actually protected in this way from the effects of a moderate abnormal increase in oxygen pressure. With a great increase, however, fatal effects are produced very rapidly. The tissues of the lungs themselves cannot be protected by varying the rate of circulation, and though they are probably much less sensitive than nerve-cells they become, in time, irreparably damaged, as Lorrain Smith showed, by continued exposure to an arterial oxygen pressure which is quite insufficiently high to cause any sign of damage in the central nervous system.
Of the damage which results from interference with regulation of the blood composition we have also striking evidence in the fatal effects of paralysis by inflammation, or by excision, of the action of the kidneys, with consequent disturbance in the normal balance of the crystalloid constituents of the blood. In one case after another similar damage, and of the most widespread character, has been found to result from serious disease, or excision, of other organs. It has thus become evident that not only the lungs, intestines, and kidneys, but various other organs, such as the liver, pancreas, thyroid gland, sexual organs, suprarenal and pituitary glands, are constantly engaged in regulating the composition of the blood, and that this regulation is essential to the maintenance of normal structure and behaviour of the cells in all parts of the body. On a wider view every part or tissue of the body, including muscular tissue and bone, appears to be engaged in this regulation.
Let us, however, push the physiological analysis still further. The medium in which any individual cell in the body exists must depend, not merely on the composition of the blood-plasma in indirect contact with this medium, but also on the influence of the living cells in its immediate neighbourhood. On this subject much light has in recent times been shed by the cultivation of living cells in artificial media outside the body. Such cells can be kept alive for long periods if the medium is maintained of suitable composition and temperature, and can divide and so multiply. The cells thus grown are, however, of an undifferentiated type unless they contain among them cells derived from another type of tissue normally existing in the original organism side by side with them. Epithelial cells, for instance, cease to present the normal appearances and arrangement of epithelial cells unless cells of connective-tissue origin are present in the culture along with them.
We thus see at once how essential for the normal development and functioning of any kind of cell in the living body is the influence on its medium of neighbouring cells. The medium in every separate part of the body must be normal for that part; and the great outstanding fact is that this normality is maintained, the normality constituting what we call health. We can also see clearly that in embryonic development the two daughter cells of a cell which has divided are no longer in the same medium as the original cell if the daughter cells remain in close contact with one another. In the new environment new growth-stimuli are provided, and the effects of these must lead to structural differentiation, and moreover will be different in different individuals of a collection of cells, since those on or near the surface of such a collection will be in a different medium from those farther from the surface, though the medium surrounding the collection may remain the same throughout.
Let us now consider the bearing of the facts discussed in this lecture on the mechanistic theory of life. In tracing in the last lecture the development of the mechanistic theory we saw that on this theory the peculiar behaviour of living organisms must be regarded as due to the peculiar ultramicroscopic structure of the cell-units composing the organism. Claude Bernard himself still clung to this conception, as he did not realize how far the development of his own reasoning would carry physiology. Now, however, it appears that both the behaviour and the structure of the cell-units depend upon the local medium in which the cells are placed. On the other hand, it is equally evident that the medium, whether it be a general one such as the blood-plasma, neglecting local differences in its composition, may be regarded as being, or whether it be the special local medium, is determined by the activities of the cells. We are therefore reasoning in a circle if we attribute the peculiarities of cell behaviour to their particular structure, since these peculiarities, and the accompanying structure, depend upon the local medium. Thus all that we can really say, in view of the facts which Claude Bernard drew attention to, is that the behaviour of a living organism and its environment is such that the normal life of the organism is maintained. We are forced, however, by the mechanistic theory of life to reason in the circle first alluded to.
That theory is, therefore, bankrupt. It has, in fact, ceased to interest physiologists in recent times, though almost with one accord they refuse to turn back to vitalism, and for very sufficient reasons, as will be shown in the next lecture. The actual development of ordinary physiological investigation has thus carried physiological knowledge to a point where the mechanistic speculations of last century no longer afford any prospect of understanding life; but a little consideration is sufficient to show us that from the beginning there was not the slightest prospect for a complete systematic treatment of biology as a part of physics and chemistry. To explain the fact that organisms, in spite of the extreme lability of their protoplasm, develop and maintain their specific structure and behaviour, it is necessary, on the mechanistic conception, to assume the presence in them of all kinds of specific structure. But that structure is also reproduced from generation to generation, and is apparently being reproduced constantly in ordinary metabolic processes. Of this reproduction the mechanistic theory can give no account whatever. Not by the widest stretch of imagination can we conceive of structural machinery which goes on reproducing itself indefinitely; and the more structure and chemical complication we actually discover or assume in an organism, the more hopeless does the problem of its reproduction and maintenance become from a mechanistic standpoint. Thus from its first beginnings the mechanistic theory of life was embarked on a hopeless task. The more recent developments of physiology, as described in the present lecture, have only brought this home in a new way. It may be that there are still some physiologists who believe that the progress of physiology is bringing us nearer to a physico-chemical conception of life. But if there are, I can only say that their intellectual vision seems to me to be very defective.
In current physiological literature it is still customary, in describing what is known as to different bodily activities, to refer to them as “mechanisms”—for instance, the “mechanisms” of reproduction, respiration, secretion, etc. This is of course a mere matter of custom, handed down from a previous generation. There are perhaps few physiologists who now consider that they have any real conception of these mechanisms. I should like, however, to point out that such a mode of expression is extremely misleading to that miscellaneous body which we call the public.
Looking back at the means through which the progress reviewed in the present lecture has been reached, we can see that it has been reached through the application to physiological phenomena of accurate quantitative methods, and particularly by the measurement, in relation to one another, of differences which may be very small. Much of my own time, and that of most other physiologists, has been taken up in devising sufficiently accurate methods of measurement. It was only, for instance, through the accurate chemical analysis of blood, urine, and alveolar air, and through the application of the principles of physical chemistry and physics, that the co-ordinated activity manifested in excretion, respiration, and circulation became clear. Similarly, it has only been through accurate measurement of intake and output of material and energy that the co-ordinated metabolic activity of the body as a whole has been progressively revealed. Thus the fundamental fact of organic co-ordination has become progressively more evident, while the idea of a physico-chemical mechanism of this co-ordination has faded more and more into the background.
One often meets the statement, repeated, parrot-like, by various persons, that scientific physiology is progressively revealing the mechanism of life. In the light of actual progress this is quite untrue, and can only be described as claptrap. What physiology is progressively revealing is the detail of co-ordinated physiological activity. Knowledge of this detail is of the utmost importance in medicine, both on its therapeutical and preventive sides, in agriculture, and in all the arts which have to deal with the activities of living organisms from yeast and bacteria upwards. Many biologists still hold before themselves as an ideal the discovery of a physico-chemical mechanism of life. But assuredly that ideal seems to them far more distant than it did to Schwann and the other leaders of the mechanistic movement in physiology of last century, though even to the latter, if they had only thought a little more, and not suffered themselves to be carried away by a child-like enthusiasm, the knowledge then existing would have shown that ideal to be unattainable. In view of the facts as to heredity, what, for instance, could have been more futile than Schwann's conception of the formation of living cells by a process of precipitation?
Quantitative experiments bearing on this point are described by Haldane and Priestley, Journ. of Physiol., vol. 1, p. 296.
In my book, Gases and Liquids, 1928, it is shown that what is at present known, in the language of van 't Hoff's confused theory of osmotic pressure, as the osmotic pressure of the blood, is in reality deficiency in the diffusion pressure of water as compared with the diffusion pressure of pure water.
See my book Respiration, 1922.