The new physiology and other addresses

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UBRARy

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Contents

PAGES

Preface v

1. The Relation of Physiology to Physics and

II. The Place Of Biology In Human Knowledge And Endeavour.1

We meet in the shadow cast by the greatest war in human history. To many of us that shadow is specially deep. We see our fellow-men willingly offering their own lives, and the lives of their best and dearest, for great ideals. The main problems as to the meaning of human life and endeavour are thus thrust upon us, and specially on those who have to remain behind.

We are a body of scientists or of persons interested in, and willing to devote such time as we can to science. What, in the last resort, are" our aims, and are they worthy aims ? This is the question which I wish to bring before you to the best of my ability, and with special reference to biology, and more particularly the physiological side of it — the branch of science on which I feel most qualified to speak.

Many persons would, I think, incline to the opinion that science is essentially the pursuit of pure truth, apart from any practical needs and interests ; and that while the practical applications of scientific discovery are all to the good, the real aims of science are altogether

unconnected with practical applications. There is evidently much to be said in support of this view. The Societies represented at this meeting are certainly not devoted to what would ordinarily pass for practical objects, and the interest which attracts so many persons to science does not on the surface appear to be a practical interest.

It is nevertheless equally true that scientific work excites our emotions in a high degree — a fact difficult to explain if we are only pursuing the bare truth about facts which in no way enter into our lives. What does it matter to us, for instance, whether certain stimuli cause an Arcella to produce bubbles of gas within its protoplasm, or what gas these bubbles consist of ? Yet why does such a problem seem to physiologists so interesting as a matter of fact ? And why are we not equally interested in endless other occurrences which are constantly taking place around us, and about which, if we were only seeking for abstract truth, we might be expected to be equally interested ? Something is evidently lacking in our provisional definition of the aims of science, and we must try to get nearer to this something.

Let me try to follow out the case of the gas-bubbles in the Arcella. Perhaps I may remind you that Arcella vulgaris is a microscopic unicellular organism found in rivers and ponds. It has a more or less transparent shell, shaped something like the top of a mushroom, with an opening where the stalk would come. Through this opening it protrudes delicate pseudopodia, by means of which it can creep about. When a living and healthy Arcella is examined in a drop of water under the microscope, the presence of one or more gas-bubbles inside its protoplasm can at times be observed, particularly if hv accident or design the animal has been turned on its back, with the opening of its shell upwards. The bubbles of course make the animal lighter, so that it rises towards the surface of the water, and also comes right side up, after which they rapidly disappear again. The occurrence of these phenomena was described many years ago by Engelmann. Quite recently Dr Bles took up the subject again at my suggestion, and elicited the very interesting fact that a comparatively slight deficiency in the normal oxygen percentage of the water causes the animal to develop bubbles at once, and come to the surface.

Now this is apparently a case of visible and easily observed intra-protoplasmic gas-secretion, and for various reasons it is probable that the gas liberated is oxygen. The occurrence of oxygen-secretion was already known, as an isolated fact, in the case of the swim-bladder of the fishes. The original discovery of this was made over one hundred years ago by the French physicist and chemist Biot. Being engaged in some survey work on the Mediterranean, he was attracted by the observation that deep-sea fishes caught with a line at great depths come to the surface with their swim-bladders distended with gas, or even bursting. Led by a sure scientific instinct, he determined to analyse the gas, but expected it to be something like air in composition. He added hydrogen to some of the gas in a eudiometer and passed a spark, in order to determine the oxygen in the usual way. But instead of the ordinary mild explosion in analyses of air there was a violent explosion which broke his instrument. He then knew that he had made a most significant discovery, as the gas he was dealing with must be nearly pure oxygen ; so he got another eudiometer and with proper precautions made a large number of analyses, which he published in the Memoir es de la Societe oVArcueil of 1807. These analyses showed that the greater the depth from which a fish was taken the more nearly did the gas from the swim-bladder approximate to pure oxygen.

A long time elapsed before the significance of Biot's discovery was realised by physiologists, and it was seventy years later before the subject was again effectively taken up in a very interesting monograph by Moreau,1 a French physiologist. He showed experimentally what the real functions of the swim-bladder are ; while later physiologists have added many further contributions on : which I must not stop to dwell. Perhaps the most noteworthy of these is the discovery by Bohr of Copenhagen that the secretion of oxygen is under the control of the nervous system, the secretory nerve being a branch of the vagus.

As nearly pure oxygen has been obtained from the swim-bladders of fishes living at a depth of 4500 feet, it follows that oxygen may be secreted into the swim-bladder and retained in it in the gaseous form at a pressure of over 120 atmospheres, whereas the partial pressure of oxygen in the surrounding sea- water is only about one-fifth of an atmosphere. It seems perfectly clear, therefore, that the liberation of oxygen and its retention by the semi-liquid wall of the swim-bladder is the result of an active physiological process in the 1 Memoires de physiologie, Paris, 1877.

living cells lining its walls, and cannot be explained mechanically.

The case of the swim-bladder threw grave doubt on the current mechanical explanation of the absorption of oxygen into the blood through the epithelial cells lining the alveoli of the lungs ; for this might also be partly or wholly a case of active absorption and not of mere diffusion. The question was taken up by Bohr and others, but the evidence was not conclusive. Experiments with improved methods by Krogh x of Copenhagen, and by Douglas and myself 2 at Oxford, then showed that under normal resting conditions the phenomena are consistent with the diffusion theory. Our own experiments gave, however, the clear result that under conditions where oxygen-want is produced in the tissues, active absorption occurs. Perhaps the most striking results were obtained as the outcome of an expedition to the summit of Pike's Peak, Colorado, in order to observe to what extent, and by what means, acclimatisation to diminished atmospheric pressure occurs.3 It was experimentally shown many years ago by Paul Bert in his book La pression barometrique, Paris, 1878, that the various physiological disturbances, such as mountain sickness, associated with exposure to diminished atmospheric pressure, are due to want of oxygen, depending on the fact that although the oxygen percentage in air at high altitudes is precisely the same as elsewhere, the partial pressure of the oxygen in the

2 Journal of Physiology, xliv. p. 305, 1912.

■' Douglas, Haldane, Henderson and Schneider, Philosophical I'ransactions, b, vol. 203, p. 185, 1913.

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North Caro.ma S air is diminished in proportion to the fall of atmospheric pressure. Paul Bert's conclusions have again and again been attacked or misunderstood by subsequent writers, but as to their substantial correctness there is not now a shadow of doubt.

We selected Pike's Peak for the observations because of the existence of a cog-wheel railway to the summit at 14,100 feet, and a substantial building, in which we were promised, and were given, excellent accommodation for ourselves and all our apparatus, and where we had ample opportunities of observing the effects of the air on the numerous people who came up. When we first went up we were, like other newcomers, slightly blue in the lips and face, and after a few hours began to suffer from the very unpleasant symptoms of mountain sickness. In the course of the next two or three days these symptoms of oxygen- want passed off, and though we were still unusually short of breath after muscular exertion, we remained extremely well, and of a perfectly normal colour, like the other persons living on the summit. There was thus no doubt about the acclimatisation. Our measurements now showed that the partial pressure of oxygen in the arterial blood was considerably higher than in the air of the lung alveoli. An active secretion of oxygen inwards into the blood had thus, established itself, even during rest ; and on this active secretion the main phenomena of acclimatisation depend, so far as we could judge. But for this active secretion it would be hard to understand, for instance, how the Due d'Abruzzi and his party could have climbed in deep snow to a height of 24,600 feet in the Himalayas. Even on Pike's Peak at only 14,000 feet many people who came up fainted from want of oxygen, and we could revive them promptly by administering pure oxygen.

It has thus been established that living animal cells, and not merely living and chlorophyll-containing vegetable cells, have the power of liberating or secreting free oxygen. This is an important scientific generalisation, , which will certainly be used as a lamp for guiding future investigation, and may also be of practical importance, for instance in medicine. The same may be said of all scientific generalisations ; but it would be absurd to claim that all, or indeed any considerable proportion, of scientific wTork has immediate practical objects. We certainly did not go to Pike's Peak as medical philanthropists. I can remember a secret spasm of joy when a newcomer with blue lips and tottering legs challenged one of us to a pugilistic encounter, and I thus recognised the psychological symptoms of want of oxygen, familiar to me already through experience of carbon monoxide poisoning in mines. I fear also that we behaved with arrant hypocrisy to a newspaper representative who came to ask for an interview. We were about to express our great regret that we were too busy, when we noticed that he was particularly blue and rather shaky. We immediately asked him to come in, and proceeded to ply him with " copy," waiting until both his hands and legs gave way. Meanwhile we had some oxygen ready, and with much show of sympathy got him to breathe it when he was just on the point of fainting. To our great satisfaction his lips became red again, and he entirely revived, after which we again continued the interview, and again had the satisfaction of seeing him blue and faint, and revive with oxygen, though after this he felt he had had enough of Pike's Peak, and made a sudden bolt for a car which was just starting

downwards.

The case of oxygen secretion has a far wider interest than those of practical medicine, and I must now try to follow this wider interest. At present there are two very different views as to the aims and tendencies of biological investigation. The first view, which the present generation of biologists has inherited from the leaders of the immediately preceding generation, is the mechanistic one, that life is, in ultimate analysis, a physical and chemical process, and is thus only capable of being understood in terms of the physical and chemical conceptions through which we interpret inorganic phenomena. The second view is that life can only be understood and successfully investigated by means of conceptions derived from the study of life itself. For a recent re-statement of the first view I may perhaps refer to Sir Edward Schafer's Presidential Address to the British Association in 1912, though I confess at once to standing here as an uncompromising upholder of the second view. According to the first view, biology is only a department of applied physics and chemistry. I wish to claim for biology that ' ; place in the sun " to which it seems to me that she is entitled as an independent science.

The fact of oxygen secretion is one among many facts, all of which tend to show that from the physical and chemical standpoint the functional activities of a living organism are very far from being the comparatively simple processes which they were formerly believed to be. Orthodox text-books still, it is true, speak of the " mechanism " of such processes as secretion ; and the unwary are thus led to believe that these processes are more or less understood as physical and chemical processes. But the blunt truth, enforced again and again by actual investigation, is that if there be any physical or chemical explanation of them, it remains for the present unknown, and with advancing knowledge seems to recede further and further away. This fact is so evident when one looks back over the progress of the last half-century that I need hardly illustrate it. It does not follow, however, that because the supposed physical and chemical processes are too complex for our present powers of analysis, they do not exist. The upholders of the mechanistic theory of life maintain that all the facts hitherto ascertained with regard to the activities of living organisms are simply physical and chemical facts : the movements of living organisms are simply physical movements ; and the chemical products of physiological activity are simply ordinary chemical products. For instance, the oxygen liberated in gas-secretion is simply ordinary oxygen, discovered and measured by ordinary chemical and physical methods. When we set ourselves to the task of physiological investigation all we can really do is to investigate the physical causes of the movements and the chemical sources of the products. No other course has any meaning. As a matter of fact, we never actually run up against some mysterious entity, such as the supposed ' vital force." We can always push physical and chemical analysis further ; and there is nothing for it but to pursue this process from the known and firm ground of physical and chemical observation into the unknown ground within the living substance we are investigating. The very presupposition of physiology as a science is the assumption that life is a physical and chemical process ; and for this reason it is justifiable to speak of the " mechanism " of life, even though we are not yet in a position to understand this mechanism.

Now, it seems to me that this reasoning is radically fallacious ; and I shall try to point out the source of fallacy as clearly and shortly as I can. First of all, I wish to emphasise a fact which few biologists seem to realise — namely, that our present interpretation of the inorganic world in terms of such conceptions as mass, movement, atoms, energy, and even space and time themselves, is only an interpretation or working hypothesis. It has been arrived at gradually and laboriously in the course of human history ; but we have no reason to suppose that it is a final interpretation, though for the present we cannot dispense with it, and though we can be certain that any truer and deeper interpretations of the physical universe must cover the facts which our present interpretation covers, just as Lavoisier's conception of chemical change covered all the facts interpreted by StahPs phlogiston theory, to which such able investigators as Priestley and Cavendish held throughout. As a matter of fact, we are living in a time when the ablest mathematicians, physicists and chemists clearly perceive the limitations of the interpretations in which they were brought up, and are striving after deeper and truer interpretations.

To those biologists, therefore, who argue that all the facts which biological investigation reveals are, and can only be, physical and chemical facts as interpreted in the light of current physics and chemistry, it must be pointed out that they are referring not to bed-rock reality, but to interpretations of that reality ; and, moreover, to interpretations which physical science itself is showing to be imperfect, not to mention objections which seem to me of an even more formidable character from the philosophical side.

In the interpretation of Nature we have to look, not merelv at the immediate sense data, but at the accompanying phenomena. When a piece of metal burns, the residue is heavier than the original metal. This might be due to the loss from the metal of something with a negative weight, phlogiston, or to gain by the metal of something of a positive weight. It was only by investigating the accompanying phenomena — the disappearance of what we now call free oxygen in the process — that Lavoisier showed the second hypothesis to be better than the first. Now, in the interpretation of the phenomena life we are equally bound to look at the phenomena which accompany each phenomenon which we are investigating ; and it is here, as it seems to me, that the mechanistic biology has signally failed. It takes individual physiological data, as interpreted in the light of current physical and chemical theory, and assumes them to represent bed-rock fact. It then endeavours to piece these individual data together, so as to represent an intelligible physico-chemical process ; and the result has been failure, which with advancing knowledge seems only to become more and more hopeless.

In investigating a living organism we have no right to take our data one by one ; for, as I shall presently show in more detail, it is characteristic of a living organism that the details of form, movement, chemical composition, and change which we distinguish in it are essentially, and not merely accidentally, connected with one another. We are accustomed to the fact that a limb, or even a bone, of a certain build is associated with a whole body of a certain build. We know also that if an animal is breathing we may expect to find its heart beating and all its other organs in a state of more or less evident activity. We associate together the details of structure and activity as those of a living animal ; we think and speak of it as alive, and we regard its structure and activities as the expression or manifestation of its life. What I - wish to maintain is that in so regarding a living organism we use a hypothesis which is for biology just as intelligible, just as elementary, just as true to the facts known, and just as good a scientific working hypothesis, as is the hypothesis of the indestructibility of matter for physics and chemistry.

The mechanistic theory of life assumes that in ultimate analysis it is only an accident that material particles of which the living body is composed are aggregated and combined in the form actually met with, and another accident that they display the activities actually observed in the living body. This follows from the conception of organisms as simply material systems in motion or at rest ; for the physical world as it is ordinarily conceived consists of matter and energy which are eternal and unchangeable, while of their actual distribution no explanation is given except that it depends on their previous actual distribution, of which no account is given.

Now let us try to analyse an actual example of physiological investigation. I have sometimes been good-naturedly chaffed by physiological brethren for preaching anti-mechanistic doctrines, and actually employing rigid physical and chemical methods in experimental work, and reaching equally definite physico-chemical results ; so I will select for analysis the corner of physiology at which I have mainly worked, namely, the physiology of respiration.1

The act of breathing consists of rhythmic muscular movements of the chest-walls, causing the lungs to expand and contract, and air to enter and leave them. These movements of the air are accompanied by chemical changes, oxygen being absorbed from it in the lungs, and carbon dioxide being given off. This is a general statement in physical and chemical terms of the most evident phenomena connected with respiration, and we have now to follow up the physico-chemical analysis. The oxygen which disappears in the lungs passes into the blood through the very delicate epithelium lining the walls of the lung alveoli ; and during rest under ordinary physiological conditions the passage inwards has been found to occur in strict accordance with the known laws of physical diffusion of gases. Nearly all of this oxygen then enters into a loose and easily dissociable chemical compound with the haemoglobin contained in the red blood-corpuscles of the venous blood

1 The papers published by my pupils and myself on this subject will be mostly found in the Journal of Physiology from 1892 onwards.

supplied by the right side of the heart to the lungs. In this form the oxygen is then carried on in the arterialised blood, and is distributed by the action of the left ventricle to the capillary blood-vessels all over the body. In these delicate vessels the partial pressure of oxygen is lowered owing to the passage of oxygen outwards into the living tissues ; consequently the oxyhemoglobin is partly dissociated, so that the red corpuscles deliver up the extra charge of oxygen which they had received in the lungs ; and the blood returns through the veins to the heart and lungs, where it receives a fresh charge of oxygen and repeats the cycle.

The carbon dioxide of the expired air is also carried by the blood in easily dissociable chemical combination. It is given up to the lung air by diffusion through the alveolar walls ; and the arterial blood returns to the systemic capillaries, where it takes up a fresh charge, owing to the higher partial pressure of carbon dioxide in and around these capillaries. Both the final disappearance of free oxygen, and the production of carbon dioxide, appear to occur within the living cells of the tissues.

The muscular movements associated with respiration are initiated by nerve impulses controlled from a " centre " situated in the medulla oblongata. The rhythmic activity of this centre is influenced by afferent stimuli of different kinds, and by stimuli proceeding from other centres ; but all the main control of the centre has been found to depend on the chemical state of the blood supplied to the centre from the heart. Of this latter control we must now consider the nature. We

know from the most casual observation that the breathing varies considerably in both depth and frequency, and becomes very irregular during irregular exertions such as speaking or singing. There are many people who think that the lungs may not be getting enough oxygen, and who in order to remedy this imaginary defect recommend increased breathing.1 Now exact investigation shows that the breathing in each person is so regulated as to maintain during rest a certain absolutely definite mean percentage, or more correctly, partial pressure, of carbon dioxide in the air of the lung alveoli. This percentage depends on the balance between the varying amount of carbon dioxide coming off from the venous blood, and the amount of fresh air introduced into the lung alveoli by the breathing. By an effort of will we can temporarily increase the breathing so as to dilute the carbon dioxide further ; but a dilution of as little as one-thirtieth in the mean alveolar carbon dioxide percentage causes the disappearance of all spontaneous impulse to breathe, until the carbon dioxide balance has been restored ; while an increase from any cause of one-twentieth in the mean alveolar carbon dioxide percentage is accompanied by an increase to more than double in the volume of air breathed. The average breathing is thus regulated with almost incredible exactitude in accordance with the varying rate at which carbonic dioxide is produced in the body, and brought to the lungs by the blood.

The percentage or partial pressure of carbon dioxide in the alveolar air determines the partial pressure of

1 By one of Nature's ironies, one effect of forced breathing is to produce dizziness, and even loss of consciousness, due possibly to want of oxygen induced indirectly.

this gas in the arterial blood ; and it has been found that it is to this that the activity of the centre responds in regulating the breathing so exactly. Now, carbon dioxide when dissolved in a liquid such as the blood acts as a very weak acid, although its influence as an acid is far less in the blood than in pure water. Careful investigation has shown that the arterial blood is faintly alkaline, and that what the respiratory centre is doing in regulating the partial pressure of carbon dioxide in the blood is in reality to regulate this faint alkalinity. No existing physical or chemical method of demonstrating changes in alkalinity approaches in delicacy the discrimination of the respiratory centre ; but by indirect means the proof has been given that the variations in the activity of the centre are caused by minute variations in the alkalinity of the blood.

In the respiratory centre we thus have, to use orthodox mechanistic language, a " mechanism " tuned to react with astounding delicacy and constancy to the minutest changes in the alkalinity of the blood. This supposed mechanism consists of what is called " protoplasm " ; and protoplasm is something which from the physical and chemical standpoint is excessively unstable, and sensitive to every slight change in its environment. Yet this unstable mechanism reacts in the human body hour after hour, day after day, year after year, true as tempered steel, to one absolutely definite and absolutely puny stimulus ! How can we conceive that such constancy is maintained ? Knowing what we do of the nature of living protoplasm, the answer must be that the physiological environment of the respiratory centre remains constant. But how, considering only the varying quality and amounts of the substances we eat and drink, and which pass through our blood, can this physiological environment be at all constant ? I will leave this question for the moment and meanwhile follow up another path in the analysis.

The actual faint alkalinity of the blood and its power of carrying carbon dioxide in readily dissociable chemical combination depend on the presence in the blood in certain amounts, and in a certain mutual balance, of a number of substances ; and it is clear that, if an alteration in this balance occurred, the degree of alkalinity in both arterial blood and tissues would also be very seriously disturbed unless compensated by considerable variations in the alveolar carbon dioxide percentage and the rate of circulation. Now, during rest under normal conditions of health such variations do not occur to any extent which is appreciable except by unusually exact measurement, or which is more than a very temporary or passing change. Among the many exact regulations which exact quantitative research is rapidly revealing within the living body none is more remarkable than the exactitude with which the capacity of the blood for carrying carbon dioxide is regulated. Such variations as ordinarily occur are within the limits of error of the most exact methods which we have been able to devise for the purpose. The balance can, it is true, be upset temporarily by artificial means ; but in a very short time it rights itself.

The salts of the blood, on which this balance mainly depends, must, in the long run, be regulated by the balance between absorption from the intestine and excretion by the kidneys. So far as we know, all soluble salts are absorbed more or less quickly by the intestines ; and it is therefore to the kidneys that we must mainly look for the explanation of this marvellous regulation of the composition of the blood.

Now, all we know of the mode of action of the kidneys goes to show that they have the same delicate and exact power of regulating the liquid and crystalloid constituent parts of the blood as the respiratory centre possesses in regulating the reaction or hydrogen ion concentration. We actually find that salts and other soluble crystalloids introduced into the body by the mouth or in other ways in excess are promptly excreted by the kidneys. On the other hand, we also find that the kidneys have an equally marked power of holding back substances which are not in excess. If, for instance, a diet free from sodium chloride is given, the chloride in the urine, normally abundant, practically disappears, although there is still nearly the usual high proportion of sodium chloride in the blood-plasma.

Let me give another illustration. We know that when a person who is not thirsty drinks a large amount of water, the consequence is an approximately equal secretion of urine by the kidneys. Further investigation shows that the urine secreted is practically nothing but pure water. When, during the enormous kidney secretion produced by this means, the blood was examined, we found that it was sensibly undiluted by the water passing through it; for the percentage of haemoglobin in the blood remained sensibly the same during, before, and after the secretion.