An Introduction to the Study of Experimental Medicine

Every definite substance, whether inorganic, organic or organized, is autonomous; that is to say, it has characteristic properties and exhibits independent action. Nevertheless, each one of these bodies is inert, that is, it is incapable of putting itself into action; to do this, it must always enter into relation with another body, from which it receives a stimulus. Thus every mineral body in the cosmic environment is stable; it changes its state only when the circumstances in which it is placed are rather seriously changed, either naturally or through experimental interference. In any organic environment, the substances created by animals and vegetables are much more changeable and less stable, but still they are inert and exhibit their properties only as they are influenced by agents outside themselves. Finally, anatomical units themselves, which are the most changeable and unstable of substances, are still inert, that is, they never break into vital activity unless some foreign influence invites them. A muscle-fibre, for instance, has the vital property peculiar to itself of contracting, but this living fibre is inert in the sense that if nothing changes in its environmental or its inner conditions, it cannot bring its functions into play, and it will not contract. For the muscular fibre to contract, a change must necessarily be produced in it, by its coming into relation with a stimulation from without, which may come either from the blood or from a nerve. We may say as much of all the histological units, nerve units, blood units, etc. Different living units thus play the part of stimuli, one in relation to another ; and the functional manifestations of an organism are merely the expression of their harmonious reciprocal relations.

The histological units react either separately or one against another by means of vital properties which are themselves in necessary connection with surrounding physico-chemical conditions; and this relation is so intimate that we may say the intensity of physico-chemical phenomena taking place in an organism may be used to measure the intensity of its vital phenomena. Therefore, as has already been said, we must not set up an antagonism between vital phenomena and physico-chemical phenomena, but, on the contrary, we must note the complete and necessary parallelism between the two classes of phenomena. To sum up, living matter is no more able than inorganic matter to get into activity or movement by itself. Every change in matter implies intervention of a new relation, i.e., an outside condition or influence. The role of men of science is to try to define and determine the material conditions producing the appearance of each phenomenon. These conditions once known, experimenters master the phenomenon in this sense, that they can give movement to matter, or take it away, at pleasure.

What we have just said is equally true for the phenomena of living bodies and the phenomena of inorganic bodies. Only in the case of the complex higher organisms, physiologists and physicians must study the stimuli of vital phenomena, not in the relations of the whole organism with the general cosmic environment, but rather in the organic conditions of the inner environment. Considered in the general cosmic environment, the functions of man and of the higher animals seem to us, indeed, free and independent of the physico-chemical conditions of the environment, because its actual stimuli are found in an inner, organic, liquid environment. What we see from the outside is merely the result of physico-chemical stimuli from the inner environment ; that is where physiologists must build up the real determinism of vital functions.

Living machines are therefore created and constructed in such a way that, in perfecting themselves, they become freer and freer in the general cosmic environment. But the most absolute determine ism still obtains, none the less, in the inner environment which is separated more and more from the outer cosmic environment, by reason of the same organic development. A living machine keeps up its movement because the inner mechanism of the organism, by acts and forces ceaselessly renewed, repairs the losses involved in the exercise of its functions. Machines created by the intelligence of man, though infinitely coarser, are built in just this fashion. A steam engine's activity is independent of outer physico-chemical conditions, since the machine goes on working through cold, heat, dryness and moisture. But physicists going down into the inner environment of the machine, find that this independence is only apparent, and that the movement of its every inner gear is determined by phys-

ical conditions whose law they know. As for physiologists, if they can go down into the inner environment of a living machine, they find likewise absolute determinism that must become the real foundation of the science of living bodies. IX. The Limits of Our Knowledge Are the Same m the Phenomena of Living Bodies and in the Phenomena The nature of our mind leads us to seek the essence or the why of things. Thus we aim beyond the goal that it is given us to reach ; for experience soon teaches us that we cannot get beyond the how, i.e., beyond the immediate cause or the necessary conditions of phenomena. In this respect the limits of our knowledge are the same in biological as in physico-chemical sciences.

When, by successive analyses, we find the immediate cause determining the circumstances in which a phenomenon presents itself, we reach a scientific goal beyond which we cannot pass. When we know that water, with all its properties, results from combining oxygen and hydrogen in certain proportions, we know everything we can know about it; and that corresponds to the how and not to the why of things. We know how water can be made; but why does the combination of one volume of oxygen with two volumes of hydrogen produce water? We have no idea. In medicine it is equally absurd to concern one's self with the question "why." Yet physicians ask it often. It was probably to make fun of this tendency, which results from lack of the sense of limits to our learning, that Moliere put the following answer into the mouth of his candidate for the medical degTee. Asked why opium puts people to sleep, he answered : ''Quia est in eo virtus dormitiva, cujus est natura sensus assoupire/' This answer seems ludicrous and absurd ; yet no other answer could be made. In the same way, if we wished to answer the question: "Why does hydrogen, in combining with oxygen, produce water?" we should have to answer: "Because hydrogen has the quality of being able to beget water." Only the question "why," then, is really absurd, because it necessarily involves a naive or ridiculous answer. So we had better recognize that we do not know ; and that the limits of our knowledge are precisely here.

In physiology, if we prove, for instance, that carbon monoxide is deadly when uniting more firmly than oxygen with the hemoglobin, we know all that we can know about the cause of death. Experience teaches us that a part of the mechanism of life is lacking; oxygen can no longer enter the organism, because it cannot displace the carbon monoxide in its union with the hemoglobin. But why has carbon monoxide more affinity than oxygen for this substance? Why is entrance of oxygen into the organism necessary to life ? Here is the limit of our knowledge in our present state of learning ; and even assuming that we succeed in further advancing our experimental analysis, we shall reach a blind cause at which we shall be forced to stop, without finding the primal reason for things.

Let us add that, when the relative determinism of a phenomenon is established, our scientific goal is reached. Experimental analysis of the conditions of the phenomenon, when pushed still further, gives us fresh information, but really teaches us nothing about the nature of the phenomenon originally determined. The conditions necessary to a phenomenon teach us nothing about its nature. When we know that physical and chemical contact between the blood and the cerebral nerve cells is necessary to the production of intellectual phenomena, that points to conditions, but it cannot teach us anything about the primary nature of intelligence. Similarly, when we know that friction and that chemical action produce electricity, we are still ignorant of the primary nature of electricity.

We must therefore, in my opinion, stop differentiating the phenomena of living bodies from those of inorganic bodies, by a distinction based on our own ability to know the nature of the former and our inability to know that of the latter. The truth is that the nature or very essence of phenomena, whether vital or mineral, will always remain unknown. The essence of the simplest mineral phenomenon is as completely unknown to chemists and physicists to-day as is the essence of intellectual phenomena or of any other vital phenomenon to physiologists. That, moreover, is easy to apprehend ; knowledge of the inmost nature or the absolute, in the simplest phenomenon, would demand knowledge of the whole universe; for every phenomenon of the universe is evidently a sort of radiation from that universe to whose harmony it contributes. In living bodies absolute truth would be still harder to attain ; because, besides implying knowledge of the universe outside a living body, it would also demand complete knowledge of the organism which, as we have

long been saying, is a little world (microcosm) in the great universe (macrocosm). Absolute knowledge could, therefore, leave nothing outside itself; and only on condition of knowing everything could man be granted its attainment. Man behaves as if he were destined to reach this absolute knowledge; and the incessant why which he puts to nature proves it. Indeed, this hope, constantly disappointed, constantly reborn, sustains and always will sustain successive generations in the passionate search for truth.

Our feelings lead us at first to believe that absolute truth must lie within our realm ; but study takes from us, little by little, these chimerical conceits. Science has just the privilege of teaching us what we do not know, by replacing feeling with reason and experience and clearly showing us the present boundaries of our knowledge. But by a marvellous compensation, science, in humbling our pride, proportionately increases our power. Men of science who carry experimental analysis to the point of relatively determining a phenomenon doubtless see clearly their own ignorance of the phenomenon in its primary cause; but they have become its master; the instrument at work is unknown, but they can use it. This is true of all experimental sciences in which we can reach only relative or partial truths and know phenomena only in their necessary conditions. But this knowledge is enough to broaden our power over nature. Though we do not know the essence of phenomena, we can produce or prevent their appearance, because we can regulate their physico-chemical conditions. We do not know the essence of fire, of electricity, of light, and still we regulate their phenomena to our own advantage. We know absolutely nothing of the essence even of life; but we shall nevertheless regulate vital phenomena as soon as we know enough of their necessary conditions. Only in living bodies these conditions are much more complex and more difficult to grasp than in inorganic bodies; that is the whole difference.

To sum up, if our feeling constantly puts the question why, our reason shows us that only the question how is within our range; for the moment, then, only the question how concerns men of science and experimenters. If we cannot know why opium and its alkaloids put us to sleep, we can learn the mechanism of sleep and know how opium or its ingredients puts us to sleep; for sleep takes place only because an active substance enters into contact with certain organic substances which it changes. Learning these changes will

give us the means of producing or preventing sleep, and we shall be able to act on the phenomenon and regulate it at pleasure. In the knowledge that we acquire, we should distinguish between two sets of notions : the first corresponds to the cause of phenomena, the second to the means of producing them. By the cause of a phenomenon we mean the constant and definite condition necessary to existence; we call this the relative determinism or the how of things, i.e., the immediate or determining cause. The means of obtaining phenomena are the varied processes by whose aid we may succeed in putting in action the single determining cause which produces the phenomenon. The necessary cause in the formation of water is the combination of two volumes of hydrogen with one of oxygen; this is the single cause which always determines the phenomenon. We cannot conceive of water apart from this essential condition. Subordinate conditions or processes in the formation of water may be extremely varied; only all these processes reach the same result, viz., combination of oxygen and hydrogen in invariable proportions. Let us take another example. I assume that we wish to transform starch into glucose; we have any number of means or processes for doing this, but fundamentally there will always be the identical cause, and a single determinism will beget the phenomenon. This cause is fixation of one more unit of water in the substance, to bring about its transformation. Only we may produce this hydration in any number of conditions and by any number of methods: by means of acidulated water, of heat, of animal or vegetable enzymes; but all these processes finally come to a single condition, hydrolysis of the starch. The determinism, i.e., the eause of the phenomenon, is therefore single, though the means for making it appear may be multiple and apparently very various.

It is most important to establish this distinction especially in medicine, where the greatest confusion reigns, precisely because physicians recognize a multitude of causes for the same disease. To convince ourselves of what I am urging we have only to open a treatise on pathology. By no means all the circumstances enumerated are causes ; at most they are means or processes by which a disease can be produced. But the real and effective cause of a disease must be constant and determined, that is unique; anything else would be a denial of science in medicine. It is true that determining causes are much harder to recognize and define in the phenomena of living beings ; but they exist nevertheless,

in spite of the seeming diversity of means employed. Thus in certain toxic phenomena we see different poisons lead to one cause and to a single determinism for the death of histological units, for example, the coagulation of muscular substance. In the same way, varied circumstances producing the same disease must all correspond to a single and determined pathogenic action. In a word, determinism which insists on identity of effect bound up with identity of cause is an axiom of science which can no more be transgressed in the sciences of life than in the sciences of inorganic matter.

X. In the Sciences of Living Bodies, as in Those of Inoeganio Bodies, Experimenters Create Nothing ; They Simply Obey the Laws of Nature We know the phenomena of nature only through their relations with the causes which produce them. Now the law of phenomena is nothing else than this relation numerically established, in such a way as to let us foresee the ratio of cause to effect in any given case. This ratio, established by observation, enables astronomers to predict celestial phenomena ; this same ratio, established by observation and experiment, again enables physicists, chemists, physiologists, not only to predict the phenomena of nature, but even to modify them at pleasure and to a certainty, provided they do not swerve from the ratio which experience has pointed out, i.e., the law. In other terms, we can guide natural phenomena only by submitting to laws that govern them.

Observers can only observe natural phenomena; experimenters can only modify them; it is not given them to create or to destroy them utterly, because they cannot change natural law. We have often repeated that experimenters act, not on phenomena themselves, but on the physico-chemical conditions necessary to their appearance. Phenomena are just the actual expression of the ratio of these conditions; hence, when conditions are similar, the ratio is constant and the phenomenon identical, and when conditions change, there is another ratio, and a different phenomenon. In a word, to make a new phenomenon appear, experimenters merely bring new conditions to pass, but they create nothing, either in the way of force or of matter. At the end of the last century science proclaimed a great truth, to wit, that with respect to matter, nothing is lost, neither

is anything created in nature ; the bodies whose qualities ceaselessly vary under our eyes are all only transmutations of aggregations of matter of equal weight. In recent times science has proclaimed a second truth which it is still seeking to prove and which in some sense is truly complementary to the first, to wit, that with respect to forces nothing is lost and nothing created in nature ; it follows that all the infinitely varied forms of phenomena in the universe are only equivalent transformation of forces, one into another. I reserve for treatment elsewhere the question whether differences separate the forces of living bodies from those of inert bodies; let it suffice for the moment to say that the two preceding truths are universal, and that they embrace the phenomena of living bodies as well as those of inert bodies.

All phenomena, to whatever order they belong, exist implicitly in the changeless laws of nature ; and they show themselves only when their necessary conditions are actualized. The bodies and beings on the surface of our earth express the hannonious relation of the cosmic conditions of our planet and our atmosphere with the beings and phenomena whose existence they permit. Other cosmic conditions would necessarily make another world appear in which all the phenomena would occur which found in it their necessary conditions, and from which would disappear all that could not develop in it. But no matter what infinite varieties of phenomena we conceive on the earth, by placing ourselves in thought in all the cosmic conditions that our imagination can bring to birth, we are still forced to admit that this would all take place according to the laws of physics, chemistry and physiology, which have existed without our knowledge from all eternity; and that whatever happens, nothing is created by way either of force or of matter; that only different relations will be produced and through them creation of new beings and phenomena.

When a chemist makes a new body appear in nature, he cannot flatter himself with having created the laws which brought it to birth; he produced only the conditions which the creative law demanded for its manifestation. The case of organic bodies is the same. Chemists and physiologists, in their experiments, can make new beings appear only by obeying the laws of nature which they cannot alter in any way. It is not given to man to alter the cosmic phenomena of the whole universe nor even those of the earth; but the advances of science

enable him to alter the phenomena within his reach. Thus man has already gained a power over mineral nature which is brilliantly revealed in the applications of modem science, still at its dawn. The result of experimental science applied to living bodies must also be to alter vital phenomena, by acting solely on the conditions of these phenomena. But here our difficulties are greatly increased by the delicacy of the conditions of vital phenomena and the complexity and interrelation of all the parts grouped together to form an organized being. This is why man can probably never act as easily on animal or vegetable, as on mineral, species. His power over living beings will remain more limited, especially where they form higher, i.e., more complicated organisms. Nevertheless, the difficulties obstructing the power of physiologists do not pertain to the nature of vital phenomena, but merely to their complexity. Physiologists will first begin by getting at phenomena of vegetables and of animals in easier relations with the outer cosmic environment. It appears, at first sight, as if man and the higher animals must escape from its power to change, because they seem freed from the direct influence of the outer environment. But we know that vital phenomena in man, as in the animals nearest him, are connected with the physico-chemical conditions of an inner organic environment. This inner environment we must first seek to know, because this must become the real field of action for physiology and experimental medicine.

So far we have been explaining experimental considerations applicable to both living and inorganic bodies; for living bodies the difference consists merely in the greater complexity of phenomena, making experimental analysis and determination of the conditions incomparably harder. But in the behavior of living bodies we must call the reader's attention to their very special interdependence; in the study of vital functions, if we neglected the physiological point of view, even if we experimented skilfully, we should be led to the most false ideas and the most erroneous deductions.

We saw in the last chapter that the object of the experimental method is to reach the determinism of phenomena, no matter of what nature, whether vital or mineral. We know, moreover, that what we call determinism of a phenomenon means nothing else than the determining cause or immediate cause determining the appearance of phenomena. Thus we necessarily obtain the conditions in which the phenomena exist, and on which the experimenter must act to make the phenomena vary. We therefore consider the various expressions above as equivalents; and the word determinism sums them all up.

It is indeed true, as we have said, that life brings absolutely no difference into the scientific experimental method which must be applied to the study of physiological phenomena, and that in this respect physiological science and physico-chemical science rest on exactly the same principles of investigation. But still we must recognize that determinism in the phenomena of life is not only very complex, but that it is at the same time harmoniously graded. Thus

complex physiological phenomena are made up of a series of simpler phenomena each determining the other by associating together or combining for a common final object. Now the physiologist's prime object is to detemiine the elementary conditions of physiological phenomena and to grasp their natural subordination, so as to understand and then to follow the different combinations in the varied mechanism of animal organisms. The ancient emblem representing life as a closed circle, formed by a serpent biting its own tail, gives a fairly accurate picture of things. In complex organisms the organism of life actually forms a closed circle, but a circle which has a head and a tail in this sense, that vital phenomena are not all of equal importance, though each in succession completes the vital circle. Thus the muscular and nervous organs sustain the activity of the organs preparing the blood ; but the blood in its turn nourishes the organs which produce it. Here is an organic or social interdependence which sustains a sort of perpetual motion, until some disorder or stoppage of a necessary vital unit upsets the equilibrium, or leads to disturbance or stoppage in the play of the animal machine. The problem for experimenting physicians consists, therefore, in finding the simple determinism of an organic disorder, that is to say, in grasping the initial phenomenon which brings all the others in its train through a complex determinism as necessary in character as the initial determinism. This initial determinism is like Ariadne's thread guiding the experimenter in the dark labyrinth of physiological and pathological phenomena, and enabling him to understand how their varied mechanisms are still bound together by absolute determinisms. By examples cited further on, we shall see how a dislocation of the organism or an apparently highly complex disorder may be traced back to an initial simple determinism which later produces more complex determinisms. A case in point is poisoning by carbon monoxide (cf. Part III).

I am devoting my whole course at the College de France this year to the study of curare, not for the sake of the substance itself, but because this study shows us how the simplest single determinism, such as the lesion of a terminal motor nerve, re-echoing successively from all the other vital units, leads to secondary determinisms which grow more and more complicated till death ensues. I wish thus to establish experimentally the existence of intra-organic determinisms to which I shall later return, because I consider study of them the true basis of pathology and of scientific therapeutics.

Physiologists and physicians must never forget that a living being is an organism with its own individuality. Since physicists and chemists cannot take their stand outside the universe, they study bodies and phenomena in themselves and separately without necessarily having to connect them with nature as a whole. But physiologists, finding themselves, on the contrary, outside the animal organism which they see as a whole, must take account of the harmony of this whole, even while trying to get inside, so as to understand the mechanism of its every part. The result is that physicists and chemists can reject all idea of final causes for the facts that they observe ; while physiologists are inclined to acknowledge an harmonious and pre-established unity in an organized body, all of whose partial actions are interdependent and mutually generative. We really must learn, then, that if we break up a living organism by isolating its different parts, it is only for the sake of ease in experimental analysis, and by no means in order to conceive them separately. In- deed when we wish to ascribe to a physiological quality its value and true significance, we must always refer it to this whole, and draw our final conclusion only in relation to its effects in the whole. It is doubtless because he felt this necessary interdependence among all parts of an organism, that Cuvier said that experimentation was not applicable to living beings, since it separated organized parts which should remain united. For the same reason, other physiologists or physicians, called vitalists, have proscribed and still proscribe experimentation in medicine. These views, which have their connect side, are nevertheless false in their general outcome and have greatly hampered the progress of science.

It is doubtless correct to say that the constituent parts of an organism are physiologically inseparable one from another, and that they all contribute to a common vital result ; but we may not conclude from this that the living machine must not be analyzed as we analyze a crude machine whose parts also have their role to play in a whole. With the help of experimental analysis we must transfer physiological functions as much as possible outside the organism; segregation allows us to see and to grasp hidden conditions of the phenomena, so as to follow them later inside the organism and to interpret their vital role. Thus we establish artificial digestion and fecundation, so as to know natural digestion and fecundation better. Thanks to their organic self-regulation, we can also detach living tissues, and by means of artificial circulation or otherwise, we can place them in conditions where we can better study their characteristics. We occasionally

isolate an organ by using anesthetics to destroy the reactions of its general group; we reach the same result by cutting the nerves leading to a part, but preserving the blood vessels. By means of experimental analysis, I have even transformed warm-blooded animals, as it were, into cold-blooded animals, so as to study better the characteristics of their histological units ; I have succeeded in poisoning glands separately and in making them work, by means of dissected nerves, quite apart from the organism. In this last case we can have a gland, at will, in a state, first, of absolute rest, then, of exaggerated action; when both extremes of the phenomenon are known we can later easily grasp all the intervening stages, and we then understand how a completely chemical function can be regulated by a nervous system, so as to supply organic fluids in conditions that are always the same. We will not further amplify these suggestions about experimental analysis; we sum up by saying that proscribing experimental analysis of organs means arresting science and denying the experimental method ; but, on the other hand, that practising physiological analysis, while losing sight of the harmonious unity of an organism, means misunderstanding the science of life and individuality, and leaving it characterless.

After carrying out an analysis of phenomena, we must therefore always reconstruct our physiological synthesis, so as to see the joint action of all the parts we have isolated. A propos of the phrase physiological synthesis, we must further explain our thought. It is generally agreed that synthesis reunites what analysis has divided, and that synthesis therefore verifies analysis, of which it is merely the counterproof or necessary complement. This definition is entirely true for analysis and synthesis of matter. In chemistry, synthesis produces, weight for weight, the same body made up of identical elements combined in the same proportions ; but in the case of analyzing and synthesizing the properties of bodies, i.e., synthesizing phenomena, it is much harder. Indeed, the properties of bodies result not merely from the nature and proportions of matter, but also from the arrangement of matter. Moreover, as we know, it happens that properties, which appear and disappear in synthesis and analysis, cannot be considered as simple addition or pure subtraction of properties of the constituent bodies. Thus, for example, the properties of oxygen and hydrogen do not account for the properties of water, which result nevertheless from combining them.