In considering the nature of the equilibrium of metabolism one factor has been disregarded which must be taken into account at every point; this is growth. Growth changes, although varying more or less, are never absent during the life of the organism. An equilibrium of metabolism never exists in a strictly mathematical sense, and here again we are working with a conception which is faulty, because it is an abstraction, originating from experience with rather too restricted boundaries. But an error of which one is aware is not dangerous. In mathematics we also consciously reckon with errors, without the result being altered. In the before mentioned cases the equilibrium of metabolism was maintained, because the investigations involved only a short time in an adult mammal. In the adult mammal the growth processes occur very slowly, so that alterations within a relatively short time are not demonstrated.
If it were possible to subject the adult mammal to metabolic or calorimetric experiments, extending for years, it would be found that the intake would be qualitatively and quantitatively different at the end of the investigation and that the same would apply to the outgo. In the growing egg cell this takes place with much more rapidity. In the organism which rapidly grows, it can be seen at once that the quantity of the outgo of the products of disintegration cannot be equal to that of the intake of foodstuffs. If biotonus were equal to one, the organism could not grow. Equilibrium of metabolism can only be understood when we take into consideration a period of time in which the alterations in growth take place with such imperceptible slowness that the resultant error is inconsiderably minute. This period of time is of greatly varying length in different living organisms and this fact must be taken into account in every living form. Only with this restriction can we justify the use of the term “equilibrium of metabolism.” Then, however, its use is of great value.
The metabolism of stimulation is then a disturbance of the metabolism of rest, that is, a disturbance of the equilibrium of metabolism through the effect of stimuli.
The question here follows: Is there a constancy of this interruption of the equilibrium of rest produced by the stimulus which can be formulated into a general law? To begin with, the number of possible responses are greater than the variety of forms of living substance, for every living organism with its specific properties can undergo alteration in its metabolism in various directions. Thereby results an infinite number of manifold reactions to stimuli. However, in answer to the question, in which direction the change in the specific metabolism of rest in response to a stimulus takes place, we find a comparatively simple scheme of general reaction. All phenomena can change in their rapidity as well as in their nature. That is quantitatively and qualitatively. In this way the specific vital process of an organism can be altered by the stimulus, on the one hand, in its rapidity; on the other, in the manner of its action.
The majority of all temporary responses to stimuli consist in alterations of rapidity of the vital process, and form either a quickening or retardation of its course. The former is manifested in a strengthening or an increase, the latter in a decrease or repression of the specific action of the living organism. The stimuli have the same effect as in the case of the catalysers in chemical processes. According to Ostwald’s[43] well-known definition of catalysis a catalyser is a substance which, without appearing in the final product of a chemical reaction, alters its rapidity. This group of reactions can, therefore, be referred to as “catalytic stimulation and response.” When the response consists in increase, we speak, in a physiological sense, of an excitation, and when there is decrease in the vital processes, we speak of a depression.
The conception of excitation and depression are purely empirical. They are terms for real things, referring, in fact, simply to alterations in rapidity of life process, which can be as readily observed as the process itself. I wish to lay particular stress on this fact, for the reason that Cremer[44] has recently made the extraordinary statement that I have introduced hypothetical processes into the definition of the conception of excitation. I have always considered excitation as merely an increase or change of intensity of the specific actions of a living system, and as such is an established process without a trace of the hypothetical element.[45] If, however, the excitation process is to be regarded as something absolute, as a mysterious state sui generis, which is entirely independent and totally unlike the metabolism of rest, then, of course, it would appear utterly incomprehensible and would be without purpose. As an absolute process excitation is merely a meaningless word. Excitation and depression are relative conceptions and can only acquire meaning when the process which is excitated or depressed is more closely defined. This is the specific vital process of a given organism, and the two conceptions only have meaning in relation to it. The conception of the vital process, however, is one directly gained from experience. However complex or difficult to analyze the process may be, it still is as little hypothetical as that of the combustion of carbon into carbon dioxide, or the revolving of the earth around the sun. It can be looked upon as something positive and real. Quite another question is the manner in which we are to consider the mechanism of the vital process. In analyzing this mechanism we cannot, at least in the present state of our knowledge, entirely dispense with hypothesis. But these hypotheses are in no way involved in the definition of the process of excitation. If we look upon every excitation or depression produced by a stimulus as an alteration in rapidity in the specific vital process of a given organism, we are thereby expressing the same fact which Johannes Müller has termed “specific energy.” We give, however, the doctrine of specific energy a more general application in so far as it comprehends not only the increase but likewise the decrease of activity in response to stimuli. Johannes Müller’s doctrine of specific energy of the living substance at all times has been the subject of most animated discussion. When I refer here to the specific energy of living substance, it is with the knowledge that Johannes Müller did not use this expression of “living substance” in this connection. He was already acquainted, however, as we have seen, with the fact of the existence of the specific energy of all living structures. For appertaining to the muscle he says: “This is universal in all organic reaction.” The reason why the doctrine of sense energy has become of importance in the discussion of the specific energy of the living substance, is in consequence of the theoretical interest, resulting from its connection with the nature of the specific energy of our sense substances. The controversies on this subject are still far from settled.[46] Indeed, according to the special philosophical standpoint taken by an observer, the existence of a specific energy of the senses is acknowledged or disputed. For any one acquainted with the general physiological reaction to stimuli, such a discussion is wholly without purport. The sense substances have as a matter of course in common with all living substances their specific energy, that is, the influence of stimuli can produce an increase or decrease of their specific vital processes. “Specific energy” of “sense substance” in this sense is like that of all other living substances, a fact. In that the psychical capability of these sense substances, in which we include not only the peripheral, but also the central portion, are dependent upon their specific vital processes, it must be self-evident that the excitation and the suppression of sense sensation can be brought about by adequate and inadequate stimuli, no matter what one may think of the relations between physical and psychical phenomena.
The only debatable question is that concerning the limits of the validity of the doctrine of the specific energy of living substances. This question will involve our attention when we have analyzed somewhat more closely the happenings in the living substance taking place under the influence of stimuli. We will, therefore, return later on to a more detailed consideration of the last question. Nevertheless, we will here refer to a fact which, upon a superficial observation, seems to restrict the validity of the conception of the specific energy of living substance.
In contrast to those reactions to stimuli, which consist merely in the changes of a rapidity of the specific vital process, are another group of reactions in which the influence of stimuli leads to qualitative alterations in the specific vital process. In these instances, the influence of the stimulus directs the metabolism of rest into new channels, so that chemical processes occur in the cell, which under ordinary circumstances do not take place. This group of reactions, which I wish to term “metamorphic stimulation and response,” are chiefly observed where weak stimuli act continuously upon the living substance. These are essentially weak chemical stimuli, which last for a prolonged period or frequently reoccur in the life of the cell community. Examples of this are found in the continual ingestion of alcohol and other poisons by the human being, or in the formation of metabolic products of bacteria, etc. The majority of chronic diseases belong to this group of reactions; disease being simply response to stimulation. Disease is life under altered vital conditions and altered vital conditions are stimuli. This simple and self-evident fact shows the immense importance which the knowledge of the general laws of the physiology of stimulation has for pathology. The pathologist, who does not wish to confine his observations to a purely superficial symptomatology or a merely histological morphology, must seek above all to penetrate as deeply as possible into the nature of the general reactions to stimulation in the living organism. It is the essential point which meets him everywhere. In spite of their great interest for pathology, however, it is just these qualitative alterations of the normal vital process produced by continuous stimulation which have up to now been least analyzed. In this field we expect much from pathological investigation which alone has the immense amount of material at its command. This will take place only when pathology adds to the almost exclusively histological direction of investigation, that also of experimental physiology. It is true that the problems of the qualitative alterations of a vital process by chronic stimulation are much more complicated than those of the rapid responses to temporary stimuli, consisting simply in mere alterations of rapidity of the specific vital process. An understanding of the nature of the former can only be expected when a deeper knowledge of the latter is gained, for, as will be seen presently, there is the closest relation between the two groups.
The reactions to catalytic stimuli of short duration, which produce merely an alteration of rapidity in the specific phenomena of a living organism, show on a closer analysis the interesting fact, that it is not always the entire metabolic processes of the cell which are perceptibly quickened, but that only certain constituent processes of the same are affected by the action of excitation. This is the more noticeable, as, considering the close correlation which all the individual links of the chain of metabolism bear to each other, it is to be expected that the alteration in rapidity of one would be followed at once by a corresponding change in all the others. An example of the case in question, in which a special constituent process may be predominately affected, is that of the specific activity of a muscle which is repeatedly stimulated by nervous impulses. Since the classical investigation of Fick and Wislicenus[47] on themselves, and of Voit[48] on the dog, we know that the nitrogen metabolism is practically unaltered by the functional use of the muscle and there is a remarkable increase only in the breaking down of the nitrogen-free groups of the living substance. Sufficient importance has not as yet been attached to this knowledge. This fact not only has a particular interest for the much-discussed question of the source of muscle energy, but also affords a deeper insight into the metabolic activity of the living substance. It shows us that we must not imagine a purely linear linking of the individual constituent metabolic processes, but rather, at least at certain points, a branching formation, the individual members spreading in various directions. An alteration in an individual member can occur without an immediate change in the other branches. This would not be the case if there were only a linear connection of the constituent processes, for the breaking of a single member of the chain would be followed by a change in all the following members.
It shows us, further, that certain branches are more labile than others. In the case referred to here, the branches of this system, which bring about the nitrogen metabolism, are relatively firm and stable, the branches, which are disturbed by the stimulus producing functional activity of the muscle, are particularly labile. I should like in passing to call here your attention to the fact that as is well known, Ehrlich,[49] in another field involving other conditions and other experiences and considerations, has arrived in analogous manner at his “side chain theory.” In order to have an expression for those stimuli which involve rapid alteration of the labile constituent processes and which are connected with the specific action of the particular organism, I have called them “functional stimuli,” and contrasted with them the “cytoplastic stimuli.” In the latter the alterations produced include all the constituent processes extending even to the stable processes of nitrogen changes, and sometimes extend to complete disintegration and rebuilding of living substance.[50] To the first group belong all adequate stimuli within certain limits of duration and intensity, and the greater part of inadequate stimuli of brief duration so long as they do not exceed a certain intensity. To the latter group belong in general all the stronger adequate and inadequate stimuli of prolonged duration; such as extreme temperature, the stronger electric currents, constant alteration in the supply of food, water, oxygen, the prolonged or stronger influence of extraneous chemical matter, etc.