In the foregoing lectures we have had occasion to touch more or less often on the subject of the effects of the stimuli. This was the case, however, only when it appeared necessary to obtain a systematic knowledge of the stimuli and the differentiation of the individual factors. We will now proceed to consider the effect of stimulation in a more systematic manner. The conditional method of observation, however, will remain our guide.

We have already pointed out the relations between the conception of stimulation and that of vital conditions, now we will consider that of the effect of stimulation with that of vital processes. Nevertheless, the effect of stimulation being a manifestation of the vital process is not, therefore, in opposition to the latter as such. Hence the question presents itself as to the connections between vital process and the effect of stimulation.

When we study the motile flagellate infusorium Peranema swimming undisturbed in water, we observe that the swimming movements are absolutely regular in character. The elongated cell body remains unaltered in shape. The long flagellum is extended in a perfectly straight line in the axis of the body and only the extreme end lashes with regularity through the water (Figure 8, A). There is majestic grace in this perfect uniformity of motion. The picture suddenly alters the moment the Peranema is influenced by the slightest jar. The whole flagellum at once executes a few violent movements (Figure 8, B), the body draws together, soon stretches itself again and swims immediately after, in another direction, with the same majestic calm as before.

Another instance. A number of fertilized eggs of the sea urchin are placed in a watch glass in sea water. The temperature of the water should correspond with the mean temperature in which the animals live in the sea, averaging about 15° C. The eggs begin to form grooves and to develop slowly by progressive division. In another glass we observe a second sample of fertilized eggs of the same kind and under the same conditions, but in this case we increase the temperature to 25° C. The increased temperature brings about a decided increase of segmentation and the same stage of development is reached in less than half the time. The increased temperature, therefore, increases the development. Further we take a third sample of the same urchin eggs in a watch glass with sea water of 15° C. and add a little sea water mixed with ether. The development of the eggs now comes to a standstill. The narcotic has produced an inhibition of development.

To quote another instance. Bacterium phosphorescens having been bred upon a putrid fish are exposed in the culture fluid to the air. In the dark the bacteria give forth a phosphorescent light. Then the culture fluid containing the bacteria is put into a glass receptacle, which can be rendered air-tight and all oxygen excluded. After a short time the light formation ceases completely. The absence of oxygen has here had a depressing effect and it is only after air has been again introduced that light is once more produced.

Lastly, an example from the group of mammals may be cited. The metabolism of a dog in complete rest is examined for a prolonged length of time and we ascertain the values of the oxygen consumption, the carbon dioxide production, and the nitrogen elimination in the urine. Under the same nutritive conditions the animal is then allowed to work from time to time in a treadmill. During these working periods impulses of excitation are continually conducted to the muscles from the nervous system. It is now found that under the influence of the constantly recurring stimuli the quantity of nitrogen in the urine has only very slightly augmented, whereas the consumption of oxygen and the production of carbon dioxide has markedly increased.

What conclusions can be drawn from these instances of response to stimuli, of which any number could still be quoted? They show us, first of all, that a state or process existing under given conditions, is altered by the influence of the stimulus. This is a fact, however, which could be expected from the beginning and is self-evident, for stimuli are alterations in the vital conditions, and when these are altered the state of the system or the happenings thereof must also alter. The question with which we are here more closely concerned, however, is a somewhat more detailed characterization of the state or process itself, as well as that of alterations produced by the influence of the stimulus. The instances of response to stimuli already cited furnish us with information in both kinds.

In all these examples, the living processes occur with equal constancy and unaltered rapidity, provided a stimulus is not operative. Here, however, the gradual alterations, the result of development, must not be overlooked. An excellent example of this is seen in the eggs of sea urchin, where the development is readily perceptible. In all these instances, however, the condition is immediately changed by the influence of the stimulus. The previous state of constancy in the vital process is disturbed. The rapidity of its course is changed, being either increased or decreased, and the specific vital manifestations concerned are, therefore, augmented or diminished. We will now study the vital process with the methods of chemical investigation and consider the problem from the standpoint of metabolism. It may be noted here, that other methods, such as the transformation of energy or changes of form of the living system, would serve equally well as indicators for this purpose. In every instance there is a uniformity of the processes; the difference, however, is in the nature of the indicators and the terms used. The methods and the terms used in chemical investigation and description reach proportionately much deeper than those employed when the transformation, energy or the variations of form of the organisms are studied, and permit of the finest differentiation of the processes. The atomistic terminology is, for this reason, preëminently fitted for the description of vital processes. When we study the vital process metabolically, we can, as shown in the above-mentioned instance, divide the processes into a metabolism of stimulation in contradistinction to a metabolism of rest.

The comprehension of the metabolism of rest demands a closer consideration. On closer observation we must say that this much-used conception is merely an abstraction nowhere realized in a strict sense. In truth, there is nowhere in nature a metabolism of rest. No cell exists which in a mathematical sense remains for even two successive moments under absolutely the same external conditions. If we imagine a single living cell of the simplest kind living in a fluid nutritive medium, and if we suppose its body and surroundings so magnified that the single molecules and atoms were respectively of the size of cannon and rifle balls, the boundary between cell and medium would represent a battlefield, on which a heavy bombardment is constantly taking place. The rain of shot of food and oxygen molecules penetrating into the cell from the medium, would produce an explosion in the existing ammunition depots, now at one point, now at another, creating great breaches through which new masses of shot would reach the interior. The fragments of these exploding molecules would be flung out here and there into the medium and would stem, now at this, now at that point the besieging masses of shot. In this wild confusion on the whole boundary line between cell and medium there can be no question of rest or even equilibrium at any point. The human mind, superior to the material world as we may deem it, is yet always dependent upon the results of experience, and even in its highest flights cannot become wholly emancipated from the concrete objects. For this reason it is of great purport to conceive processes whose dimensions cannot be observed even microscopically, as enlarged and transformed to that method of expression most familiar to the human mind, namely, in the field of optical presentation. This method is of great help in aiding our understanding, and likewise here, even in the resting state, the cell is constantly exposed to local effects of stimulation, now at one point, now at the other. The conception of the metabolism of rest is, therefore, in a strict sense fiction.

Nevertheless, the conception of the metabolism of rest as an abstraction can be of value provided always that it is strictly and definitely limited. It must, for instance, not be applied to short periods of time. The continued local and temporary responses to stimulation constitute a mean value which, although composed of numberless small sub-threshold responses, we can still call a metabolism of rest. Weak stimuli have, however, as already seen, the property, provided their influence is constant, of effecting an adaptation to the stimulus on the part of the living organism, so that the stimulus becomes a vital condition for this state of the organism. Hence the continued existence of a vital process resulting from the constant action of stimulation is made possible. That which we are in the habit of calling metabolism of rest, would, therefore, be metabolism of stimulation, but one that is characterized by a constantly existing metabolic equilibrium.

This “equilibrium of metabolism” distinguishes the metabolism of rest from that form which is developed in response to temporary stimulation, in that every temporary stimulation has the effect that it disturbs the existing metabolic equilibrium for a longer or shorter time. This disturbance of the equilibrium of metabolism can in contrast to the metabolism of rest be termed “metabolism of stimulation.” In this, but only in this sense, can these two conceptions be placed in opposition and used to characterize the processes in the living organism. The conception of the metabolism of stimulation must always stand in relation to that of an equilibrium of metabolism characterized by a constantly existing metabolism of rest, just as the conception of stimulus can likewise only be defined relatively to that of vital conditions.

Nevertheless, the conception of the equilibrium of metabolism requires a somewhat more accurate definition before we can feel justified in using this term. Definitions are always trite, nevertheless they are the basis of all our thinking and a definite understanding is impossible unless we first clearly fix their contents. The history of theology and philosophy even to the most recent times furnishes a long line of instances in which the most eminent minds, for the want of fixed definitions of the conceptions which they made use of, failed to find a mutual basis for their ideas. Without a sharp definition every conception is a mere word, which each individual, according to his personal experiences and views, endows with a different meaning. To such conceptions we may apply Mephisto’s ironical comment to his pupil:

“Mit Worten lässt sich trefflich streiten,
Mit Worten ein System bereiten.”

The natural sciences, if they are to retain their reputation for exactness and precision, require the strictest and clearest definitions of all conceptions. If we seek to penetrate more deeply into the varied happenings in concrete conditions, we must reconcile ourselves to dry pedantic definitions. In the case of that of the equilibrium of metabolism indeed we have before us one of the most important conceptions in physiology.

The justification to speak of an equilibrium of metabolism arises from investigations of metabolism in mammals. The classical experiments of the previous century, as is well known, have shown that in the adult mammal receiving a necessary quantity of nourishment and in a state of rest, the intake and outgo of the constituent elements are the same. The carbon, hydrogen, nitrogen, oxygen, sulphur, phosphorus, etc., taken in during a lengthened period in the form of food and respired air, appear again in equal quantity, in other combinations, in the products of excretion of the organisms. Calorimetric experiments likewise show an equilibrium of the consumption and elimination of energy. If there thus exists an equilibrium of metabolism for the whole cell community, it is clear that the same must also apply to the individual cell, that is, for all living substance. The quantitative relations of the foodstuffs taken in, and the excreted metabolic products given off, are, however, merely a standard of the metabolism. We know that the former are used to build up new living substance and that the latter represent the result of disintegration of that previously existing living substance; for we find, as in the case of the plant, complicated protein combinations, which are built up from comparatively simple constituents of the food and are again broken down into comparatively simple substances. And so the building up and breaking down processes form the two great processes of metabolism, which with Hering41 we can briefly call “assimilation” and “dissimilation.” In the terms assimilation and dissimilation are comprised the sum of all processes of construction and disintegration in the living organism. It is apparent that equilibrium of metabolism occurs when assimilation and dissimilation are equal. The formula A : D, that is, the relation of the sum of all assimilation to the sum of that of all dissimilative processes, is a factor of fundamental importance in the study of the course of the vital processes, for upon its value depends individual vital manifestation, and, in fact, the continuation of life. I have, therefore, designated the formula A = D “Biotonus.” The equilibrium of metabolism would then be characterized by the biotonus42 of a living organism being equal to one. This would be the metabolism of rest of a system, whilst its metabolism of stimulation would consist in an alteration of the biotonus. But is this state of living substance strictly speaking ever realized?

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’s43 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 Cremer44 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 Wislicenus47 on themselves, and of Voit48 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.

Considering the close correlation of the individual part processes it would appear very strange, however, if a single one of these could undergo an alteration of its rapidity without the course of the rest of the processes being in the least influenced. One cannot comprehend such absolute independence of a process brought about by functional stimulation from all the other constituent processes, particularly when this is of prolonged duration and involves to a considerable extent the alterations in rapidity, for the individual constituent processes are dependent in a high degree upon the quantity of the particular chemical substances of which the living system is composed. The cycle of the individual constituent processes of this system is determined in the most delicate manner in its rapidity and extent, by the relative quantities of the individual substances. Associated with an alteration in the rapidity of an individual constituent process, there would also be a relative alteration quantitatively of the substances. And with the increase in the quantity of the disintegration products, and also the increase of the substances for their replacement, there would result, during this time, an alteration in the amount of interaction of the molecules of the other constituent processes, so that these processes secondarily suffer an alteration in rapidity which is perceptible after long continued involvement of the functional part of metabolism.

In fact, in the previously mentioned case of the functional stimulation of the muscle, the proof has been furnished that a long-continued increase of the functional metabolism is followed, although to a less extent, by an increase in the entire cytoplastic metabolism. Argutinski showed this on himself in 1890 in Pflüger’s laboratory. He found, namely, that after the exertion of a long walk in a hilly district, a considerable increase of nitrogen excretion in the urine took place, which extended over the succeeding two or three days. This increase of the nitrogen metabolism in its totality is not nearly as great as that of the breaking down of nitrogen-free substances, but it is, nevertheless, present and shows us that functional metabolism cannot experience a lasting excitation without being followed by secondary results in the entire cytoplastic metabolism. This fact is even more strikingly illustrated in the alteration of the entire volume of a living organism as produced by the lengthened duration of functional stimulation. It has been long known, that the muscle as the result of frequent functional excitation by means of adequate nerve impulses, that is, prolonged activity, is considerably increased in size, whereas in the absence of such it loses more and more in volume. A hypertrophy of activity, produced by functional stimuli, and the atrophy of inactivity, the result of the discontinuance of the functional excitation, is universal and can be observed in the various tissues of our body. We see it, for example, in the glands; we see it in the skin and we see it in the elements of the nervous system. Berger,51 for instance, established the fact that the ganglion cells of the optic lobe in the cerebrum of newborn dogs only reach their full development when functionally excitated by adequate light stimuli (Figure 9, B), coming from the eye, whereas they remain in the embryonic state when these light stimuli are eliminated. (Figure 9, A.) The cytoplastic increase of volume of the neurons under the influence of functional stimuli is a fact of fundamental importance for the entire happenings of the nervous system and forms the physiological basis for reinforcement of reflexes, which, in its turn, is essential for all acts of memory and intelligence. For the increase in volume of the ganglion cell body is, when functionally activated, accompanied at the same time by an increase of specific capabilities and the intensity of discharge. Its excitation impulses can, therefore, be conducted through a greater number of neurons, with which it is connected, than would be the case if development of the volume of the ganglion cell increased to a less extent.

The increase in volume under the influence of stimuli further shows the relation between the group of those solely catalytic effects of stimulation consisting in mere alterations of rapidity of the specific vital process, and that of the metamorphotic effects of stimulation, which manifest themselves in qualitative alterations of the vital process. Simple observation shows us that a qualitative change of individual constituent processes must necessarily result from the increase of volume of a cell, and that considering the close correlation of all the individual processes a profound alteration of the entire metabolism must be produced. I have already at another place52, 53 treated these conditions more in detail and will, therefore, only briefly refer to them here. If we study the growth of a ball-shaped cell, we find that the surface then increases as a square, and the volume as the cube. It therefore follows that, by progressive volume increase, the conditions for the interchange of substance with the surrounding medium must become more and more unfavorable for those cell portions situated in the interior, whereas those at the exterior are at much greater advantage. This must lead to a constantly increasing difference of the rapidity of the metabolic processes between the peripheral and central portions. Accordingly, the intricate interworkings of the individual constituent processes, the rapidity of action of all which is intimately connected, are, therefore, followed by corresponding alterations in the entire metabolism. Sooner or later a stage is reached in which the individual constituent processes become so limited that certain metabolic products, which previously were broken down as soon as formed, can be no longer eliminated and remain in the cell acting as foreign bodies. In this way the relative quantity of the individual cell substances become more and more altered, and as the course of chemical processes occurs in accordance with the law of mass action, the whole metabolism is directed into another channel, so that finally new constituent processes take place, which were formerly not possible. These in their turn produce deep-seated alterations of the relations of the cell to its surrounding medium, etc. Hence this mere increase of volume of the cell in growth forms the source of an infinite mass of alterations in the activities of cell metabolism, which we briefly term its “development,” and which by constant progression, leads either to a process of cell division, and with this to a correction of existing disorder, or finally to irreparable disturbances ending in death. In this way an inseparable relation exists between increase of volume and the development of living substance. We have seen, however, that the catalytic reactions of stimulation, which at first only produce an alteration of rapidity of the individual constituent processes, if of prolonged duration or of frequent recurrence, secondarily effect a change of volume of the entire living organism. One can, therefore, hardly reject the conclusion that seeing the close interworkings of the individual part process of metabolism, every change of rapidity of a single member, if of prolonged duration or of frequent occurrence, must finally lead to qualitative alterations of the entire metabolism. In consequence there results an important dependence between catalytic stimulation and metamorphic reaction. Indeed, it is not unlikely that the metamorphic reactions, which are especially seen in the continued effect of weak stimuli, result from alterations of rapidity, which the individual members of the vital processes have primarily undergone from this influence.

It is perhaps expedient to cite a concrete instance in illustration. A simple example is furnished by asphyxiation. If oxygen is withdrawn from any living organism, the result is a depression of its oxydation processes. Here there is primarily only a change in rapidity, especially a retardation of oxydation processes. The metabolism, however, proceeds, the disintegration of living substance continues, although at a slower rate, but produces an accumulation of other products. Whereas formerly during the existence of a sufficient supply of oxygen an oxydative disintegration of nitrogen-free groups into carbon dioxide and water took place, both of which could easily be eliminated from the cell, the anaërobic disintegration furnishes only complex products, having a higher carbon content, such as lactic acid, fatty acids, aceton, etc. These, being more difficult to excrete from the cell, accumulate. These asphyxiation products have in their turn a depressing effect and so on. In this way the whole metabolism is forced into a wrong course. The accumulation of fat in those tissue-cells with an insufficient blood supply, as we have seen in the case of the fat metamorphosis, is doubtless brought about in the same manner by relative oxygen insufficiency. The fatty acids accumulate as products of an incomplete combustion and combine with glycerine to form neutral fats. In like manner it may be that the accumulation of amyloid substance in amyloid metamorphosis, of lime salts in arteriosclerosis, etc., is produced by a primary depression of the individual constituent processes of the particular cells.

The relation here described, of the catalytic stimuli to the production of the metamorphic processes, leads us to the distinctions between primary and secondary effects of stimulation. Should the general fact be established, which has up to now only been pointed out in individual cases, that all the metamorphic processes are merely secondary results of primary alterations in rapidity of individual metabolic constituent processes, then the primary reactions of every stimulus would consist purely in the excitation or depression of the directly concerned constituent. Whether or not, as may be assumed, this primary effect of stimulation applies to all stimuli, is a question which only the future can answer.

The metamorphic processes are not, however, the only secondary effects of stimulation. The influence of long-continued excitation of the functional constituent processes upon the entire cytoplastic metabolism can be looked upon as a secondary response. Therefore, they may be considered as a secondary effect of stimulation which, in contrast to this primary excitation, may be called the secondary excitation.

Further: While the secondary excitation and metamorphic processes are generally produced by the continued existing effects of weak stimulation, we also observe as the result of a stimulus of short duration or frequently repeated at brief intervals, but otherwise not exceeding the physiological limits of intensity, a secondary effect, which plays a very important part in the activity of the organism. I refer to fatigue. Here a secondary depression is developed in connection with the primary excitation, for fatigue of a living organism must be characterized as a depression of activity. This case shows that we have to distinguish between a primary depression, as for example, produced by temperature reduction, withdrawal of food, deficiency of oxygen, etc., which occurs as a direct effect of stimulation, and secondary depression, which as in fatigue is an indirect result of primary excitation.

After the cessation of a briefly catalytic stimulus, not exceeding the physiological limit of intensity, another secondary result is observed, which is of the greatest importance for the continued existence of the living substance. The catalytic stimulus brings about a disturbance of the equilibrium of metabolism, which after cessation of the stimulus is reestablished by the living substance. In other words: recovery takes place. This fundamental principle has been known for a long time as the result of observation. If a skeletal muscle of our body has been activated for a prolonged period by nerve impulses, until it has become completely fatigued and incapable of work, a recovery takes place on the cessation of these impulses and the muscle is again capable of action. Likewise, as the result of strong mental activity during the day, we are mentally fatigued in the evening; recovery, however, occurs during the night, which results from the removal of the source of activity. The next morning finds us refreshed. This restitution occurs in every cell, and the return of its former capability of action, which had disappeared under the influence of stimulation, shows that compensation has taken place of the metabolism of rest, disturbed by the effects of the stimulus. Hering54 has aptly termed this restitution as “the internal self-regulation of metabolism.” All recovery after disease is based on this self-regulation. The physician simply provides, by means of therapy, for the possibility of its taking place. Healing itself is brought about by the organism. “Natura sanat, medicus curat.”

Finally, a third kind of secondary effect of stimulation claims our interest. This is the secondary extension of the result of stimulation from the part of a living organism directly and primarily affected by the stimulus, to the surrounding structures. All living substance has the capability of conducting an excitation, which is produced locally through a catalytic stimulus, to a neighboring part, not directly affected by the stimulus. It finds its highest development in the nerve, but in no living structure is it completely absent. This capability has been frequently termed “conductivity of stimulation.” It is more precise, however, to speak of conductivity of excitation, for it is not the primary influencing external stimulus which is conducted in the living substance, but the excitation which it has produced. I have intentionally considered only the excitating effects of stimulation, and not those of the depressing reactions, as only excitations, not depressions, are conducted by the living substance. These questions, however, demand a closer analysis. Here we were concerned only with a survey of the general effects of stimulation. If I, therefore, once more summarize the results which have been gained, this is most clearly demonstrated by the following scheme:

Primary Effects of Stimulation

Excitation  Depression
Functional  Cytoplastic  Functional

Secondary Effects of Stimulation

Secondary excitation  Secondary depression
Conduction of excitation, Metamorphic processes, Self-regulation of metabolism

This, however, is simply a scheme, like all other schemes, having for its purpose a superficial survey of the subject.

It brings to some extent order into the overwhelming mass of manifold effects of stimulation but tells us nothing of the mechanism and genesis. Our further task must, therefore, be a more thorough analysis of this field.