General Physiology: An Outline of the Science of Life

In an hypothesis upon the nature of assimilation, Hatschek ('94) has also established a relation between this process and growth. He assumes that in growth the simple molecule of living proteid continually attracts elements to itself from the food until it has become a polymeric molecule ; it then breaks down into simple molecules, and the latter gradually develop chemically anew into a polymeric molecule by the union of the necessary atoms and the groups of atoms, and so on. In other words, Hatschek likewise sees in growth a chemical process, which does not differ fundamentally from regeneration. After all these considerations it appears advantageous to employ the conceptions of assimilation and dissimilation in the more general sense, including therein the formation of new and the disappearance of old molecules, and to give to them the above exact wording :

Assimilation comprises all those transformations that lead up to the construction of bio gens, dissimilation all those that extend from the decomposition of biogens down to the complete formation of the excretion-products. the relation of these two processes. Living substance is continually performing both. Hering believes that these processes, which constitute the metabolism of living substance, " take place simultaneously in all the most minute parts of the latter." Hatschek has expressed a view differing from this, and emphasises the difficulty of the idea " that the proteid molecule simultaneously receives and gives off carbon." When only a single particle is considered, it is very difficult to conceive this process, for the splitting-off and the regeneration of any groups of atoms by a molecule exclude each other chronologically, and, when considered strictly, although instantaneous, they are only able to take place in succession, unless it is assumed that corresponding groups of atoms, separated from the molecule at one place, are added to it at another place. This latter idea Hering himself rejects, since he emphasises the following : " We ought not to be misled into picturing living substance as a mass that is at rest internally, while being consumed upon one side and built up upon the other." If we are unable to conceive the dissimilation and assimilation of the minutest individual particle or biogen molecule as absolutely simultaneous, within a larger quantity of living substance these two processes can take place at the same time. In this latter case there are always different molecules that are destroyed and rebuilt at the same moment, for only the residue of the biogens already present is capable of regeneration, and, vice versa, only the complete biogen molecules already present are capable of decomposition.

If we consider the quantitative relation of assimilation to dissimilation in a considerable mass of living substance, for example such as is contained in a cell, we find it very variable, and even without the influence of stimuli it changes within wide limits. This relation of the two processes in the unit of time, which can be expressed by the fraction — and will be termed, in brief, Hot onus, is of fundamental importance for the various phenomena of life. The variations in the value of the fraction effect all changes in the vital manifestations of every organism.

of biotonus. In reality, assimilation and dissimilation are not simple processes; on the contrary, the events that lead to the construction of the biogen molecule and the formation of the decomposition-products are very complex and consist of many processes closely interwoven. Hence, if we would express biotonus in a specialised way, we must give the fraction the form represent the partial processes that combine to form the whole. With our extremely slight knowledge of the more special transformations that take place in living substance, it is at present impossible even approximately to review the manifold possibilities resulting from changes of the individual components of the biotonous quotient. Therefore, we shall here refer only to some of the more important of the known cases.

If the sum of all the members of series A is equal to the sum of series D, i.e., if assimilation and dissimilation are equal in the unit of time, the fraction yj=l- This case is realised in the condition termed metabolic equilibrium. That is, in the unit of time the sum of the excreted substances of every kind is equal to the sum of the ingested substances. If the individual members of series A increase in a constant relation to one another, while the members of series D remain equal or decrease, so that in the unit of time the sum of the members of A is greater than that of the members of D, then the metabolic quo-

If, vice versa, the members of series D grow proportionately to one another, while those of series A remain unchanged or become smaller, biotonus ^<C1- This condition is the basis of atrophy But it is wholly unnecessary that all members of the one or the other series change always simultaneously and proportionately ; individual members can also increase or decrease independently of the others. Thus, the metabolism of carbon in an organism may be augmented without that of nitrogen experiencing a corresponding increase. In this way occur the formation and accumulation of reserve-substances, which are consumed later. Upon such changes of the individual members of the two series depend all the phenomena that appear in an organism in the course of development. In many cases, as is shown best by the changes appearing during development, there exists a certain mutual independence of the individual members of the metabolic series. On the other hand, there are very many cases in which not only the individual members of each series, but also the two series, are dependent upon one another in such a manner that the change of the one results in a similar change of the other. E.g., if there is metabolic equilibrium and the numerator of the fraction increases, the denominator increases equally; if the denominator decreases, the numerator does the same ; in other words, every increase of assimilation results in a corresponding increase of dissimilation.

In this manner the metabolic quotient -y- remains always equal to 1, i.e., metabolic equilibrium continues to exist in spite of the absolute change in the extent of metabolism. Bering very fittingly terms this maintenance of equilibrium " the internal selfregulation of the metabolism of living substance." Such a selfregulation of metabolism within definite limits is realised in man in the behaviour of the body toward ingested nitrogen. With a definite quantity of ingested proteid, which Voit has found to be approximately 118 gr. in the labouring man, nitrogenous equilibrium continues to be maintained ; i.e., the more nitrogen is introduced in the proteid, the more is excreted in the urine, a sign that the dissimilation of proteid increases in the same proportion as the assimilation.

This last example leads us to the action of stimuli upon biotonus, and we must consider this in some detail. It has been seen that biogens are very labile compounds containing much intramolecular heat ; in other words, the atoms of their molecules are in active vibration. As a result of this, certain atoms come occasionally into the sphere of attraction of others, and becoming united with them into a more fixed combination, separate off as an independent molecule. In this way the spontaneous dissimilation of the biogen molecule results. But the chemical affinities made available by the withdrawal of the separated groups of atoms have in the constituents of the food that is taken in and transformed in manifold ways, an opportune possibility of combining again, so that the residue of the biogen can be rebuilt into a whole biogen molecule. Thus spontaneous assimilation of the biogen molecule follows its spontaneous dissimilation.

Since the dissimilation of the biogens is conditioned by the intramolecular vibrations of the atoms, it is evident that all factors that increase such vibrations must assist the process of dissimilation. In this way is explained the increased decomposition of living substance that can take place under the influence of chemical, mechanical, thermal, photic, and galvanic stimuli. If the external influences are so strong that a profound decomposition of the molecule takes place, and no residue capable of regeneration is left, there results a decrease of the living substance, and with overstimulation death. On the other hand, the process of dissimilation is depressed by all factors that diminish the intramolecular vibrations of the atoms in the biogen molecule, such as cooling and the action of substances that fixate single atoms in a definite position by chemical attraction. All of these stimuli that either excite

or depress the process of dissimilation, we shall term dissimilatory stimuli. Upon the other side, it is clear that assimilation also can be promoted by external influences. This process depends upon the union of chemical affinities belonging to both the residue of the biogens and the complete biogen molecules themselves, the participation of the latter following from their inclination to polymerisation. Hence all those factors can increase assimilation, which procure and put into proper form the substances that are necessary for the union of the existing affinities. The increased introduction of food-material and oxygen is more than all else efficient in this direction. Examples of other agencies are light in the cells of green plants, which is necessary to split up carbonic acid and make carbon available, and all stimuli that incite the production of ferments, which are needed to make solid food-stuffs soluble. But, on the other hand, there are factors that depress the process of assimilation. Special examples of these are lack of food and oxygen, in the plantcell lack of light, and the absence of ferments. We shall term all these factors that either excite or depress the process of assimilation, assimilatory stimuli.

Four important cases of reactions can thus be distinguished Stimuli are able to produce : — But the possibilities are not yet exhausted. For the individual events in living substance are in extremely close correlation with one another, and, as has been seen, in certain cases a complete internal self-regulation of metabolism is thereby occasioned, so that, e.g., every change of assimilation results in an equal change of dissimilation. Hence it is possible that a stimulus can call forth simultaneously excitation or depression of both dissimilation and assimilation. The following must, therefore, be added to the four cases above : —

In connection with these it is to be noticed that different parts of the metabolic series can be excited or depressed in unequal degrees. But still other possibilities are conceivable. Internal selfregulation of metabolism does not exist everywhere, and where it exists it is confined within certain limits ; for, if it were effective at all times and in all places, continual metabolic equilibrium would exist, and growth, development, and atrophy would be impossible. Hence, cases are conceivable in which a stimulus produces simultaneously excitation of assimilation and depression of dissimilation,

or, vice versa, depression of assimilation and excitation of dissimilation. There would thus be added to the above six cases of reactions the last conceivable ones as follows : — These various possible effects of stimulation, which Hering ('88) has fully treated in his short dissertation upon the events occurring in living substance, give us an idea of the manifold ways in which biotonus can change under the influence of different stimuli. But in reality the relations are much more complex.

When we remember that the numerator as well as the denominator of the fraction -— represents a whole series of single members, and that these members are able to change in a certain degree independently of one another, we obtain an approximate picture of the extraordinary variety of effects which stimuli are able to produce in living substance. In a previous chapter it was found possible to arrange the reactions to stimuli in the living cell according to their external appearances in a few groups. It was found that the changes undergone by spontaneous vital phenomena as the result of stimulation are either quantitative or qualitative. The quantitative changes were termed excitation when they consisted of an augmentation of the vital phenomena, and depression when characterised by a diminution of the latter. In accordance with the foregoing considerations, we now obtain an approximate idea of the great complexity of the events the external expression of which was termed briefly excitation and depression. But the acme of the complexity is to be seen in those reactions that are at the basis of the qualitative changes of the normal vital phenomena. The metamorphic processes of necrobiosis, typified by amyloid metamorphosis, show clearly that here individual members of series A and series D must slowly and gradually change independently of one another, otherwise accumulations of individual substances that normally do not occur in the cell can not take place. Metamorphic processes constitute a stimulation-phenomenon that is conditioned by changes of biotonus analogous to those conditioning the phenomena that occur spontaneously in development. The differentiation of glandcells, muscle-cells, nerve-cells, etc., from the ovum must depend upon changes in the individual members of series A and I) that are independent of one another ; but these changes occur spontaneously in the course of development, while in amyloid metamorphosis and analogous phenomena they are produced by external influences.

Because of our very faulty knowledge of the special members of the two metabolic series, it is evident that at present we are quite unable to review even approximately the special changes that biotonus experiences in concrete cases under the action of a stimulus. For the present it is only possible to analyse step by step the outward expression of these changes, which have been termed schematically phenomena of excitation, depression and metamorphosis. Physiology will draw nearer to the solution of this problem the more the methods of cell-investigation are developed.

The question of the effects of the interference of two different stimuli is of special interest with reference to a group of very important phenomena belonging to the special physiology of vertebrates. Unfortunately up to the present time there has been no systematic treatment of this subject, and it is only possible to present a few intimations of its connection with certain facts from widely separate physiological fields. Since biotonus can be influenced very differently by different stimuli, according as this one or that one of its components is excited or depressed, in a systematic investigation of the effects of the interference of two stimuli the manner of action of each must form the starting-point. In order to understand any such effect it must first be decided whether or not the two stimuli act in the same manner, i.e., to excite or depress, and to what component of biotonus their action extends, assimilation or dissimilation. The general laws of interference-effects can be discovered only by answering these questions.

If two stimuli of medium intensity produce effects of the same kind, for example an excitation, and act upon the same components of biotonus, for example upon dissimilation, the general result will be a summation of the excitations. The details of this cannot be predetermined, because the intensity of the stimuli, the varying extent to which the individual components are influenced, the duration of the stimuli, the fact of the self-regulation of metabolism, etc., are factors which, under the circumstances, are capable of playing important roles in bringing about the final result. Here belongs, for example, the whole variety of phenomena that we have become acquainted with in nerve and muscle physiology as cases of increase of irritability. Through the action of an exciting stimulus, such as a chemical or thermal stimulus upon a nerve, the irritability of the latter toward a second, such as a galvanic stimulus, is increased, and the latter causes a greater reaction than if it had been employed alone.

A contrast to this is afforded by the phenomena that result when living substance is acted upon by two stimuli that work in opposite senses upon like components of biotonus, one depressing and the other exciting. The usual result is a decrease of irritability. For example^ if a narcotic be allowed to act upon a cell, or if a cell be depressed by over-stimulation, every exciting stimulus will produce a smaller reaction than if it had acted alone ; under certain circumstances the cell will be completely inexcitable.

But much more interesting are the phenomena that result when two stimuli have the same kind of effect, for example, an excitation, but act upon different, and especially upon antagonistic, components of biotonus, that is, one pre-eminently upon dissimilation, the other upon assimilation. In such a case the one stimulus inhibits, opposes, restrains the other.1 A striking example of this is afforded by the polar action of the galvanic current upon contractile substances, for example, Amoeba. The current acts antagonistically at the two poles, exciting the amoeba-cell to contraction at the anode, and to expansion at the kathode. This fact can be confirmed with surprising clearness in fairly large freshwater Amoebce. If a constant current be passed through an amoeba that has been made to contract into a ball by means of strong stimuli, at the moment of making the current the contraction begins to give way at the kathode, and phenomena of expansion begin to appear, i.e., a large pseudopodium projects ; while at the opposite pole the phenomena of contraction become still more distinct. A sudden reversal of the current suffices to put an immediate end to the processes at the two ends of the body of the Amoeba, and to supplant expansion by contraction and contraction by expansion. Analogous phenomena, except with the poles reversed, are exhibited by muscle. We can observe subjectively in the eye the interesting results of excitation of antagonistic metabolic processes. According to Bering's theory of colour vision, the perception of colours is the psychical expression of metabolic processes taking place in the visual substance, each pair of complementary colours corresponding to antagonistic phases of metabolism.

Hence, if two complementary colours be mixed upon the rotating disc of the colour-top, the effect of each ceases, and the whirling disc appears a colourless grey. These facts show that t\vo mutually interfering excitations of antagonistic links in the metabolic chain are able to inhibit or arrest their external effects. In other words, there are two wholly different ways in which the suppression, the jnhibition, of a vital phenomenon can be accomplished: on the one hand, by the depression of those components of biotonus upon which itdepends; on the other hand, by the excitation of antagonistic components.

Finally, it is conceivable that two stimuli will interfere when they act upon antagonistic components of biotonus in opposite senses — i.e., one to excite, the other to depress. The outward result of this would be an augmentation of those vital phenomena that correspond to the excited components of biotonus. But it is questionable whether this case is actually realised in nature. Among the various cases of interference between two stimuli there is a very great variety of phenomena which have not yet been analysed at all, but which ought to receive new light from the foregoing reflections. One group, particularly, which pertain to the functions of the central nervous system, and thus far have been among the most obscure phenomena of nerve-physiology, will be elucidated ; these are the so-called phenomena of " inhibition " \_Hernmung\.

Heretofore there have been considerable difficulties in the way of a physiological explanation of the simple fact of the voluntary interruption of a movement, for example, the simple letting-down of a raised arm. The lack of clearness in the problems of inhibition depends chiefly upon insufficient sharpness in distinguishing the conceptions. Inhibition [ffemmung] and depression [Lahmung] have often been confused with each other upon the ground of purely external features ; yet, as has been seen, an inhibitory reaction in the cell is not necessarily due to depression, but may be caused by the excitation of processes that oppose existing ones. The stopping or retarding of a muscular movement by a motor ganglion-cell can be the expression of two very different processes. According to the general view, as is well known, the contraction of a muscle is caused by an excitation of dissimilation in its motor ganglion-cells. An expansion can, therefore, originate in the ganglion-cell in two ways : first, by a depression of dissimilation, and, second, by an excitation of assimilation. As regards the muscle, the tw^o have the same result. Hence it is necessary to decide in any one case what processes are taking place in the participating ganglion-cells. Among the manifold phenomena of the inhibition of motion doubtless both cases are present. The frog whose hinder extremities will not perform reflex movements with the strongest stimuli for some time after the upper part of its spinal cord is severed, has evidently experienced a temporary depression of the ganglion-cells of its cord through over-stimulation, just as in surgical shock as a result of a severe operation the nervous system is depressed. But the voluntary relaxation of a contracted muscle can hardly be due to such depression.

In this case there must be an inhibition of contraction caused by the excitation of antagonistic, i.e., expansory processes. The fact that the expression of an excitation can be stopped by the excitation of antagonistic metabolic processes appears to play a very important role in the life of ganglion-cells, and to afford a very important factor in the explanation of many processes in the central nervous system. Especially the phenomena of sleep and hypnosis in animals and

men may be explained, as to their essential factors, by the inhibition of an existing excitation through antagonistic metabolic pro- FIG. 245.— /, Naja haje (Egyptian hooded snake or asp). Experiment of the Egyptian snakecharmers. At the left, above, the asp is in the excited position of attack (shield-position). At the right, above, the animal has been made motionless by pressure in the neck-region and has been laid upon its back. Below, it is in a similar condition, extended, and lying upon its belly. II, Fowl made motionless by being firmly held and laid upon its back. Experimentum mirabile of Father Kircher.

cesses. It may suffice to recall a few well-known phenomena. The ancient experiments of the Egyptian snake-charmers, which Moses and Aaron performed before the Egyptian Pharaoh more than three thousand years ago, belong in this category. By slight pressure in the neck-region it is possible to make a wildly excited, hissing, erect asp (hooded snake) suddenly motionless, so that the dangerous creature can be put into any desired position without fear of its fatal bite (Fig. 245, I). The well-known experimentum mirabile de imaginatione gallinae of Father Kircher depends upon the same causes. If an excited fowl be seized suddenly with a firm grip and laid carefully upon its back, after a few brief attempts to escape it lies motionless (Fig. 245, II). Guinea-pigs (Fig. 151, p. 358), rabbits, pigeons, frogs, lizards, crabs and numerous other animals behave similarly. The hypnosis of human beings depends likewise essentially upon inhibition of the activity of the ganglioncells in the cerebral cortex, in common language upon an inhibition of the will, and in sleep the inhibition of the activity of all the higher brain-centres is evident. These cases do not depend upon depression; the stimuli that act as causes of them are too feeble. We must recognise in them, as in numerous other phenomena of inhibition, the other case, i.e., the inhibition of an existing excitation by the excitation of antagonistic components of biotonus in the participating ganglion-cells.

It will be a promising task of the future to investigate systematically interference-reactions and to ascertain their relations to the interesting processes in the central nervous system. 3. Polar Changes of Biotonus and the Mechanism of Axial Orientation upon Unilateral Stimulation Thus far we have considered merely the changes of biotonus that are caused by general stimulation of living substance. But the changes that result from local stimulation are worthy of attention, because in certain cases they give rise to very characteristic external effects. These are the directive effects of stimuli upon motile organisms, which we have become acquainted with as chemotaxis, barotaxis, thermotaxis, phototaxis and galvanotaxis. These interesting phenomena are called out, as has been seen, by the unilateral, or unequal, action of stimuli upon the activity of contractile elements. In other words, all these cases of stimulation depend upon changes in those members of the biotonic series A and D, that mediate the contraction and expansion of contractile elements. A movement in a definite direction can take place only where differences as regards contraction or expansion exist in two different parts of the cell-body. Since, as regards the motor effect, contraction (c) and expansion (e) are two antagonistic phases of the movement, we can express the mutual relation of these two members of biotonus by a fraction in a manner analogous to that of the expression of biotonus itself, without, however, at the same

time expressing to which of the two biotonic series c and e belong. The conditions that exist in a resting cell at the two different parts of the body can then be represented as follows : in which - expresses the relation of contraction to expansion In a cell in which c and e are equal and an equal tendency toward contraction and expansion exists upon all sides, no movement can take place in any direction. But this is at once changed, when differences in biotonus appear at two points upon the surface, when c or e under the influence of a stimulus acting unilaterally becomes greater or smaller at one pole than at the other. Then a cause is afforded for a unilateral movement.

Since the remarkable phenomena of chemotaxis, barotaxis, thermotaxis, phototaxis and galvanotaxis are even now often considered as mysterious "attractions" and "repulsions" of unicellular organisms proceeding from the source of the stimulus, the origin of which thus far it has not been possible to explain mechanically, it is of great interest to see how their mechanism follows with absolute necessity from the special kinds of motion of each form of cell as the result of polar differences in the biotonus. Such a fact is of more interest because many of the phenomena mentioned, especially the chemotaxis of Bacteria and leucocytes, are of far-reaching significance in the pathology of the human body.

If the following three factors be considered, namely, the special modes of motion of any organism (protoplasmic, flagellar, ciliary motion, etc.), the change of this motion under the influence of stimuli, and the part of the body in which with unilateral stimulation the effect in each case is localized, the mechanism of these tactic phenomena, impressive because of their exactness, will appear very simple to any one who is accustomed to the study of motile mechanisms.

Let us imagine a unicellular organism, which is longitudinally differentiated, moving undisturbed in a desired direction through the medium in which it exists, and then suddenly affected upon one side by a stimulus. It is a general rule that all uniaxially differentiated organisms move in the direction of their long axis. Hence, in order to approach toward or remove from the source of the stimulus, it would be necessary for the stimulated organism first to assume a definite position with reference to its longitudinal axis, so that it would direct its anterior or its posterior pole toward the source of the stimulus. If this axial position be once assumed, a movement toward or away from the source of the stimulus must at once take place by the usual method of locomotion, while the further action of the stimulus prevents or corrects occasional devia-