I have treated the views of Glisson somewhat in detail for on the one hand this seemed to me to be only due to the founder of the doctrine of irritability, and on the other we have here for the first time, although in somewhat vague and little worked out form, the discovery of a general property of all living substance, and its fundamental importance for the life of the organisms. One might, therefore, in a certain sense, date from Glisson the beginning of general physiology, and all the more so, because Glisson from the very first connected the irritability of the living substance through its possessing universal energy with the phenomena in nature generally, just as we do today two hundred years after, on the basis of the modern teachings of energy.
It might appear strange that a teaching of such fundamental importance as that of Glisson’s theory of irritability was not at once accepted on all sides and further developed. There were two reasons, however, which prevented this. Firstly, Glisson did not devote himself to his post of teacher at the University of Cambridge with any particular zeal and so consequently did not establish a school of his own, to further work out and develop his ideas. Secondly, his doctrines were so speculative and difficult to understand, his differentiations and definitions so artificial and labored, that it required the greatest effort to penetrate to his fundamental conceptions and so it happened that Glisson’s theory of irritability received attention only at a comparatively late date. Even then, of his speculative theories hardly more than the name “doctrine of irritability” was adopted. Since the middle of the eighteenth century this name, however, was destined to lead to excited controversies.
The first attempt to give Glisson’s expression “irritability” a more concrete meaning was made by Haller (1708–1777)[3]. Unfortunately, though, he confined this conception solely to muscles, in that he understood by the term irritability “the capability of the muscles to contract, when stimulated, as the result of vital force (vi viva).” He, therefore, applied the term “irritability” to that which we today refer to as “contractility.” On the other hand he applied the term contractility solely to a property possessed by other living and dead animal as well as vegetable matter, elasticity, that is, the capability to resume its original form after distortion. He makes a sharp distinction between “irritability,” which manifests itself by a contraction of the muscles after stimulation by its own vital force (vi viva), and the “sensitivity,” which is possessed only by the nervous system. “Sola fibra muscularis contrahitur vi viva; sentit solus nervus et quæ nervos acciperunt animales partes.” By confining the conception of irritability to a single living substance, the muscle, Haller’s theory represents a great regression in comparison to the correct fundamental thoughts of Glisson. This unfortunate use of the term of “irritability,” “contractility” and “sensitivity” has opened wide the gates to confusion and misunderstanding. This confusion was still further augmented by the fact that the vitalistic school of Montpelier confused the idea of vital force with that of irritability. In the works of Bordeu (1722–1776) these views are comparatively clear, if one bears in mind that he substitutes Glisson’s term of “irritability” with that of “sensitivity.” He assumes a “sensibilité générale” or a common property of all living structures, both solid and fluid. Besides this, each different part has according to him its “sensibilité propre.” Here in place of the clear conception of irritability we find one of more or less mythical nature possessing traces of Stahl’s “anima.” Nevertheless we observe here the idea that all living organisms possess in common a capability to respond to stimuli. Even though Bordeu’s differentiation of the “sensibilité propre” and the “sensibilité générale” is too artificial and the coexistence of both not justifiable, his discussion of the “sensibilité propre” shows that he is already on the track of the characteristics of the effect of stimuli which only later under the name of “specific energy” was clearly recognized as a fundamental property of all living substance. On the other hand the celebrated pupil of Bordeu, Barthez (1734–1806), accepted the existence of a meaningless vital principle, the “principe vitale,” governing all vital manifestations. The two forms of vital force of all living substances, the “forces sensitives” and the “forces motrices,” were according to his views manifestations of this vital principle. He differentiates the “force sensitive” into a “sensibilité avec perception” and “sensibilité sans perception,” using the term sensibility in the sense adopted by Bordeu and which today we, with Glisson, call irritability.
In this way serious thinkers of that time trifled with the words irritability, sensitivity, contractility, perception. This led to futile conceptions, which equalled the phantasies of the worst period of speculative philosophy and which in no way led to progress. Hence it is easy to understand that numerous attempts were made in those days to reconcile in some way these different conceptions. An explanation, which was the beginning of further development, came from England in the works of John Brown (1735–1788),[4] a man who was as talented as he was dissolute. Brown was an independent thinker, not without genius, whose knowledge in practice and theory, however, was limited. This combination in his mentality enabled him to observe the problems somewhat differently than through the glasses of the usual conceptions of that time. In direct opposition to his teacher Cullen (1712–1790), one of the leading minds in the medical school of Edinburgh, who considered irritability only as an effect of sensibility and pronounced the latter a specific property of the nervous system, Brown took the standpoint that all living substance, vegetable as well as animal, in contrast to lifeless matter, possessed a fundamental property which he designated as excitability, that is to say, the capability of being stimulated to specific vital manifestations through external factors or “stimuli,” in which sensitivity and indeed all mental processes as well as movement are interpreted as specific effects, which the “stimuli” produce on the irritable organs. This was an important advance and from a wilderness of trifling conceptions his observations led to a clearer knowledge of this subject. But Brown went even further. In his so-called “theory of irritation,” he has presented a whole system of responsivity to stimulation, which in the first chapters of his chief work he expounds with wonderful clearness. The fundamental principles here established must be accepted even today. The essential basis of this “theory of irritability” which he worked out especially for his doctrine of disease, and which has also played an important part in pathology, is the following: Every living, that is, excitable system, is continually influenced by stimuli. The stimuli consist of either external factors, such as heat, food, foreign matter, poisons, etc., or inner factors which result from the influence of the activity of one organ upon another. Only as a result of the continual action of stimuli is life maintained, in that the stimuli produce continual “excitement” in the irritable substance. The degree of irritability differs in various plants, animals, in different structures of the body, and even in the same individual at different times under different circumstances. The strength of the “excitement” depends on the one hand upon the degree of irritability, and on the other upon the strength of the stimulus. The irritability itself is influenced and changed by the action of the stimuli. If the stimuli are too strong and are of prolonged duration, the irritability diminishes as a result of exhaustion; if weak stimuli act during a prolonged time, the irritability increases. The healthy organism has a mean degree of irritability. Disease occurs when this state is altered by strong stimuli or by an absence of stimulation. Disease and health, therefore, differ not qualitatively but only quantitatively. It is here seen that we have the first attempt at a systematic interpretation of the effects of stimulation, and it is astonishing how sharply and successfully Brown has pointed out the foundations of this important field. He has in this way not only amply compensated for the great setback in the history of the teaching of irritability produced by the confusions of conceptions created by Haller and the vitalists, but also placed the whole of the physiology of stimulation on a firm foundation upon which it is possible to build further. Though it is true that many of his special theories, in particular those on nature and the origin of disease, are quite erroneous, still a just critic must judge work in relation to the period in which it was written, and I question if at the present day the science of medicine does not contain teachings which in a hundred years will also prove untenable.
Johannes Müller (1801–1858) then added an important stone to the building up of our knowledge of irritability. This was the clear recognition of the specific energy of living substances. We have already found the germ in Bordeu’s term “sensibilité propre” or “sensibilité particulière.” Brown was also of the opinion that different living objects possessed different types of irritability and that excitation of their special functions was not dependent upon the kind of stimulus acting upon them. Johannes Müller, grasping the idea hidden in this presentation, transformed it into a clear and fundamental conception. Already in the work written in his early years treating of optical illusions he says:[5] “It is immaterial by which means the muscle is stimulated, whether by galvanism, chemical agents, mechanical irritation, inner organic stimuli or sympathetic response from quite different organs; to every means by which it is stimulated and an effect produced, it responds by movement. Movement is, therefore, the effect and the energy of the muscle at the same time.” “Thus it is throughout with all reactions in the organisms.” “The sensory nerve, responding to any stimulus of whatever kind, has its specific energy; pressure, friction, galvanism and inner organic stimuli produce in nerves of sight that which is peculiar to them, light sensation; in the nerves of hearing, that which is peculiar to them, sound sensation; and in the nerves of touch, touch sensations. On the other hand, everything which affects a secretory organ produces change of the secretion; that which affects the muscle, movement. Galvanism is not superior to any other methods, of whatever kind, which can bring about stimulation.” And in his handbook of physiology Johannes Müller[6] formulates the law of specific energy for the sensory structures briefly in the following words: “The same external factor produces different sensations in the different senses according to the nature of each sense, namely, the sensation of the particular sensory nerves; and the reverse: the characteristic sensations peculiar to every sensory nerve can be produced by several internal and external influences.” This doctrine of the specific energy of the sense substance possesses an importance which extends far beyond the domain of the physiology of stimulation, for it forms the basis on which the whole theory of human knowledge must be built up, no matter how it may be constructed in detail.
As Johannes Müller already clearly emphasizes, it is here not the question of a law confined to the sense substance, but one that applies to all living substances. Every living substance has its “specific energy,” that is, its characteristic vital phenomena and this is produced by stimuli of the most varied kind. This doctrine received an extension of inestimable value for its future development by the great discovery of Schleiden, that the cell is the elementary building stone of the plant organism. Subsequently Schwann at the instigation of Schleiden made further investigations and found that this discovery applied also to the animal organism. Irritability having been recognized as a general property of living substance, it followed that, after the foundation of the cell doctrine, every cell must possess irritability and have its own specific energy. It now became necessary to study the manifestations of irritability of the cells in their specific form. Strange to say, this was done at an earlier date in pathology than in physiology. Indeed, since the time of Brown the study of irritability was furthered far more by pathology than by physiology. The chief reason for this is probably the great practical interest that the investigation of disease possesses, Brown having already quite correctly ascribed the existence of disease to the relations of the organism or its parts to stimuli. Rudolph Virchow then, after the establishment of the cell doctrine, arrived at the momentous conclusion, that disease must be considered as reactions of the body cells to stimuli. In his epoch-making “Cellular pathologie,”[7] he has carried out this idea in a classical manner. By irritability Virchow understands “a property of the cells, by virtue of which they are set into activity, when affected by external influences.” There are, however, various kinds of actions which can be brought about by external influences. But essentially there are three kinds. The effects produced are functional, nutritive, formative. The result of excitation, or if one will, of stimulation of a living part, can, therefore, according to circumstances, be either merely a functional process, or there can be a more or less intense nutritive activity produced without the function being necessarily at the same time activated, or finally, it is possible that a process of formative change may occur which produces new elements in greater or less numbers. Virchow touches here for the first time upon a question of extraordinary moment, the important bearings of which have only now begun to be recognized and seriously considered. We now know, for example, that the functional excitation can be separated to a certain degree from the cytoplastic excitation of the muscle. If the muscle is acted upon by functional stimuli, the excitation takes place mainly in the form of functional metabolism, nitrogen-free substances are broken down in increased quantities, whereas cytoplastic metabolism, which produces more profound alteration in the living substance, and which goes so far as to bring about a breaking down and building up of the nitrogen containing atom groups, is hardly at all increased. It would be an error, however, to look upon these different kinds of metabolism as quite independent. Considering the close correlation which all the phases of metabolism bear to each other, this idea cannot well be entertained. If, however, we question in what manner, for instance, the functional and the cytoplastic metabolism are linked together, we have a problem before us which does not belong to the past, but to the present and future. Indeed, Virchow seems already to have felt that a sharp division between the different phases and parts of functional metabolism in the cell does not exist, for he says: “It is true that it cannot be denied that, especially between the nutritive and formative processes and likewise between the functional and nutritive, intermediate gradations occur.” Still they differ essentially in their characteristic action and in the internal alterations which the stimulated part undergoes, depending on whether it functionates, nourishes itself, or is the seat of special growth. Disease consists of the influence of stimuli upon these physiological processes. The law of the specific energy of living substance is as clearly expressed in functional disease as it is in the physiological effects of stimuli. The pathological disturbance of function is purely quantitative, “nowhere is there a qualitative divergence.” The function exists or it does not exist. If it is present, it is either strengthened or weakened. This gives the three fundamental forms of disturbance: absence, weakening and strengthening of the function. No function other than the physiological, even under the greatest pathological alterations, exists in any structure of the body. “The muscle does not perceive, the nerve moves no bone, the cartilage does not think.” In this way Virchow rediscovered in the domain of pathology the law that his great teacher, Johannes Müller, had already clearly established in the field of physiology. But this law can no longer be applied to all pathological disturbances of the nutritive and formative activities of the cell. Here processes occur which do not consist of a quantitative change of the normal phenomena, but in the appearance of wholly foreign states, as in the case of amyloid degeneration or heteroplastic tumors. The question today and for the future arises, therefore, as to where the limits of the validity of the law of the specific energy of living substances are to be placed, a question closely connected with the other before mentioned, of the relations between functional and cytoplastic metabolism.
By means of cell pathology Virchow has laid the foundations upon which our modern medical attitude is built and which must remain essentially forever the basis of all future medical thought. Certain critics, lacking in appreciation of the interrelations between things and ignoring the safer and established knowledge, have considered, in view of the unfoldings of the researches on immunity and of serum therapy, that the time of cell-pathology was passed and must be replaced by the humoral-pathological teaching. These ultramodern critics, however, have here completely ignored the fact that, on the one hand, the life of our body is built up from the life of all of the contained cells, for life in our body exists only in the cells; and on the other, a fact not considered by them is that the components of the body fluids originate from vital activity of the cells either directly or indirectly. No result, indeed, of present serology can alter in the least degree the fact that every disease represents only a disturbance of the physiological processes of cell life of the organism and the harmony in their combined workings. Indeed the more recent observations of serology and chemotherapy are so little opposed to cell-pathology that they are in fact only possible when based on the latter. They are only comprehensible then from the unfoldings of cellular pathology.
Until quite recently all those effects of external factors on the living substance which consist in excitation, that is, in an increase of their specific vital processes, have always stood in the foreground of all researches and observations on irritability. It was gradually, however, more and more recognized that the depressing influence of stimuli played a great rôle in the vital process of the organism. Brown was acquainted with exhaustion produced by stimuli, and the discussion of “asthenic” diseases, in which the irritability was reduced, occupied an important place in his pathology. That, however, in the normal activities of the organism such depression or lessening of vital manifestation could result from the influence of stimulation, first became clear after the brothers Weber[8] in 1846 discovered the inhibitory effects of the galvanic stimulation of the vagus upon the heart.
Since then the inhibitory processes in nerves have been frequently investigated by Schiff (1823–1896), Goltz (1834–1901) and others, who gave us a theory concerning the same. Only a small number of inhibitory processes were known at that time, as for instance the inhibition of the croak reflex of the frog, or the inhibition of the grasp reflex during copulation of these animals through skin stimuli, and a few other cases. They regarded the inhibitory nervous processes as a special state, of which the inhibition of the heart through the vagus was the best illustration. Further, the Russian physiologist Setschenow succeeded by directly stimulating certain parts of the central nervous system, especially the optic lobes of the frog, in producing inhibition. It was, therefore, frequently assumed, as Setschenow did, that in the brain there exist special inhibitory centers, just as there are motor centers. This view was later shown to be untenable. It is only quite recently, and especially since Sherrington has shown that inhibition plays a part in all antagonistic muscle movements, that we have obtained a broad and more thorough understanding of the inhibitory processes in the life of the organism, and a physiological explanation of this important group of activities of the central nervous system. This inhibitory effect of stimulation, brought about by the involvement of the central nervous system in the normal organism, was studied side by side with the depressing effects of stimulation. Claude Bernard (1813–1878)[9] first discovered that the excitation of all living substance could be depressed or totally suspended through the influence of certain anæsthetics, such as ether or chloroform. By a series of experiments, as simple as they were convincing, the French scientist showed that irritability could be depressed in mimosa leaves, the growth of germinating plant seeds and the ferment action of yeast cells stopped, likewise the disintegration of the carbon dioxide in the cells of the green leaf, as well as the development of the egg cells, and also the movements of the animal organism and the sensations of man. By this means he recognized that not only does all living protoplasm possess irritability, but that it can also by means of certain substances be put into the condition of “anæsthesia,” a state dependent upon a change of the protoplasm, which he termed “semi-coagulation.” Finally, besides the more apparent processes of excitation and those less so, belonging to the group of inhibition and depression, in the last century the knowledge of the subject was greatly increased by the addition of another group, which recently in consequence of various reasons has met with particular interest. These being effects of stimuli on the direction of movements of motile organisms, it became more and more recognized that these curious manifestations of irritability, which appeared to have such a surprising likeness to the mysterious attraction and repulsion in the sphere of electricity and magnetism, occur universally in the vegetable as well as in the animal world. These movements are of the greatest biological importance for the obtaining of food, propagation, protection against disease, etc. Botanists have long known of the geotaxis of the roots and stems of plants, the heliotaxis of their leaves and flowers and of the thigmotaxis of their tendrils. Likewise the phototaxis of freely moving protistæ had been often observed, especially by Ehrenberg[10] of Berlin, well known for his researches on infusoria. Then Engelmann, Pfeffer, Strassburger, Stahl, and many others discovered and studied more carefully the facts concerning chemotaxis, thigmotaxis, rheotaxis, geotaxis, phototaxis, etc., of bacteria, motile spores, rhizopoda, and so on. The question arose if one should regard this singular behavior of the unicellular organisms as an expression of conscious sensations, discrimination or will. This view was as determinedly denied on the one hand as it was accepted on the other. Whilst even today certain scientists still consider the reactions of the unicellular organisms as a manifestation of conscious sensation, discrimination or will, others look upon them as unconscious reflex reactions of cell organism, taking place as purely mechanically as the spinal cord reflexes of vertebrates. This divergence of opinion would have practically no value for the development of our knowledge of irritability had not here, as in the case of the relations between the mental and physical processes in man, the view been entertained with more or less fervor, that at some stage or other in the chain of the purely physiological processes of responsivity, an intangible factor had been introduced which was considered as the essential “cause” of the peculiar reactions to stimuli. It is not here the place to enter into the question if, and in what degree, animal psychology may be a field of scientific research. Even if one looks upon conscious processes as effects of stimulation, in both lower animals and in man, in no case should one assume them to be factors of an essentially different nature, interrupting the chain of the mechanical reactions; neither should one consider the particular characteristic responses observed in unicellular organisms as effects of non-mechanical “causes.” As a result, a mysticism, in reality quite foreign to it, would be introduced into physiology. As a matter of fact the physiological investigations for the tropic reactions of stimuli, which have been carried out in great number since the end of the eighties, have shown more and more clearly that this peculiar behavior of unicellular organisms towards unilateral stimuli is produced by a comparatively simple mechanism. The analysis of this shows a difference in the intensity of the exciting or depressing effect produced by the stimulus. The stimulus exerts its influence unequally upon the specific activity of the motor elements of different parts of the surface of the cell body. This difference in response causes the axis of the freely moving organism to assume a different direction in which to move. It is compelled to move in a definite direction and so, in this field, the apparently mysterious attraction and repulsion of living organisms toward stimuli has, by means of the most simple analysis, been robbed of its mystical character.
Finally, I should like to touch briefly upon a view of the irritability of living substance which has recently been brought forward by Semon.[11] It assumes the proportions of a whole system and is proclaimed as a basis for the comprehension of organic phenomena. It originated with an idea which Hering[12] developed many years ago and which later was accepted by Haeckel,[13] namely that heredity is a species of memory of the living substance. Semon attributes to living substance, in contrast to non-living, a “Mneme.” By “Mneme” he understands the capability of living substance to assume, through the influence of a stimulus, a permanently altered condition. The latent alteration resulting from the stimulus he terms “Engramm.” These “Engramms” can later, however, not only be activated by the reapplication of the original stimulus, but also by other stimuli, so that the state of excitation once brought about by the original stimulus reappears. Semon calls the reproduction of the state of primary excitation by a later stimulus “Ekphorie.” A great number of other new word formations, such as “chronogene Engramme,” “phasogene Ekphorie,” “mnemische Homophonie,” “mnemisches Protomer” and countless others are supposed to serve for the better understanding of a series of special facts, chiefly in the domain of the processes of heredity. That which is termed “Mneme” and “Engramm” is not further analyzed. Semon expressly declines to discuss the kind of alterations in which the physical or chemical nature of an “Engramm” consists. Hence physiological analysis has not been advanced in any way by Semon’s new formation of words applied to long-known facts. With a series of new expressions the originator of the “Mneme doctrine” deceives himself, as well as a number of his readers not endowed with the critical faculty, into supposing that he has achieved a serious analysis. Of such, however, there is not a trace. As can be conceived, this way of treating the manifestations of life has met with no further attention from the physiological side. For indeed, what physiologist would consider that the fact of muscle responding by a contraction to an induction shock, or to any other stimulus, is sufficiently analyzed by the explanation that we have the “Ekphorie” of a state of excitation that was once previously produced by an original stimulus of some unknown kind, and of which the living substance of the muscle, in consequence of its “Mneme,” has retained a latent “Engramm”? Here the deep gulf is apparent which exists between the demands of a physiological analysis and the futile explanation of the mneme doctrine. Physiological investigation must reject such a manner of treating its problems.