General Physiology: An Outline of the Science of Life

With all those organisms that do not exist in a constantly uniform nutrient medium, that rather must seek their food, food is available only at irregular intervals. Periods of lack and periods of superfluity alternate with one another. If such an organism has had no food for some time, if, e.g., an Amceba, which nourishes itself upon Algce, has been deprived of food for some time and by chance comes to a place where Algae exist, these food-organisms operate as a stimulus upon it and cause it to creep toward and ingest them. Here food acts as a stimulus, although it is a necessary vital condition. Analogous cases exist in the cellcommunity. The simplest example is afforded by the green plants. Light forms one of their most important vital conditions. Without light no cleavage of carbonic acid, no formation of starch, no assimilation, takes place in the green parts of the plant ; the plant dies. Yet this condition undergoes the widest variations in intensity, for light continually alternates with darkness and, therefore, acts as a stimulus. Not only can the process of assimilation be regarded as a phenomenon of stimulation, but the light-stimulus produces, in addition, a series of other, very evident reactions which express themselves in motion. In the animal cell-community, also, cases in which stimuli are a vital condition are known in great number. The stimulating impulses that are produced in the central nervous system become transmitted to the tissue-cells through the nerve-fibres. A muscle, e.g., moves only when a stimulus is conducted to it from the brain or the spinal cord through its nerve. If the nerve be cut or in any other way be made incapable of transmitting the impulse from the central nervous system, the muscle can no longer move, and after a time atrophies.

In less degree a muscle becomes feeble and decreases in mass when it is used little, i.e., when few impulses are sent to it from the central nervous system. This condition is termed atrophy from disuse. This is true not only of musclecells, but of all tissues to which, through their nerves, stimulating impulses are no longer conducted. In cases where, by disease, a portion of a nerve has become temporarily impassable to stimuli, medical treatment endeavours, often with success, to hinder the atrophy of the tissue supplied by the nerve by stimulating it artificially by electrical currents, and in this action of the galvanic current lies the sole therapeutic importance of electricity. The strengthening of an organ by use belongs also in this category. By continued use, as every gymnast, fencer, oarsman, and mountainclimber knows, a muscle of moderate strength can be transformed in a short time into one of marked strength and endurance, the mass increasing very considerably. The effect of all exercise depends upon the fact that stimulating impulses are sent continually into the organ in question, putting it into activity.

From these examples it is evident that certain stimuli can be at the same time very important vital conditions; and these stimuli, which are necessary to the continued maintenance of life, without which the nutrition, the metabolism, of the organs in question cannot continue undisturbed, are termed trophic stimuli. Trophic stimuli do not stand in contrast with other stimuli ; the term " trophic " simply signifies a special peculiarity of the action, and very different stimuli can have a trophic effect. As regards trophic stimuli that in the animal organism are transmitted through the nerves to the tissues, it has been believed that special trophic nerve-fibres and nerve-centres must be assumed in addition to the fibres and centres of known function ; such nervefibres are asserted to have nothing whatever to do with the peculiar function of the tissue supplied by them, but merely regulate its nutrition and metabolism. This idea of so-called trophic nerves has produced in physiology and medicine much mischief and confusion, and recently has misled many men of science into the most fantastic ideas and supposed discoveries. But for every critical investigator, who is wont to associate a definite idea with the conceptions with which he deals, the confused idea of trophic nerves is simply a piece of the old mysticism of the vitalists. It is seen that the assumption of special trophic nerves and peculiar trophic stimuli, existing in addition to other stimuli, is not needed in order to explain the phenomena, but that the nerves that influence the characteristic function of every tissue regulate thereby the metabolism of the cells in question ; in other words, every nerve serves as a trophic nerve for the tissue that it supplies, since the impulse which it conveys represents a vital condition for the tissue.

1. The Conception of Irritability and the Nature of Reactions Every process of stimulation requires two factors : a stimulus, and a body that is irritable. If the two factors come into correlation there results a phenomenon of stimulation, a reaction. We have considered stimuli ; we will now consider irritability. A definition of irritability (excitability) that shall have general application, must be formulated somewhat as follows : The irritability of living substance is its capacity of reacting to changes in its environment by changes in the equilibrium of its matter and its energy. All other factors that might be included in the definition would be applicable to special cases only. Yet, frequently, the general conception, without being exactly defined, has more or less unconsciously been made to include special factors. For example, as regards the quantitative relations of the stimulus and the reaction, that case has been regarded as the type in which an

enormous quantity of energy, the reaction, is produced by an excessively small quantity acting as the stimulus ; hence the onesided view of irritability as the capacity of responding to slight stimuli with a disproportionately great evolution of energy. This case, although representing a special condition, is very obvious and wide-spread, and it is worth while to consider its details. If, as an irritable body, a muscle with its nerve be selected, and as a stimulus the mechanical stimulus of pressure, the following arrangement can be made (Fig. 150). The calf-muscle (gastrocnemius) of a frog, the nerve of which (sciatic) has been freed,

is suspended in a muscleholder, the thigh-bone to which the muscle is attached at its upper end being fastened by a clamp. The lower end of the muscle with the tendon of Achilles is separated from the bone, and in the tendon a slit is made, into which a hook attached to a long thread is fastened. This thread is carried over two easily moving wheels, and, at its other end, is attached to a pan containing a weight of 100 gr. The nerve of the muscle-preparation lies stretched out upon a horizontal stand. Every stimulation of the nerve causes a twitch of the muscle. If, now, a weight of 10 gr. be allowed to fall upon the nerve from a height of about 1 cm., so that the nerve is mechanically stimulated by the pressure, at the moment of stimulation a twitch of the

muscle occurs, and the muscle raises the weight of 100 gr. to a height of about 1 cm. Here the quantity of energy that corresponds to the work of the muscle is approximately ten times greater than the quantity of energy that has operated as a stimulus upon the muscle; and under favourable conditions the disproportion can be even much greater. According to the law of the conservation of energy it is clear that the considerable quantity of energy that is set free externally in the reaction cannot be derived by the transformation of the small quantity that has been introduced into the organism in the stimulus. It must, therefore, have come from the organism itself, and must have been stored pre-

Fio. 150. — Apparatus for the demonstration of the inequality of the stimulus and the reaction. A nerve-muscle preparation is suspended upon a myograph ; the muscle is loaded with a weight of 100 gr. and its nerve is laid over a glass plate supported by a stand. Upon the nerve rests a small aluminium pan having a sharp keel on the lower side, and into this a weight of 10 gr. falls from a height of about 1 cm. At the moment of stimulation the muscle contracts and raises the 100 gr. about 1 cm.

viously in the latter as potential energy. Hence in this case the irritability depends upon the fact that great quantities of potential energy are accumulated in the living substance of the muscle, so that the introduction of only a small quantity is needed to transform it into actual energy. But such irritability and such a reaction are not limited to living substance solely. Analogous conditions may be established in lifeless bodies. A spring stretched and held by a fine thread that maintains the tension in equilibrium represents a body in which a great quantity of potential energy is stored, although the body is in complete rest. If the thread that holds the spring be touched lightly with the edge of a sharp knife, the spring flies back with great force and performs external work. By a small stimulus, represented by the cutting of the thread, the potential energy of the spring has been transformed into actual energy ; the cutting of the thread has, as is said, "discharged" the energy of the spring. In explosive bodies also there is such a discharge, and since there it is a discharge of chemical tension, the similarity of it with the processes of discharge in living substance is still greater, for in the latter also potential energy is stored up in the form of chemical tension. In a quantity of nitroglycerine the size of a pea there is contained such a quantity of potential energy that it needs only a slight impulse to produce a powerfully destructive effect. Like the nitroglycerine molecule, living substance is explosive, although in a manner that does not call forth so injurious effects.

But the processes of discharge, as has been said, are only special cases of reactions, and the relation between stimulus and reaction may be wholly different in other cases ; for, on the one hand, there are stimuli, such as fall of temperature, withdrawal of food, and exclusion of oxygen, which consist not in the action but in the withdrawal of energy ; and, on the other hand, there are reactions, such as those of narcotics, which are expressed not by an increase, but by a decrease and even a complete suppression of the production of energy. Accordingly, it is characteristic of the process of stimulation that no definite, generally valid, relation as regards the quantity of energy exists between the stimulus and the reaction. Hence, a conception of irritability that is to be generally valid must be formulated as above. As regards reactions, it must be said : The general action of all stimuli upon living substance consists in a change of spontaneous vital phenomena.

With the enormous multiplicity of vital phenomena in accordance with the composition of living substance, and with the great variety of stimuli, it is a priori conceivable that the phenomena of stimulation must be very manifold. Moreover, to increase the variety of the reactions still more, not only the different varieties of the stimulus, but also the different intensities, as well as the time and place of the stimulation, can call forth under circumstances very

different phenomena. This great multiplicity in the phenomena of stimulation, in combination with the fact that general reactions have not yet been investigated systematically, make it at present very difficult to deduce from the facts general laws for reactions. Nevertheless, it is possible to establish empirically for groups of stimulation-phenomena common peculiarities. The changes that spontaneous vital phenomena experience under the influence of stimuli are of various kinds. In the first place, the phenomena may continue unchanged in quality and undergo quantitative changes only. This may be expressed either in an augmentation of all, or of single phenomena — the reaction is then termed excitation [Erregung] — or in a diminution of all or single phenomena — the reaction is then termed depression [Ldhmung].1

In the second place, spontaneous vital phenomena may be wholly changed in kind, so that wholly new phenomena appear which otherwise do not occur at all in the life of the cell. Such reactions occur, e.g., in the metamorphic phenomena of necrobiotic processes,2 where under many influences not yet wholly known the cells of the body form substances, such as amyloid substance, which are completely foreign to them in normal life. These reactions have been very little investigated, and, so far as one can now judge, it appears as if they are only secondary results of quantitative changes of normal vital phenomena. Thus, it can be imagined that in metamorphic processes the appearance of foreign substances in the cell depends upon the fact that, as a result of chronic stimulation, one or more processes in the normal metabolism are gradually decreased or have entirely dropped out, so that compounds that normally are formed, but on account of immediate further transformation do not accumulate, are now stored in quantity, because the processes in the metabolism that are necessary to their transformation no longer exist. For the present, however, this must remain an hypothesis. The following consideration will have to do chiefly with the phenomena of excitation and depression. It is not superfluous sharply to emphasize our conceptions of stimulus, excitation, and depression, as well as the relations of these to one another, since not rarely in physiology because of the false idea, usually assumed, that a stimulus must always produce excitation, much confusion and difficulty in the judgment of phenomena have arisen. These can be avoided if the following definitions be accepted :

1 [The best English equivalent of the word Erregung seems to me to be "excitation." The translation of the word Lahmung has given some trouble. The customary English equivalent of the word is " paralysis," but it is easy to see that such a rendering would not convey the exact meaning of the author. After considering and rejecting various proposed terms, I have finally decided to adopt as the opposite of excitation the comparatively unobjectionable word < ' depression."— F. S. L.]

1. Every change in the external vital conditions of an organism 2. Every augmentation of a vital phenomenon, either of one or of 3. Every diminution of a vital phenomenon, either of one or of all, 4. The action of stimuli can consist of excitation or depression. Another question, that of the duration of reactions, which naturally thus far has received much less systematic treatment, is of no less interest, for it is in the closest relation with subjects, such as those of adaptation, immunisation, etc., which are of far-reaching practical importance. It is to be expected that these subjects, which afford very promising problems for experimental cell-physiological research, will soon attract more attention. For the present only a few disconnected discoveries of a very general nature can be specified.

In general, it may be said that the duration of the reaction depends primarily upon the duration and intensity of the stimulus, and that after the cessation of the latter the reaction passes away the more rapidly, the briefer and feebler the stimulus was. A few special cases demand particular attention. To consider first the relations under prolonged stimulation, usually during the continuance of the stimulation the reaction undergoes a change in accordance with the intensity of the stimulus. With feeble stimuli there is, after some time, an abatement and finally a cessation of the reaction : the living substance becomes accustomed, or adapted to the stimulus. Such phenomena may easily be observed in very different objects and with very different varieties of stimuli. Thus, as Engelmann (79, 1) and others1 have shown, it is possible to accustom many unicellular organisms to relatively strong salt solutions which at first call out distinct phenomena of stimulation. If an Actinosphcerium that has extended its pseudopodia in the customary, ray-like manner be placed in a weak solution of sodium bicarbonate, it gradually draws in its pseudopodia from all sides and becomes spherical. But soon minute projections reappear upon the surface, extend and lengthen, until the organism has assumed its original form and become completely normal. By successively increasing the concentration, the same result can be produced many times in succession. Such adaptations may be brought about to weak solutions of poisons, high temperatures, strong light, etc. If the stimuli are strong, no adaptation takes 1 Cf. Verworn ('89, 1).

place, but the phenomena of fatigue and exhaustion develop (these will be discussed elsewhere) ; irritability gradually decreases, and death finally results. In contrast to these phenomena both of adaptation and fatigue, in a few cases with prolonged stimulation the reactions continue with equal intensity. An example of such cases is afforded by the muscles of the mammalian body, which exist in a certain state of excitation, or, to use the common term, possess a " tone." Such are especially the muscles that close the urinary bladder and the anus. These muscles are in a constant state of contraction, which is caused by stimuli that come from the cells of the nervous system and act uninterruptedly upon the former. The skeletal muscles also possess a constant, feeble tone, which is maintained by feeble stimuli coming mostly from the periphery and transmitted to them through the nervous system.

With brief stimulation the reactions give place, usually soon after its cessation, to the normal condition of the organism, but FIG. 151.— Guinea-pig, lying motionless upon his back, with the muscles of the extremities tonically contracted. The legs stand out stiffly. there are cases in which the extinction does not begin immediately, but a long, under some circumstances a very long, after-effect exist?,. Thus, a single brief stimulus can put into long-continued, tonic excitation certain ganglion-cells and the muscles innervated by them. If, e.g., we seize a guinea-pig with the hands firmly but without great pressure, and turn him suddenly upon his back, he makes a few, brief, defensive movements and then lies motionless. It can be seen that the muscles of the extremities, which just before had made the defensive movements, are strongly contracted, so that the limbs stand out stiffly (Fig. 151). When the animal is undisturbed, this condition of tonic excitation may continue for a half-hour.

The phenomena of prolonged reflex tone after brief stimulation may be seen still more clearly in frogs that have been deprived of their cerebrum. If such a frog sitting quietly in the customary squatting attitude (Fig. 152, A) be gently stroked by two fingers along the sides of the spinal column, he raises himself upon his extremities by contracting their muscles, and stands, sometimes more than an hour, in this grotesque position (Fig. 152, B). By the proper operations it can be determined that by the mechanical stimulation of the skin the ganglion-cells at the base of the mid-

FIG. 152.— Frog that has been deprived of his cerebrum. A, In the customary squatting attitude. B, In the attitude of general reflex tone ; the muscles of the limbs and the back are in constant contraction, so that the frog stands immobile upon his raised legs in the attitude of a frightened cat. brain are put into a tonic state of excitation, which is communicated to all the body-muscles that are innervated from that point.1 The after-effects of many chemical stimuli, especially the bacterial poisons, are the most interesting and of most practical importance. It is an old experience that after recovery from certain infectious diseases, such as small-pox, scarlet fever, and measles, the bodies of men and animals are immune to further infection from the same source. It is well known that the modern thera- 1 Cf. Verworn ('96, 5).

peutics and prophylaxis of the infectious diseases are based upon this fact, especially the inoculation- and injection-methods of Jenner, Koch, Pasteur, Behring, Roux and others. We know how to produce immunity at will by the artificial introduction of weakened inoculation-substance, of metabolic products of the excitant of the disease in question, or of blood-serum from animals that have been exposed to the infection. In all these purely empirical methods of treatment we are totally ignorant of what goes on in the body ; we can only say that the poisoning by the bacterial poisons produces in the cells an after-effect, which can continue in many cases, such as diphtheria, only a relatively short time, but in others, such as small-pox, for many years. A phenomenon is here presented, the explanation of which is as yet scarcely hinted at. But it is to be expected that cell-physiological researches, which replace with the simplest relations the complex and abstruse conditions presented by human and animal bodies, will be of the greatest service in assisting toward an understanding. In fact, investigations upon unicellular organisms with various chemical substances have shown that analogous phenomena are to be met with in these forms. Thus, by accustoming Infusoria to weak solutions of corrosive sublimate, Davenport ('96) has made them immune toward solutions of such strength as were at once fatal to non-immunised individuals. Cell-physiological research opens here an uncommonly wide and fruitful field. The systematic investigation of reactions in the single cell is of fundamental importance not only theoretically, but also for practical medicine.1

Inseparably connected with irritability is another property of living substance, viz., the power of conduction of the stimulus. If a mass of living substance be stimulated locally, as can be done very simply by touching it or pricking it with a fine needle, the reaction is not limited to the point stimulated, but spreads from that place more or less over the neighbouring parts. The capacity of conducting the stimulus belongs to all living substance, but in very different degrees. While one kind conducts rapidly and far, another conducts slowly and only to the nearest surroundings.

The capacity of conduction is most pronounced in those forms that are developed exclusively for that purpose, viz., the animal nerve-fibres. Nerves conduct with enormous rapidity and to distances measured by meters. Helmholtz has computed that in a frog's nerve the stimulus is transmitted at a rate of 26 m. per second. In man the rate is still greater^ approximately 34 m. in 1 Cf. Verworn ('96, 2). a second ; in the lobster, as Leon Fredericq and Van de Velde have shown, it is less and amounts to about 6 m. in a second. Various methods have been devised for determining the rate of transmission in the nerve, an undertaking that with the great rapidity of the process is not easy. The principle of all these methods depends upon the determination of the difference in time between the appearance of a muscle-contraction, when the nerve belonging to it is stimulated very near the muscle, and its appearance upon stimulation of the nerve at a more remote place (Fig. 153). For this purpose the spring-myograph of du Bois- Reymond can be employed, an apparatus that serves for the graphic representation of a muscular movement (Fig. 154). The apparatus consists of a muscle-holder in which the gastrocnemius muscle of a frog, the nerve of which is freed, is fastened by the femur ; the muscle is connected with a lever, which accompanies every contraction and by means of a fine point records it upon a smoked glass plate which is shoved rapidly by. The glass plate moves in a sledge-like frame in a vertical plane in front of the writing-lever, and is put in motion by a spring. Simultaneously with the release of the spring an electrical stimulus is let loose upon the nerve ; moreover, a tuning fork is made to vibrate, and traces its vibrations, likewise by means of a writing-point, upon the blackened glass plate. If the nerve be stimulated once at a distance of about 3 cm. from the muscle, and once immediately at the muscle, the first contraction follows a short time later than the second, because the first stimulus has a longer stretch than the second to pass over before it can act upon the muscle.

This difference in time that in both cases elapses between the moment of stimulation and the appearance of the contraction, can be measured with extreme exactness upon the blackened plate, upon which the contraction is traced in the form of a curve, by the number of vibrations of the tuning fork that are traced simultaneously (Fig. 155). Since the number of vibrations of the tuning fork in one second is known, the duration of a single vibration can easily be computed, and from the number of vibrations that lie between the beginning of the second contraction and that of the first, the time can be calculated that elapsed

FIG. 153. — Gastrocnemius muscle of a frog with the sciatic nerve. ^The femur to which the muscle is attached, is clamped in a muscle-holder, and the nerve is stimulated first at 1, then while the stimulus was passing over a piece of nerve 3 cm. in length. It is thus found that the rate of conduction of the stimulus in a frog's nerve under normal conditions amounts to approximately 26 m. in the second. Other forms of living substance conduct the reaction considerably more slowly and some to a very short distanee only, the effect being gradually extinguished with the distance. In very slowly conducting objects the rate of conduction can be followed with the

FIG. 155. — Ascending limb of the myographic curve taken with the spring-myograph. R, Moment of stimulation ; 1, beginning of the contraction upon stimulation of the nerve at a remote place (Fig. 153) ; 2, beginning of the contraction upon stimulation immediately at the muscle. Below, the curve of the tuning fork. eye. Thus, in Difflugia the rate of conduction of the excitation can be very easily recognised under the microscope in the long finger-shaped pseudopodia by the fact that drop-like projections form on the surface of the pseudopodial plasma, beginning at the place of stimulation. If such a pseudopodium be stimulated only slightly at the tip by contact with a needle, the reaction extends a short distance only, the surface of the pseudopodium becoming slight!}7" undulating (Fig. 156, a). But if it be stimulated more strongly, the reaction is stronger and is transmitted considerably farther (Fig. 156, b). The reaction diminishes in extent as the distance from the place of stimulation increases, and finally it is extinguished.1 Very slight conduction is found in many rhizopods that have thread-like pseudopodia, e.g., OrUtolites (Cf. Fig. 98, p. 238). Here even with the strongest stimulation, such as cutting across a pseudopodium, the excitation is limited to the immediate vicinity of the place stimulated, the protoplasm there being drawn together into one or more small globules. These globules glide centripetally for a very considerable distance along the pseudopodial thread, which thus begins to shorten, while

the globules gradually dis- Fio.l^.-Difflugiaurceolata. Three finger-shaped, hyaline Solve and allow their Subpseudopodia are projected out of the urn-shaped shell Stance tO DOW into the at & somewhat more strongly stimulated. Their movement is not to be regarded as a conduction of the excitation,2 but only as the expression of the transport of substance by the stimulated protoplasmic mass to the cell-body ; for the protoplasm in the vicinity of the globules exhibits no phenomena of excitation, but streams on quietly in a centrifugal direction.

2 In the first edition of this book this was so regarded; but later studies upon the Rhizopoda of the Red Sea have convinced me that conduction of excitation and transport of substance are to be separated from one another in naked protoplasmic masses. Cf. Verworn ('96, 3). But between the very slight power and rate of conduction possessed by Orbitolites, and the very great power and rate possessed by the nerve, there are found in the various living forms the greatest variety of transitions. The cross-striated muscle-fibre

FIG. 157. — Pseudopodium of Orbitolites. a, At * cut across ; b, effect of stimulation (formation of protoplasmic globules) limited to the immediate vicinity of the place stimulated ; c-f, transport of substance. The stimulated masses are transported along the pseudopodium to the central cell-body, and their substance becomes gradually spread out (e, /) ; the unstimulated protoplasm exhibits no phenomena of excitation but continues to flow centrif ugally . and the pseudopodium soon lengthens again (e, f).

conducts considerably more slowly than the nerve, the smooth muscle-fibre still more slowly than the cross-striated, and so on. Thus, according to the rate of conduction, living substances can be arranged in a long series showing most delicate transitions. After this general discussion of the individual elements of the process of stimulation we can pass to the consideration of the phenomena of stimulation themselves. Since the single cell does not allow the various vital phenomena to be recognised with equal readiness, but according to its specific