Chapter IX: Part I: The Individual Organism with Regard to Form and Metabolism (6)

We know that the *state of functioning* must be altered in order to call forth any sort of adaptation at all. Now, there can be no doubt that *a priori* it would seem to be very useful for the organism, if it never would let enter into its blood, lymph, etc., be it through the skin or through the intestine, any chemical compound that would prove to be a poison afterwards. In fact, a man, judging on the principle of the general usefulness of all the phenomena of the living, might suppose that there would exist a sort of adaptation against all poisons to the extent that they would never be allowed to enter the real interior of the body. We know that such reasoning would be incorrect. But we also can understand, I suppose, that an *a priori* analysis of a more careful kind would have reasoned differently. How could the functional state of the organism be changed, and how, therefore, could adaptation be called forth by any factor of the medium which had not yet entered the organism, but was only about to enter it? Not at all therefore is such a regulation to be expected as we have sketched; if there is to be any adaptation to poisons, it only can occur after the poison has really acted in some way, and in this case we shall indeed find regulations.

You may perhaps regard this discussion as a little too academical and hair-splitting, but here again it was for the sake of ensuring a perfectly sound foundation of our chief principles that I undertook it. Very often, indeed, the question has been raised by the defenders of a mechanistic theory of life, Why then did the organisms not reject all poisons from the very beginning? We now may reply to that only--how *could* they do so? How could they “know” what is a poison and what is not, unless they had experienced it?--if we are allowed for a moment to use very anthropomorphistic language.

We repeat, therefore, that the functional conditions of the organism must have been actually changed in order that an adaptation may occur. Nothing is more essential to a clear understanding of our problems than to keep fully in mind the exact sense of this definition.

ON CERTAIN GROUPS OF PRIMARY PHYSIOLOGICAL ADAPTATIONS

*General Remarks on Irritability.*--Turning now to more special groups of problems concerning physiological adaptations, let us begin with the primary class of them, and let us first say a few words on a subject which occasionally has been regarded as the basis of physiological regulation in general. I refer to a most important fact in the general physiology of irritability. Irritability of any kind is known to be re-established, after it has been disturbed by the process of reacting to the stimulus, and in certain cases, in which two different--or rather two opposite--kinds of reactions are possible on the same substratum, which increase with regard to one process whilst decreasing at the same time with regard to the other. The irritability of the muscle or of the leaves of *Mimosa* is a very good instance of the first case, whilst the second more complicated one cannot be illustrated better than by what all experience has taught us about the irritability of the retina. The retina is more irritable by green rays and less by red ones the more it has been stimulated by the latter, and more sensitive to light in general the more it has been exposed to darkness; and something very similar is true, for instance, as regards phototactic irritability in plants, all these phenomena being in relation to the so-called law of Weber.[91]

[91] I only mention here that certain modern psychologists have assigned the true law of Weber to the sphere of judgment and not of sensation. If applied to objective reactions only, in their dependence on objective stimuli, it, of course, becomes less ambiguous, and may, in a certain sense, be said to measure “acclimatisation” with regard to the stimulus in question. The mathematical analogy of the law of Weber to the most fundamental law of chemical dynamics seems very important.

As to “acclimatisation” in the more usual meaning of the word, with regard to a change of the general faculty of resisting certain agents of the medium, “immunity” proper is to form a special paragraph of what follows, and to “acclimatisation” towards different degrees of salinity (in algae or fishes) some special remarks will also be devoted on a proper occasion. There remains only “acclimatisation” to different temperatures; but on this topic not much more than the fact is known (see Davenport, *Arch. f. Entw. Mech.* 2, p. 227). “Acclimatisation” does not allow of a sharp general definition; it may be the result of very *different* kinds of adaptations in our sense of the word.

It seems to me that there would be little difficulty in harmonising the phenomenon of the inversion of irritability with the so-called principle of the “action of masses” and with the laws of certain “reversible” processes well known in chemistry. As to the simple fact of the re-establishment of irritability after stimulation has occurred, or, in certain other cases, the fact that in spite of permanent stimulation irritability seems to exist permanently also, physical analogies or even explanations might very well be found.[92]

[92] I should think that the problem of the re-establishment of irritability, in principle at least, arises even when there is not a trace of so-called “fatigue” or of a “refractory period.” The process of restoring may be so rapid as not to be noticeable, nevertheless some sort of restoring is to be postulated. We may say the “irritability” of an elastic ball is re-established by its elasticity. A certain analogy to this case may perhaps be found in the muscle. But the irritability of nerves with respect to nervous conduction, and of glands with respect to secretion, or of the articulations of *Mimosa* may be well understood, hypothetically at least, if we assume that the ordinary course of metabolic events is apt in itself to lead to a certain state or condition of the organs in question upon which their irritability is based. Certain general conditions of functioning, as for instance the presence of oxygen for the contraction of the muscle, would better be looked upon as necessary “means” of functioning than as being part of irritability as such. “Fatigue,” of course, may also be due to the absence of such “means” or to abnormal conditions originated by functioning itself.

If now we ask whether there is anything like an adaptation appearing in the general characteristics of irritation and irritability, it seems to me that we may answer the question in an affirmative manner, as far as primary regulation comes into account. We, certainly, have not studied any abnormal regulatory lines of general functioning, we only have studied general functioning itself; but, indeed, there was a certain sort of regulation *in* functioning. Of course, by showing that one of the most general features of all functioning is primary-regulatory in itself, we do not deny the possibility of many specific functions in which real secondary regulations actually do exist. Nothing indeed is asserted about the *specific* character of functioning in its different types, by proving that one of the *general* features of *all* functioning may comparatively easily be understood. It seems to me that this important logical point has not always received the attention it deserved.

*The Regulation of Heat Production.*[93]--Having finished our introductory remarks we now turn to the proper study of special physiological functioning with regard to its adaptive side, and begin with the most simple cases.

[93] Rubner, *Die Gesetze des Energieverbrauches bei der Ernährung*, Leipzig u. Wein, 1902.

The so-called “regulation of heat” in warm-blooded vertebrates is an instance of a special function which can be said to be regulatory in itself. There exists a normal blood heat for each species, which is maintained no matter whether the temperature of the medium rise or fall. It might seem at first as if in this case there were a little more of an adaptive regulation than only its well-known primary type; no reversion, one might say, of the direction of one and the same process occurs in the regulation of heat production, but one kind of process is called into action if it is necessary to raise the temperature, and another whenever it is necessary to lower it. Even in the dilatation and constriction of capillary vessels there are different nerves serving for each operation respectively, and far more important are the increasing of transpiration for cooling, the increasing of combustion for heating--two radically different processes. But, nevertheless, there is a certain unity in these processes, in so far as a specific locality of the brain has been proved to be the “centre” of them all; it is to this centre of course that the analysis of heat production considered as a kind of regulation or adaptation must be directed. Such an ultimate analysis, it seems to me, would have to classify heat regulation under the primary type of adaptations in physiology without any restriction. The centre acts in one sense or in the other, if stimulated by any temperature beyond a very limited range, and it is in the action of the centre that the “regulation” of heat consists.[94]

[94] The phenomenon of fever we leave out of account here; it is regarded by some as regulation, by others as a disturbance of heat regulation. Of course, if the first view should ever prove to be the right one, fever might be classified among the real regulations of the secondary type.

*Primary Regulations in the Transport of Materials and Certain Phenomena of Osmotic Pressure.*--Very similar phenomena of regulation are present in many processes concerned in the whole of metabolism. Let us consider for a moment the migration of materials in plants. Whenever any compound is used at a certain place, a permanent afflux of this compound to that place sets in from all possible directions. No doubt this is a “regulation,” but it is also the function itself, and besides that, a very simple function based almost entirely on well-known laws of physical chemistry. And in other cases, as in the ascent of water to the highest tops of our trees, which purely physical forces are said to be insufficient to explain, we can appeal to the unknown organisation of many cells, and there is nothing to prevent our attributing to these cells certain functions which are, if you like to say so, regulatory in themselves. Among other facts of so-called regulations there is the stopping of metabolic processes by an accumulation of their products: as, for instance, the transformation of starch into sugar is stopped, if the sugar is not carried away. Of course that is a regulation, but it again is an intrinsic one, and it is one of the characteristics of reversible chemical processes to be stopped in that way. I know very well that in this particular case a certain complication is added by the fact that it is a so-called ferment, the diastase, which promotes the transformation of starch into cane-sugar, and that this ferment is actively produced by the organism: but even its production would not prove that any real kind of secondary regulation exists here, if nothing more were known about such an active production than this single case.

In a special series of experiments almost all carried out in Wilhelm Pfeffer’s botanical laboratory at Leipzig, an attempt has been made to discover in what manner the cells of plants are able to withstand very high abnormalities of the osmotic pressure of the medium--that is to say, very great changes in the amount of its salinity. That many, particularly the lower plants, are able to stand such changes had been ascertained already by the careful examinations of Eschenhagen; but recent years have given us a more profound insight into what happens. Von Mayenburg[95] has found that sundry of the species of *Aspergillus*, the common mould, are able to live in very highly concentrated solutions of several salts (KNO_3 and Na_2SO_4). They were found to regulate their osmotic pressure not by taking in the salts themselves, but by raising the osmotic pressure of their own cell sap, producing a certain amount of osmotically active substances, probably carbohydrates. If in this case it were possible to assume that the osmotic pressure of the medium were the real stimulus for the production of the osmotic substances in the cell, stimulus and production both corresponding in their degree, we should be entitled to speak of a primary though physiological[96] regulation only; and it seems to me that despite the discoveries of Nathansohn that certain algae and cells of higher plants are able to change the permeability of their surfaces in a way which regulates the distribution of single salts or ions in the sap of their cells without any regard to pure osmotic equilibrium, such a simple explanation might be possible.[97]

[95] *Jahrb. wiss. Bot.* 36, 1901.

[96] Carbohydrates cannot be ionised, and therefore there is no doubt that in von Mayenburg’s experiments the organism itself is actively at work. As to compounds liable to ionisation, it has been noticed by Maillard that a certain regulatory character is contained simply in the physical fact that the degree of ionisation changes with concentration: decrease of concentration for instance would be followed by an increase of ionisation, and so the osmotic pressure may be preserved (*C. rend. Soc. Biol.* 53, 1901, p. 880).

[97] In the different experiments of Nathansohn (*Jahrb. wiss. Bot.* 38, 1902, and 39, 1903) the salinity of the medium was changed in such a way that there was in each case either an abnormal increase or an abnormal decrease in the concentration of one single ion necessary for metabolism. The cell was found to stand these abnormal changes in such a way that in the case of the increase of the concentration of the medium it did not allow more than a certain amount of the ion in question to come in, and that in the case of the decrease it did not allow more than a certain quantity of the ion to go out. It thus seems as if the permeability of the surface were adjusted to a certain minimum and to a certain maximum of every single ion or salt, the permeability being stopped from within to without, whenever the minimum, and from without to within, whenever the maximum is reached in the cell sap; both irrespective of proper physical osmotic equilibrium (“Physiologisches Gleichgewicht”). Thus, in fact, there only would be a case of primary regulation, nothing more. It would all appear rather similar to what occurs in the kidney. Of course we do not assert that our explanation is right, but it is possible and is at the same time the most simple, and it is our general practice always to prefer the most simple hypotheses.

There are many regulation phenomena connected with osmotic pressure and permeability in animal physiology also, though at present they are not worked out as fully as possible. The works of Frédéricq, J. Loeb, Overton and Sumner[98] would have to be taken into account by any one who wished to enter more deeply into these problems. We can only mention here that permeability to water itself also plays its part, and that, according to Overton’s experiments, it is a kind of solubility of the media in the very substance of the cell surface on which all permeability and its regulation depend.

[98] Many fishes are able to withstand great changes in the osmotic pressure of sea-water; the osmotic pressure of their body fluids, though never in a real physical equilibrium with the pressure of the medium, nevertheless may vary whenever the abnormal conditions of the latter exceed certain limits.

*Chromatic Regulations in Algae.*--The phenomena of osmotic pressure and its regulation may be said to be the preliminaries of metabolism proper, conditions necessary for it to take place. Now there is another branch of such preliminaries to metabolism, in which the most interesting regulation phenomena have been lately discovered. It is well known that what is called assimilation in plants, that is, the formation of organic compounds out of carbon dioxide (CO_2) and water, occurs only in the light by means of certain pigments. This pigment is in all higher plants and in many others the green chlorophyll, but it may be different in certain species of algae, and can generally be said[99] to be of the colour complementary to the colour of those rays which especially are to be absorbed and to be used for assimilation. But here we have “adaptedness,” not adaptation. It was in some species of primitive algae, the *Oscillariae*, that Gaidukow[100] found a very interesting instance of an active regulation in the formation of pigments. These algae always assume a colour which corresponds to the accidental colour of the rays of the medium and is complementary to it; they become green in red light, yellow in blue light, and so on--that is, they always actively take that sort of colouring which is the most suitable to the actual case.[101] There indeed occurs a sort of complementary photography in these algae; but, though adaptive, it could hardly be said to exceed the limits of “primary phenomena.”

[99] See Stahl, *Naturw. Wochenschrift*, N. F. 5, 1906, No. 19.

[100] *Arch. Anat. Phys.*, Phys. Abt. Suppl., 1902.

[101] The adaptive phenomena discovered by Gaidukow depend upon a real alteration in the formation of pigments. In the (primary) chromatic adaptation of pupae of Lepidoptera with respect to the colour of the ground they live upon, we only have the variable effects of pre-established chromatophores (Poulton, *Phil. Trans. London*, 178 B, 1888; Merrifield, *Trans. Ent. Soc. London*, 1898). The same holds for chromatic adaptations in crabs (Gamble and Keeble, *Quart. Journ. Micr. Sci.* 43, 1900; Minkiewicz, *Arch. Zool. exp. et gén.* sér. 4, 7, notes, 1907).

*Metabolic Regulations.*--And now we enter the field of regulations in metabolism itself. There are two kinds of outside factors of fundamental importance for all metabolic processes: food is one, and oxygen is the other. And metabolism as a whole is of two different aspects also: it both serves for assimilation proper--that is, building up--and it supplies the energy for driving the functional machine. It is clear that food alone--together of course with the assimilating means of the organism, can account for the first type of metabolism, while both food and oxygen, or some sort of substitute for the latter, as in certain bacteria, supply functional energy. Of course we are not entitled to say that the importance of so-called oxidation or respiration is exhausted by its energetic rôle: it certainly is not, for if it were, the organism would only be stopped in its functions if deprived of oxygen but would not die. It seems that certain substances always arise in the metabolism, in the processes of decomposition, which have to be burnt up in order not to become poisonous. But we shall return to the phenomena of organic oxidation in another chapter of the book, and shall deal with them from a more general point of view.[102]

[102] The theory of oxidation we have shortly sketched here was developed in chapter B. 5, of my *Organische Regulationen*. Recent discoveries of Winterstein’s (*Zeitschr. allg. Physiol.* 6, 1907) have given the strongest support to my hypothetic statements, and, in fact, can be said to have brought the doctrine of organic oxidation to a critical point. There can be no doubt that oxygen not only plays the “antipoisonous” rôle I had assigned to it, but that it is not even of such great importance for the supply of functional energy as former times had assumed. No doubt it serves to drive the functional machine, but decomposition of certain chemical constituents of the organism serves this purpose even more. The latter does so in the most fundamental and original manner, so to speak, whilst oxidation only burns up its products. Almost all elemental functions, in nerve-tissue at least, go on very well in the absence of oxygen, provided that certain “poisonous” substances, resulting from this anaërobic metabolism, are constantly removed. In normal conditions that is done by oxygen, and in doing so oxygen certainly assists the supply of energy, but it does not furnish the whole of it. The difference between so-called “aërobic” and “anaërobic” life almost completely disappears under such a view, and many so-called “regulations,” of course, disappear at the same time; there is no more “intramolecular respiration.”

Let us now try to take a short survey of all the regulations discovered relating to the substitution of one kind of food for another. We have said that food serves in the first place as building material, in the second place as fuel. It only deserves brief mention that, as all recent investigations have shown, fats, carbohydrates, and albumen are equally well able to serve as fuel.[103]

[103] But nevertheless albumen is not to be replaced altogether in vertebrates by fat or carbohydrate; it probably serves some special function besides combustion, even in the adult.

It is in the state of fasting, *i.e.* in the case of a real absence of *all* nourishing materials, that the organism has proved to be capable of regulations of the most marked nature, with regard to the combustion of its own materials. Respiration, we know, must go on if death is to be avoided, and now indeed it has been found that this process attacks the different tissues of the organism subjected to fasting in such an order that, after the combustion of the reserves, the most unimportant tissues with regard to life in general are destroyed first, the most important ones last. Thus in vertebrates the nerve cells and the heart are preserved as long as possible; in infusoria it is the nucleus; in flatworms, as the very careful studies of E. Schultz[104] have lately shown, it is the nerve cells and the sexual cells which longest resist destruction, whilst almost all the rest of the organisation of these animals may disappear. I should not say that we can do very much with these facts at present in our theoretical discussion, but they are certainly witness of very astonishing adaptive powers.[105]

[104] *Arch. Entw. Mech.* 18, 1904.

[105] To a physiological friend of mine I owe the suggestion that it is the permanently functioning tissues which stand hunger better than the others, at least if the sexual cells might be regarded as capable of a *sécrétion interne* in all cases. Then the adaptations in the state of hunger might be said to be reduced in some degree to “functional adaptation.” But it must remain an open question, it seems to me, whether such a view may indeed hold in the face of the facts observed in *Planaria* and infusorians.

We now turn to study the cases of a compensation of nourishments serving for the real building up of the organism. Albumen, we know, is absolutely indispensable for animals, even for adults, though nothing is known about the purpose it serves in the latter; its place can be taken of course by those less complicated compounds which result from its first decomposition, effected by pepsin and trypsin, but nothing else will do. The salts of sea-water, according to Herbst’s experiments, may only vary to a very small degree if the development of marine animals is to go on well; potassium may be replaced by caesium or rubidium, and that is all. Much the same is true of the salts necessary to plants. It will not surprise us very much to hear that algae can also be successfully fed with the potassium salts of organic compounds, and higher plants with acid amides or glucoses instead of carbonic acid, as those products are normal steps in their assimilation; and it may also be fairly easily understood that nitrogen can be offered in organic form instead of as a nitrate.

It was in the group of fungi that really important adaptations with regard to the proper form-producing alimentation were first discovered, and these are of a very complicated kind indeed. Fungi are known to be satisfied with one single organic compound instead of the group of three--fat, carbohydrate and albumen--necessary for animals. Now Pfeffer showed that the most different and indeed very abnormal compounds were able to bring his subjects to a perfect growth and morphogenesis; and, moreover, he found that, if several kinds of such food were offered together, they were consumed quite indifferently as to their chemical constitution, but only with regard to their nutritive value: that sort of food which had produced a better growth than another when both were offered separately was found to save the latter from consumption whenever both were offered together.

Here we are faced by one of the most typical cases of regulations in metabolic physiology: the organism is able to decompose compounds of the most different constitution, which have never been offered to it before; but nevertheless, it must remain an open question whether real “secondary” regulation has occurred, as nothing is known in detail about the single steps of metabolism in these fungi. There *might* be some ferments equally able to destroy different classes of compounds,[106] and that the most nutritive compound is used up first *may* be a question of physico-chemical equilibrium.

[106] In all cases where fungi of the same species are able to live on different hosts, that is, to penetrate membranes of a different chemical character, a similar objection as to the “secondary” type of such a regulation may be made.

That is almost all[107] that is actually known of adaptation with regard to the use of an abnormal food supply. Though important, it cannot be said to be very much. But could we expect very numerous regulations here at all after what we laid down in a former paragraph about the possibilities of adaptive regulation in general? The functional state must have been altered in order that such regulations may occur. Now there is no doubt that this state may be really altered only if an abnormal food has first been taken in altogether by the cell-protoplasm of the body-surfaces, but never if it has only entered the cavity of the intestine, which, strictly speaking, is a part of the exterior medium. Fungi indeed not only take in the abnormal food, but also know what to do with it, but all animals are obliged to treat first with their chemical secretions what happens to be present in their intestine, in order that it may be taken up by their living cells, and one hardly can wonder that these secretions are only formed in correspondence to a limited number of outside stimuli. In fact, as soon as we look upon what adaptive or regulatory work happens in metabolism *inside* the body interior, we meet, even in animals, regulations of a far more developed type.

[107] The discovery of Weinland that adult dogs are able to produce “lactase” in their pancreas, whenever they are fed, quite abnormally, with milk-sugar, has recently been said to be vitiated by an analytical mistake.

Discoveries of the last few years have taught us that almost all metabolic processes in the organism, including oxidation, are carried out by the aid of special materials, the so-called enzymes or ferments. These are known to exist in the most different forms even in the inorganic world. They are simply chemical compounds, of specific types, that bring about chemical reactions between two other chemical materials, which in their absence would either not go on at all or would go on very slowly. We cannot enter here into the much disputed chemical theory of what is called “catalysis”: we can only say that there is no objection to our regarding almost all metabolic processes inside the organism as due to the intervention of ferments or catalytic materials, and that the only difference between inorganic and organic ferments is the very complicated character of the latter and the very high degree of their specification.

Such a statement, of course, does not say that all metabolism has proved to be of a chemical nature: the *action* of the ferment when produced is chemical, but we do not know at all *how* the ferment is produced; we only know that a high degree of active regulation is shown in this production. In fact, it has been proved in some cases, and probably will be proved in a great many more in the near future, that all metabolic ferments, whether they promote oxidation or assimilation proper or chemical decomposition, are produced in a regulatory manner with regard to the specific compound to be dissociated or to be built up. In this way the whole field of metabolism is really covered by “regulations.” Are they real “secondary” ones? Of course the regulatory correspondence applies to the process of *secretion* in the *first* place, not to the actual formation of the ferment inside the cell. The correspondence as to secretion, no doubt, is of the primary type; is there any secondary regulation with regard to the real *production* of the ferment? I am sorry that I cannot answer this question affirmatively. Nothing is *known* at present, even here, that really proves the existence of adaptation of the secondary type: there *might* be a sort of statical “harmony” at the base of it all, established before all functioning *for* functioning.[108]

[108] Compare the excellent review of the subject by Bayliss and Starling in the *Ergebnisse der Physiologie*, 5, 1906, p. 664. The reader who misses here an analysis of the brilliant discoveries of Pawlow and his followers, relating to so-called “psychical and associative secretion,” will find these facts dealt with in another section of the book. These facts, indeed, would prove vitalism, it seems to me.

The only facts of secondary metabolic regulations which are known at present have been found in combination with phenomena of restitution after real disturbances of organisation, where, indeed, numbers and numbers of regulatory changes of metabolism, both in animals and plants, have also been recorded. But there is not one case of a secondary regulation really known to affect pure metabolism alone.[109] This is a new indicium of the primacy of *form* in the organism.

[109] It would be a true secondary metabolic regulation, if after the extirpation of one gland another different one were to assume its function. Nothing is known in this respect except a few rather doubtful observations about the interchange of functions between thymus and thyroid, except also the fact that the so-called lymph-glands increase in size after the extirpation of the spleen. Even here, of course, a sort of “restitution” would be included in adaptation proper.

IMMUNITY THE ONLY TYPE OF A SECONDARY PHYSIOLOGICAL ADAPTATION

There is only one class of physiological processes in which the type of the real secondary regulation occurs. The discoveries of the last twenty years have proved beyond all doubt, and future discoveries will probably prove even more conclusively, that the so-called *immunity* against diseases is but one case out of numerous biological phenomena in which there is an adaptive correspondence between abnormal chemical stimuli and active chemical reactions on the part of the organism and in its interior, exceeding by far everything that was formerly supposed to be possible in organic regulation.

The adaptive faculty of the organism against inorganic poisonous substances[110] is but small comparatively, and is almost always due not to a real process of active regulation but to the action of substances pre-existing in the organism--that is, to a sort of adaptiveness but not adaptation. Metallic poisons, for instance, may be transformed into harmless compounds by being combined with albumen or sulphuric acid and thus becoming insoluble, or free acids may be neutralised, and so on; but all these processes go on to a certain extent only, and, as was mentioned already, are almost always the result of reactions with pre-existing materials. Only in a few cases is there any sort of true adaptation to metallic substances, such as sublimate and, in a very small degree, arsenic, comparable in some respects with the adaptation to abnormally high temperatures. The organism which has been accustomed to receive at first very small amounts, say, of sublimate, and then receives greater and greater amounts of this substance by degrees, will at the end of this treatment be able to stand a quantity of the poison that would have been instantly fatal if administered at the first dose.[111] But the explanation of this adaptation is not known in any case; there seems to be some similarity between it and the so-called histogenetic immunity against organic poisons.

[110] A good review is given by E. Fromm, *Die chemischen Schutzmittel des Tierkörpers bei Vergiftungen*, Strassburg, 1903.

[111] Davenport, *Arch. Entw. Mech.* 2, 1895-1896, and Hausmann, *Pflüger’s Arch.* 113, 1906.

It is in the fight against animal and vegetable poisons, such as those produced by bacteria, by some plants and by poisonous snakes, that the true adaptation of the organism reaches its most astonishing degree. The production of so-called “anti-bodies” in the body fluids is not the only means applied against noxious chemical substances of this kind: the existence of so-called histogenetic immunity is beyond all doubt, and Metschnikoff[112] certainly was also right in stating that the cells of the organism themselves repel the attack of living bacteria. Cells of the connective tissue and the white blood cells, being attracted by them as well as by many other foreign bodies, take them in and kill them. This process, called “phagocytosis” is of special frequency among lower animals, but it also contributes to what is called inflammation in higher ones.[113] And there are still other kinds of defence against parasites, as for instance the horny or calcareous membranes, employed to isolate trichinae and some kinds of bacteria. But all this is of almost secondary importance as compared with the adaptive faculties of the warm-blooded vertebrates, which produce anti-poisonous substances in their lymph and blood.

[112] *Leçons sur la pathologie comparée de l’inflammation*, Paris, 1902.

[113] The other steps or phases in the process of inflammation have also been regarded as adaptive: the increased quantity of body fluid for instance is said to serve to dilute poisonous substances.

It is impossible to say here[114] more than a few words about the phenomena and the theory of immunity proper, which have attained the dimensions of a separate science. Let me only mark those general points which are of the greatest theoretical interest. Discoveries of the most recent years have shown not only that against the “toxins” of bacteria, snakes, and some plants, the organism is able actively to produce so-called “anti-toxins”--that is, soluble substances which react with the toxins and destroy their poisonous character--whenever required, but that against any foreign body of the albumen group a specific reaction may occur, resulting in the coagulation of that body. But the destruction of the noxious substance or foreign albumen actually present is not all that is accomplished by the organism. “Acquired immunity” proper, that is, security against the noxious material for a more or less extensive period of the *future*, depends on something more. Not only is there produced as much of the so-called “anti-body” as is necessary to combine with the noxious, or at least foreign substances which are present, but *more* is produced than is necessary in the actual case. On this over-production depends all active immunity, whether natural or, as in some kinds of vaccination, artificial; and so-called “passive” immunity, obtained by the transfusion of the serum of an actively immune organism into another also depends upon this feature.[115]

[114] See Jacoby, *Immunität und Disposition*, Wiesbaden, 1906.

[115] *Collected Studies on Immunity by Ehrlich and his Collaborators*, translated by Ch. Bolduan, New York and London, 1906.

This phenomenon in particular--the production of *more* of the antitoxin or the “precipitin” than is actually necessary--seems to render almost impossible any merely chemical theory of these facts. The reaction between toxin and antitoxin, albumen and precipitin is indeed chemical; it may in fact be carried out in a test-tube; but whether the production of the anti-body itself is also chemical or not could hardly be ascertained without a careful and unbiassed analysis. There can be no doubt that the well-known theory of Ehrlich,[116] the so-called theory of side-chains (“Seitenkettentheorie”) has given a great impulse to the progress of science; but even this theory, irrespective of its admissibility in general, is not a real chemical one: the concept of a regeneration of its so-called haptophore groups is a strictly biological concept.[117]

[116] So-called genuine or innate immunity, in contrast to the immunity which is acquired, is of course a case of adaptedness only and not of adaptation. There also exists a high degree of specific adaptedness in some animals with regard to their faculty of coagulating blood. (See Leo Loeb, *Biol. Bull.* 9, 1905.)

[117] We cannot do more than barely mention here the problem of the localisation of anti-body production. In general it seems to be true that anti-bodies are produced by those cells which require to be protected against toxins; that would agree with the general rule, that all compensation of the change of any functional state proceeds from the part changed in its function.

And, indeed, here if anywhere we have the biological phenomenon of adaptation in its clearest form. There are very abnormal changes of the functional state of the organism, and the organism is able to compensate these changes in their minutest detail in almost any case. The problem of the specification of the reactions leading to immunity seems to me, as far as I can judge as an outsider, to stand at present in the very forefront of the science. There cannot be the slightest doubt that especially against all sorts of foreign albumens the reaction is as strictly specific as possible; but there are some typical cases of specificity in the production of antitoxins also. It is, of course, the *fact* of specific correspondence between stimulus and reaction, that gives to immunity its central position among all adaptations, no matter whether the old hypothesis of the production of specific anti-bodies proves tenable, or whether, as has been urged more recently by some authors, the anti-body is always the same but reacts differently according to the medium. In the latter case it would be the medium that is regulated in some way by the organism in order to attain a specific adaptedness.

NO GENERAL POSITIVE RESULT FROM THIS CHAPTER

But now let us look back to the sum of all the physiological reactions studied, and let us see if we have gained a new proof of the autonomy of life from our long chapter.

We freely admit we have not gained any really new *proof*, but we may claim, I think, to have gained many indicia for the statement that the organism is not of the type of a machine, in which every single regulation is to be regarded as properly prepared and outlined.

It is precisely in the field of immunity that such a machine-like preparation of the adaptive effects seems almost impossible to be imagined. How indeed could there be a machine, the chemical constituents of which were such as to correspond adaptively to almost every requirement?--to say nothing of the fact that the production of *more* of the protecting substance than is actually necessary could hardly be said to be “chemical.”

In fact, we are well entitled to say that we have reached here the very heart of life and of biology. If nevertheless we do not call the sum of our facts a real proof of vitalism, it is only because we feel unable to formulate the analysis of what happens in such a manner as to make a machine as the basis of all reactions absolutely unimaginable and unthinkable. There *might* be a true machine in the organism producing immunity with all its adaptations. We cannot disprove such a doctrine by demonstrating that it would lead to a real *absurdity*, as we did in our analysis of differentiation of form; there is only a very high degree of improbability in our present case. But an indirect *proof* must reduce to *absurdity* all the possibilities except one, in order to be a proof.

Mechanistic explanations in all branches of functional physiology proper, so much in vogue twenty years ago, can indeed be said to have failed all along the line: the only advantage they have brought to science is the clearer statement of problems to which we are now accustomed. But we are not fully entitled to say[118] that there never will be any mechanistic explanation of physiological functions in the future. It may seem as improbable as anything can be; but we wish to know not what is improbable but what is not possible.

[118] Here again I should like to except from this statement the discoveries of Pawlow. See page 204, note 1.

Now of course you might answer me that after we have indeed shown that the production of form, as occurring on the basis of harmonious-equipotential systems, is a fact that proves vitalism, the acts taking place on the basis of that form after its production would have been proved to be vitalistic also, or at least to be in some connection with vitalistic phenomena. Certainly they would, and I myself personally should not hesitate to say so. But that is not the question. We have to ask: Is any new proof, *independent of every other*, to be obtained from the facts of physiological adaptation in themselves? And there is really none. Mere regulatory correspondence between stimuli and reactions, even if it be of the adaptive type and occur in almost indefinite forms, never really disproves a machine as its basis so long as the stimuli and reactions are *simple* and uniform. Next summer, however, we shall see that vitalism may be proved by such a correspondence if the two corresponding factors are not simple and not uniform.

We most clearly see at this point what it really was in our analysis of differentiation that allowed us to extract a real proof of vitalism from it. Not the mere fact of regulability, but certain specific relations of space, of locality, lay at the very foundation of our proof. These relations, indeed, and only these relations, made it possible to reduce *ad absurdum* any possible existence of a machine as the actual basis of what we had studied. In our next chapter again it will be space-relations, though analysed in a different manner, that will enable us to add a second real proof of vitalism to our first one.

With this chapter we conclude the study of organic regulation in all its forms, as far as morphogenesis and metabolism are in question.

But our analysis of these regulations would be incomplete and indeed would be open to objections, if we did not devote at least a few words to two merely negative topics, which will be taken more fully into consideration later on.

A FEW REMARKS ON THE LIMITS OF REGULABILITY

There has never been found any sort of “experience” in regulations about morphogenesis or in adaptations of the proper physiological type. Nothing goes on “better” the second time than it did the first time;[119] everything is either complete, whenever it occurs, or it does not occur at all.

[119] The few cases of an “improvement” of morphogenetic acts in hydroids described by myself are too isolated at present to be more than mere problems (*Arch. Entw. Mech.* 5, 1897). The same is true, it seems to me, with regard to certain recent discoveries made by R. Pearl on *Ceratophyllum* (*Carnegie Inst. Wash. Publ.* No. 58, 1907); and by Zeleny on a medusa (*Journ. exp. Zool.* 5, 1907). Pawlow’s discovery, that the enzymotic composition of the pancreatic fluid in dogs becomes more and more adapted to a specific composition of the food (either meat or bread and milk) the longer such a specific composition is offered to the individual animal, may probably be understood as a case of mere functional adaptation of the cells of the digestive glands, if it stands criticism at all (see Bayliss and Starling, *Ergeb. Physiol.* 5, 1906, p. 682).

That is the first of our important negative statements about regulations; the second relates to the phrase just used, “or it does not occur at all.” There are indeed limits of regulability; adaptations are not possible to every sort of change of the physiological state: sickness and death could not exist if they were; nor is restitution possible in all cases where it might be useful. It is a well-known fact, that man is only able to heal wounds but is altogether destitute of the faculty of regeneration proper. But even lower animals may be without this faculty, as are the ctenophores and the nematodes for instance, and there is no sort of correspondence between the faculty of restitution and the place in the animal kingdom. It is not altogether impossible that there may be found, some day, certain conditions under which every organism is capable of restoring any missing part; but at present we know absolutely nothing about such conditions.[120]

[120] Experiments carried out in the “Biologische Versuchsanstalt” at Vienna indeed have shown that many animal types are capable of at least a certain degree of restitution, although they had previously been denied this faculty by zoologists.

But no amount of negative instances can disprove an existing positive--which is what we have been studying. Our analysis based upon the existence of regulations is as little disparaged by cases where no regulability exists as optical studies are by the fact that they cannot be undertaken in absolute darkness.

*D.* INHERITANCE: SECOND PROOF OF THE AUTONOMY OF LIFE

All organisms are endowed with the faculty of re-creating their own initial form of existence.

In words similar to these Alexander Goette, it seems to me, has given the shortest and the best expression of the fact of inheritance. Indeed, if the initial form in all its essentials is re-created, it follows from the principle of univocality, that, *ceteris paribus*, it will behave again as it did when last it existed.

By the fact of inheritance life becomes a rhythmic phenomenon, that is to say, a phenomenon, or better, a chain of phenomena, whose single links reappear at constant intervals, if the outer conditions are not changed.

THE MATERIAL CONTINUITY IN INHERITANCE

It was first stated by Gustav Jaeger and afterwards worked out into a regular theory by Weismann, that there is a continuity of material underlying inheritance. Taken in its literal meaning this statement is obviously self-evident, though none the less important on that account. For as all life is manifested on bodies, that is on matter, and as the development of all offspring starts from parts of the parent bodies, that is from the matter or material of the parents, it follows that in some sense there is a sort of continuity of material as long as there is life--at least in the forms we know of. The theory of the continuity of “germ-plasm” therefore would be true, even if germ-cells were produced by any and every part of the organism. That, as we know, is not actually the case: germ-cells, at least in the higher animals and in plants, are produced at certain specific localities of the organism only, and it is with regard to this fact that the so-called theory of the “continuity of germ-plasm” acquires its narrower and proper sense. There are distinct and specific lines of cell-lineage in ontogenesis, so the theory states, along which the continuity of germ-protoplasm is kept up, which, in other words, lead from one egg to the other, whilst almost all other lines of cell-lineage end in “somatic” cells, which are doomed to death. What has been stated here is a fact in many cases of descriptive embryology, though it can hardly be said to be more than that. We know already, from our analytical and experimental study of morphogenesis, that Weismann himself had to add a number of subsidiary hypotheses to his original theory to account for the mere facts of regeneration proper and the so-called vegetative reproduction in plants and in some animals, and we have learned that newly discovered facts necessitate still more appendixes to the original theory. In spite of that, I regard it as very important that the fact of the continuity of some material as one of the foundations of inheritance has clearly been stated, even if the specialised form of the theory, as advocated by Weismann in the doctrine of the “germ-lineages” (“Keimbahnen”) should prove unable to stand against the facts.

The important problem now presents itself: What is the material, the matter, which is handed down from generation to generation as the basis of inheritance? Weismann, as we know, regarded it as a very complicated structure, part of which by its disintegration became the foundation of individual embryology. We have disproved, on the authority of many facts, the latter part of this assumption; but of course the first part of it may turn out to be true in spite of this. We have no means at present to enable us to say *a priori* anything positive or negative about the important question of the nature of that matter, the continuity of which in inheritance is in some sense a self-evident fact, and we therefore shall postpone the answer until a later point of our analytical discussion.

ON CERTAIN THEORIES WHICH SEEK TO COMPARE INHERITANCE TO MEMORY

It will be advisable first to study some other theoretical views which have been put forward with regard to inheritance. The physiologist Hering, as early as 1876, compared all heredity to the well-known fact of memory, assuming, so to say, a sort of remembrance of all that has happened to the species in the continuity of its generations; and several German authors, especially Semon, have lately made this hypothesis the basis of more detailed speculation.

It is not clear, either from Hering’s paper[121] or from Semon’s book,[122] what is really to be understood here by the word “memory,” and, of course, there might be understood by it very different things, according to the author’s psychological point of view. If he is a “parallelist” with regard to so-called psychical phenomena, he would use the word memory only as a sort of collective term to signify a resultant effect of many single mechanical events, as far as the material world of his parallel system comes into account, with which of course the problem of inheritance alone deals; but if he maintains the theory of so-called psycho-physical interaction, the psychical would be to him a primary factor in nature, and so also would memory. As we have said, it is by no means clear in what sense the word “memory” is used by our authors, and therefore the *most* important point about the matter in question must remain *in dubio*.

[121] *Ueber das Gedächtnis als eine allgemeine Function der organischen Materie*, Wien, 1870. New edition in *Klassiker d. exakt. Wiss.*, Leipzig, Engelmann.

[122] *Die Mneme*, Leipzig, 1904.

But another topic is even more clear in the theory of inheritance, as stated in Hering’s and Semon’s writings. The hypothetical fact that so-called “acquired characters” are inherited is undoubtedly the chief assumption of that theory. Indeed, it would be difficult to understand the advantage of the ambiguous word memory, had it not to call attention to the hypothetic fact that the organism possesses the faculty of “remembering” what once has happened to it or what it once has “done,” so to speak, and profiting by this remembering in the next generation. The zoologist Pauly indeed has stated this view of the matter in very distinct and clear terms.

As we soon shall have another occasion to deal with the much-discussed problem of the “inheritance of acquired characters,” we at present need only say a few words about the “memory-theory” as a supposed “explanation” of heredity. Undoubtedly this theory postulates, either avowedly or by half-unconscious implication, that all the single processes in individual morphogenesis are the outcome either of adaptations of the morphological type, which happened to be necessary in some former generation, or of so-called contingent “variations,” of some sort or other, which also happened once in the ancestral line. Such a postulate, of course, is identical with what is generally called the theory of descent in any of its different forms. This theory is to occupy us in the next lectures; at present we only analyse the “memory-theory” as a theory of heredity in itself. In any case, to regard memory as the leading point in inheritance, at least if it is to signify what is called memory in any system of psychology, would be to postulate that either adaptation or contingent “variation” has been the origin of every morphogenetic process. Indeed, the American physiologist Jennings did not hesitate to defend such a view most strongly, and many others seem to be inclined to do the same.

But such an assumption most certainly cannot be true.