# Defensive Ferments of the Animal Organism/Defensive Ferments of the Animal Organism/Section 3

​If these views are correct, it should be possible to trace such substances as are in harmony with the body, but not with the blood and its plasma, by looking for definite ferments. It is quite conceivable that, in certain diseases, the cells only partially effect the decomposition of the nutritive material and of the constituents of the body, and that, to a certain extent, materials that are harmonious only with the cells are handed on to the lymph. The lymph, as already pointed out, would in many cases do its best to correct this failure by means of its cells, the ​leucocytes, and its special organs, the lymphatic glands, and would attempt to decompose some of the disharmonious products before they reach the blood. In many cases, however, disharmonious material will get into the blood, and produce all kinds of disturbances.
We know of at least two conditions in which disharmonious substances undoubtedly circulate in the blood, namely, Bence Jones's albuminuria, and pregnancy. In the latter case it is certain that we are deal in cj 1 with substances that are in harmony with the species, while in the first case there is a possibility that disharmonious substances are present. Bence Jones's albuminuria is nearly always found in conjunction with sarcoma of the bones. Whether the sarcoma is to be regarded as a harmonious tissue or not, we are not yet in a position to decide.
As to pregnancy, we know, thanks to the important observations of Schmorl, that the cells of the chorionic villi may be torn off, and be carried into the circulation. Veit has indeed proved that these cases are relatively frequent. Weichardt, and later also Richard Freund, tried to connect the appearance of chorionic villi in the circulation with eclampsia. Weichardt was thinking of a dissolution of the cells—cytolysis—in which case toxic products are supposed to appear.
​To us these observations and views had this much value: that they directed our attention to the fact that, during pregnancy, the appearance of substances, that were in harmony with the species but not with the plasma, might be possible. If our view is correct, that the animal organism sets free ferments of a special kind, as soon as material that is in harmony with the species, but not with the plasma, passes into the blood, then it ought to be possible to demonstrate the existence of such ferments during pregnancy. As, however, the ferments, as we know from experience, disappear fourteen to twenty-one days after the actual introduction of disharmonious substances, it was scarcely possible to expect that defensive ferments should be met with during the whole period of pregnancy. One had to experiment with a great many cases, before striking that one in which dissolution of the cells of the villi had just taken place.
Experience, however, soon showed that the serum of pregnant individuals always contains defensive ferments which are directed against placenta albumen. We cannot, therefore, maintain that the tearing off of the epithelium of the chorionic villi is the only cause of the appearance of the defensive ferments. It must be remembered that even the mare exhibits, during pregnancy, defensive ferments which are directed against placenta albumen; yet the placenta of the mare is related to the circulation in ​such a way as to exclude the possibility of the cells of the chorionic villi getting into the blood.
How can we then explain the existence of the defensive ferments during pregnancy? It can only be in very exceptional cases that they are produced by the invasion of morphological elements. In most cases it must be the result of the transfer of particular bodies—the constituents of particular cells, or the products of their decomposition. It may be, of course, that the extraordinarily active metabolic processes, which arise at the junction of the maternal and fœtal organisms, result in an insufficient reduction of many of the products of the cells of the placenta; the metabolism, in short, overreaching itself through its own rapidity. It is, however, also conceivable that the cells themselves break up easily.
The following view is probably the correct one. The organism of the mother has at its disposal, up to the appearance of pregnancy, a certain amount of cells of a certain kind, which all harmonize, in their metabolism, with each other. Now, with conception, comes the appearance of an entirely new kind of tissue, which has to perform particular duties. Although the impregnated egg and the developing placenta, with all its various cells, are in harmony with the species, nevertheless the metabolism of all these cells appears as something quite new and strange to the complex of cells composing the ​organism of the mother. The blood probably receives substances—perhaps also secretions—which are out of harmony with the plasma, and remain so; and the time is too short for the blood to accustom itself entirely to these new kinds of substances. The placenta, according to this point of view, together with the fœtus, never settles down completely within the organism of the mother. With the expulsion of the placenta, in which process, again, ferments probably play a preparatory part, the ferments which are directed against its albumen disappear fairly quickly. It is, of course, quite possible that these placentally active ferments are conditioned by many different forces.
The view we have just discussed gives us an opportunity of demonstrating the initiation of the function of a particular organ. Were an organ to suddenly take up a particular function at a particular moment—say the delivery of a particular secretion—then it is quite conceivable that its activities would, at first, be disharmonious with the plasma. We might possibly expect something of this kind from the sexual glands at the onset of puberty; but experiments carried on in this direction upon animals in heat have not as yet given any certain result. On the other hand, the cessation of the functions of a particular organ might lead to the appearance of substances out of harmony with the blood; for these functions do not cease suddenly, and it may be that their gradual ​discontinuance leads to the appearance of insufficiently decomposed products. Involution, too, may be the cause of the formation of products that are out of harmony with the blood; in which connection we have in mind more especially the degeneration of the thymus, and the climacterium.
Many of our own researches, and those of various observers, have shown that, during the whole period of pregnancy, defensive ferments circulate in the blood, which are able to reduce placenta albumen. These ferments may be demonstrated within about eight days after impregnation. Their presence is, without any doubt, dependent upon the circulation of disharmonious substances originating in the placenta; since the defensive ferments disappear within fourteen to twenty-one days, when the relations of the placenta with the maternal organism have ceased.
Attempts have also been made to decompose placental tissues by means of the blood serum of the fœtus. No digestion could be induced; nor can the serum of pregnant individuals be made to attack the tissues of the fœtus. In any case these observations must be carefully followed up. It might be imagined, a priori, that there are developmental stages, in which the tissues of the fœtus are as yet so little differentiated, that they are still of a generalized character. Nor did umbilical blood ​serum show any decomposition, when mixed with the serum of impregnated individuals. Had that been the case, then a very simple method for the diagnosis of pregnancy would have been found.
From the experience we have already gained, we may venture to say that the behaviour of blood serum towards coagulated placental tissue, or to placenta peptone, enables us to diagnose a state of pregnancy in the clearest possible way; or, expressed more correctly, to decide whether a placenta is in existence which is still in communication with the organism of the mother. A limitation is only necessary, because the defensive ferments can still be traced for a certain time after the expulsion of the placenta. For the practical sero-diagnosis of pregnancy this circumstance is of little importance, because the case under observation can be examined clinically. Normal non-pregnant individuals do not show any disintegration of the placental tissue.
We now had to decide the extremely important question, whether defensive ferments of a more general nature appear, when the organism contains other substances that are out of harmony with the plasma. This problem may be precisely expressed in the following manner: Does the serum of individuals, who suffer from infectious diseases, or from carcinoma, or who exhibit a disease of any other kind, decompose placental tissue? A priori, one was driven ​to the conclusion that they would do so, because it had been noticed that, after the introduction of disharmonious substances into the circulation, not only do ferments appear which reduce the particular compound inoculated, but the defensive ferments produced attack many other substances of the same order. There was no production of strictly specific ferments, but only of those which are limited in their action to a particular class of compounds. And when substances that were in harmony with the body, but not with the plasma, were chosen for these experiments, no ferments appeared that were strictly specific.
We tested the sera of tuberculous individuals, of sufferers from carcinoma, of persons with salpingitis, and others, for their behaviour towards placental tissue, but in not a single case did decomposition take place. To our great surprise it appeared, that the animal organism only sets free strictly specific ferments, when particular cells are themselves giving off substances which are not in harmony with the plasma.
How can we explain this different mode of behaviour, according to whether we introduce such disharmonious substances, or whether the organism itself supplies them? There are various possibilities to be considered. In the first place the cell may give off the substances in question only in minute quantities, a condition which we are unable to imitate. Our methods of interference are ​always brutal, and at once produce pathological conditions. We cannot imitate this method of supplying a substance in minute quantities, simply because we have no means of controlling the essential mechanism of regulation, owing to our ignorance of its nature. By our injections of disharmonious material we suddenly alter the composition of the blood, and injuriously affect the whole organism. It is, in this respect, most interesting that defensive ferments which only decompose cane sugar, can be obtained when, for instance, cane sugar is injected in very small quantities. As the quantity of cane sugar is increased then, very often, the blood serum is able to dissociate milk sugar as well. But, if too much of the above kind of sugar be introduced into the blood, then as a rule defensive ferments do not appear at all.
Further, it is possible that the substances, which we artificially introduce into the body, are not sufficiently fine in structure to produce specific ferments, specially directed against them. The cell gives off its particular disharmonious substances with their specific features stamped on them, while we, on the contrary, bring into the circulation material that has already been altered. This difference may be illustrated in the following manner. Suppose, on the one hand, that two persons start to fight each other with two "specifically" chosen weapons. Such a fight is premeditated; the weapons are precise, and the ​defensive measures adopted depend on their nature. In another case two individuals throw themselves brutally one upon the other without any previous choice of weapons; then any means is good, if it only succeeds in overcoming the opponent somehow.
One fact must always be kept in mind. When we introduce proteins or peptones and the like into the blood-vessels, these are never pure compounds. Together with the peptones we certainly introduce into the circulation a number of different stages of the decomposition of proteins. Suppose we take the white of an egg, then without doubt innumerable albuminous substances are present, which greatly differ one from the other. We must not forget the fact, that traces of particular substances are quite sufficient to cause the formation of ferments. The cells, on the contrary, set free substances that are probably of a very precise character.
If we artificially introduce material that is out of harmony with the blood, the animal organism reacts against it with a whole complex of defensive ferments, because our material is always a mixture of substances. It is to a certain degree prepared for all eventualities. It has no actual knowledge of the characteristics of the introduced product. If, at any point, particular cells exhibit a deficiency of function in respect of their metabolism, then there always appears in the blood plasma, from one moment to ​another, just a trace of some specifically organized substance, and this is at once deprived of its essential properties by means of the opposing defensive ferment. It might be thought that the same cells which give off the disharmonious material would themselves supply the ferments, and transfer their further reduction into the plasma; but at present there are no proofs for such a suggestion.
This view may be opposed on the ground, that it is difficult to understand how specifically directed ferments can be distinguished in boiled tissues. Many of the finer features in the structure of the substrate must surely be obliterated in the process of boiling. This probably holds only for the physical properties and hardly at all for the chemical. We may boil a substance having a composition A B C D, and another having a structure B C D A, for a long time; both would still retain their original composition or structure, although their physical properties might undergo alteration. Thus, for instance, their rotation might alter, and to this extent their biological behaviour might be affected. Thus there is nothing against the idea, that the substrate against which the ferment is directed may, in spite of its newly acquired properties, be still liable to attack by the ferment. With a key corresponding to a particular lock we can still unlock the latter, even though it has been badly damaged, provided only ​that the key can fit into the guide, and push back the bolt. The whole of the rest of the lock may, in this case, have suffered considerable alterations.
The ferments attack a particular substrate at a particular point, and very probably always combine with the groups against which they are directed. It is only secondarily that disturbance occurs of the equilibrium of the compound. So long as this point of attack remains unchanged the ferments are able to act, but the conditions become very different when the much altered product, with all its groupings, is brought into the circulation. If the decomposition is to be a complete one, then a number of ferments has to act. The new conditions, caused by the denaturation, produce their full effect after the introduction into the circulation. When we search for ferments by means of boiled tissues, we expose a variety of proteins to the action of ferments. Only that grouping of atoms, towards which the ferment is directed, has to be considered here. All other groups may be neglected, because it would be scarcely possible to presume that the boiling has produced structural conditions which are accessible to ferments, although the natural substrate was not so accessible. Rather must we reckon with the possibility that a too extensive denaturation will so strongly modify an original grouping, that is accessible to ferments, that the ferment then becomes inactive. The grouping has now become foreign to it.
​Much weightier still, at first sight, is the following objection. In the dialysation process we make use of coagulated albumens, when looking for defensive ferments. In the optical method peptones are used which are produced from these. Is there not a contradiction between our methods of research, and the ideas developed above with respect to the cause of the origin of the defensive ferments? If we surmise that the defensive ferments serve the purpose of decomposing disharmonious substances, built up from numerous units, into their single units, then we must further agree that ferments are present which can carry on the decomposition at least so far, that the specific characteristics of the cells are entirely destroyed. Therefore we ought to expect that, where proteins are decomposed by defensive ferments, peptones will also be destroyed provided we take, as substrates, those which correspond with the normal fermentative reduction stages of the original material. If, then, we agree that a substance that is out of harmony with the plasma always has an albuminous character, i.e., that the defensive ferments commence their decomposition at this stage, then there is no difficulty in imagining that the dialysation process and the optical method lead to similar results. In the first case we allow the defensive ferment to commence the decomposition at the albuminous stage, and establish the appearance of the crystalloidal, ​fusible stages (peptones). In the second case, we prepare the way for the ferments by producing peptones, which we then allow the ferments to decompose. So we allow serum of pregnancy to act upon a boiled placenta albumen, while in the optical method we use peptone produced from placenta albumen. In the first case, the appearance of diffusible stages of decomposition in the dialysate shows us that the decomposition has begun. In the second case, the change that takes place in the rotation enables us to infer a change in the composition of the added substrate, namely, of the peptone mixture.
Now very often, and probably in the great majority of cases, albumen itself does not pass into the circulation, but rather the products of its decomposition. We may easily understand that the optical method gives us trustworthv results, because it is quite possible that the peptone mixture used may also contain those stages of decomposition which have acted disharmoniously with the plasma. How, then, can we establish a decomposition of albumen? In those cases, for instance, where the cells of the body give off to the blood plasma peptones which still bear the characters of the cell, we start, in the dialysing process, at a higher stage of decomposition than was the case in the blood itself.
Unfortunately, we have no knowledge whatever concerning the nature of the ferments. We realize ​them exclusively by the manner in which they act, and that is why, in must questions relating to ferments and their activity, we are only able to answer with conjectures. We may imagine that a ferment is directed against a simpler product of decomposition, and yet that it attacks at the same time a more complicated molecule, in so far as the group through which it attacks the substrate is actually present therein and within reach. It only depends on whether the ferment is able to find a group, corresponding to its own structure and configuration, in the particular molecule. We must, also, not forget that, in a body of high molecular structure, the same grouping may recur many times. In any case we consider it very possible that cases are met with in which the optical method shows a decomposition, while the dialysation process gives a negative result; although it must be admitted that, up to the present, not a single case of this kind has been satisfactorily proved.
All these discussions would be superfluous, if we only knew, on the one hand the nature of the ferments, and on the other the components that are out of harmony with the plasma. As it is, we are simply faced with the fact that ferments, directed against particular substrates, are to be found in the blood serum under very definite conditions. What is entirely new is the clear demonstration of the fact that the animal organism, within certain limits, ​generally defends itself, by means of ferments, against compounds that are capable of decomposition and that consist of many elements. New, too, is the idea that by means of these ferments we can judge as to the functions of particular organs. Finally, the idea that the animal organism sets free specifically directed ferments, and that, in so doing, it registers the fact that the components of its various kinds of cells have an exclusive structure corresponding to each kind of cell, is also new.
Objection has been taken to the idea of strictly and specifically directed ferments on the ground, that it is impossible to accept the idea that specific reactions take place, because the so-called "antitryptic power" of Henkel-Rosenthal, the "cobra-poison hæmolysis" of Heynemann, and finally the "catalysator influence" of Weichardt, are not specific. It is forgotten that the fermentative decomposition represents the primary activity, and that those substances, which are in question in the above-mentioned methods, are produced secondarily by the defensive ferments. That, during the process of decomposition, the original characteristic structure of a compound is soon destroyed, we have repeatedly affirmed. All possible stages of decomposition, of the most different origin, can in many respects act identically. Thus, for instance, it is possible to prove conclusively that the hydrolysis of the dipeptide, d-alanyl-glycin, can be ​retarded by the addition of optically active a-amino-acids. It is a matter of indifference what kind of a-amino-acid is used, provided only it belongs to the units of the protein. We demonstrate the decomposition of a specifically constructed substrate, while the methods in question are concerned only with the influence of the products that are split off.
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