Ehrlich, harmonizes with the facts established with regard to toxic action and the behaviour of antitoxins, and may now be regarded as established. His view as to the dual composition of the toxin molecule has already been mentioned, and it is evident that if the haptophorous or combining group has its affinity satisfied by union with antitoxin, the toxin will no longer combine with living cells, and will thus be rendered harmless. One other important fact in support of what has been stated is that a toxin may have its toxic action diminished, and may still require the same amount of antitoxin as previously for neutralization. This is readily intelligible on the supposition that the toxophorous group is more labile than the haptophorous. There is, however, still dispute with regard to the exact nature of the union of toxin and antitoxin. Ehrlich’s view is that the two substances form a firm combination like a strong acid and a base. He found, however, that if he took the largest amount of toxin which was just neutralized by a given amount of antitoxin, much more than a single dose of toxin had to be added before a single dose was left free. For example, if 100 doses of toxin were neutralized by a unit of antitoxin (v. supra) it might be that 125 doses would need to be added to the same amount of antitoxin before the mixture produced a fatal result when it was injected. This result, which is usually known now as the “Ehrlich phenomenon,” was explained by him on the supposition that the “toxin” does not represent molecules which are all the same, but contains molecules of different degrees of combining affinity and of toxic action. Accordingly, the most actively toxic molecules will be neutralized first, and those which are left over, that is, uncombined with antitoxin, will have a weaker toxic action. This view has been assailed by Thorvald Madsen and S. A. Arrhenius, who hold that the union of toxin and antitoxin is comparatively loose, and belongs to the class of reversible actions, being comparable in fact with the union of a weak acid and base. If such were the condition there would always be a certain amount both of free toxin and of free antitoxin in the mixture, and in this case also considerably more than a dose of toxin would have to be added to a “neutral mixture” before the amount of free toxin was increased by a dose, that is, before the mixture became lethal. It may be stated that while in certain instances the union of toxin and antitoxin may be reversible, all the facts established cannot be explained on this simple hypothesis of reversible action. Still another view, advocated by Bordet, is that the union of toxin and antitoxin is rather of physical than of strictly chemical nature, and represents an interaction of colloidal substances, a sort of molecular deposition by which the smaller toxin molecule becomes entangled in the larger molecule of antitoxin. Sufficient has been said to show that the subject is one of great intricacy, and no simple statement with regard to it is as yet possible. We are probably safe in saying, however, that the molecules of a toxin are not identical but vary in the degree of their combining affinities, and also in their toxic action, and that, while in some cases the combination of anti-substances has been shown to be reversible, we are far from being able to say that this is a general law.
The origin of antitoxin is of course merely a part of the general question regarding the production of anti-substances in general, as these all combine in the same way with their homologous substances and have the same Formation of anti-
toxin.character of specificity. As, however, most of the work has been done with regard to antitoxin production we may consider here the theoretical aspect of the subject. There are three chief possibilities: (a) that the antitoxin is a modification of the toxin; (b) that it is a substance normally present, but produced in excess under stimulation of the toxin; (c) that it is an entirely new product. The first of these, which would imply a process of a very remarkable nature, is disproved by what is observed after bleeding an animal whose blood contains antitoxin. In such a case it has been shown that, without the introduction of fresh toxin, new antitoxin appears, and therefore must be produced by the living tissues. The second theory is the more probable a priori, and if established removes the necessity for the third. It is strongly supported by Ehrlich, who, in his so-called “side-chain” (Seitenkette) theory, explains antitoxin production as an instance of regeneration after loss. Living protoplasm, or in other words a biogen molecule, is regarded as consisting of a central atom group (Leistungskern), related to which are numerous secondary atom groups or side-chains, with unsatisfied chemical affinities. “Side-
chain” theory. The side-chains constitute the means by which other molecules are added to the living molecule, e.g. in the process of nutrition. It is by means of such side-chains that toxin molecules are attached to the protoplasm, so that the living molecules are brought under the action of the toxophorous groups of the toxins. In antitoxin production this combination takes place, though not in sufficient amount to produce serious toxic symptoms. It is further supposed that the combination being of somewhat firm character, the side-chains thus combined are lost for the purposes of the cell and are therefore thrown off. By the introduction of fresh toxin the process is repeated and the regeneration of side-chains is increased. Ultimately the regeneration becomes an over-regeneration and free side-chains produced in excess are set free and appear in the blood as antitoxin molecules. In other words the substances, which when forming part of the cells fix the toxin to the cells, constitute antitoxin molecules when free in the serum. This theory, though not yet established, certainly affords the most satisfactory explanation at present available. In support of it there is the remarkable fact, discovered by A. Wassermann and Takaki in the case of tetanus, that there do exist in the nervous system molecules with combining affinity for the tetanus toxin. If, for example, the brain and spinal cord removed from an animal be bruised and brought into contact with tetanus toxin, a certain amount of the toxicity disappears, as shown by injecting the mixture into another animal. Further, these molecules in the nervous system present the same susceptibility to heat and other physical agencies as does tetanus antitoxin. There is therefore strong evidence that antitoxin molecules do exist as part of the living substance of nerve cells. It has, moreover, been found that the serum of various animals has a certain amount of antitoxic action, and thus the basis for antitoxin production, according to Ehrlich’s theory, is afforded. The theory also supplies the explanation of the power which an animal possesses of producing various antitoxins, since this depends ultimately upon susceptibility to toxic action. The explanation is thus carried back to the complicated constitution of biogen molecules in various living cells of the body. It may be added that in the case of all the other kinds of anti-substances, which are produced by a corresponding reaction, we have examples of the existence of traces of them in the blood serum under normal conditions. We are, accordingly, justified in definitely concluding that their appearance in large amount in the blood, as the result of active immunization, represents an increased production of molecules which are already present in the body, either in a free condition in its fluids or as constituent elements of its cells.
In preparing anti-bacterial sera the lines of procedure correspond to those followed in the case of antitoxins, but the bacteria themselves in the living or dead condition or their maceration products are always used in Anti-bacterial serum.the injections. Sometimes dead bacteria, living virulent bacteria, and living supervirulent bacteria, are used in succession, the object being to arrive ultimately at a high dosage, though the details vary in different instances. The serum of an animal thus actively immunized has powerful protective properties towards another animal, the amount necessary for protection being sometimes almost inconceivably small. As a rule it has no action on the corresponding toxin, i.e. is not antitoxic. In addition to the protective action, such a serum may possess activities which can be demonstrated outside the body. Of these the most important are (a) bacteriolytic or lysogenic action, (b) agglutinative action, and (c) opsonic action.
The first of these, lysogenic or bacteriolytic action, consists in
