NATURE 



[August 14, igi 



immune against fuchsin, then this race is immune 

 against all the allies of fuchsin and methyl violet, 

 &c, but it is not immune against the two other classes. 



Also a race immune against arsenic compounds is 

 only immune against such, but not against the two 

 other classes. We see, therefore, that the immunity 

 is of a specific nature inasmuch as it is limited to a 

 definite class of chemical substances. 



It was just this specific character which indicated 

 that it must be a question of purely chemical processes. 

 Earlier studies relating to another subject, i.e. those 

 relating to toxins and antitoxins, pointed to the nature 

 of the said processes. In connection with these it had 

 been shown that the destructive toxins developed their 

 injurious action on the cell by the fact that they are 

 absorbed by certain specific component parts of the 

 cell — side chains — which I have characterised as " re- 

 ceptors," and that the anti-substances represent 

 nothing else than the cell receptors produced in excess 

 under the influence of the toxin and thrown off. 



For many reasons I had hesitated about transferring 

 these views relating to receptors to chemical bodies at 

 all, and in this connection it was especially the bril- 

 liant investigations by Langley relating to the effects 

 of alkaloids which caused my doubts to disappear and 

 made the existence of chemo-receptors seem probable 

 to me. 



From this point of view, the phenomena observed 

 in connection with the " drug-fasr " strain of germs 

 can be readily explained experimentally, owing to the 

 fact that the chemo-receptors under the influence of 

 drug-fastness suffer a reduction of their affinity for 

 certain groupings connected with the remedy, which 

 can only be regarded as purely chemical. This reduc- 

 tion in affinity explains in the simplest possible manner 

 why continually increasing quantities of the arsenic 

 compound become necessary for the destruction, e.g. 

 of a race of arsenic-fast trypanosomes, for the smaller 

 avidity can only be overcome by a corresponding sur- 

 plus of the arsenic compound, if the quantity neces- 

 sary for the destruction of the parasites is to be 

 finally fixed. 



We, therefore, come to the conclusion that in the 

 parasites there are present different specific chemo- 

 receptors. for instance, the arseno-receptor, which 

 fixes the trivalent group of arsenic as such; and the 

 acetico-receptor, which fastens to itself the acetic acid 

 group, an iodine-receptor, an orthoamidophenol-recep- 

 ior, which conditions the fixation of the salvarsan, 

 and many others in addition. A complete exhaustive 

 knowledge of all the different chemo-receptors of a 

 certain definite parasite is what I should like to char- 

 acterise as the therapeutic physiology of the parasite 

 cell, and this is a sine qua non of anv successful 

 chemio-therapeutic treatment. I should like to em- 

 phasise the fact that many observations indicate that 

 ( ertain chemo-receptors are due to several different 

 kinds of parasites, not to a single one. The know- 

 ledge of these is of special practical importance, be- 

 cause remedies which are adjusted to these have a 

 healing influence on a very large series of the most 

 various pathogenic agents. The larger the number of 

 different chemo-receptors, therefore, which eati be 

 demonstrated the greater is the possibility of a suc- 

 cessful chemio-therapy. 



Now if we seek for specific remedies, then the first 

 condition is that they must possess a certain definite 

 grouping, which is chemically allied to one of the 

 chemo-receptors of the parasite. This is only a neces- 

 sary prior condition of the toxic effect, but in general 

 it is not a sufficient one in itself. Hundreds of sub- 

 stances may fix themselves on a parasite and onlv a 

 few are capable of bringing about its destruction. 



In the therapeutically suit ible substance there must, 

 therefore, in addition to the fixing group, which brings 

 NO. 2285, VOL - 9l] 



about the fixation of the haptophorae, be another, 

 which as such brings about the destruction, and 

 therefore is to be characterised as the "poisoning" 

 or toxophoric. This representation exactly corresponds 

 to_ the views which we have already long since ob- 

 tained with respect to toxins, in which we distinguish 

 the presence of a haptophoric group which conditions 

 the_ cell fixation and also the formation of the anti- 

 toxins^ and a toxophoric group which brings about 

 the injurious action on the cell. In the case of the 

 highly complicated synthetic drugs the assumption will 

 have to be made that the haptophoric group and the 

 toxophoric group are not directly connected with one 

 another, but as separate groups are linked with a 

 chemical molecule in the character of side-chains. In 

 this way we arrive in a natural manner to this, that 

 chemio-therapeutic agents, built up in a complicated 

 manner, may be compared to a poisoned arrow ; the 

 fixing group of the drug which anchors itself tn the 

 chemo-receptor of the parasite corresponds to the point 

 of the arrow, the binding member is the shaft, and 

 the poison group is the arrow poison fixed to the shaft 

 of the arrow. Corresponding to this scheme in the 

 case of salvarsan (dioxydiamidoarsenobenzol) the 

 benzol group would correspond to the shaft, the ortho- 

 amidophenol group to the point, and the trivalent 

 arsenic group would correspond to the toxophoric 

 group. 



If we continue this comparison, then the substances 

 which are used for poisoning the arrows are alkaloids 

 and similar substances, which act injuriously on cer- 

 tain definite vital organs of the body ; and so we shall 

 also have to assume that the toxophoric grouping of 

 the synthetic drugs poisons the protoplasm of the bac- 

 terial cell, and this only appears to be possible when 

 a chemical affinity exists between the toxophoric 

 grouping and the constituents of the cell. The cir- 

 cumstance that all the derivatives of arsenic which 

 contain arsenic in the pentavalent form, i.e. in the 

 fully saturated form, do not bring about any thera- 

 peutic action, but that this only commences when the 

 arsenic group exists in the unsaturated condition corre- 

 sponding to the trivalent radical, certainly points in 

 the same direction. This difference between the 

 saturated and unsaturated arsenic radical was dis- 

 covered by the master mind of Bunsen, for in the 

 year 1843, in his comparative studies relating to the 

 non-poisonous cacodylic acid with the pentavalent 

 arsenic and its poisonous reduction product, the cacodyl 

 with the trivalent arsenic, he came to the conclusion 

 that "the cacodylic acid had lost the power to form 

 an attacking point, and at the same time it had lost 

 its effect on the organism." In the subsequent period 

 a very large series of analogous cases have become 

 known corresponding to this truth, which point to 

 the increased effectivity of the unsaturated radical. 

 The best-known example is doubtless the high degree 

 of toxic power of carbon monoxide as compared with 

 the almost indifferent carbon dioxide. 



Dyes act as bactericides only as such, but not in the 

 form of their colourless products which correspond to 

 the saturated type. The fact is that all 1hcsc un- 

 saturated combinations contain unsatisfied avidities 

 which render them capable of reacting additionally 

 with other combinations. 



If, therefore, we poison a spirochaeta with salvarsan, 

 then there occur at least two different chemical fixa- 

 tions : first of all the fixation of the orthoamidophenol 

 group, which primarily fixes the salvarsan to the 

 parasite. It is only in consequence of this fixation 

 that secondarily the trivalent arsenic group is given 

 the opportunity of entering into chemical combination 

 with the arseno-receptor of the cell, and so to exert 

 its toxic effect. The avidity of the arseno-receptor can 

 in itself be such that it can only react if favouring 





