September 17, 1896] 



NA TURE 



469 



treatment of hydrophobia in the human sul)ject. We have seen 

 that I'asteur discovered that microbes might under some circum- 

 stances undergo mitigation of their virulence. lie afterwards 

 found that under different conditions they might have it exalted, 

 or, as he expressed it, there might be a reitfonentent dii virus. 

 Such proved to be the case with rabies in the rabbit ; so 

 that the spinal cords of animals which had died of it contained 

 the poison in a highly intensified condition. But he also found 

 that if such a highly virulent cord was suspended under strict 

 antiseptic precautions in a dryatmosphere at a certain temperature, 

 it gradually from day to day lost in potency, till in course of time 

 it became absolutely inert. If now an emulsion of such a harmless 

 cord was introduced under the skin of an animal, as in the subcu- 

 taneous administration of morphia, it might be followed without 

 harm another day by a similar dose of a cord still rather poisonous ; 

 and so from day to day stronger and stronger injections might be 

 used, the system becoming gradually accustomed to the poison, 

 till a degree of virulence had been reached far exceeding that 

 of the bite of a mad dog. When this had been attained, the 

 animal proved incapable of taking the disease in the ordinary 

 way ; and more than that, if such treatment was adopted after 

 an animal had already received the poison, provided that too 

 long a time had not elapsed, the outbreak of the disease was 

 prevented. It was only after great searching of heart that 

 Pasteur, after consultation with some trusted medical friends, 

 ventured upon trying this practice upon man. It has since 

 been extensively adopted in various parts of the world with 

 increasing success as the details of the method were improved. 

 It is not of course the case that every one bitten by a really 

 rabid animal takes the disease ; but the percentage of those who 

 do so, which was formerly large, has been reduced almost to 

 zero by this treatment, if not too long delayed. 



While the intensity of rabies in the rabbit is undoubtedly due 

 to a peculiarly virulent form of the microbe concerned, w'e 

 cannot suppose that the daily diminishing potency of the cord 

 suspended in dr)' warm air is an instance of attenuation of virus, 

 using the term " virus " as synonymous with the microbe con- 

 cerned. In other words, we have no reason to believe that the 

 special micro-organism of hydrophobia continues to develop in 

 the dead cord and produce successively a milder and milder 

 progeny, since rabies cannot be cultivated in the nervous system 

 of a dead animal. We must rather conclude that there must 

 be some chemical poison present which gradually loses its porency 

 as time passes. And this leads me to refer to another most 

 important branch of this large subject of bacteriology, that of 

 the poisonous products of microbes. 



It was shown several years ago by Rous and Versin, working 

 in the Institut Pasteur, that the crust or false membrane which 

 forms upon the throats of patients atfecled with diphtheria con- 

 tains bacteria which can be cultivated outside the body in a 

 nutrient liquid, with the result that it acquires poisonous quali- 

 ties of astonishing intensity, comparable to that of the secretion 

 of the poison-glands of the most venomous serpents. And I hey 

 also ascertained that the liquid retained this property after the 

 microbes had been removed from it by filtration, which proved 

 that the poison must be a chemical substance in solution, as 

 distinguished from the living element which had produced it. 

 These poisonous products of bacteria, or toxins as .they have 

 been termed, explain the deadly effects of some microbes, which 

 it would otherwise be impossible to understand. Thus, in 

 diphtheria it.self the special bacillus which was shown by Loffler 

 to be its cause, does not become propagated in the blood, like 

 the microbe of chicken cholera, but remains confined to the 

 surface on which it first appeared ; but the toxin which it 

 secretes is absorbed from that surface into the blood, and so 

 ]«)isons the system. Similar observations have been made with 

 regard to the microbes of some other diseases, as, for example, 

 the bacillus of tetanus or lockjaw. This remains localised in 

 the wound, but forms a special toxin of extreme potency, which 

 becomes absorbed and diffused through the body. 



Wonderful as it seems, each poisonous microbe appears to 

 form its own peculiar toxin. Koch's tuberculin was of this 

 nature, a product of the growth of the tubercle bacillus in 

 culture media. Here, again, great effects were produced by 

 extremely minute quantities of the substance, but here a new 

 peculiarity showed itself, viz. that patients affected with 

 tubercular disease, in any of its varied forms, exhibited in- 

 flammation in the affected part and general fever after receiving 

 under the skin an amount of the material which had no effect 

 whatever upon healthy persons. I witnessed in Berlin some 



NO. 1403, VOL. 54] 



instances of these effects, which were simply astounding. 

 Patients affected with a peculiar form of obstinate ulcer of the 

 face showed, after a single injection of the tuberculin, violent 

 inflammatory redness and swelling of the sore and surrounding 

 .skin : and, what was equally surprising, when this disturbance 

 subsided the disease was found to have undergone great improve- 

 ment. By repetitions of such procedures, ulcers which had 

 previously been steadily advancing, in spite of ordinary treat- 

 ment, became greatly reduced in size, and in some instances 

 apparently cured. Such results led Koch to believe that he had 

 obtained an effectual means of dealing with tubercular disease in 

 all its forms. Unhappily, the apparent cure proved to be only of 

 transient duration, and the high hopes which had been inspired 

 by Koch's great reputation was dashed. It is but fair to say 

 that he was strongly urged to publish before he was himself 

 disposed to do, and we cannot but regret that he yielded to the 

 pressure put upon him. 



But though Koch's sanguine anticipations were not realised, 

 it would be a great mistake to suppose that his labours with 

 tuberculin have been fruitless. Cattle are liable to tubercle, 

 and, when affected with it, may become a very serious source 

 of infection for human beings, more especially when the disease 

 affects the udders of cows, and so contaminates the milk. By 

 virtue ofthe close affinity that prevails between the lower animals 

 and ourselves, in disease as well as in health, tuberculin pro- 

 duces fever in tubercular cows in doses which do not affect 

 healthy beasts. Thus, by the subcutaneous use of a little of 

 the fluid, tubercle latent in internal organs of an apparently 

 healthy cow can be with certainty revealed, and the slaughter 

 of the animal after this discovery protects man from infection. 



It has been ascertained that glanders presents a precise 

 analogy with tubercle as regards the effects of its toxic product. 

 If the microbe which has been found to be the cause of this 

 disease is cultivated in appropriate media, it produces a poison 

 which has received the name of mallein, and the subcutaneous 

 injection of a suitable dose of this fluid into a glandered horse 

 causes striking febrile symptoms which do not occur in a healthy 

 animal. Glanders, like tubercle, may exist in insidious latent 

 forms which there was formerly no means of detecting, but which 

 are at once disclosed by this means. If a glandered horse has 

 been accidentally introduced into a large stable, this method of 

 diagnosis surely tells if it has infected others. All receive a 

 little mallein. Those which become affected with fever are 

 slaughtered, and thus not only is the disease prevented from 

 spreading to other horses, but the grooms are protected from 

 a mortal disorder. 



This valuable resource sprang from Koch's work on tuberculin, 

 which has also indirectly done good in other ways. His 

 distinguished pupil, Behring, has expressly attributed to those 

 researches the inspiration of the work which led him and his 

 since famous collaborateur, the Japanese Kitasato, to their 

 surprising discovery of anti-toxic serum. They found that if an 

 animal of a species liable to diphtheria or tetanus received a 

 quantity of the respective toxin, so small as to be harmless, and 

 afterwards, at suitable intervals, successively stronger and 

 stronger doses, the creature, in course of time, acquired such a 

 tolerance for the poison as to be able to receive with impunity 

 a quantity very much greater than would at the outset have 

 proved fatal. So far, we have nothing more than seems 

 to correspond with the eftects of the increasingly potent 

 cord in Pasteur's treatment of rabies. But what was 

 entirely new in their results was that, if blood was drawn 

 from an animal which had acquired this high degree of 

 artificial immunity, and some of the clear fluid or serum which 

 exuded from it after it had clotted was introduced under the 

 skin of another animal, this .second animal acquired a strong, 

 though more transient, immunity against the particular toxin 

 concerned. The serum in some way counteracted the toxin or 

 was antitoxic. But, more than that, if some of the antitoxic 

 serum was applied to an animal after it had already received a 

 poisonous dose of the toxin, it preserved the life of the creature, 

 provided that too long a time had not elapsed after the poison 

 was introduced. In other words, the antitoxin proved to be not 

 only preventive but curative. 



Similar results were afterwards obtained by Ehrlich, of Berlin, 

 with some poisons not of bacterial origin, but derived from the 

 vegetable kingdom ; and quite recently the independent labours 

 of Calmette of Lille and Eraser of Edinburgh have shown that 

 antidotes of wonderful efticacy against the venom of serpents 

 may be procured on the same principle. Calmette has obtained 



