Popular Science Monthly/Volume 41/September 1892/Infectious Diseases: Causation and Immunity

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INFECTIOUS DISEASES. CAUSATION AND IMMUNITY.[1]

By GEORGE M. STERNBERG, M.D.,

SURGEON UNITED STATES ARMY.

CERTAINLY, from a scientific point of view, no question in medicine is more important than that which relates to the causation of disease. An accurate knowledge of the specific etiological agents concerned in the production of specific infectious diseases forms the very basis of scientific medicine; and, as you all know, researches which have been made during the past thirty years have given us this accurate knowledge for a considerable number of these diseases. I say thirty years, in order to include the researches of Davaine upon anthrax; but, as a matter of fact, the principal portion of our knowledge relating to specific disease-germs has been acquired during the past decade.

As an introduction, a brief historical review of the progress of our knowledge will perhaps not be out of place. But first I must call your attention to the fact that this progress has been made possible by certain improvements in methods of research, and especially by the following: first, the use of a cotton filter to exclude atmospheric organisms from our culture media (Schröder and Von Dusch, 1854); second, the sterilization of culture media by heat (methods perfected by Pasteur, Koch, and others); third, the use of aniline dyes as staining agents (first recommended by Weigert in 1877); fourth, the introduction of solid culture media, and the "plate method" for obtaining pure cultures (by Koch in 1881); fifth, the perfection of methods for cultivating anaerobic bacteria. I have already referred to the researches of Davaine relating to the disease of cattle and sheep known as anthrax. Having ascertained that the blood of an infected animal constantly contained a rod-shaped micro-organism, and that the smallest quantity of this blood inoculated into a susceptible animal gave rise to the disease and caused its death, Davaine, in 1803, boldly announced his belief that the bacillus was the specific etiological agent in this disease. The experiments of Davaine were not, however, generally accepted as conclusive, because, in inoculating an animal with blood containing the bacillus, the living micro-organism was associated with material from the body of the diseased animal. This objection was subsequently removed by the experiments of Pasteur, Koch, and many others with pure cultures of the bacillus. These were shown to have the same pathogenic effects as had been obtained in inoculation experiments with the INFECTIOUS DISEASES. 617

blood of an infected animal. To-day no one questions the etio- logical relation of Bacillus anthracis to the disease anthrax. And this bacillus has served for innumerable experiments relating to the solution of a variety of questions in pathology and preventive medicine. Among these we may mention the following, each of which has an extended literature : attenuation of virulence ; pro- tective inoculation of susceptible animals ; hereditary transmis- sion of protection; passage of pathogenic bacteria through the placenta, from the mother to the foetus ; explanation of acquired immunity ; comparative value of germicidal agents and of anti- septics ; conditions governing spore formation, etc.

Proceeding with our historical review : In 1873, Obermeier, a German physician, announced the discovery, in the blood of pa- tients suffering from relapsing fever, of a minute, spiral, actively motile micro-organism the Spirochete Obermeieri which is now generally recognized as the specific infectious agent in this dis- ease. Recently (1890) a spirillum closely resembling the relaps- ing-fever spirillum has been discovered by Sakharoff, a Russian investigator, in the blood of geese. The investigations of the author named show that it is the cause of a fatal epidemic disease which occasionally prevails among geese in certain swampy localities in Caucasia.

In 1879 Hansen reported the discovery of bacilli in the cells of leprous tubercles. Subsequent researches have shown that this bacillus is constantly associated with leprosy, and presumably bears an etiological relation to the disease.

In the same year (1879) Neisser discovered the " gonococcus." The bacillus of typhoid fever was first observed by Eberth, and independently by Koch, in 1880, but it was not until 1884 that Gaffky's important researches relating to this bacillus were published. It is now well established that this bacillus is con- stantly found in the spleen and intestinal glands involved in cases of typhoid fever ; and pathologists have generally accepted it as the specific etiological agent in this disease. We can scarcely doubt the correctness of this conclusion, although it must be ad- mitted that no satisfactory experimental demonstration of the fact has yet been made, inasmuch as none of the lower animals are subject to the disease as it occurs in man, and inoculations with pure cultures do not give rise to identical morbid phe- nomena. Since the discovery of the typhoid bacillus very numer- ous researches have been made to determine in an exact manner its biological characters, its resistance to germicidal agents, the duration of its vitality in drinking-water and in the soil, its pres- ence in water the ingestion of which has been suspected of caus- ing typhoid fever in man, etc. As to the results of these in- vestigations we may say, in brief, that it has been shown that the

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bacillus as obtained from the spleen of typhoid cadavers varies somewhat in different cases; that very similar bacilli may be obtained from waters contaminated by sewage, etc., which differ from the typhoid bacillus in certain characters of growth, and yet resemble it so closely that it is still uncertain whether they are to be considered distinct species or only varieties of the typhoid bacillus ; that the character which was at first supposed to dis- tinguish the typhoid bacillus from all others viz., its invisible growth upon potato has proved to be unreliable, inasmuch as certain other bacteria have been shown to have a like invisible growth, and under certain circumstances the typhoid bacillus may form a visible growth on potato. However, in spite of these difficulties in differentiating the typhoid bacillus from nearly allied bacteria found in water or in the dejecta of man and the lower animals, there is good reason to believe that the bacillus of Eberth, of Koch, and of Gaffky is the veritable etiological agent in the widely spread endemic and sometimes epidemic disease known as typhoid fever. But in admitting this we must admit that the bacillus itself is widely distributed, and that an attack of typhoid fever does not necessarily follow its introduction into the alimentary canal of man by means of contaminated water or milk. Other secondary causes, no doubt, often determine the question of infection. Among these we may mention individual suscepti- bility ; exposure to agencies which reduce the vital resisting power, such as sewer-gas poisoning; the quantity and the viru- lence of the typhoid germs ingested; the state of the digestive function, etc.

In 1880 the present writer discovered the important pathogenic micrococcus which is now generally recognized as the usual cause of croupous pneumonia. This I now call Micrococcus pneumonic? crouposce: The German bacteriologists usually speak of it as the Diplococcus pneumonicB. I first discovered this micrococcus in the blood of rabbits inoculated with a few drops of my own saliva ; and subsequent researches have shown that it is found in the saliva of healthy individuals in various parts of the world. This fact may at first view appear to be opposed to the statement that it is the usual cause of croupous pneumonia, especially as I have never myself suffered from this disease, although for several years I frequently demonstrated the presence of this micrococcus in my salivary secretions. But, as in the case of the typhoid bacillus and several other widely distributed bacteria, while accepting, upon experimental evidence, the etiological relation of the specific micro-organism, we are also obliged to admit the essential rela- tion of predisposing or exciting causes in the development of an attack of the disease. In this connection I quote from a paper of my own, published in 1885 :

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The constant presence of this micrococcus in the buccal secretions of healthy persons indicates that some other factor is required for the development of an at- tack of pneumonia ; and it seems probable that this other factor acts by reducing the vital resisting power of the pulmonary tissues, and thus making them vulner- able to the attacks of the microbe. This supposition enables us to account for the development of the numerous cases of pneumonia which can not be traced to infec- tion from without. The germ being always present, auto-infection is liable to occur when, from alcoholism, sewer-gas poisoning, crowd-poisoning, or any other depressing agency, the vitality of the tissues is reduced below the resisting point. We may suppose, also, that a reflex vaso-motor paralysis, affecting a single lobe of the lung, for example, and induced by exposure to cold, may so reduce the resist- ing power of the pulmonary tissues as to permit this micrococcus to produce its characteristic effects. Again, we may suppose that a person, whose vital resisting power is reduced by any of the causes mentioned, may be attacked by pneumonia from external infection with material containing a pathogenic variety of the micrococcus having a potency, permanent or acquired, greater than that possessed by the same organism in normal buccal secretions."

Investigations made since the above was written show that this micrococcus does vary greatly in its pathogenic power when obtained from different sources, and that virulent cultures ob- tained from the blood of inoculated animals become attenuated when they are kept for a short time. This, indeed, is a general rule as regards the best-known pathogenic bacteria; which usually acquire increased virulence when cultivated in the bodies of sus- ceptible animals, and become attenuated as regards their patho- genic potency when they are cultivated for a certain length of time in artificial media. My own experiments with pneumonic sputum were made in January, 1885, and led me to the identifica- tion of the oval coccus, commonly in pairs, which is found in this material, with the coccus which I had previously found in my own saliva (September, 1880), and which was subsequently the ob- ject of extended experimental researches made by me in 1881-1884.

In my paper read before the Pathological Society of Philadel- phia, in April, 1885, 1 say : " It seems extremely probable that this micrococcus is concerned in the etiology of croupous pneumonia. . . . But this can not be considered as definitely established by the experiments which have thus far been made upon the lower animals." The extended researches of Frankel, Weichselbaum, Netter, Gamale'ia, G. and F. Klemperer, and others, which have been published since, have fully established the etiological role of the micrococcus in question.

In 1882 Fehleisen isolated the so-called streptococcus of ery- sipelas and proved by experiment that it is the etiological agent in the production of erysipelatous inflammations. At a later date (1884) Rosenbach isolated the micro-organisms commonly con- cerned in traumatic infections and in the production of acute abscesses. Among these was a streptococcus, called by him Strep-

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tococcus pyogenes, which, is probably identical with Streptococcus erysipelatos of Fehleisen, although some bacteriologists still in- sist that slight differences exist in the mode of growth in certain culture media which justify the view that they are well-defined varieties if not distinct species. I am of the opinion that the strep- tococcus obtained from erysipelatous inflammations is identical with the streptococcus of pus ; and we have ample evidence that the pathogenic power of this micro-organism differs as a result of conditions relating to its environment. In artificial culture media it becomes more or less attenuated, but when obtained from the tissues invaded in erysipelas, or in puerperal septicaemia, it has an increased virulence. Like the micrococcus of pneumonia, this is a widely distributed micro-organism ; it has frequently been obtained in cultures from the surface of the body or from exposed mucous membranes of healthy persons. This is also true of the other pus cocci concerned in traumatic infections. And, in the light of our present knowledge, it appears that erysipelas, wound infection, abscess formation, etc., do not depend alone upon the presence of the specific etiological agents which induce such localized infectious processes, but also upon predisposing and secondary causes relating to the infected individual, as well as upon the origin and virulence of the pathogenic micro-organ- ism. Thus the Streptococcus pyogenes from a case of erysipelas or of puerperal septicaemia introduced into a recent wound upon a healthy person would be likely to cause a severe and possibly fatal infection, while an attenuated culture of the same would perhaps give rise to no symptoms, or at most to slight local inflammation. On the other hand, if the vital resisting power of the individual is reduced by previous ill-health, by insufficient food, by sewer-gas poisoning, crowd-poisoning, etc., an attenuated variety of Streptococcus pyogenes may perhaps give rise to an erysipelatous inflammation, or to an acute abscess, if introduced by accident into an open wound. Again, in contused and lacerated wounds the vital resisting power of the tissues is diminished ; and wound infection is likely to occur from the accidental introduc- tion of the pus cocci, which lead a saprophytic existence upon the surface of the body and exposed mucous membranes, where under ordinary circumstances they are quite harmless. Secondary in- fections clue to these now well-known pyogenic micrococci are not infrequent as sequelae to the specific infectious diseases, such as scarlet fever, yellow fever, etc.

In 1882 Koch published his famous discovery of the tubercle bacillus. This will always rank as one of the most important events in the history of medicine, and as a notable triumph of well-directed scientific research. The proof that the bacillus re- ferred to is the specific cause of tuberculous processes and that

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tuberculosis is an infectious disease, was contained in Koch's origi- nal memoir announcing his discovery. Investigations made since have fully confirmed Koch's conclusions in all important particu- lars. In order to show you the interest taken by bacteriologists and pathologists in all that relates to the tubercle bacillus and the effects of its pathogenic action, I have referred to the Jahres- bericht of Baumgarten, for the year 1890, which gives abstracts of all original memoirs in this field of research. The total number of papers referred to, published during the year mentioned, is one hundred and thirty-five. By far the greater number are pub- lished in German and French journals, but the literature includes a certain number of memoirs published in Russia, in Italy, in Hungary, in Sweden, and in the United States.

Another important discovery, made in 1882, is that of the ba- cillus of glanders, by Loffler and Schutz.

Koch published his discovery of the cholera spirillum (" com- ma bacillus") in 1884.

The same year (1884) Lofner discovered the diphtheria bacillus. Subsequent researches have not only established the etiological relation of this bacillus to the disease known as diphtheria, but have given us an exact knowledge of its biological characters and pathogenic action, as tested upon lower animals.

The tetanus bacillus was discovered in 1884 by Nicolaier, a student in the laboratory of Prof. Fliigge, of Gottingen. That this bacillus is the cause of tetanus in man has been demonstrated by the subsequent researches of numerous investigators.

So far as human pathology is concerned, no important patho- genic micro-organism has been discovered since the date last men- tioned (1884) until the present year. After numerous unsuccess- ful researches by competent bacteriologists, a bacillus has been discovered by Pfeiffer, of Berlin, and independently by Canon, which there is good reason to believe is the specific cause of epi- demic influenza.

"We have, also, a recent announcement, by Canon, of the dis- covery of a minute bacillus in the blood of patients suffering with measles, but the etiological relation of this bacillus has not been established, and additional researches will be required before we can properly estimate the value of Canon's alleged discovery.

The brief historical review which we have made shows that the etiology of a considerable number of infectious diseases has been determined by the researches of bacteriologists, but it also shows that other important diseases of this class are not included in this list.

Up to the present date no satisfactory demonstration of the specific infectious agent has been made in any one of the eruptive fevers ; and in yellow fever, my own extended researches have

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failed to clear up the etiology of the disease. In the last-men- tioned disease, there are excellent a priori reasons for believing that a living micro-organism of some kind is the essential etiologi- cal factor ; but this hypothetical germ has eluded all researches. Possibly it belongs to an entirely different class of micro-organ- isms, as is the case with the blood parasite which is now recog- nized as the cause of the malarial fevers.

Having thus briefly reviewed the progress of our knowledge relating to the etiology of infectious diseases, I desire to call your attention to the question of acquired immunity from these diseases.

No questions in general biology are more interesting, or more important from a practical point of view, than those which relate to the susceptibility of certain animals to the pathogenic action of certain species of bacteria, and the immunity, natural or acquired, from such pathogenic action which is possessed by other animals. It has long been known that certain infectious diseases, now demonstrated to be of bacterial origin, prevail only or principally among animals of a single species. Thus, typhoid fever, cholera, and relapsing fever are diseases of man, and the lower animals do not suffer from them when they are prevailing as an epidemic. On the other hand, man has a natural immunity from many of the infectious diseases of the lower animals, and diseases of this class which prevail among animals are fre- quently limited to a single species. Again, several species, in- cluding man, may be susceptible to a disease, while other animals have a natural immunity from it. Thus, tuberculosis is common to man, to cattle, to apes, and to the small herbivorous animals, while the carnivora are, as a rule, immune ; anthrax may be com- municated by inoculation to man, to cattle, to sheep, to guinea- pigs, rabbits, and mice, but the rat, the dog, carnivorous animals, and birds are generally immune ; glanders, which is essentially a disease of the equine genus, may be communicated to man, to the guinea-pig, and to field-mice, while house-mice, rabbits, cattle, and swine are to a great extent immune.

In addition to this general race immunity or susceptibility, we have individual differences in susceptibility or resistance to the action of pathogenic bacteria, which may be either natural or acquired. As a rule, young animals are more susceptible than older ones. Thus in man the young are especially susceptible to scarlet fever, whooping-cough, and other "children's diseases," and after forty years of age the susceptibility to tubercular in- fection is very much diminished. Among the lower animals it is a matter of common laboratory experience that the very young of a susceptible species may be infected when inoculated with an "attenuated culture" which older animals of the same species are able to resist.

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Considerable differences as to susceptibility may also exist among adults of the same species. In man these differences in individual susceptibility to infectious diseases are frequently manifested. Of a number of persons exposed to infection in the same way, some may escape entirely, while others have attacks differing in severity and duration. In our experiments upon the lower animals we constantly meet with similar results, some individuals proving to be exceptionally resistant. Exceptional susceptibility or immunity may be to some extent a family char- acteristic, or one of race. Thus, the negro race is decidedly less subject to yellow fever than the white race, and this disease is more fatal among the fair-skinned races of the north of Europe than among the Latin races living in tropical or subtropical regions. On the other hand, small-pox appears to be exception- ally fatal among negroes and dark-skinned races generally. A very remarkable instance of race immunity is that of Algerian sheep against anthrax, a disease which is very fatal to other sheep.

The essential difference between a susceptible and immune animal depends upon the fact that in one the pathogenic germ, when introduced by accident or experimental inoculation, multi- plies and invades the tissues or the blood, where, by reason of its nutritive requirements and toxic products, it produces changes in the tissues and fluids of the body inconsistent with the vital re- quirements of the infected animal ; while in the immune animal multiplication does not occur or is restricted to a local invasion of limited extent, and in which after a time the resources of Nature suffice to destroy the parasitic invader.

Now, the question is, Upon what does this essential difference depend ? Evidently upon conditions favorable or unfavorable to the development of the pathogenic germ ; or upon its destruction by some active agent present in the tissues or fluids of the body of the immune animal ; or upon a neutralization of its toxic prod- ucts by some substance present in the body of the animal which survives infection. The composition of the body fluids, and es- pecially their reaction, is probably a determining factor in some instances. Thus, Behring has ascribed the failure of the anthrax bacillus to develop in the white rat, which possesses a remarkable immunity against anthrax, to the highly alkaline reaction of the blood and tissue juices of this animal. Behring claims to have obtained experimental proof of the truth of this explanation by feeding white rats on an exclusive vegetable diet, or by adding acid phosphate of lime to their food, by which means this ex- cessive alkalinity of the blood is diminished. Hats so treated are said to lose their natural immunity, and to die as a result of inoculation with virulent cultures of the anthrax bacillus.

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The recent experiments of Nuttall, Behring, Buchner, and others have established the fact that recently drawn blood of various animals possesses decided germicidal power, and Buchner has shown that this property belongs to the fluid part of the blood and not to its cellular elements. This power to kill bacteria is destroyed by heat, and is lost when the blood has been kept for a considerable time, but it is not neutralized by freezing. Further, this power to destroy bacteria differs greatly for different species, being very decided in the case of certain pathogenic bacteria, less so for others, and absent in the case of certain common sapro- phytes.

In the infectious diseases of man involving the system gen- erally, a single attack commonly confers immunity from sub- sequent attacks. This is true of the eruptive fevers, of typhoid fever, of yellow fever, of mumps, of whooping-cough, and, to some extent at least, of syphilis. But it seems not to be the case in epidemic influenza (la grippe), in croupous pneumonia, or in Asiatic cholera, in which diseases second attacks not infrequently occur. In localized infectious diseases, such as diphtheria, ery- sipelas, and gonorrhoea, one attack is not protective. Croupous pneumonia and Asiatic cholera should perhaps be grouped with diphtheria and erysipelas as local infections with constitutional symptoms resulting from the absorption of toxic products.

That immunity may result from a comparatively mild attack as well as from a severe one is a matter of common observation in the case of small-pox, scarlet fever, yellow fever, etc., and since the discovery of Jenner we have in vaccination a simple method of producing immunity in the first-mentioned disease. The ac- quired immunity resulting from vaccination is not, however, as complete or as permanent as that which results from an attack of the disease.

These general facts relating to acquired immunity from in- fectious diseases constituted the principal portion of our knowl- edge with reference to this important matter up to the time that Pasteur (1880) demonstrated that in the disease of fowls known as chicken cholera, which he had proved to be due to a specific micro-organism, a mild attack followed by immunity may be induced by inoculation with an " attenuated virus " i. e., by inoculation with a culture of the pathogenic micro-organism the virulence of which had been so modified that it gave rise to a comparatively mild attack of the disease in question. Pasteur's original method of obtaining an attenuated virus consisted in exposing his cultures for a considerable time to the action of atmospheric oxygen. It has since been ascertained that the same result is obtained with greater certainty by exposing cultures for a given time to a temperature slightly below that which would

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destroy the vitality of the pathogenic micro-organism, and also by exposure to the action of certain chemical agents.

Pasteur at once comprehended the importance of his discovery, and inferred that what was true of one infectious germ disease was likely to be true of others. Subsequent researches by this savant and by other bacteriologists have justified this anticipa- tion, and the demonstration has already been made for a consider- able number of similar diseases anthrax, symptomatic anthrax, rouget, etc.

In Pasteur's inoculations against anthrax, " attenuated " cult- ures are employed which contain the living pathogenic germ as well as the toxic products developed during its growth. Usually two inoculations are made with cultures of different degrees of attenuation that is to say, with cultures in which the toxic products are formed in less amount than in virus of full power.

The most attenuated virus is first injected, and after some time the second vaccine, which if injected first might have caused a considerable mortality. The animal is thus protected from the pathogenic action of the most virulent cultures.

Now, it has been shown by recent experiments that a similar immunity may result from the injection into a susceptible animal of the toxic products contained in a virulent culture, independ- ently of the living bacteria to which they owe their origin. The first satisfactory experimental evidence of this important fact was obtained by Salmon and Smith in 1886, who succeeded in making pigeons immune from the pathogenic effects of cultures of the bacillus of hog cholera by inoculating them with sterilized cultures of this bacillus. In 1888 Roux reported similar results obtained by injecting into susceptible animals sterilized cultures of the anthrax bacillus. Behring and Kitasato have quite re- cently reported their success in establishing immunity against virulent cultures of the bacillus of tetanus and the diphtheria bacillus by inoculating susceptible animals with filtered, germ- free cultures of these pathogenic bacteria.

In Pasteur's inoculations against hydrophobia, made subse- quently to infection by the bite of a rabid animal, an attenuated virus is introduced subcutaneously in considerable quantity by daily injections, and immunity is established during the interval, the so-called period of incubation, which usually occurs between the date of infection and the development of the disease. That the immunity in this case also depends upon the introduction of a chemical substance present in the desiccated spinal cord of rabbits which have succumbed to rabies, which is used in these inoculations, is extremely probable. But, as the germ of rabies has not been isolated or cultivated artificially, this has not yet been demonstrated.

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With these facts in view, let us proceed to consider briefly the various theories which have been offered in explanation of ac- quired immunity :

Exhaustion Theory. For a time Pasteur supported the view that during an attack of an infectious disease the pathogenic micro-organism, in its multiplication in the body of a susceptible animal, exhausts the suyjply of some substance necessary for its development, that this substance is not subsequently reproduced, and that consequently the same pathogenic germ can not again multiply in the body of the protected animal.

In discussing this theory, in a paper published in the Ameri- can Journal of the Medical Sciences (April, 1881), the writer says:

Let us see where this hypothesis leads us. In the first place, we must have a material of small-pox, and a material of measles, and a material of scarlet fever, etc. Then we must admit that each of these different materials has been formed in the system and stored up for these emergencies attacks of the diseases in question for we can scarcely conceive that they were all packed away in the germ-cell of the mother and the sperm-cell of the father of each susceptible individual. If, then, these peculiar materials have been formed and stored up during the development of the individual, how are we to account for the fact that no new production takes place after an attack of any one of the diseases in question ?

Again, how shall we account for the fact that the amount of material which would nourish the small-pox germ, to the extent of producing a case of confluent small-pox, may be exhausted by the action of the attenuated virus (germ) intro- duced by vaccination ? Pasteur's comparison of a fowl protected by inocula- tion with the microbe of fowl cholera, with a culture fluid in which the growth of a particular organism has exhausted the pabulum necessary for the devel- opment of additional organisms of the same kind, does not seem to me to be a just one, as in the latter case we have a limited supply of nutriment, while in the former we have new supplies constantly provided of the material food from which the whole body, including the hypothetical substance essential to the development of the disease-germ, was built up prior to the attack. Be- sides this, we have a constant provision for the elimination of effete and useless products.

This hypothesis, then, requires the formation in the human body, and the re- tention up to a certain time, of a variety of materials which, so far as we can see, serve no purpose except to nourish the germs of various specific diseases, and which, having served this purpose, are not again formed in the same system, subjected to similar external conditions, and supplied with the same kind of nu- triment.

It is unnecessary to discuss this hypothesis any further, inas- much as it is no longer sustained by Pasteur or his pupils, and is evidently untenable.

The Pretention Theory, proposed by Chauveau (1880), is sub- ject to similar objections. According to this view, certain prod- ucts formed during the development of a pathogenic micro-or-

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ganism in the body of a susceptible animal accumulate during the attack and are subsequently retained, and being prejudicial to the growth of the particular micro-organism which produced them, a second infection can not occur. Support for this theory has been found by its advocates in the fact that various processes of fer- mentation are arrested after a time by the formation of sub- stances which restrain the development of the micro-organisms to which they are due. But in the case of a living animal the con- ditions are very different, and it is hard to conceive that adventi- tious products of this kind could be retained for years, when in the normal processes of nutrition and excretion the tissues and fluids of the body are constantly undergoing change. Certainly the substances which arrest ordinary processes of fermentation by their accumulation in the fermenting liquid, such as alcohol, lactic acid, phenol, etc., would not be so retained. But we can not speak so positively with reference to the toxic albuminous substances which recent researches have demonstrated to be pres- ent in cultures of some of the best-known pathogenic bacteria. It is difficult, however, to believe that an individual who has passed through attacks of half a dozen different infectious dis- eases, carries about with him a store of as many different chemi- cal substances produced during these attacks, and sufficient in quantity to prevent the development of the several germs of these diseases. Nor does the experimental evidence relating to the action of germicidal and germ-restraining agents justify the view that a substance capable of preventing the development of one micro-organism should be without effect upon others of the same class ; but if we accept the retention hypothesis, we must admit that the inhibiting substance produced by each par- ticular pathogenic germ is effective only in restraining the devel- opment of the microbe which produced it in the first instance.

Moreover, if we suppose that the toxic substances which give pathogenic power to a particular micro-organism are retained in the body of an immune animal, we must admit that the animal has acquired a tolerance to the pathogenic action of these toxic substances, for their presence no longer gives rise to any morbid phenomena. And this being the case, we are not restricted to the explanation that immunity depends upon a restraining in- fluence exercised upon the microbe when subsequently intro- duced.

Another explanation offers itself, viz., that immunity depends upon an acquired tolerance to the toxic products of pathogenic bac- teria. This is a view which the writer has advocated in various published papers since 1881. In a paper contributed to the American Journal of the Medical Sciences in April, 1881, it is pre- sented in the following language : " The view that I am endeavor-

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ing to elucidate is that, during a non-fatal attack of one of the specific diseases, the cellular elements implicated which do not succumb to the destructive influence of the poison acquire a tol- erance to this poison which is transmissible to their progeny, and which is the reason of the exemption which the individual enjoys from future attacks of the same disease."

In my chapter on Bacteria in Infectious Diseases, in Bacte- ria, published in the spring of 1884, but placed in the hands of the publishers in 1883, I say : " It may be that the true explana- tion of the immunity afforded by a mild attack of an infectious germ disease is to be found in an acquired tolerance to the action of a chemical poison produced by the micro-organism, and conse- quent ability to bring the resources of Nature to bear to restrict invasion by the parasite." This theory of immunity has received considerable support from investigations made since that date, and especially from the experimental demonstration by Salmon, Roux, and others that, as suggested in the work from which I have quoted, immunity may result from the introduction into the body of a susceptible animal of the soluble products of bacterial growth filtered cultures.

The theory of vital resistance to the toxic products evolved by pathogenic bacteria is also supported by numerous experiments which show that natural or acquired immunity may be over- come when these toxic products are introduced in excess, or when the vital resisting power of the animal has been reduced by vari- ous agencies. Thus Roger has shown that the rabbit, which has a natural immunity against symptomatic anthrax, succumbs to infection when inoculated with a culture of the bacillus of this disease, if at the same time it receives an injection of a sterilized or non-sterilized culture of Bacillus prodigiosus. Monti has suc- ceeded in killing animals with old and attenuated cultures of the Streptococcus pyogenes or of Staphylococcus pyogenes aureus, by injecting at the same time a culture of Proteus vulgaris. A simi- lar result may be obtained by subjecting animals to physical agencies which reduce the vital resisting power of the tissues. Thus, Nocard and Roux found by experiment that an attenuated culture of the anthrax bacillus, which was not fatal to guinea- pigs, killed these animals when injected into the muscles of the thigh after they had been bruised by mechanical violence. Char- rin and Roger found that white rats, which are insusceptible to anthrax, became infected and frequently died if they were ex- hausted, previous to inoculation, by being compelled to turn a re- volving wheel for a considerable time. Pasteur found by experi- ment that fowls, which have a natural immunity against anthrax, become infected and perish if they are subjected to artificial re- frigeration after inoculation. This has been confirmed by the

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more recent experiments of Wagner (1890). According to Canalis and Morpurgo, pigeons which are enfeebled by inanition easily contract anthrax as a result of inoculation. Arloing states that sheep which have been freely bled contract anthrax more easily than others ; and Serafini found that when dogs were freely bled, the bacillus of Friedlander, injected into the trachea or the pleural cavity, entered and apparently multiplied to some extent in the blood, whereas without such previous bleeding they were not to be found in the circulating fluid. Again, the simultaneous injection of certain chemical substances may overcome the vital resisting power of the tissues or fluids of the body in such a way that infection and death may occur as a result of inoculations into animals which have a natural or acquired immunity against the pathogenic micro-organisms introduced. Thus Arloing, Corne- vin, and Thomas have shown that rabbits succumb to symptomatic anthrax when lactic acid is injected at the same time with the bacillus into the muscles. Nocard and Roux have obtained the same result by injecting various other substances, and their ex- periments show that the result is due to the injurious effects of the substance injected upon the tissues, and not to an increased virulence on the part of the pathogenic bacillus. The experi- ments of Leo are of a similar nature. By injecting phloridzin into rats he caused them to lose their natural immunity against anthrax. Certain anaesthetic agents have also been shown to pro- duce a similar result. Platania communicated anthrax to immune animals dogs, frogs, pigeons by bringing them under the influ- ence of curare, chloral, or alcohol ; and Wagner obtained a simi- lar result in his experiments on pigeons to which he had admin- istered chloral.

In view of the results of recent experimental researches which show that, in certain cases at least, acquired immunity depends upon the formation of an antitoxine in the body of the immune animal, we are convinced that the theory of immunity under dis- cussion, first proposed by the writer in 1881, can not be accepted as a sufficient explanation of the facts in general. At the same time we are inclined to attribute considerable importance to ac- quired tolerance to the toxic products of pathogenic bacteria as one of the factors by which recovery from an infectious disease is made possible, and subsequent immunity established. Of course, when we ascribe immunity to the " vital resistance " of the cellular elements of the body, we have not explained the modus operandi of this vital resistance or " reactive change/' but have simply affirmed that the phenomenon in question depends upon some acquired property residing in the living cellular elements of the body. We have suggested that that which has been acquired is a tolerance to the action of the toxic products produced by pathoge-

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nic bacteria. But, as already stated, in the light of recent experi- ments, this theory now appears to us to be untenable as a general explanation of acquired immunity.

The Theoky of Phagocytosis. The fact that in certain in- fectious diseases due to bacteria the parasitic invaders, at the point of inoculation or in the general blood-current, are picked up by the leucocytes, and in properly stained preparations may be seen in their interior, has been known for some years. Now, the theory of phagocytosis assumes that the bacilli are picked up by the leucocytes and destroyed in their interior, and that immunity de- pends largely upon the power of these " phagocytes " to capture and destroy living pathogenic bacilli.

The writer suggested this as a hypothesis as long ago as 1881, in a paper read August 18, 1881, before the American Association for the Advancement of Science, in the following language : " It has occurred to me that possibly the white corpuscles may have the office of picking up and digesting bacterial organisms which by any means find their way into the blood. The propensity ex- hibited by the leucocytes for picking up inorganic granules is well known, and that they may be able not only to pick up but to assimilate, and so dispose of, the bacteria which come in their way, does not seem to me very improbable, in view of the fact that amoebae, which resemble them so closely, feed upon bacteria and similar organisms."

At a later date (1884) Metschnikoff offered experimental evi- dence in favor of this view, and the explanation suggested in the above quotation is commonly spoken of as the Metschnikoff theory. The observations which first led Metschnikoff to adopt this view were made upon a species of daphnia which is subject to fatal in- fection by a torula resembling the yeast fungus. Entering with the food, this fungus penetrates the walls of the intestine and invades the tissues. In certain cases the infection does not prove fatal, owing, as Metschnikoff asserts, to the fact that the fungus cells are seized upon by the leucocytes, which appear to accumu- late around the invading parasite (chemiotaxis) for this special purpose. If they are successful in overpowering and destroying the parasite, the animal recovers ; if not, it succumbs to the gen- eral infection which results. In a similar manner, Metschnikoff supposes, pathogenic bacteria are destroyed when introduced into the body of an immune animal. The colorless blood-corpuscles, which he designates phagocytes, accumulate at the point of inva- sion and pick up the living bacteria, as they are known to pick up inorganic particles injected into the circulation. So far there can be no doubt that Metschnikoff is right. The presence of bac- teria in the leucocytes in considerable numbers, both at the point of inoculation and in the general circulation, has been repeatedly

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demonstrated in animals inoculated with various pathogenic bac- teria. The writer observed this in his experiments, made in 1881, in which rabbits were inoculated with cultures of his Micrococcus Pasteuri ; and it was this observation which led him to suggest the theory which has since been so vigorously supported by Metschnikoff. But the presence of a certain number of bacteria within the leucocytes does not prove the destructive power of these cells for living pathogenic organisms. As urged by Weigert, Bamngarten, and others, it may be that the bacteria were already dead when they were picked up, having been destroyed by some agency outside of the blood-cells. As heretofore stated, we have now experimental evidence that blood-serum, quite independently of the cellular elements contained in it in the circulation, has de- cided germicidal power for certain pathogenic bacteria, and that the blood-serum of the rat and other animals which have a natu- ral immunity against anthrax is especially fatal to the anthrax bacillus.

Numerous experiments have been made during the past two or three years with a view to determining whether pathogenic bacteria are, in fact, destroyed within the leucocytes after being picked up, and different experimenters have arrived at different conclusions. But in certain infectious diseases, and especially in anthrax, the bacilli included within the leucocytes often give evi- dence of degenerative changes, which would support the view that they are destroyed by the leucocytes, unless these changes occurred before they were picked up, as is maintained by Nuttall and others.

Metschnikoff concludes an address delivered at the Pasteur Institute in Paris, in December, 1890, as follows : " It is not pos- sible at the present time to state fully and accurately all these influences which are associated in aiding phagocytic action ; but already we have the right to maintain that, in the property of its amoeboid cells to include and to destroy micro-organisms, the ani- mal body possesses a formidable means of resistance and defense against these infectious agents" This statement, we think, is justified by the experimental evidence relating to phagocytosis. But in view of experimental evidence, to be referred to later we can not accept the so-called Metschnikoff theory as a sufficient explanation for the facts relating to acquired immunity in general, and must regard phagocytosis simply as a factor which, in certain infectious diseases, appears to play an important part in enabling immune animals to resist invasion by pathogenic bacteria.

Going back to the demonstrated fact that susceptible animals may be made immune by inoculating them with the toxic products produced during the growth of certain pathogenic bacteria, we may suppose either that immunity results from the continued

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presence of these toxic products in the body of the inoculated ani- mal, or to a tolerance acquired at the time of the inoculation and subsequently retained, by transmission from cell to cell, as here- tofore suggested. Under the first hypothesis retention theory immunity may be explained as due to a continued tolerance on the part of the cellular elements of the body to the toxic substances introduced and retained, or to the effect of these retained toxic products in destroying the pathogenic bacteria, or in neutralizing their products when these are subsequently introduced into the body of the immune animal. We can not understand how toxic substances introduced in the first instance can neutralize sub- stances of the same kind introduced at a later date. There is something in the blood of the rat which, according to Behring, neutralizes the toxic substances present in a filtered culture of the tetanus bacillus; but whatever this substance may be, it is evi- dently different from the toxic substance which it destroys, and there is nothing in chemistry to justify the supposition last made. Is it, then, by destroying the pathogenic micro-organism, that these inoculated and retained toxic products preserve the animal from future infection ? Opposed to this supposition is the fact that the blood of an animal made immune in this way, when re- moved from the body does not prove to have increased germicidal power as compared with that of a susceptible animal of the same species. Again, these same toxic substances in cultures of the anthrax bacillus, the tetanus bacillus, the diphtheria bacillus, etc., do not destroy the pathogenic germ after weeks or months of exposure. And, when we inoculate a susceptible animal with a virulent culture of one of these micro-organisms, the toxic sub- stances present do not prevent the rapid development of the bacil- lus ; indeed, instead of proving a germicide they favor its develop- ment, which is more abundant and rapid than when attenuated cultures containing less of the toxic material are used for the inoculation. In view of these facts it is evident that acquired immunity does not result from the direct action of the products of bacterial growth, introduced and retained in the body of the immune animal, upon the pathogenic micro-organism when sub- sequently introduced, or upon its toxic products.

But there is another explanation which, although it may ap- pear a priori to be quite improbable, has the support of recent experimental evidence. This is the supposition that some sub- stance is formed in the body of the immune animal which neutral- izes the toxic products of the pathogenic micro-organism. How the presence of these toxic products in the first instance brings about the formation of an "antitoxine" by which they are neutralized is still a mystery ; but that such a substance is formed appears to be proved by the recent experiments of Ogata, Behring and Kita-

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sato, Tizzoni and Cattani, G. and F. Klemperer, and others, in- cluding my own.

Ogata and Jasuhara, in a series of experiments made in the Hygienic Institute at Tokio (1890), discovered the important fact that the blood of an animal immune against anthrax contains some substance which neutralizes the toxic products of the anthrax bacillus. When cultures were made in the blood of dogs, frogs, or of white rats, which animals have a natural immunity against anthrax, they were found not to kill mice inoculated with them. Further experiments showed that mice inoculated with virulent anthrax cultures did not succumb to anthrax septicaemia if they received at the same time a subcutaneous injection of a small quantity of the blood of an immune animal. So small a dose as one drop of frog's blood, or one half drop of dog's blood, proved to be sufficient to protect a mouse from the fatal effect of an anthrax inoculation. And the protective inoculation was effective when made as long as seventy-two hours before, or five hours after, infection with an anthrax culture. Further, it was found that mice which had survived anthrax infection as a result of this treatment were immune at a later date (after several weeks) when inoculated with a virulent culture of the anthrax bacillus. Bearing and Kitasato have obtained similar results in their experiments upon tetanus and diphtheria, and have shown that the blood of an immune animal, added to virulent cultures before inoculation into susceptible animals, neutralizes the patho- genic power of these cultures. Tizzoni and Cattani ascribe the protection of animals which have acquired an immunity against tetanus to the presence of an albuminous substance which they call the tetanus antitoxine. This they have isolated from the blood of immune animals ; and have shown by experiment that it neutralizes the potent toxalbumin of tetanus in test-tube cultures as well as in the bodies of infected animals. G. and F. Klemperer have recently (1891) published an important memoir in which they give an account of their researches relating to the question of immunity, etc., in animals subject to the form of septicaemia produced by the Micrococcus pneumonic?, crouposce. They were able to produce immunity in susceptible animals by introducing into their bodies filtered cultures of this micrococcus, and proved by experiment that this immunity had a duration of at least six months. They arrive at the conclusion that the immunity induced by injecting filtered cultures is not directly clue to the toxic substances present in these cultures, but that they cause the production in the tissues of an antitoxine which has the power of neutralizing their pathogenic action. Emmerich, in a commu- nication made at the recent (1891) International Congress for Hygiene and Demography, in London, reports results which cor-

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respond with those of G. and F. Klemperer so far as the produc- tion of immunity is concerned, and also gives an account of ex- periments made by Donissen in which the injection of twenty to twenty-five cubic centimetres of blood or expressed tissue juices, filtered through porcelain, from an immune rabbit into an unpro- tected rabbit, subsequently to infection with a bouillon culture of " Diplococcus pneumonia?" prevented the development of fatal septicaemia. Even when the injection was made twelve to fifteen hours after infection, by inhalation, the animal recovered. Em- merich and Mastraum had previously reported similar results in experiments made upon mice with the Bacillus erysipelatos suis (rothlauf bacillus). White mice are very susceptible to the pathogenic action of this bacillus. But mice which, subsequently to infection, received by injection the expressed and filtered tissue juices of an immune rabbit, recovered, while the control animals succumbed. According to Emmerich, the result in these experi- ments was due to a destruction of the pathogenic bacilli in the bodies of the injected animals ; and the statement is made that at the end of eight hours after the injection of the expressed tissue juices all bacilli in the body of the infected animal were dead. The same liquid did not, however, kill the bacilli when added to cultures external to the body of an animal. The inference, there- fore, seems justified that the result depends, not upon a substance present in the expressed juices of an immune animal, but upon a substance formed in the body of the animal into which these juices are injected. We have, however, an example of induced immunity in which the result appears to depend directly upon the destruction of the pathogenic micro-organism in the body of the immune animal. In guinea-pigs, which have an acquired im- munity against Vibrio Metschnikovi, the blood-serum has been proved to possess decided germicidal power for this " vibrio," whereas it multiplies readily in the blood-serum of non-immune guinea-pigs. (Behring and Nissen.)

The antitoxines thus far referred to are from animals which have an acquired immunity against virulent cultures of well- known pathogenic bacteria. But we have also experimental evi- dence showing the presence of antitoxines in animals immune against rabies and against vaccinia, two infectious diseases in which the specific infectious agent has not been demonstrated. Prof. Tizzoni, and his associate, Dr. Schwarz, have recently (1892) published the results of their experiments relating to the presence of an antitoxine in the blood of rabbits which have an acquired immunity against rabies. And I have shown by experi- ments made during the past two months that the blood of vac- cinated and consequently immune calves contains an antitoxine which neutralizes the specific virulence of vaccine virus, both

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human and bovine ; also that blood-serum from a person who has recently suffered an attack of small-pox neutralizes vaccine virus after contact for two or three hours.

The account which I have given of the experimental evidence relating to the presence of antitoxines, or, as they are called by Hankin, " defensive proteids," in the body of immune animals has been largely taken from a paper which I read at the recent meet- ing (May, 1892) of the Association of American Physicians, en- titled Practical Results of Bacteriological Researches. Time will not permit me on the present occasion to consider the ques- tion of therapeutic possibilities in the use of antitoxines, but I may mention that already we have reports of six cases of trau- matic tetanus successfully treated with the tetanus antitoxine ob- tained by Prof. Tizzoni from the blood of immune dogs. I con- fess I have sanguine hopes that other infectious diseases may prove to be amenable to a similar specific treatment. But, what- ever may be the practical results following the discovery of these " defensive proteids " in the bodies of immune animals, it must be admitted that this addition to our knowledge is an important event in the history of scientific medicine. For this reason, and because the experimental evidence is of such recent date that the facts are not generally known, I have made this the principal topic of my address. It is scarcely necessary to add that the ex- perimental evidence detailed gives strong support to the view that acquired immunity depends upon the formation of antitoxines in the bodies of immune animals. It is also probable that recovery from an infectious disease depends upon the formation of an anti- toxine during the attack, by which the toxic substances giving rise to the morbid phenomena characterizing each specific disease are neutralized in the body of the infected individual.

��A recent notice in the Monthly of a book on Right-handedness has called forth from Mr. George Wilson, President of the Lafayette County Bank, Lexing- ton. Mo., the story of the "office cat of the bank, Ephraim, who is decidedly and persistently right-handed. " "He sometimes," says Mr. Wilson, "laps milk like other cats, and sometimes sits close up to the pan and dips his paw in the milk and carrying it to his mouth, licks the drop of milk off. Noticing that he always used his right paw, I tried to get him to use the left one, first by setting the pan of milk on his left side and afterward by dipping his left foot in the milk, so as to get him started in the use of the left. He would shake the milk off his left paw and go on eating with the right one, and we have never by any expedient been able to get him to eat with the left paw."

A Polynesian Society has been formed in Wellington, New Zealand, the chief object of which is to secure as far as possible a systematic study of the ethnology and philology of the island groups collectively designated as Polynesia.

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  1. Address in Medicine, delivered at Yale University, June 28, 1892.