XIX.

SOME OBSERVATIONS ON THE ORIGIN AND SOURCES OF PATHOGENIC BACTERIA.

BY THEOBALD SMITH, M. D.,

OF THE BUREAU OF ANIMAL INDUSTRY, DEPARTMENT OF AGRICULTURE,

Washington, D. C.

That all pathogenic micro-organisms have been derived at some time in the past from those living in the soil, water, and decomposing organic matter will be seriously questioned by no one who has paid any attention to them. The marked similarity in form and physiological characters of pathogenic and harmless species strikingly confirms this view. Thus, we have several forms of bacilli which resemble those of Asiatic cholera in most of the features which serve us as means of differentiation. Typhoid-fever bacilli resemble ordinary forms so closely that a diagnosis between them is rendered very difficult. Hog-cholera bacilli cannot be distinguished from many putrefactive forms, except by their peculiar and fatal effect upon experimental animals. Anthrax bacilli differ so slightly from the ubiquitous hay bacilli that Büchner was at one time led to try to transform one into the other, but without success. Not much more than ten years ago Nägeli saw no necessity for separating the various bacteria into distinct species. The morphological monotony which presented itself under the microscope led him to say that "the same species assumes in the course of generations forms unlike both morphologically and physiologically, which in the course of years and decades produce the souring of milk, the formation of butyric acid in sauerkraut, the gelatinification of wine, the putrescence of albuminoids, the decomposition of urea, the reddening of foods containing starch, typhoid, relapsing fever, cholera, or intermittent fever."

Such views, if true, would make us totally helpless in our conflict with this microscopic world. If the most harmless can become our deadly enemies in the course of a few years, the problem would be war against all bacteria. But the great majority are indispensable to the great rotation of matter which goes on incessantly between the organic and the inorganic household of nature.

Nägeli's extreme views, happily for us, have very little ground to stand upon. We do not believe that the transformation of harmless into pathogenic forms may take place at any time, or that variation among bacteria goes on constantly within very wide limits. We have learned that there is a marked fixity of characters in these simplest forms, which

seems the more remarkable the longer we devote ourselves to their study. This fixity has very likely been reached by a gradual adaptation to special conditions extending over very long periods of time. As a necessary consequence of this adaptation there are bacteria corresponding to various grades and forms of parasitism, ranging from those which produce disease only incidentally to those which cannot subsist excepting in the animal body. We now know of bacteria, such as the cholera spirilla, which can only live outside of the body itself in the alimentary tract, and poison the organism with the products of their metabolism; and we know of bacteria, such as the bacilli of tuberculosis and leprosy, which have adopted, perhaps, the most complete parasitic habit, an existence within the protoplasm of the cell body itself.

Granted a marked fixity of physiological characters and a scale of forms corresponding to different degrees of parasitism, we cannot evade the inference that there must be going on even now imperceptible changes in the characters of some bacteria, and hence of diseases caused by them. The question may then be asked, Have we any evidence in history of the changes in the nature of prevailing diseases, or of the appearance of new ones? This could only be approached by a careful study of infectious diseases, and the epidemics they have caused from antiquity up to the present. Even if I were sufficiently familiar with the literature of this subject, I doubt whether much could be gained by such a study, owing to the doubtful value of the testimony of medical history. Have we not witnessed, as late as our day, the confounding of one disease with another, because nothing was known of their etiology? It is not very long ago that typhus, typhoid, and relapsing fever were looked upon as one disease. Now we know that typhoid and relapsing fever are due to very different organisms; and as to typhus, we are aware of its claim to a separate place in the list of maladies, although its etiology is still unknown. Scarcely a decade ago all swine diseases Now, this one disease turns out to be three, caused by readily distinguishable microbes. These illustrations will suffice to show that the history of medicine cannot be relied upon to help us in tracing any changes which the same disease may have undergone, or in heralding the presence of a new disease during centuries and tens of centuries. The problem is still more complicated by the fact that epidemic diseases have frequently come from unknown quarters of the globe.

were one.

There are a few indications, however, which point to variations in the severity and character of some infectious diseases. The Black Death of the fourteenth century manifested a character somewhat different from that of the Oriental plague, with which it has been in general identified. Liebermeister states that typhoid fever has become modified in severity since the beginning of this century. It is believed that Asiatic cholera may have developed its endemic character not before the last century, having been a sporadic disease before that time, like the cholera nostras of European nations. Only during the present century has it invaded Europe as an epidemic disease. Attention has been called in Germany

to the recent development of an epidemic character in cerebro-spinal meningitis. We may not be far from the truth, therefore, when we assume that there is a birth, change, and decay of diseases due to very gradual changes in the micro-organisms which are the causes. In weighing evidence of this kind, however, we must not lose sight of another factor-the varying power of resistance presented by individuals. and races under different internal and external conditions to the same micro-organism.

When we pass to present bacteriological researches, we obtain some positive facts concerning the variation of pathogenic bacteria within narrow limits. We have become familiar with the conception of variability through the persistent successful labors of Pasteur. He has taught us that anthrax bacilli can be attenuated by heat so as to form physiological varieties. This change is, no doubt, a degeneration on the part of the bacilli needing no comment, for it is the common heritage of all organisms to degenerate. But to cause an increase of pathogenic activity is an important and striking fact, not only in biology, but in epidemiology. Pasteur succeeded in increasing the virulence of rouget bacilli by passing them through a series of pigeons, i. e., inoculating each with the blood of the one preceding in the series. The bacilli obtained from the last of the series were more fatal to swine than those obtained directly from the latter animal. We may draw upon his investigations of rabies for another valuable illustration in variability. In commencing to inoculate a series of rabbits beneath the dura with the virus of rabies from the streets, the animals lived about fifteen days. From the spinal cords of these a second pair were inoculated, from the second a third, and so on. Later on in the series, the duration of the disease fell from fifteen to twelve, eleven, nine, and eight days. After the eightieth to the one hundredth passage it was shortened to seven days. It remained at seven days after the one hundred and thirty-third passage, rarely falling to six.

Gamaleia, in a recent communication to the French Academy of Sciences, claims to have found a method of augmenting the virulence of cholera spirilla. After passing the germs through a guinea-pig, he inoculates a pigeon, which dies of a " dry cholera," with exfoliation of the intestinal epithelium. The germ appears in the blood, and after several successive inoculations it acquires such a virulence that one or two drops of blood are sufficient to kill pigeons in from eight to twelve hours; guinea-pigs are likewise destroyed by the inoculation of very small quantities. If we bear in mind that guinea-pigs could only be infected by Koch through the stomach made strongly alkaline, and that the comma bacilli did not appear in the blood, the experimental results obtained by Gamaleia are certainly very remarkable. The same observer came to very interesting conclusions of a similar bearing concerning the microbe of fowl cholera. It is well known among bacteriologists that a certain number of animal diseases, such as fowl cholera, rabbit septicamia, swine plague, and an infectious disease among game, which has been described in Germany under the name of Wildseuche, are caused

by what is supposed to be the same micro-organism under different conditions. Just what these conditions are, whether depending on variations in the germ itself, or in the infected animals, or both, it is impossible to state. I have encountered this same organism as a saprophyte in the nasal mucus of healthy swine, as well as the cause of a fatal infectious pneumonia in the same species. I have found it in a few cases of interstitial pneumonia in cattle and in diseased rabbits. In these different situations it presented minor physiological variations, the most important of which had reference to its sensitiveness to temperature while multiplying, and its pathogenic activity when tested upon the same species of animal, as, for example, the rabbit. Gamaleia found this same species of organisms as ordinary inhabitants of the digestive tract of pigeons. By passing them through several rabbits in succession, they became virulent enough to prove fatal to pigeons and fowls after inoculation.

Besides this physiological modification of bacteria produced experimentally in the laboratory, by which their pathogenic effect is augmented, we are frequently brought face to face with modifications going on in nature. Several years ago I pointed out certain minor differences between hog-cholera bacilli from two different localities. In culture liquids one variety always formed a surface membrane; the other, not. This tendency was not lost or changed, even after the germ had been passed through a series of animals. The same variety was also more sensitive to the reaction of the solid media employed. So far as pathogenic activity was concerned, they were the same. The production of coagulation-necrosis in the liver of mice and rabbits, peculiar to hogcholera bacilli, was common to both.

But differences in form and growth upon artificial media are less common than sameness of form and growth combined with a difference in virulence. Thus, I have had occasion to observe in the study of infectious pneumonia in swine, that the germ of one epizootic, when introduced beneath the skin of rabbits, caused a septicemia fatal in less than twenty-four hours. The bacteria inoculated were present in large numbers in the blood and spleen. In another epizootic, the germ was incapable of destroying rabbits in less than from three to eight days. Instead of a true septicemia, there would be an extensive sanguinolent, gelatinous, or cellular infiltration of the subcutis extending from the point of inoculation, together with a partly cellular, partly fibrinous, exudate in the neighboring abdominal cavity. While the bacteria were very numerous in this exudate, they were nearly absent from the blood and spleen. I have also observed a difference in the virulence of glandders bacilli as manifested in inoculated guinea-pigs. In many the disease lasted three or four weeks, accompanied by swelling of the limbs, suppuration of the testes, and ulcers on the surface of the body. In one animal, however, it lasted but ten days without external lesions, but with extensive formation of nodules or tubercles in spleen and lungs. The reaction of these experimental animals is usually so uniform that I

should not credit this to any weakness on the part of the guinea-pig. Moreover, the source of the material confirmed the view taken of a difference in virulence.

I do not intend to convey the impression that it has not been frequently asserted that variations in the severity of epidemics were due to differences in the specific germ. I simply call attention to some facts which demonstrate what have been hitherto rather vague and unproved assertions. They serve to illustrate variations going on, or already existing, in nature and revealed in the laboratory, not so much by form or culture as by inoculation, which brings into play the very delicate vital forces of the animal in opposition to the invasive tendency of the temporary par

asite.

We have thus far taken for granted that our disease germs are derived from forms like those living in our surroundings, and that they have adapted themselves in some unknown way to various degrees of destructive parasitism. In some this habit has become so perfected that they have nearly or quite lost the capacity of living outside of their hosts. They fail to grow in artificial media, or else develop only when their natural environment has been imitated as closely as possible. Among these forms are the well known bacilli of tuberculosis, leprosy, and the still hypothetical microbes of syphilis and rabies. In a number of other disease germs the parasitic habit is but slightly developed, and the saprophytic mode of life still as marked as with many harmless germs. They are cultivated on various substrata without difficulty, and it seems as if their invasion of the living animal organism were more of an accident. If this be so, and it seems very probable, then we must conclude that they have acquired their pathogenic properties outside of the body. Hüppe, in a recent address on the relations between putrefaction and infectious diseases, is the first, to my knowledge, who has presented this view as a deduction from present bacteriological researches. He discusses it in a very suggestive way, and points out the important fact that this property must have been acquired under circumstances very near those obtaining in the animal body, such as are presented by the decomposition of albuminoids or putrefaction.

Let us see how far this theory accords with facts. Conditions favorable to putrefaction are offered, first of all, in the digestive tract of man and animals. Hence, we may expect to find some pathogenic bacteria in this locality. Dr. Sternberg has found a microbe in saliva, not distinguishable from the organism identified later on as the cause of one form of croupous pneumonia and cerebro-spinal meningitis in man. Gamaleia, the author already referred to for several valuable discoveries, recently discussed at length in Pasteur's journal the etiology of croupous pneumonia. With the aid of animal inoculation he was able to demonstrate the presence of the diplococcus pneumonia in every case of this disease which he examined. He concludes that this organism is the sole cause of pneumonia, and that the pneumococcus of Friedländer is a mere saprophyte in the diseased lung tissue. One of his co-workers made