Popular Science Monthly/Volume 81/July 1912/Research in Medicine III

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THE

POPULAR SCIENCE

MONTHLY

 

JULY, 1912




RESEARCH IN MEDICINE[1]
By Professor RICHARD M. PEARCE

UNIVERSITY OF PENNSYLVANIA

III. Pasteur and the Era of Bacteriology

THE story of bacteriology can best be told by recounting the labors of Pasteur, for while bacteria were known and theories of infection had been elaborated and vaccination practised before his time, it was he who definitely established the importance of bacteria in putrefaction, fermentation and disease, and gave to vaccination a scientific basis. The influence of these labors is compatible in medicine only to that of Virchow in his field and is as great as that exerted in general biology by Darwin's researches. The story of rapid sequence of Pasteur's brilliant discoveries in science, each of crucial importance and establishing a new principle have, I believe, no parallel in biology or, for that matter, any other science.

But before presenting Pasteur's labors it is necessary to outline the knowledge of bacteria and the theories of fermentation, infection and allied processes which were current at the beginning of his era.

Bacteria were first seen by Leeuwenhoek, a Dutch lens-maker in 1673. This was long before the day of the compound microscope, but Leeuwenhoek was able to make such excellent short focus single lenses that he could study red blood corpuscles and spermatozoa, detect minute globular particles in yeast, and, as we know from his drawings, even discover some of the larger microorganisms in the tartar of the teeth, in saliva and intestinal and other fluids. In 1838, about the time of the development of the compound microscope, Ehrenberg attempted a classification of bacteria based on sixteen species. Our exact knowledge, however, begins with Cohn's studies which extended from 1853 to 1875, and were the first to differentiate between the spherical forms which we call cocci, and the rod-like forms or bacilli. These early studies were almost exclusively botanical in nature and it was not until 1872 that Cohn could include definite disease-producing bacteria in his classification of the vegetable microorganisms.

Bacilli had been found, it is true, as early as 1850 in diseased animals, for example, the anthrax bacillus in animals dying of splenic fever. So also Schonlein in 1839 had discovered a vegetable parasite, a mycelial form, higher than the bacteria, in the disease of the skin known as favus; Malmsten in 1848 had found a somewhat similar form in barber's itch, and Bassi about 1832 had demonstrated that a disease of the silkworm was due to a minute cryptogamic plant. But the importance of these observations was not widely appreciated and no general relation was established between bacteria and disease in man.

Likewise, theories of infection which explained disease as due to invisible microorganisms had been propounded as early as 1762, as for example that of Plenciz, which, based on Leeuwenhoek's discoveries, ascribed to every disease its particular microorganism, explained the decomposition of animal and vegetable material as due to microorganisms, postulated the growth of bacteria in living tissues and suggested the possibility of the transmission of disease virus by the air. Such views, naturally, were without experimental basis and without even an objective knowledge of the microorganisms supposed to be etiologically concerned. In other words the propounder of this theory, as others after him, believed more than he could prove. By the middle of the century, however, observations on bacteria, largely as the result of the labors of botanists, were accumulating, and views about spontaneous generation, fermentation and infection were being discussed, but the fundamental experiments necessary to settle these problems were yet to be made, and, curiously enough, it was to a chemist, influenced by the methods of physics, who was to establish bacteriology as a biological science and to give to it the important place in medicine which it has occupied for the past thirty years.

Pasteur was this chemist, and his first great discovery was in crystallography, the explanation of the behavior of one of the tartaric acids to polarized light. This acid obtained from the lees of wine was, unlike other acids of the group, inactive to polarized light. This inactivity Pasteur demonstrated to be due to the fact that it was made up of two isomeric constituents. The crystals of one of these constituents bore hemihedral facets on the right side and rotated the plane of polarized light to the right, and those of the other bore similar facets on the left, and therefore, rotated to the left, but, as Pasteur found, when combined, these crystals did not rotate the plane of polarized light at all. This, the first of his discoveries, was in 1818, the year that Virchow was investigating typhus fever in Silesia. If it is necessary to fix contemporary events more definitely I may introduce the fact that two years later Pasteur quotes Professor Biot as referring to his recent discoveries in crystallography as "a very California."

Now, this work of Pasteur on the tartaric acids not only opened a new field in crystallographic studies, hut, of far greater importance, led to the discoverer's studies in fermentation. In the course of his work on the tartaric acids he found that if salts of the inactive acid were acted upon by a mould (Penicilium glaucum) the right-handed constituent was destroyed, but the left-handed remained unchanged; and from this he concluded that the change from an optically inactive to an optically active fluid, under such experimental conditions, could be due only to the presence of living matter causing the destruction of one component. This was the beginning of his studies of fermentation, and from this time his labors were those which eventually established the sciences of bacteriology and immunity.

The opportunity to study alcoholic fermentation came at Lille in 1854, at a time when Pasteur was professor of chemistry and dean to the faculty at that place. The manufacturers of the region had met with disappointment in the making of alcohol from beets, and one of them came to the new professor of chemistry for advice. Pasteur undertook daily visits to the factory and from these visits came the idea of studying the fermenting beet juice in the laboratory.

Fermentation, at the time Pasteur entered the field, was a subject involved in great obscurity, with only here and there a ray of light. Cagnaird-Latour, in 1836, had studied that ferment of beer called yeast, and had observed that it was composed of cells "susceptible of reproduction by a sort of budding, and probably acting on sugar through some effect of their vegetation." Schwann and Kützing a few years later reached the same conclusion, but were opposed at once by Liebig, who enunciated a theory of mechanical decomposition and denied in its entirety the theory that fermentation was a biological process. Also Berzelius, second only to Liebig as an authority, believed fermentation was due to contact, and elaborated a theory of catalytic force. With such weighty opposing opinion the observations of Cagnaird-Latour and Kützing were neglected and fermentation was regarded by all as a strange and obscure process and was so characterized by Claude Bernard in 1850.

Uninfluenced by these views, however, Pasteur, having recognized that living matter is essential for alcoholic fermentation, adhered strictly to the experimental method, and taking up the problem of lactic acid fermentation (the souring of milk), discovered that the same budding and multiplying of a cell went on in it as in alcoholic fermentation, but that the cell of lactic acid fermentation was different from that of alcoholic fermentation. He observed also that the form of the cells changed according to the conditions of fermentation. Incidentally he demonstrated in alcoholic fermentation, the formation of glycerin and succinic acid in addition to the well-known products alcohol and carbonic acid. In short, the outcome was that Pasteur completely demonstrated that the fermentations which lead to the production of alcohol, vinegar, lactic acid and butyric acid are all due to the presence and growth of minute organisms, or, in his own words, "The chemical act of fermentation is essentially a correlative phenomenon of a vital act beginning and ending with it."

The demonstration of the part played by specific microorganisms in the different fermentations was, as may readily be seen, suggestive of the etiology of infectious diseases. It was in the midst of these labors that the Académie des Sciences conferred upon Pasteur the Prize for Experimental Physiology (for 1859), and it was Claude Bernard who drew up the report and dwelt upon the "physiological tendency in Pasteur's researches." Ten years before, Bernard had characterized the process of fermentation as "obscure."

The results of the investigation of fermentation led naturally to a debate among the academicians concerning spontaneous generation, and in this dispute Pasteur took a most important part. The older examples of spontaneous generation, as, for example, the development of mice from a mixture of soiled linen and cheese and of maggots from decomposing meat, had long been discarded, but the demonstration that fermentation and putrefaction were due to microscopic living organisms raised the question: Whence comes this microscopic life? Do or do not these bodies arise spontaneously in putrescible and fermentable fluids? The results of several investigations were already at hand. Thus Spallanzani (1769) had shown that if a putrescible fluid was hermetically sealed in flasks and the flasks heated in boiling water, decomposition did not occur; Schulze (1836) had obtained the same result by filtering through strong solutions of acids and alkalies the air which entered such flasks, as had also Schwann (1837), by first passing the air through heated tubes; and likewise Schroeder and Dusch (1854) by filtering the air through cotton plugs. All these procedures robbed the air of the suspended microorganisms and, as the fluids had previously been sterilized by heat, decomposition did not occur. But at the time these procedures, though now recognized as the basic principles of bacteriological technique, as applied to sterilization and asepsis, did not gain general credence. "Philosophic argumentation always returned to the fore." The theory of spontaneous generation would not down, and from 1858 to 1862 it was the most important matter of debate in the discussions of the Académie des Sciences.

Pouchet and Pasteur were the disputants, the former defending the thesis that "animals and plants could be generated in a medium abso lately free from atmospheric air, and into which, therefore, no germ or organic bodies could have been brought by the air"; the latter insisting that only through the entrance of such living organisms could the changes in question take place. The discussion lasted several years, and to-day presents many interesting details, but it may suffice to state that it was ended by Pasteur's demonstration that if the neck of a flask was drawn out into a fine tube and bent into a double curve and the flask then heated by boiling, no decomposition occurred. The flask was open to the atmospheric air, but the microorganisms of the air were arrested by the drop of water of condensation, in the lower point of the curved neck. This demonstration, with the later work of Cohn on spores and of Tyndall on floating matter in the air, disposed of the doctrine of spontaneous generation and led to the universal acceptance of Harvey's law Omne vivum ex ovo, or as it was modified, Omne vivum ex vivo.

It is not surprising that Pasteur at this time foresaw the possibilities in the study of the etiology of the infectious diseases. The process of fermentation, due to living microorganisms, and beginning with a period of apparent inactivity, passing on to a stage of very evident activity and finally sinking gradually into quiescence, was analogous to the period of incubation, the stage of active manifestations and the gradual defervescence of an infectious disease. Also the specificity of the ferments was evidently suggestive of the specific etiology of disease, and altogether we see from several of Pasteur's statements at this time that the relation of microscopic organisms to disease occupied his mind. Thus in a letter to his father, in 1860, he expressed the hope that he may, "bring a little stone to the frail and ill-assured edifice of our knowledge of those deep mysteries of Life and Death where all our intellects have so lamentably failed" and in 1863, after an audience with Napoleon III., he writes, "I assured the Emperor that all my ambition was to arrive at the knowledge of the causes of putrid and contagious diseases."

And now with that peculiar trick of coincidence that is so surprising in the course of culture and inquiry, we find that about this time bacteriology began to make advances along three general lines of study: (1) The etiology of the acute infectious diseases; (2) the prevention of infection, and (3) the achievement of cure or immunity by vaccination. In the first and third of these, Pasteur played a prominent part and it was his work on fermentation which suggested the second to Lister. Pasteur's entrance into the field of etiology and the results he there accomplished form one of the most interesting phases of the history of science and its outcome, a matter of the greatest economic importance to France. The opportunity to study an infectious disease was offered by an epidemic of a mysterious disease which was ruining the silkworm industry. Whence the disease came or how it was contracted no one knew. Its onset was recognized only by the presence of the little brown or blackish spot from which it got its name (pébrine). Pasteur, who undertook the investigation at the request of his old master Dumas, now a senator, knew nothing of the industry and, as he wrote Dumas, "had never touched a silkworm." But under pressure of Dumas's solicitation he finally yielded, and found himself, a chemist, hitherto interested chiefly in the study of crystallography and fermentation, thrown at once into a new and strange field. That his results were due largely to the training and the point of view obtained through the study of fermentation and the use of the microscope, there can be little doubt, and one is inclined to apply to Pasteur at this stage of his work his own statement of ten years before; "in the fields of observation, chance favors only the mind which is prepared."

Once in the silkworm country he applied himself energetically to the study of the "fatal spots." The story of the complete investigation is a long one, but the main points are that within a month he found that although worms, moths and eggs were infected, the critical stage was the infection of the moths, and that, in these, the infection could be readily demonstrated with the aid of the microscope, and, that having demonstrated this, the remedy lay in using the eggs of non-infected moths only. Thus a new breed of worms free from infection could be obtained and the extension of the disease arrested. In the course of this work he reproduced the disease experimentally by feeding healthy moths with infected mulberry leaves, a novel procedure then, but one, which, with its modifications, was soon to become a commonplace principle of bacteriological investigation. The investigation of the silkworm problem lasted for five years, or until Pasteur cleared up not only the difficulties connected with pebrine, a disease due to infection with a psorosperm, but unmasked also a second disease of the silkworm (flâcherie), a bacterial infection of intestinal origin.

In the meantime Pasteur continued his studies of the diseases of wines (sour, bitter and muddy wines) and invented the process known then and now as "pasteurization." This was the simple process of heating the wine in order to free it of all germs of wine disease and make it suitable for storage and exportation. In this connection he expresses the greatest satisfaction that he was thus able to contribute to the national riches through the practical application of his observations. In 1867 he said:

Nothing is more agreeable to a man who has made science his career than to increase the number of discoveries, but his cup of joy is full when the result of his observations is put to immediate practical test.

The term, pasteurization, is now most frequently heard in connection with milk, but when it is recalled that all commercial and domestic methods of canning and preserving solid and fluid foods are based on the laboratory experiments of Pasteur one obtains an adequate idea of the importance of his observations and likewise appreciates his satisfaction at the practical application of his methods.

As the silkworm problem began to clear up, Pasteur's thoughts turned more and more to the etiology of the acute infectious diseases of man and animals and their experimental study. This is shown in his appeal to the government (1867) for a laboratory. In this appeal he refers to the advisability of investigating splenic fever and asks. "How can researches be attempted on gangrene, virus or inoculations, without a building suitable for the housing of animals?" and in 1871, in his book on beer, with the diseases of which he had busied himself, we again find a reference to the possibility of the disease of man and animals being due to microorganisms. Here again it is evident that he was influenced by the idea of microorganisms invisibly introduced into fermentable fluids, for in this connection he says, "it is impossible not to be pursued by the thought that similar acts may, must, take place in animals and in man "; but without experimental proof he refused to go further.

Pasteur's attack on animal diseases was, however, delayed, first by a cerebral hemorrhage in 1868 which left him partly paralyzed, and then by the Franco-Prussian war which interrupted all scientific efforts in Paris.

Here it is well to pause a moment to consider the attitude of the medical profession towards the theory which was beginning to take shape as the "germ theory." The following decade was to see the bacterial etiology of several important diseases established, Lister's practise of antisepsis in surgery quite generally accepted, and the principle of specific vaccine treatment demonstrated. To-day no phase of medicine is so well understood by the world at large as that of bacteriological principles and aims. Germs and sera, prophylaxis and quarantine, antisepsis and pasteurization, are matters of common knowledge and of ordinary conversation, but it is difficult for one unfamiliar with pre-bacteriology days to appreciate the views which had to be combated only forty years ago. A brief glance at the conditions in 1873 may therefore give you a better appreciation of the events of the succeeding decade. If it is necessary to fix the period, let me remind you that 1873 was the year the University of California removed to its present site.

The Franco-Prussian war had come to a close. Surgeons remembered that though soldiers were killed in battle by tens and hundreds, they died of surgical diseases by thousands.

In the hospitals surgical sepsis ran rampant. Secondary hemorrhage, erysipelas, pyemia and "hospital gangrene" were endemic. Sometimes wards, wings or whole institutions were closed in vain attempts to stamp out these disorders. (Mumford.)

The causes were unknown and the remedies, therefore, not at hand. Of this period we read with amazement that

Sometimes a surgeon would wear the same old operating coat for years, and would pick waxed ligatures from the button hole of his assistant who carried them there for the convenience of his chief. (Mumford.) To-day, we refer to it as "a barbarous era" but before Lister the most conscientious surgeon had no reason to do otherwise than has been described.

And, likewise, internal medicine, although it had benefited by improvements in the methods of physical diagnosis and by the application of the principles of pathological anatomy, had made no progress in the prevention and treatment of the infectious diseases. In the presence of these scourges of humanity the physician was not only helpless, but indifferent to the occasional illuminating discoveries of the exact thinker or investigator. Many examples of this indifference are at hand. In the writings of Henle (1840-1853) was announced a rational theory of infection, but it was ignored. Oliver Wendell Holmes (1843 and 1855) had brought forth a great body of facts indicating that puerperal fever was "so far contagious as to be carried from patient to patient by physicians and nurses" and Semmelweis in 1847, working in the old Vienna hospital, had asserted that the mortality from this disease could be reduced from 12 and 16 per cent, to 3 per cent, (later he reduced it to less than 1 per cent.) by the simple procedure of cleansing, in a solution of chlorinated lime water, the hands of those concerned in obstetrical work. The views of Holmes and Semmelweis, however, were ridiculed and the simple antiseptic procedure of the latter was not continued, and when Villemin, thirteen years before Koch discovered the tubercle bacilli, demonstrated by exact experimentation the transmission of tuberculosis to animals, and announced that the disease was a specific transmissible disease, "he was treated almost as a perturber of medical order." I know of nothing which so clearly shows the state of mind of the profession of that day as the remark of Pidoux in criticizing Villemin's work. Referring to the doctrines of specificity he says,

These doctrines condemn us to the research of specific remedies or vaccines and all progress is arrested. . . . Specificity immobilizes medicine.

This representative of traditional medicine could see no relation between Villemin's experiments in which guinea pigs were brought into contact with the dried sputum of tuberculous patients and Pasteur's theory of germs floating in the air being responsible for the various fermentations.

So, likewise, it was with Davaine's demonstration (1863) of bacteria in the blood of animals dying with anthrax. His view that these microorganisms, multiplying rapidly in the blood, were in their action analogous to Pasteur's ferments and responsible for the death of the animal, was received only with arguments and did not immediately stimulate investigation, despite his proof of experimental production of the disease by inoculation. To us, who know to-day the fruits of the study of specific etiology and specific therapy, the opposition to the views of Villemin and Davaine and others is almost incomprehensible, but it must be remembered that these views were the fruits of a new type of investigation in practical medicine, that of laboratory research which came close to the sacred precincts of the clinic. "This was the time," in France at least, "when the princes of science 5 or those who were considered as such, were chiefly physicians. The almost daily habit of advising and counselling" gave them a haughty superiority, and views not based on clinical researches were set aside as unsound. Physiology and chemistry applied to the normal individual were well enough, and pathological anatomy with the post-mortem room as an adjunct to the clinic was very proper, but for the laboratory investigator to invade the clinic and present his views concerning the cause of disease or to explain its phenomena was another matter. A well-known surgeon of that time stated:

Laboratory results should be brought out in a circumspect, modest and reserved manner, as long as they have not been sanctioned by long clinical researches.

But at the very time (1873) of this statement, the forces which were to make the era of laboratory research the greatest of medical eras were already at work; Hoppe-Seyler was establishing (1872) the first laboratory of physiological chemistry, v. Piecklinghausen was studying the wanderings of the white blood cell, Weigert was staining bacteria with carmine, Ehrlich was applying dyes to the study of the cells of the blood (both later developed the use of the aniline dyes in histological and bacteriological technic), Abbe was developing his condensing system of illumination for the microscope, Cohn was classifying bacteria according to their morphology, Klebs was separating bacteria from their culture fluid by filtration through animal cells, Pettenkoffer was studying the relation of water to epidemics of typhoid fever and cholera, Obermeier had found a parasite in the blood of relapsing fever, and Koch, a country physician, was carrying on those early researches which were soon to make him the leader in the science of bacteriology. At the same time (since 1866), pathologists (Eindfleish, v. Piecklinghausen, Waldeyer, Birch-Hirschfeld and Klebs) had been examining individuals dying of septicemia, pyemia, erysipelas, abscess, inflamed wounds, etc., and had found bacteria in all these lesions, Birch-Hirschfeld, moreover, had called attention to the resemblance, in pyemia, between the bacteria of the local lesion and those in the internal organs, and had observed bacteria within the leucocyte. To us, who view these activities in retrospect, they are phases of a general advance, the culmination of which is common knowledge, but in the early seventies they were merely the non-related efforts of individual workers. Some practical demonstration was necessary to give to the newer type of laboratory work an importance which would impress the profession. Such a demonstration came through Lister's antiseptic treatment of wounds and was followed shortly by the observations of Koch on anthrax, and of Pasteur on vaccination against bacterial disease.

Lister's first publication concerning his treatment of wounds was in 1867, but it was not until the late seventies that his views were quite generally accepted. In the meantime his methods and their results served to concentrate attention on bacteria and their relation to the diseases of man. He regarded wound infection as putrefaction due to the invasion of the wound by minute microorganisms of the air; a conception which, as he acknowledges in his first publication, was suggested by Pasteur's work on fermentation. In a letter to Pasteur in 1874 he offers "most cordial thanks for having demonstrated to me the germ theory of putrefaction, and thus furnished me with the principle upon which alone the antiseptic treatment can be carried out."

His method was to combat this air-borne infection with an antiseptic—carbolic acid. He cleaned a wound by wiping it out with carbolic acid and then sealed it with lint soaked in this acid. All instruments, sponges and dressings coming in contact with the wound or the hands of the operator or assistants, as well as the site of operation, were cleansed in the same way. Also, by means of a vaporizer, carbolic acid was sprayed into the atmosphere about the site of operation. As years passed the details of this method changed. We now speak of the suppuration of wounds, not of putrefaction; the carbolic spray has been abandoned and our ideas about sepsis have been modified in several ways, but the principle remains as Lister conceived it. The beneficial results of this new treatment in Lister's hands were immediate, but its general application came slowly. We find Pasteur in 1874 referring to Lister's "marvellous surgical methods" and recommending to the surgeons of Paris the use of instruments and dressings sterilized by heat. The complete acceptance of Lister's principle would appear to correspond to the year 1883, when he was made a baronet.

The benefits of antisepsis are now so familiar to us, and its use so much a matter of routine, that we cease to wonder at the revolution it brought about in surgery. Some diseases, as hospital gangrene, it has abolished entirely; others as the septic surgical diseases of former days have been reduced almost to nil; it has robbed the period of child-bearing of one of its chief perils, and has opened to surgery regions and cavities of the body previously closed on account of the great mortality due to sepsis. Antisepsis shares with anesthesia, as its discoverer, Lister, shares with Morton, Warren and Simpson, the honor of the great advances surgery has made in the treatment of disease and injuries of the abdomen, thorax and the cranial cavity. Who can compute the relief from suffering and the saving of life which may be traced through Lister to Pasteur's laboratory experiments on fermentation?

The recognition of the principle of asepsis by the surgeons was, then, as we have seen, slow and grudging enough; among the profession at large the theory of infection as applied to acute diseases gained more slowly still. It was not until 1880 that advance in the knowledge of the bacterial etiology of infectious diseases assumed such definite shape as to attract general attention. As we look back upon this early work we see clearly that one reason for this slow advance was the absence of proper methods of isolating bacteria in what we now call pure cultures. Pasteur and his co-laborers made (1) direct search for bacteria in the secretions, blood or tissue juices, or (2) inoculated fluid media or animals with such material. By the first of these methods it was possible to recognize bacteria if they were especially abundant, as in anthrax, and it was by this method that Neisser discovered the gonococcus (1879) and Hansen the leprosy bacillus (1879), bacteria which are particularly abundant in the local lesions of the respective diseases. The second method, the use of fluid media, was satisfactory if the material for study contained only one type of organism; if more than one it was obviously difficult to study the life history of a bacterium or to obtain exact results by the inoculation on account of the simultaneous growth of associated or contaminating organisms. This difficulty was overcome by Koch, in 1881, through the introduction of solid culture media. Koch had already, while a country practitioner, definitely and clearly established the relation of the anthrax bacillus to the splenic fever of cattle and had demonstrated in this organism the formation of spores and their importance; also he had published most important observations on the bacteriology of wound infection. The use of solid media, which it is said was suggested to Koch by the growth of mould on potato, led at once to rapid advance, for as each bacterium placed on a solid medium causes, as it multiplies, the growth of a visible colony, it was possible to distinguish colonies having different characteristics and by transplantation to secure pure cultures. The demonstration of Koch's solid media and plate method at the Congress of Hygiene in London in 1881 caused Pasteur to exclaim "C'est un grand progrés." This advance and the use of microscopes equipped with the oil immersion lens and the Abbe condenser, and the increased knowledge concerning the use of the aniline dyes for staining purposes gave to bacteriology the technique necessary for its rapid development. Koch was called to the Imperial Board of Health in Berlin in 1880, and started the first laboratory founded for the study of bacteriology and public health problems. In this laboratory, methods of studying and photographing bacteria were developed, methods of disinfection based on the knowledge of spore resistance were elaborated, and the study of the bacteriology of individual diseases inaugurated. As a result of the latter activity, he announced, in 1882, the discovery of the bacillus of tuberculosis, and it is not too much to say that his announcement astounded and profoundly stirred the entire civilized world. In the same year Löffler and Shütz announced the discovery of the bacillus of glanders, and Pasteur published an account of the bacteriology of swine erysipelas; this was the beginning of an active period with discovery crowding on discovery. In 1883 came Koch's announcement of the comma bacillus as the cause of cholera; in 1884 Löffler's description of the bacillus of diphtheria and Nicolaier's discovery of the bacillus of tetanus. So the march of discovery continued until the roll of diseases of known etiology in a short time included typhoid fever, pneumonia, meningitis, influenza, bubonic plague and the various surgical suppurations.

The rapid discoveries of disease-producing microorganisms established definitely Pasteur's doctrine of specificity as applied to etiology and led at once to an interest in public health measures which increased as the years passed, until now it has become one of the most vital interests of our social system. Even in the early eighties, with a knowledge of the etiology and mode of transmission of a few diseases and of Lister's results in antiseptic surgery, it was possible to postulate general prophylactic measures safeguarding the individual and the community, and as knowledge of etiology and transmission increased, so did prophylaxis. Hygeia was again enthroned and it was recognized that "an ounce of prevention is worth a pound of cure."

But prophylaxis was not entirely satisfying. If a specific etiology, why not a specific therapy for bacterial diseases? Men remembered inoculation for smallpox introduced into England by Lady Mary Wortley Montagu early in the eighteenth century. This procedure, the inoculation of healthy individuals with material from the pustules of those ill with a mild form of smallpox had materially reduced the fatality of the disease. The procedure, it is true, had been made illegal in England in 1840, because of the greater success and less danger of Jenner's wonderful discovery (1798) of vaccination with the fluid of the pustule of cowpox. Inoculation, however, despite the fact that it sometimes caused severe and fatal cases of smallpox and perpetuated foci for the dissemination of the disease, had demonstrated that the mild inoculation disease visually protected against the more severe forms. That Jenner's vaccine was a transmitted cowpox did not militate against the general theory of protecting the individual against a severe form of a disease by the production of a mild form, for cowpox was generally considered to be smallpox modified by passage through another host, the bovine animal. If such results could be obtained against a disease, small-pox, the causal agent of which was unknown, how much easier to vaccinate against a disease of known etiology!

This was therefore the first line of attack in the battle for a specific therapy of the infectious diseases. Already Pasteur was at work. An epidemic of chicken-cholera, in 1880, offered the opportunity for extended experiments. In the course of this work, a chance observation gave him the clue to vaccination with bacteria of attenuated virulence. It had been his routine practise in the experimental production of chicken cholera to use fresh 24-hour cultures; these always produced the disease readily. But in the course of the work it happened that an old culture which had been set aside for a few weeks and forgotten, was used, with the unexpected result that the inoculated hens, although ill for a while, promptly recovered, and what was more surprising, remained refractory to subsequent inoculation of fresh cultures, though the same cultures were virulent for untreated hens. This phenomenon, the attenuation of virulence clue to artificial cultivation, Pasteur used as the basis of a treatment by vaccination, which had the immediate effect (1880) of reducing the mortality of chicken cholera to one per cent, and the more remote but far more important effect of stimulating the study of specific therapy. Incidentally it was the link between Lady Mary Wortley Montagu's preventive inoculation and Jenner's vaccination, on the one hand, and modern theories of the production of immunity on the other.

The next step was with anthrax, a disease, of cattle. The attenuation of chicken cholera virus had been due to artificial cultivation, but about this time Toussaint, of the veterinary school of Toulouse, made some observation on the attenuation of anthrax bacilli under the influence of increased temperature (heating to 55° C. for ten minutes). His observations, however, were without constant results. Pasteur, who was familiar with Toussaint's work, took up the matter and after a thorough investigation found that anthrax bacilli cultivated at a temperature of 42° to 43° C, became attenuated, and this attenuation persisted on artificial cultivation (1881). The inoculation of such organisms did not cause anthrax, and when later virulent bacilli of anthrax were inoculated, the animals were found to be immune. This was the scientific basis of the celebrated public test at Melun. Sixty sheep and ten cows were placed at the disposal of Pasteur; twenty-five of the sheep and six of the cows were to be vaccinated with attenuated anthrax bacilli, and after an interval of twelve to fifteen days this was to be repeated. Later this lot, and also twenty-five untreated sheep and four untreated cows, were to be inoculated with a virulent culture of anthrax bacilli. Ten sheep were to have no treatment at all. "The twenty-five unvaccinated sheep will all perish," wrote Pasteur, "the twenty-five vaccinated ones will survive." This magnificent faith based on exact experimentation was justified. All happened as Pasteur predicted. For medicine a new era was at hand; Huxley, in 1880, estimated that the money value of the results of Pasteur's vaccination treatment was sufficient to cover the war indemnity paid by France to Germany in 1879. As the years go by and the influence of Pasteur widens the horizon of preventive medicine and the treatment of disease by immunizing methods, civilization's indebtedness to Pasteur is almost beyond the grasp of the imagination.

His discoveries in vaccination against swine erysipelas and hydrophobia are as fascinating, in their "mingling of experimental skill and scientific imagination" (Herter), as all that he did before. But while Pasteur is an engaging figure, worthy of much more than this simple lecture that we are devoting to him, yet he is not the whole story, and at this point we must turn away from him and proceed to another line of advance: one, however, which was in part the result of his genius and his indefatigable labor. This, the discovery of antitoxic sera, will be discussed in the next lecture, in connection with other modern problems and methods in medical research. But here let me remind you that it was Pasteur, afflicted at the age of 46 with a hemiplegic paralysis—which, by the way, left its traces during the remaining twenty-five years of his life—who said,

Work can be made into a pleasure, and alone is profitable to a man, to his country, to the world.

It would be difficult to find in any field of human endeavor an individual whose life and labors exemplified this precept better than do the life and labors of Louis Pasteur.

  1. The Hitchcock lectures, delivered at the University of California, January 23-26, 1912.