A History of Science Volume IV Part 12

There was nothing in these studies bearing directly upon the question of animal diseases, yet before they were finished they had stimulated progress in more than one field of pathology. At the very outset they sufficed to start afresh the inquiry as to the role played by micro-organisms in disease. In particular they led the French physician Devaine to return to some interrupted studies which he had made ten years before in reference to the animal disease called anthrax, or splenic fever, a disease that cost the farmers of Europe millions of francs annually through loss of sheep and cattle. In 1850 Devaine had seen mult.i.tudes of bacteria in the blood of animals who had died of anthrax, but he did not at that time think of them as having a causal relation to the disease. Now, however, in 1863, stimulated by Pasteur's new revelations regarding the power of bacteria, he returned to the subject, and soon became convinced, through experiments by means of inoculation, that the microscopic organisms he had discovered were the veritable and the sole cause of the infectious disease anthrax.

The publication of this belief in 1863 aroused a furor of controversy.

That a microscopic vegetable could cause a virulent systemic disease was an idea altogether too startling to be accepted in a day, and the generality of biologists and physicians demanded more convincing proofs than Devaine as yet was able to offer.

Naturally a host of other investigators all over the world entered the field. Foremost among these was the German Dr. Robert Koch, who soon corroborated all that Devaine had observed, and carried the experiments further in the direction of the cultivation of successive generations of the bacteria in artificial media, inoculations being made from such pure cultures of the eighth generation, with the astonishing result that animals thus inoculated succ.u.mbed to the disease.

Such experiments seem demonstrative, yet the world was unconvinced, and in 1876, while the controversy was still at its height, Pasteur was prevailed upon to take the matter in hand. The great chemist was becoming more and more exclusively a biologist as the years pa.s.sed, and in recent years his famous studies of the silk-worm diseases, which he proved due to bacterial infection, and of the question of spontaneous generation, had given him unequalled resources in microscopical technique. And so when, with the aid of his laboratory a.s.sociates Duclaux and Chamberland and Roux, he took up the mooted anthrax question the scientific world awaited the issue with bated breath. And when, in 1877, Pasteur was ready to report on his studies of anthrax, he came forward with such a wealth of demonstrative experiments--experiments the rigid accuracy of which no one would for a moment think of questioning--going to prove the bacterial origin of anthrax, that scepticism was at last quieted for all time to come.

Henceforth no one could doubt that the contagious disease anthrax is due exclusively to the introduction into an animal's system of a specific germ--a microscopic plant--which develops there. And no logical mind could have a reasonable doubt that what is proved true of one infectious disease would some day be proved true also of other, perhaps of all, forms of infectious maladies.

Hitherto the cause of contagion, by which certain maladies spread from individual to individual, had been a total mystery, quite unillumined by the vague terms "miasm," "humor," "virus," and the like cloaks of ignorance. Here and there a prophet of science, as Schwann and Henle, had guessed the secret; but guessing, in science, is far enough from knowing. Now, for the first time, the world KNEW, and medicine had taken another gigantic stride towards the heights of exact science.

LISTER AND ANTISEPTIC SURGERY

Meantime, in a different though allied field of medicine there had been a complementary growth that led to immediate results of even more practical importance. I mean the theory and practice of antisepsis in surgery. This advance, like the other, came as a direct outgrowth of Pasteur's fermentation studies of alcoholic beverages, though not at the hands of Pasteur himself. Struck by the boundless implications of Pasteur's revelations regarding the bacteria, Dr. Joseph Lister (the present Lord Lister), then of Glasgow, set about as early as 1860 to make a wonderful application of these ideas. If putrefaction is always due to bacterial development, he argued, this must apply as well to living as to dead tissues; hence the putrefactive changes which occur in wounds and after operations on the human subject, from which blood-poisoning so often follows, might be absolutely prevented if the injured surfaces could be kept free from access of the germs of decay.

In the hope of accomplishing this result, Lister began experimenting with drugs that might kill the bacteria without injury to the patient, and with means to prevent further access of germs once a wound was freed from them. How well he succeeded all the world knows; how bitterly he was antagonized for about a score of years, most of the world has already forgotten. As early as 1867 Lister was able to publish results pointing towards success in his great project; yet so incredulous were surgeons in general that even some years later the leading surgeons on the Continent had not so much as heard of his efforts. In 1870 the soldiers of Paris died, as of old, of hospital gangrene; and when, in 1871, the French surgeon Alphonse Guerin, stimulated by Pasteur's studies, conceived the idea of dressing wounds with cotton in the hope of keeping germs from entering them, he was quite unaware that a British contemporary had preceded him by a full decade in this effort at prevention and had made long strides towards complete success. Lister's priority, however, and the superiority of his method, were freely admitted by the French Academy of Sciences, which in 1881 officially crowned his achievement, as the Royal Society of London had done the year before.

By this time, to be sure, as everybody knows, Lister's new methods had made their way everywhere, revolutionizing the practice of surgery and practically banishing from the earth maladies that hitherto had been the terror of the surgeon and the opprobrium of his art. And these bedside studies, conducted in the end by thousands of men who had no knowledge of microscopy, had a large share in establishing the general belief in the causal relation that micro-organisms bear to disease, which by about the year 1880 had taken possession of the medical world. But they did more; they brought into equal prominence the idea that, the cause of a diseased condition being known, it maybe possible as never before to grapple with and eradicate that condition.

PREVENTIVE INOCULATION

The controversy over spontaneous generation, which, thanks to Pasteur and Tyndall, had just been brought to a termination, made it clear that no bacterium need be feared where an antecedent bacterium had not found lodgment; Listerism in surgery had now shown how much might be accomplished towards preventing the access of germs to abraded surfaces of the body and destroying those that already had found lodgment there.

As yet, however, there was no inkling of a way in which a corresponding onslaught might be made upon those other germs which find their way into the animal organism by way of the mouth and the nostrils, and which, as was now clear, are the cause of those contagious diseases which, first and last, claim so large a proportion of mankind for their victims.

How such means might be found now became the anxious thought of every imaginative physician, of every working microbiologist.

As it happened, the world was not kept long in suspense. Almost before the proposition had taken shape in the minds of the other leaders, Pasteur had found a solution. Guided by the empirical success of Jenner, he, like many others, had long practised inoculation experiments, and on February 9, 1880, he announced to the French Academy of Sciences that he had found a method of so reducing the virulence of a disease germ that when introduced into the system of a susceptible animal it produced only a mild form of the disease, which, however, sufficed to protect against the usual virulent form exactly as vaccinia protects against small-pox.

The particular disease experimented with was that infectious malady of poultry known familiarly as "chicken cholera." In October of the same year Pasteur announced the method by which this "attenuation of the virus," as he termed it, had been brought about--by cultivation of the disease germs in artificial media, exposed to the air, and he did not hesitate to a.s.sert his belief that the method would prove "susceptible of generalization"--that is to say, of application to other diseases than the particular one in question.

Within a few months he made good this prophecy, for in February, 1881, he announced to the Academy that with the aid, as before, of his a.s.sociates MM. Chamberland and Roux, he had produced an attenuated virus of the anthrax microbe by the use of which, as he affirmed with great confidence, he could protect sheep, and presumably cattle, against that fatal malady. "In some recent publications," said Pasteur, "I announced the first case of the attenuation of a virus by experimental methods only. Formed of a special microbe of an extreme minuteness, this virus may be multiplied by artificial culture outside the animal body. These cultures, left alone without any possible external contamination, undergo, in the course of time, modifications of their virulency to a greater or less extent. The oxygen of the atmosphere is said to be the chief cause of these attenuations--that is, this lessening of the facilities of multiplication of the microbe; for it is evident that the difference of virulence is in some way a.s.sociated with differences of development in the parasitic economy.

"There is no need to insist upon the interesting character of these results and the deductions to be made therefrom. To seek to lessen the virulence by rational means would be to establish, upon an experimental basis, the hope of preparing from an active virus, easily cultivated either in the human or animal body, a vaccine-virus of restrained development capable of preventing the fatal effects of the former.

Therefore, we have applied all our energies to investigate the possible generalizing action of atmospheric oxygen in the attenuation of virus.

"The anthrax virus, being one that has been most carefully studied, seemed to be the first that should attract our attention. Every time, however, we encountered a difficulty. Between the microbe of chicken cholera and the microbe of anthrax there exists an essential difference which does not allow the new experiment to be verified by the old.

The microbes of chicken cholera do not, in effect, seem to resolve themselves, in their culture, into veritable germs. The latter are merely cells, or articulations always ready to multiply by division, except when the particular conditions in which they become true germs are known.

"The yeast of beer is a striking example of these cellular productions, being able to multiply themselves indefinitely without the apparition of their original spores. There exist many mucedines (Mucedinae?) of tubular mushrooms, which in certain conditions of culture produce a chain of more or less spherical cells called Conidae. The latter, detached from their branches, are able to reproduce themselves in the form of cells, without the appearance, at least with a change in the conditions of culture, of the spores of their respective mucedines.

These vegetable organisms can be compared to plants which are cultivated by slipping, and to produce which it is not necessary to have the fruits or the seeds of the mother plant.

"The anthrax bacterium, in its artificial cultivation, behaves very differently. Its mycelian filaments, if one may so describe them, have been produced scarcely for twenty-four or forty-eight hours when they are seen to transform themselves, those especially which are in free contact with the air, into very refringent corpuscles, capable of gradually isolating themselves into true germs of slight organization.

Moreover, observation shows that these germs, formed so quickly in the culture, do not undergo, after exposure for a time to atmospheric air, any change either in their vitality or their virulence. I was able to present to the Academy a tube containing some spores of anthrax bacteria produced four years ago, on March 21, 1887. Each year the germination of these little corpuscles has been tried, and each year the germination has been accomplished with the same facility and the same rapidity as at first. Each year also the virulence of the new cultures has been tested, and they have not shown any visible falling off. Therefore, how can we experiment with the action of the air upon the anthrax virus with any expectation of making it less virulent?

"The crucial difficulty lies perhaps entirely in this rapid reproduction of the bacteria germs which we have just related. In its form of a filament, and in its multiplication by division, is not this organism at all points comparable with the microbe of the chicken cholera?

"That a germ, properly so called, that a seed, does not suffer any modification on account of the air is easily conceived; but it is conceivable not less easily that if there should be any change it would occur by preference in the case of a mycelian fragment. It is thus that a slip which may have been abandoned in the soil in contact with the air does not take long to lose all vitality, while under similar conditions a seed is preserved in readiness to reproduce the plant. If these views have any foundation, we are led to think that in order to prove the action of the air upon the anthrax bacteria it will be indispensable to submit to this action the mycelian development of the minute organism under conditions where there cannot be the least admixture of corpuscular germs. Hence the problem of submitting the bacteria to the action of oxygen comes back to the question of presenting entirely the formation of spores. The question being put in this way, we are beginning to recognize that it is capable of being solved.

"We can, in fact, prevent the appearance of spores in the artificial cultures of the anthrax parasite by various artifices. At the lowest temperature at which this parasite can be cultivated--that is to say, about +16 degrees Centigrade--the bacterium does not produce germs--at any rate, for a very long time. The shapes of the minute microbe at this lowest limit of its development are irregular, in the form of b.a.l.l.s and pears--in a word, they are monstrosities--but they are without spores.

In the last regard also it is the same at the highest temperatures at which the parasite can be cultivated, temperatures which vary slightly according to the means employed. In neutral chicken bouillon the bacteria cannot be cultivated above 45 degrees. Culture, however, is easy and abundant at 42 to 43 degrees, but equally without any formation of spores. Consequently a culture of mycelian bacteria can be kept entirely free from germs while in contact with the open air at a temperature of from 42 to 43 degrees Centigrade. Now appear the three remarkable results. After about one month of waiting the culture dies--that is to say, if put into a fresh bouillon it becomes absolutely sterile.

"So much for the life and nutrition of this organism. In respect to its virulence, it is an extraordinary fact that it disappears entirely after eight days' culture at 42 to 43 degrees Centigrade, or, at any rate, the cultures are innocuous for the guinea-pig, the rabbit, and the sheep, the three kinds of animals most apt to contract anthrax. We are thus able to obtain, not only the attenuation of the virulence, but also its complete suppression by a simple method of cultivation. Moreover, we see also the possibility of preserving and cultivating the terrible microbe in an inoffensive state. What is it that happens in these eight days at 43 degrees that suffices to take away the virulence of the bacteria? Let us remember that the microbe of chicken cholera dies in contact with the air, in a period somewhat protracted, it is true, but after successive attenuations. Are we justified in thinking that it ought to be the same in regard to the microbe of anthrax? This hypothesis is confirmed by experiment. Before the disappearance of its virulence the anthrax microbe pa.s.ses through various degrees of attenuation, and, moreover, as is also the case with the microbe of chicken cholera, each of these attenuated states of virulence can be obtained by cultivation. Moreover, since, according to one of our recent Communications, anthrax is not recurrent, each of our attenuated anthrax microbes is, for the better-developed microbe, a vaccine--that is to say, a virus producing a less-malignant malady. What, therefore, is easier than to find in these a virus that will infect with anthrax sheep, cows, and horses, without killing them, and ultimately capable of warding off the mortal malady?

We have practised this experiment with great success upon sheep, and when the season comes for the a.s.sembling of the flocks at Beauce we shall try the experiment on a larger scale.

"Already M. Toussaint has announced that sheep can be saved by preventive inoculations; but when this able observer shall have published his results; on the subject of which we have made such exhaustive studies, as yet unpublished, we shall be able to see the whole difference which exists between the two methods--the uncertainty of the one and the certainty of the other. That which we announce has, moreover, the very great advantage of resting upon the existence of a poison vaccine cultivable at will, and which can be increased indefinitely in the s.p.a.ce of a few hours without having recourse to infected blood."(8)

This announcement was immediately challenged in a way that brought it to the attention of the entire world. The president of an agricultural society, realizing the enormous importance of the subject, proposed to Pasteur that his alleged discovery should be submitted to a decisive public test. He proposed to furnish a drove of fifty sheep half of which were to be inoculated with the attenuated virus of Pasteur. Subsequently all the sheep were to be inoculated with virulent virus, all being kept together in one pen under precisely the same conditions. The "protected"

sheep were to remain healthy; the unprotected ones to die of anthrax; so read the terms of the proposition. Pasteur accepted the challenge; he even permitted a change in the programme by which two goats were subst.i.tuted for two of the sheep, and ten cattle added, stipulating, however, that since his experiments had not yet been extended to cattle these should not be regarded as falling rigidly within the terms of the test.

It was a test to try the soul of any man, for all the world looked on askance, prepared to deride the maker of so preposterous a claim as soon as his claim should be proved baseless. Not even the fame of Pasteur could make the public at large, lay or scientific, believe in the possibility of what he proposed to accomplish. There was time for all the world to be informed of the procedure, for the first "preventive"

inoculation--or vaccination, as Pasteur termed it--was made on May 5th, the second on May 17th, and another interval of two weeks must elapse before the final inoculations with the unattenuated virus. Twenty-four sheep, one goat, and five cattle were submitted to the preliminary vaccinations. Then, on May 31 st, all sixty of the animals were inoculated, a protected and unprotected one alternately, with an extremely virulent culture of anthrax microbes that had been in Pasteur's laboratory since 1877. This accomplished, the animals were left together in one enclosure to await the issue.

Two days later, June 2d, at the appointed hour of rendezvous, a vast crowd, composed of veterinary surgeons, newspaper correspondents, and farmers from far and near, gathered to witness the closing scenes of this scientific tourney. What they saw was one of the most dramatic scenes in the history of peaceful science--a scene which, as Pasteur declared afterwards, "amazed the a.s.sembly." Scattered about the enclosure, dead, dying, or manifestly sick unto death, lay the unprotected animals, one and all, while each and every "protected"

animal stalked unconcernedly about with every appearance of perfect health. Twenty of the sheep and the one goat were already dead; two other sheep expired under the eyes of the spectators; the remaining victims lingered but a few hours longer. Thus in a manner theatrical enough, not to say tragic, was proclaimed the unequivocal victory of science. Naturally enough, the unbelievers struck their colors and surrendered without terms; the principle of protective vaccination, with a virus experimentally prepared in the laboratory, was established beyond the reach of controversy.

That memorable scientific battle marked the beginning of a new era in medicine. It was a foregone conclusion that the principle thus established would be still further generalized; that it would be applied to human maladies; that in all probability it would grapple successfully, sooner or later, with many infectious diseases. That expectation has advanced rapidly towards realization. Pasteur himself made the application to the human subject in the disease hydrophobia in 1885, since which time that hitherto most fatal of maladies has largely lost its terrors. Thousands of persons bitten by mad dogs have been s.n.a.t.c.hed from the fatal consequences of that mishap by this method at the Pasteur Inst.i.tute in Paris, and at the similar inst.i.tutes, built on the model of this parent one, that have been established all over the world in regions as widely separated as New York and Nha-Trang.

SERUM-THERAPY

In the production of the rabies vaccine Pasteur and his a.s.sociates developed a method of attenuation of a virus quite different from that which had been employed in the case of the vaccines of chicken cholera and of anthrax. The rabies virus was inoculated into the system of guinea-pigs or rabbits and, in effect, cultivated in the systems of these animals. The spinal cord of these infected animals was found to be rich in the virus, which rapidly became attenuated when the cord was dried in the air. The preventive virus, of varying strengths, was made by maceration of these cords at varying stages of desiccation. This cultivation of a virus within the animal organism suggested, no doubt, by the familiar Jennerian method of securing small-pox vaccine, was at the same time a step in the direction of a new therapeutic procedure which was destined presently to become of all-absorbing importance--the method, namely, of so-called serum-therapy, or the treatment of a disease with the blood serum of an animal that has been subjected to protective inoculation against that disease.

The possibility of such a method was suggested by the familiar observation, made by Pasteur and numerous other workers, that animals of different species differ widely in their susceptibility to various maladies, and that the virus of a given disease may become more and more virulent when pa.s.sed through the systems of successive individuals of one species, and, contrariwise, less and less virulent when pa.s.sed through the systems of successive individuals of another species. These facts suggested the theory that the blood of resistant animals might contain something directly antagonistic to the virus, and the hope that this something might be transferred with curative effect to the blood of an infected susceptible animal. Numerous experimenters all over the world made investigations along the line of this alluring possibility, the leaders perhaps being Drs. Behring and Kitasato, closely followed by Dr. Roux and his a.s.sociates of the Pasteur Inst.i.tute of Paris. Definite results were announced by Behring in 1892 regarding two important diseases--teta.n.u.s and diphtheria--but the method did not come into general notice until 1894, when Dr. Roux read an epoch-making paper on the subject at the Congress of Hygiene at Buda-Pesth.

In this paper Dr. Roux, after adverting to the labors of Behring, Ehrlich, Boer, Kossel, and Wa.s.serman, described in detail the methods that had been developed at the Pasteur Inst.i.tute for the development of the curative serum, to which Behring had given the since-familiar name ant.i.toxine. The method consists, first, of the cultivation, for some months, of the diphtheria bacillus (called the Klebs-Loeffler bacillus, in honor of its discoverers) in an artificial bouillon, for the development of a powerful toxine capable of giving the disease in a virulent form.

This toxine, after certain details of mechanical treatment, is injected in small but increasing doses into the system of an animal, care being taken to graduate the amount so that the animal does not succ.u.mb to the disease. After a certain course of this treatment it is found that a portion of blood serum of the animal so treated will act in a curative way if injected into the blood of another animal, or a human patient, suffering with diphtheria. In other words, according to theory, an ant.i.toxine has been developed in the system of the animal subjected to the progressive inoculations of the diphtheria toxine. In Dr. Roux's experience the animal best suited for the purpose is the horse, though almost any of the domesticated animals will serve the purpose.

But Dr. Roux's paper did not stop with the description of laboratory methods. It told also of the practical application of the serum to the treatment of numerous cases of diphtheria in the hospitals of Paris--applications that had met with a gratifying measure of success.

He made it clear that a means had been found of coping successfully with what had been one of the most virulent and intractable of the diseases of childhood. Hence it was not strange that his paper made a sensation in all circles, medical and lay alike.

Physicians from all over the world flocked to Paris to learn the details of the open secret, and within a few months the new serum-therapy had an acknowledged standing with the medical profession everywhere. What it had accomplished was regarded as but an earnest of what the new method might accomplish presently when applied to the other infectious diseases.

Efforts at such applications were immediately begun in numberless directions--had, indeed, been under way in many a laboratory for some years before. It is too early yet to speak of the results in detail. But enough has been done to show that this method also is susceptible of the widest generalization. It is not easy at the present stage to sift that which is tentative from that which will be permanent; but so great an authority as Behring does not hesitate to affirm that today we possess, in addition to the diphtheria ant.i.toxine, equally specific ant.i.toxines of teta.n.u.s, cholera, typhus fever, pneumonia, and tuberculosis--a set of diseases which in the aggregate account for a startling proportion of the general death-rate. Then it is known that Dr. Yersin, with the collaboration of his former colleagues of the Pasteur Inst.i.tute, has developed, and has used with success, an ant.i.toxine from the microbe of the plague which recently ravaged China.

Dr. Calmette, another graduate of the Pasteur Inst.i.tute, has extended the range of the serum-therapy to include the prevention and treatment of poisoning by venoms, and has developed an ant.i.toxine that has already given immunity from the lethal effects of snake bites to thousands of persons in India and Australia.

Just how much of present promise is tentative, just what are the limits of the methods--these are questions for the future to decide. But, in any event, there seems little question that the serum treatment will stand as the culminating achievement in therapeutics of our century.

It is the logical outgrowth of those experimental studies with the microscope begun by our predecessors of the thirties, and it represents the present culmination of the rigidly experimental method which has brought medicine from a level of fanciful empiricism to the plane of a rational experimental science.

IX. THE NEW SCIENCE OF EXPERIMENTAL PSYCHOLOGY

BRAIN AND MIND