Popular Science Monthly/Volume 81/August 1912/Research in Medicine IV
|RESEARCH IN MEDICINE
By Professor RICHARD M. PEARCE
UNIVERSITY OF PENNSYLVANIA
IV. Present-day Methods and Problems
THE important activities in scientific medicine at the present time may be said, without fear of contradiction, to be in. the departments of (1) immunology, (2) protozoology, (3) chemotherapy, (4) physiological chemistry, (5) experimental pharmacology and (6) experimental pathology. The methods and problems of these various phases of medicine it is my intention to discuss, some at length, others briefly, in the present lecture.
Immunology is the science which would explain and apply the mechanisms by means of which the animal body is enabled to resist disease. As has been shown, the efforts of bacteriologists until about 1890 were devoted almost entirely to the study of the etiology of the infectious diseases and to attempts to combat these by vaccination with attenuated viruses. Another phase of bacteriology was, however, already under way, and this, in the earlier nineties, not only yielded results of great practical importance, but opened a new and ever-widening field of investigation. This was the study of the mode of action of invading bacteria and their products, that is, of the process of infection and intoxication, and the mechanism by which the host combats the invasion and absorbs or cures such infection by overwhelming the foreign organism. One of the first results was the study of a group of soluble poisons, toxins—formed by certain bacteria and which it has been found are responsible not only for the symptoms which follow certain infections, but also for that effect on the cells of the host which stimulates the formation of the antibodies which we call antitoxins. Pasteur in his study of chicken-cholera had noticed that a bacteria-free filtrate of a culture of the specific microorganism of this disease could cause the symptoms produced by the bacilli themselves, but does not seem to have given much importance to the observation. Later (1888) two of his assistants, Roux and Yersin, found the same to be true of filtered cultures of the diphtheria bacillus. Later it was found that the tetanus bacillus and the bacillus (B. botulismus) of meat poisoning yielded similar soluble poisons.
Further study showed that the various bacterial toxins produce not only a fatal intoxication, but that each has its distinctive effect, as shown by symptoms or anatomical lesion, when injected into animals, thus demonstrating that the poison of each bacterium possessed a specific action. This led not only to a better understanding of the pathology of such diseases as diphtheria and tetanus, but eventually, and of far greater importance, to the discovery of curative and prophylactic sera, or as they are generally known, antitoxic sera. The first step in this direction was taken when Behring and Kitasato (1890) showed that animals could be immunized against weakened diphtheria toxin and that the serum of such animals is capable of protecting other animals against its intoxication, and, moreover, demonstrated that such a serum can be used to cure the toxic symptoms produced by the diphtheria bacillus. This curative power, furthermore, was found to be due not to an action on the bacteria, but to a neutralization of the toxin which the bacteria produced; also the serum was strictly specific, that is, the serum of an animal immunized against diphtheria toxin protects only against diphtheria; that prepared by the use of tetanus bacilli, only against tetanus. This led directly to the production by Behring and Knorr of diphtheria antitoxin for therapeutic purposes (1894) on a large scale and to a general awakening as to the possibilities of serum therapy. The great benefits of diphtheria antitoxin as a curative and prophylactic serum are known to all; since its general use, in 1896, a reduction of the death rate in diphtheria from 45 per cent, to 10 per cent, marks this therapeutic measure as one of the most brilliant discoveries of medicine and of the brilliant century in which this discovery occurred.
The success with diphtheria antitoxin aroused the hope that a general principle—that of the formation of antibodies for the toxins of all bacteria—had been established on the basis of which it would be possible to develop curative sera for all infections. This expectation—on account of the simple fact that most bacteria do not produce soluble poisons—has not been fulfilled; but the impetus which the principle of serum-therapy gave to investigation has led to activity of great and permanent value, and to the development of a new science, immunology or serology, as it is variously called, which attempts to establish laws for the conditions which determine natural resistance to infectious diseases and the factors which increase or diminish this resistance. I approach this subject with hesitation, for the many difficulties it offers can not readily be overcome in a short presentation such as this must be. A few brief statements, stripped of the less familiar terms may, however, serve to elucidate the main lines of investigation.
All immunological studies are based on the known fact of the reinforcement of natural resistance to disease, as illustrated by serum therapy in diphtheria and by vaccine therapy in anthrax. The attempts to elucidate the principles underlying these two methods have led to the development of many fruitful hypotheses and theories, and many diagnostic and curative procedures of great value. It was early evident that the explanation of resistance to infection, either natural or acquired, must be sought in the cells or fluids of the body and especially of the blood. Metschnikoff (1884) was the first to show the, importance of the white cells of the blood in combating infection through their power of engulfing and dissolving bacteria, and his pupils have supported his views, both as to the direct and indirect influence of these cells, the leucocytes, in the production of immunity. On the other hand, since Nuttall, in 1888, demonstrated the bactericidal power of the fluids of the body, and particularly of the blood serum, the relation of the body fluids to infection and immunity has been incessantly studied. As a result, schools have arisen, some supporting the cellular theory and others the humoral theory, and still others combining both theories in the attempt to reach an adequate explanation of the process of immunity. With these schools are associated most prominently the names of Metschnikoff, Ehrlich and Bordet.
One of the earliest and most important observations, after the discovery of antitoxins, was that of Pfeiffer (1894). This was the demonstration that a guinea-pig, into which has been injected the spirillum of cholera, develops in its body-fluids a substance capable of dissolving the cholera spirillum. This bacteriolytic substance is specific, that is, it destroys only the cholera spirillum; and Pfeiffer and his followers, pushing their investigations further, found that this principle of a specific lytic body could be applied to other bacteria and to foreign animal cells as well. Its development led to great advances in the theory of immunity, to the development of the fruitful hypothesis known by Ehrlich's name, and to the production of antibacterial sera, e. g., antistreptococcus serum, as contrasted with antitoxic sera.
Likewise, it was discovered that the serum of animals receiving injections of a given bacterium had the power to agglutinate this organism; and moreover that this principle held good for the blood serum in certain diseases of man. Upon these observations was based (1896) the serum (Widal) reaction for typhoid fever, a definitely specific and reliable diagnostic method which has been followed by many other valuable tests based on the same principle and grouped under the general head of serum diagnosis.
At the same time older procedures were not forgotten, as is shown by Haffkine's extension of Pasteur's principle of vaccination to include protective vaccination against cholera (1893) and plague (1896) and more recently Wright's application of it to typhoid fever. Thus the last decade of the nineteenth century is marked by the birth of both serum-therapeutics and serum-diagnosis and by the extension of the idea of preventive inoculation. As may readily be seen, the fundamental observations of Pasteur, of Behring and of Pfeiffer had been elaborated into some of the most serviceable principles, acknowledged at the moment, in the science and practise of medicine. Nor is this influence a matter of the past. In our own day has been established the theory of specific precipitation of foreign proteins (Uhlenhuth, 1901). This has led to the elaboration of a specific test for the differentiation of both vegetable and animal proteins, a method which has been adopted for the determination of species, not only in bacteriology, but also as a medico-legal test for determining the origin of blood stains and as a general biological procedure.
So also, through the work of Denys and later of A. E. Wright, a body has been recognized in the serum which had the power to prepare bacteria for ingestion and digestion by the leucocyte. To this body the name of opsonin or tropin has been given. You will remember that Metchnikoff discovered the fact that the white cells of the blood have the power to engulf bacteria, Wright supplemented this conception of demonstrating that a substance in the serum could so affect bacteria that they would be taken up more readily and in greater numbers; also he demonstrated that this opsonic power of the serum could be increased, and as the results of his teachings a definite opsonic therapy has developed. This treatment depends on the principle of vaccination with bacterial products. Before Wright, with the exception of Pasteur's treatment for hydrophobia, vaccination was used as a preventive measure only, but the studies which his observations have stimulated have led to very satisfactory results in the treatment of certain local infections as those due to the pus cocci and colon bacillus. Also, these studies have extended the practise of immunizing vaccination, as a prophylactic measure with, it has been claimed, most favorable results in the prevention of typhoid fever. For example the sanitary record of the maneuver division of the United States Army recently stationed on the Mexican border shows that in a body of 8,097 enlisted men, careful sanitation and antityphoid inoculation prevented almost entirely the occurrence of typhoid fever; only one case of typhoid fever was observed, and it was not fatal; while at the same time in the near-by city of San Antonio 49 cases were reported. Comparing the record of the maneuver division with that of a division of the Seventh Army Corps stationed at Jacksonville, under quite similar circumstances in 1898, we have one case of typhoid among the 8,097 men of the former and 2,693 undoubted cases among the 10,759 men of the latter division. It must be admitted in regard to this record of the maneuver division, that it is difficult to say to what extent the excellent showing was due to careful sanitation and to what extent to the antityphoid inoculation, but past experience with troops in camp would indicate that inoculation was an important factor at San Antonio. The question of the value of preventive inoculation is, however, still an open one. So also are other applications of the principles of immunity, as the production of anti-sera for snake-venom, and for the irritant (and perhaps intoxicating) vegetable agent causing hay fever.
I have earlier in this lecture referred to methods of serum diagnosis depending on agglutination or solution of bacteria or on the precipitation of protein. Immunology has recently contributed to medicine another diagnostic method of great value. Its principle is that of complement fixation, the theory of which is too complicated for brief explanation, but the method as applied to syphilis, in the well-known Wassermann test, has since 1906 occupied a most prominent position in the diagnosis and treatment of this disease, and is now accepted as a method of great value in the more obscure cases, and numerous attempts are being made to apply the principle to other diseases.
Another phase of immunological study is that of anaphylaxis, a subject concerning which the professor of pathology in this university is one of the best known authorities. Anaphylaxis, the condition of increased susceptibility dependent on the sensitization of an organism to a foreign protein, is by no means thoroughly understood, but it has thrown light upon immunity from a new angle and has stimulated an enormous amount of investigation. Its utilization in the detection of specific proteins, its apparent explanation of the tuberculin, mallein and similar reactions, the light it has thrown on serum sickness, so-called, and the possibility it offers of explaining diseases characterized by critical phases, have attracted a host of investigators, who see in it the key to many little understood phenomena of disease. As yet the practical results are meager, but the ultimate outcome promises much for medicine.
Another field, and one in which American investigations have been of the greatest importance, is the study of diseases the etiology of which is unknown, but which, it has been supposed, are in some instances due to filtrable or ultramicroscopic viruses. The recent work on poliomyelitis by Flexner and his associates is an example. This disease, appearing irregularly in sporadic and epidemic form, was in the past not definitely grouped among the infectious diseases. All attempts to find a causative microorganism have failed. The workers of the Rockefeller Institute and also certain European investigators have shown that the tissues of the central nervous system contain the virus, and that when the fluids of such tissues are injected into monkeys, typical poliomyelitis results. Moreover, the experimental evidence points to an elimination of the virus through the upper respiratory passages, thus offering a substantial basis for scientific prophylaxis through the proper care of the secretions of the nose and throat. Such investigations show how important the methods of immunology are, for here we have a disease which, as the result of the application of such methods, is definitely placed among the transmissible diseases and is given a satisfactory theory for prophylaxis in spite of an utter absence of knowledge concerning its causal agent. An analogy is seen in yellow fever, the microorganism causing which we do not know and for which we have no specific treatment, but which is controlled simply through our knowledge of its transmission by the mosquito.
While on the subject of Flexner and his work mention must be made of the most important contribution in recent years to our list of curative sera, the antimeningococcus serum. The production of this serum, which in the best form is the result of the labors of Flexner and his associates, is an accomplishment which, in reducing enormously the mortality of epidemic meningitis, is in itself a sufficient justification for the establishment of the Rockefeller Institute. The beneficial results of its use are very definite and the mode of its administration, by direct injection into the spinal canal, has been of great value in emphasizing the importance of the local treatment of localized infections.
Many other phases of activity in the field of immunity might be presented, but this brief and disconnected summary will, I hope, suffice to indicate something of actual accomplishment in this field, the main lines of present endeavor, and the many opportunities for future achievement. Much of present-day effort may not lead immediately to tangible results—an outcome not uncommon in medical research—but the volume of work in progress and the vigor with which it is being prosecuted promises ultimately the solution of the many problems of the infectious diseases.
The Investigation of Cancer.—In no field of medical science has the modern experimental method given greater results in a few brief years and offered greater promise for the future than in the study of that fatal and obscure disease, cancer. Owing to the brilliant initiative of Jensen in Denmark and Leo Loeb in this country, it has been shown that a form of cancer occurs in certain lower animals, particularly in rats and mice, that can be artificially transmitted from one animal to another of the same species. This fact has afforded a means of studying in detail the method by which a malignant tumor grows in the body and more particularly has thrown light on the resistance or immunity to tumor growth which may occur naturally in certain individuals and which may even be artificially produced. Scattered over the world are small groups of individuals, more particularly in England, in Germany and in America, who are devoting their entire energies to the solution of this problem. From several divergent sources have come published results of experiments which offer the greatest promise that we may soon learn a method of curing these tumors. Already Ehrlich and Wassermann have shown the possibility of preparing specific cellular poisons for cancer analogous to those used in curing protozoan diseases. The final clue which will unravel the mystery of this complex disease would not appear to be as yet fully in hand, and yet I think no one of those most conversant with the problem would be surprised to find to-morrow that it has been discovered and that cancer was curable.
Protozoology.—It is of interest that about the year 1890, when bacteriologists ceased to announce discoveries with their accustomed regularity, owing to the fact that all readily recognized pathologenic bacteria had been discovered, the systematic study of protozoa began and some of the single-cell forms of life in the animal kingdom soon took a place as disease-producers alongside the corresponding form of the vegetable kingdom. Until this time, protozoa had been found in only two diseases of man, dysentery and malaria. In the year 1890 appeared the first books on the subject of protozoa as causes of disease, a small volume of one hundred pages by L. Pfeiffer, followed in the next year by Doflein's more extensive discussion of the same subject from the broader biological point of view. The bacteriologists of the preceding decade had by their efforts limited the number of diseases in which a bacterial etiology could be readily shown and it was natural, therefore, that the attention of investigators turned to the study of other microorganisms as factors in the production of disease. The careful technique of the bacteriologist had shown the methods to be used in the study of etiology, and, undoubtedly, the publications of Pfeiffer and Doflein stimulated general interest in the search for pathogenic protozoa. However this may be, it is a matter of record that in 1890 "only two human diseases were suspected of being caused by protozoa. . . . To-day more than fifteen are known or suspected to be of protozoan origin" (Calkins).
In the discussion of bacteriology I have referred to Leeuwenhoek as the first to see bacteria; he was likewise the first to see protozoa (1675). Two hundred years later, Bütschli (1875) offered conclusive evidence of the unicellular nature of these minute forms of animal life. In the intervening period, however, owing largely to the work of O. F. Muller (1786), Ehrenberg (1833-38) and Dujardin (1835-41), many forms had been removed from the "chaos animalculæ," the name under which Cuvier had classified them and their structure had been studied by Siebold (1845) and Max Schultze (1863). In this later period also several forms now familiar to us as occasional parasites of man had been described; as the Trichomonas vaginalis (Donné in 1837), the Cercomonas hominis (Davaine, 1857), the Balantidium coli (Malmsten, 1857) and the Lamblia intestinalis (Lambl, 1859).
The first parasitic protozoon, however, to be definitely associated with a specific disease of man was the ameba discovered by Lambl (1860), first observed in the human intestine by Lösch in 1875, and said by the latter to be the cause of amebic dysentery. In 1891 Councilman and Lafleur, after a very accurate study of this disease, as it occurred in Baltimore, came to the conclusion that two types of amebse must be recognized; one, the Ameba coli, was harmless, another, which they called Ameba dysenteriæ, they claimed to be the cause of tropical dysentery. In this view they were supported later by the feeding experiments of Casagrandi and Barbagallo (1897) and of Schaudinn (1903); the latter also introduced the name Entameba histolytica for the pathogenic form, and Entameba coli for the harmless form. It has since been found that two forms of tropical dysentery exist, one of which, as shown by Shiga, Kruse and Flexner, is due to bacteria—but equally definitely has the etiology of an amebic form been established.
In the meantime another protozoan disease was being investigated. Laveran, a French military physician, stationed in Algiers, announced in 1880 that the dancing pigmented bodies frequently seen in the red blood cells in malaria were altered hemoglobin granules within a protozoon to which he gave the name Oscillaria malariæ. This name was altered by Marchiafava and Celli to Plasmodium malariæ, in 1885, and Golgi, in 1886, by demonstrating that the characteristic paroxysms of the disease coincide with the segmentation or sporulation of this parasite, settled definitely the question of its etiologic relation to malaria.
The work on malaria constituted a very large part of the activity in medical investigation at this time. Until the middle of the nineties, many investigators were interesting themselves in the study of the different forms of parasites concerned, their life history and the methods for demonstrating them; these activities, with the study of similar parasites in birds, gave a great impetus to the study of pathogenic protozoa, and prepared many workers for a wider field.
Nevertheless, but few were prepared for the wonderful announcement by Smith and Kilbourne, in 1893, of the transmission of a protozoan disease through a blood-sucking insect. In this, the work of our own countrymen, on a malaria-like disease of cattle, Texas fever, the tick was shown to be the carrier of the Pirosplasma bigeminum, the organism responsible for the disease. The importance of this observation can not be over-estimated. It was the finger-post indicating the way to progress in the study of the transmission, and therefore of the prevention, of protozoan disease, and to Smith and Kilbourne belongs the credit of this great advance, which, it must be admitted, had a great influence on the study of the transmission of malaria and yellow fever. Many suggestions had been made from time to time that these diseases might be due to transmission by the mosquito; and these theories became indisputable fact when Ross announced from India in 1897-99 that the malaria of birds was transmitted by a species of mosquito (Culex) and when Grassi, Bignami and Bastianelli (1898-99) likewise demonstrated that malaria of man is transmitted by another species of mosquito (Anopheles) . But before this, Bruce's study (1894-97) of the South African disease of cattle, which you may remember Living- ston refers to as the "tse-tse fly disease," resulted in the discovery of the protozoan origin of the disease and the importance of the tse-tse fly (Glossina morsitans) in its transmission.
Soon followed (1900-01) the discovery by the United States Army Yellow Fever Commission — Keed, Carroll, Agramonte and Lazear — of the transmission of yellow fever by a third species of mosquito, the Stegomyia, and in 1903 Bruce announced that the sleeping sickness of Africa, due to a trypanosome, is transmitted by the tse-tse fly (Glossina palpalis). So also certain closely allied diseases of the far east, known as dum-dum fever, kala-azar, oriental sore, etc., were shown to be due to protozoa and to be probably transmitted by an insect.
The importance of these discoveries for prophylaxis was far reach- ing. It had long been known that malaria could be cured by quinine, but physicians in face of constant infections and reinfections were helpless. Now, the knowledge that the disease is transmitted by a mos- quito, and by but one genus of mosquito, the Anopheles, allows the health officer to step in and by draining the breeding places of the mos- quito to destroy the agent of transmission or, if this is impossible, to prevent contact with the mosquito by screens and other mechanical means. As far as we know, the parasite of malaria exists only in infected man and in infected mosquito. Perpetuation of the disease is due to the perpetuation of the cycle, man to mosquito, mosquito to man. If the parasite is destroyed in man or the Anopheles is not allowed to breed, the disease disappears. Not only has this been demonstrated experimentally, but it is in many communities a commonplace of sanitation.
Yellow fever is a disease, the causal agent of which is unknown, but so carefully has its prophylaxis been worked out on the basis of its transmission by the mosquito, as a result of the work of Read, Carroll, Lazear and Agramonte, that an epidemic of yellow fever would now be considered as due to ignorance or criminal carelessness on the part of those responsible for the public health. It is unnecessary for me to remind this audience of the heroism of Lazear and his associates and of the non-immune enlisted American soldiers, who offered themselves for experimental inoculation through the bite of mosquitoes infected with yellow fever. To their labors we, as a people, owe the present magnificent progress in the Canal Zone, the absence of yellow fever in the Gulf ports, an increase in human comfort and happiness and an increase in national prosperity and national progress ; but still more, to them, as also to Ricketts, who investigated Mexican typhus and succumbed to it, and to Walter Myers and Everett Dutton, of the Liverpool School, our science owes much in methods and in ideals.
Truly, no field of medicine offers so much of tragedy, of romance and of spectacular discovery as that of the pathogenic protozoa, and few offer such great difficulties. It is, however, one of the most promising fields of present-day effort and one which I would like to present more in detail. It must, however, suffice to end this presentation with mere mention of the successful cultivation of amebæ (Mesnil and Mouton), the cultivation of the trypanosomes (Novy and MacNeal), the discovery by Schaudinn and Hoffman of the spirochete, which we now know to be the cause of syphilis, and the finding of a very similar organism in yaws. Time might also be given to the various trypanosomes, to the spirochetes causing diseases of cattle and poultry and to the Negri bodies of rabies; also the discussion might be extended to include the broader field of tropical medicine, but instead, as it is the direct outcome of the study of protozoa, I must turn to a new phase of research in medicine, that known as chemotherapy.
As the study of protozoan diseases progressed it soon became evident that the method of combating such diseases must be different from that used against diseases due to bacteria. The chronicity of amebic dysentery and relapses in malaria indicated that the protozoan diseases are not self-limited and therefore not characterized by the development of immune bodies, similar to those of the acute bacterial diseases; also artificial cultivation failed to demonstrate that protozoa yielded bodies analogous to bacterial toxins, capable of producing, on injection, bodies with efficient antitoxic power. These and other facts precluded, therefore, a therapy based on the principles applied to bacterial vaccines or antitoxins.
The beneficial effect of quinine in the treatment of malaria and the cellucidal action of quinine on the ameba and other protozoan forms indicated that a therapy, to be successful, must be one in which a substance toxic for the protozoa in question is brought into direct contact with it. The establishment of such therapy and incidentally the creation of a new science, that of specific chemical therapeutics, has been the work, in the past seven years of Professor Ehrlich, of the Royal Prussian Institution for Experimental Therapeutics at Frankfurt. This new therapy is based on the principle that "a specific chemical affinity exists between specific living cells and specific chemical substances." This principle has always been the main theme of Ehrlich's work, as is seen in his application of the aniline dyes to the study of the cells of the blood, his studies on vital staining and the selective action of methylene blue on the nervous system, the use of methylene blue in the study of the oxidations and reductions occurring in tissues, and his extensive studies in immunity. This experience, covering a period of twenty-five years, led Ehrlich to the belief that "for each specific parasite a specific curative drug must and could be found." And upon this assumption he began his experiments.
To appreciate thoroughly the difficulties of this task and the magnitude of the results, it must be understood that Ehrlich proposed a sterilization of the body in so far as the microorganism, against which the specific remedy was aimed, was concerned. The destruction of bacteria or protozoa outside the body by chemical means is a commonplace of surgical and public health measures; but the destruction of living microorganisms within the living body had never, until Ehrlich accomplished it, been possible without, at the same time, destroying also, in part or in toto, the cells of the host. To avoid the latter it was necessary, therefore, that the protozoa-destroying substance should have a specific chemical affinity for the protozoa in question, but little or no chemical affinity for the cells of the host.
It is impossible to give the details of Ehrlich's seven years of work on this problem; a brief description of the main results must suffice. The first work was done with trypanosomes, the mouse, which could be readily infected, being used as an experimental animal. After testing, with the aid of his assistant, K. Shiga, many hundreds of dye-stuffs, some old and some new, one, a member of the benzidin group, was found which retarded the progress of the trypanosome infection for several days. This led to a limitation of the experimentation to a study of the synthetic products of the benzidin group, many of which were made for the first time by Ehrlich and his assistants. The result was the discovery of a substance which exerted an actual curative effect upon trypanosomiasis. This substance, a red dye destroying trypanosomes, was given the name trypan red (trypan roth). If twenty-four hours after mice had been infected with the trypanosome of Mal de Caderas, a single injection of this dye was made, animals which ordinarily died in four to five days went on to permanent recovery. The blood, twenty-four hours after injection, was found to be free of trypanosomes, which indicated that the effect of the injection was to destroy absolutely every infecting protozoan. Thus was demonstrated for the first time the possibility of completely sterilizing the animal body by a chemical disinfectant without injury to the cells of the host.
In the course of this work an interesting observation was made. If, instead of a dose necessary to destroy all the trypanosomes, a slightly smaller dose was injected, the trypanosomes would disappear from the circulation for a short time and later reappear. If such injection was repeated at intervals, the period of disappearance of the trypanosome would gradually shorten until finally the drug would have no effect on the infecting organism; in other words, a strain of trypanosomes had been developed which were resistant, immunized as it were, to trypan red and this resistance could be transmitted through many generations. Also, it was found that trypan red was a curative agent only for the infection in mice; on the trypanosome diseases of larger animals, as horses and cattle, it had no curative effect. However, the experience with trypan-red pointed the way to a solution of the difficulty; either a drug must be found which by a single injection would kill every parasite, or several different drugs must be used, which, acting on the same parasite, and thus allowing a combination treatment, would lead to a cure without the danger, to the host, of a single massive dose. It is impossible in the scope of these lectures to follow in detail Ehrlich's work or to go into the complicated chemistry of the substances used. It must suffice to say that as the work went on, Ehrlich and Weinberg found a substitution produced of trypan-red, amidotrypan-red, which destroyed the virulent parasite of nagana, the tse-tse fly disease, and that Mesnil and Nicolle, using the blue and violet azo-dyestuffs, prepared a trypan blue and trypan violet which caused the disappearance of the parasites of nagana, surra and mal de Caderas.
Another line of progress was through various combinations of anilin with arsenic. Before Ehrlich entered this field, Bruce had found arsenic to be a drug of value in treating the trypanosomiasis of horses (surra) and Thomas had found that atoxyl, a combination of arsenic and anilin, would cure a large percentage of infected animals. This latter substance had also been used in the treatment of the human disease, sleeping sickness. Ehrlich made a thorough study of arsenic compounds, and the result was the combination, arsenophenylglycin, a single dose of which absolutely and permanently cures all animals suffering from trypanosome infection.
At about this stage of the development of chemotherapy, Uhlenhuth and Salmon published an account of the brilliant use of atoxyl in the treatment of syphilis, which as we have mentioned, is due to a protozoan, the spirocheta pallida. Unfortunately, as atoxyl sometimes caused blindness, its use was not without danger and therefore not desirable. So Ehrlich immediately turned his attention to the protozoan diseases caused by spirilla, as chicken spirillosis, relapsing fever and syphilis. His labors on these diseases constitute one of the most fascinating of modern laboratory studies and his results are among the greatest of scientific discoveries. His intimate knowledge of the constitution of atoxyl and other arsenic preparations allowed him to proceed rapidly with "a great variety of substitutions, and innumerable arsenic derivatives were synthetized." As human syphilis could be transmitted to the rabbit and relapsing fever to the mouse, the power of these preparations, as soon as manufactured, could be tested in the laboratory. The object, of course, was to find a substance which would kill the spirochetes without injury to the host. The result was the justly celebrated Ehrlich-Hata 606, chemically known as dioxydiamidoarsenobenzol, sometimes shortened to arsenobenzol, and, more recently, receiving the commercial name, Salvarsan. This substance in a single dose, 58 times smaller than the dosis tolerata (the largest dose which could be given with safety), cured definitely chicken spirillosis; a single small dose destroyed the spirolla of relapsing fever in infected mice, and a single injection of one seventh the dosis tolerata, caused the spirochete of syphilis to disappear completely from the experimental lesions of the rabbit within twenty-four hours. This last experience naturally aroused the hope of curing syphilis in man by a single injection given in the early stages. Such treatment, if successful, would supersede, or at least supplement, the empirical treatment by mercury which required a course of several years' treatment before a cure could be assured. The toxicity of the substance was, therefore, tested on dogs and then, to make sure it had no ill effects, on healthy men (assistants of Professor Alt), who volunteered for the purpose and finally the therapeutic effect was tried on relapsing fever in man. Iversen, of Russia, to whom this work was entrusted, found that one injection completely cured relapsing fever in 90 per cent, of his patients. Finally the substance was used in the treatment of syphilis in man. The completeness and rapidity of the curative action have been astounding. The effect on the lesions of the primary and secondary stages is to cause them to heal or disappear promptly; the spirochetes can not be found after a few days and the effect is apparently one of complete sterilization. Thousands of reports in the medical press confirm the general beneficial effect of this remedy and testify to the absence of ill-effects when properly administered. Even though further experience may modify the present optimism, nothing can detract from the magnificent service by which Ehrlich and his pupils have benefited humanity and added to the glory of medical science by establishing the principle of specific chemotherapy. With a record of about a dozen drugs which can be used to cure or modify diseases caused by nearly a dozen different protozoa, chemotherapy offers promise of results which, with serumtherapy and vaccination in bacterial diseases, will sharply limit the ravages of the transmissible diseases of man and animals.
Here we must leave the story of the infectious diseases, which has occupied our attention from the beginning of the third lecture to this point, and turn to a brief discussion of other methods of modern research in medicine, those of physiological chemistry, pharmacology and experimental pathology, which had their beginnings in the subjects (chemistry, physiology and pathology) discussed in the second lecture. The presentation must, however, necessarily be but brief and fragmentary, a mere summary, in fact, of aims and methods.
Physiological Chemistry.—The beginnings in this most important field of research were in Liebig's exact methods for the study of organic chemistry and Wöhler's studies which are famous on account of his synthesis of urea. It is usually stated that the cultivation of physiological chemistry as a distinct science, with independent institutes of its own, dates from the eighth decade of the past century, when HoppeSeyler in 1872 established his laboratory at Strassburg and in 1877 founded the Zeitschrift f. physiologische Chemie. But although this period does represent the first attempt to sharply separate laboratories of physiological chemistry from those of organic chemistry, on the one hand, and of physiology, on the other, the first independent chair of physiological chemistry was established as my colleague, Dr. John Marshall, informs me, at the University of Tübingen in 1845 and was held by Eugen Schlossberger; likewise Schlossberger's laboratory was the first one to be devoted exclusively to the study of physiological chemistry. It was to this chair that Hoppe-Seyler was appointed in 1861, and which he held until shortly after the close of the Franco-Prussian war, when he accepted a similar chair in the University of Strassburg.
Before and for some time after these events a great volume of work in physiological chemistry was done in laboratories of organic chemistry and of physiology; but the events at Tübingen and Strassburg served to concentrate attention on physiological chemistry and eventually to hasten the establishment of independent laboratories. For the first few years progress was slow; in 1882, to quote Dr. Marshall again, only two such independent laboratories, those of Tübingen and Strassburg, existed in Germany. In the intervening thirty years the situation has changed. Now, such laboratories exist wherever adequate teaching or intelligent research in medicine is attempted.
The early physiological chemistry was quite different from that with which we are familiar to-day. It was largely the analysis of the chemical composition of various body tissues and fluids. This early conception, however, soon gave way to a dynamic conception, the idea of function, and present-day investigators in physiological chemistry are concerned chiefly with the ways and means of cell action. The chemical constitution of the cell, its enzymes, the methods by which it builds up complex bodies from simple substances, or disintegrates a compound to its simplest constituents; in brief, the problems of digestion, metabolism and secretion in health and disease. These are the problems which concern this science and which, as its methods have been extended to include the study of the vegetable kingdom, as well as the lower forms of animal life, is now more frequently known by the broader term, biological chemistry. The dynamic point of view which to-day characterizes physiological chemistry is largely due to two influences which have come from the outside: (1) The study of intramolecular structure as carried out on the sugars, purins and proteins by the Fischer school, and (2) the study of the nature of chemical reactions, as taught by the modern school of physical chemistry, led by van't Hoff.
Its fundamental problems which during recent years have engaged the attention of its best workers and which still hold their attention are (1) the chemical composition of the protein molecule, (2) the part played by ferments or enzymes in the metabolic changes which occur within the cell and which are responsible for the functions of the various organs and tissues, (3) the general problems of nutrition and the relative values of different food-stuffs, (4) the question of the interrelation of function, that is, of the influence of the secretion of the cells of one organ or tissue on the cells of a remote organ or tissue, (5) the mechanism, from a chemical point of view, of natural and acquired resistance to disease and of phenomena associated with such resistance.
All of these investigations, it is seen, have for their object a better knowledge of the mechanism of cell activity.
Experimental Pharmacology or pharmaco-dynamics, as it is sometimes called, applies the methods of physiology and chemistry to the study of the action of drugs, poisons and other substances which may alter normal function. Its early development corresponds to the period of the application of exact experimental methods to physiology which, as has been shown in an earlier lecture, dates from about 1840. Buchheim, professor of materia medica at Dorpat, established in his own house, in 1849, a laboratory for the study of pharmacological problems; somewhat later this laboratory became a part of the University of Dorpat and was, therefore, the first laboratory to procure for pharmacology, recognition as a science of university rank. Furthermore, Buchheim in 1876 in the Archiv f. experimentelle Pathologie und Pharmakologie, (founded in 1873) defined the methods and aims which have guided pharmacological work for the past thirty-five years. He also made the first classification of drugs according to their physiological action.
The proper study of pharmacology is all-embracing. It includes not only the study of the mode of action of remedial agents in healthy individuals and the influence on such action of various abnormal or pathological conditions, but, also, the effect of a great variety of substances, as bacterial toxins, the secretions of venomous serpents and the products of metabolism, in short, all animal, vegetable or mineral substances in any way capable of altering normal physiology. Moreover, the study of the effect of these various substances is not limited to man and the higher animals, but includes the use of the lower invertebrate forms, bacteria and protozoa. It is, therefore, an all-inclusive branch of biology, dealing with the "comparative study of the action of chemical bodies on invertebrate and vertebrate animals." Its achievements are of interest to physiology, to which science it has contributed much, both in method and in fact; to chemistry, in that pharmacology has added largely to the data concerning the interaction of cell and chemical substance; and to practical therapeutics, in that it presents new remedies, explains the action of old remedies and defines the limitations of drug-therapy. Finally it has a definite relation to the general public welfare in that, by its methods, it establishes procedures for determining the potency of therapeutic remedies, thus preventing, on the one hand, ill effect from a drug of unusual power, and, on the other, guaranteeing a remedial agent of standard strength.
Experimental Pathology and Pathological Physiology are branches of pathology and physiology which, combining the methods of both these sciences with those of chemistry, attempt, by the study of abnormal conditions experimentally produced, to explain the disturbance in function consequent upon cell or tissue injury or disturbances in physiological or chemical equilibrium. Combining as they do the methods of several of the medical sciences, and having for their object the elucidation of definite problems in clinical medicine, they are essentially the methods of a science of clinical medicine and have aided materially in the advance of this branch of medicine.
Such are the methods and problems of present-day research in medicine. The history of medicine teaches us that new methods and fruitful hypotheses may be brought forth at any time; new diseases, on the other hand, can now be expected only through changes in social relations and practises or as the result of new industries. Advance, therefore, would appear to lie in the concentrated application of present methods to present problems and in the application of such new methods, as may be confidently expected to appear from time to time, in any science which is so actively cultivated as is the science of modern medicine.
In this narrative of research medicine I have grouped the various phases of my presentation about men or events. These, as Hippocrates and Galen in antiquity; Vesalius and his influence on anatomy; Paré and his observations in surgery; Harvey, Hunter and Haller and their more or less isolated discoveries in physiology; Morgagni and his observations in pathological anatomy; and Jenner and his discovery of vaccination, represent the epoch-making efforts of workers widely separated and more or less isolated. In the early part of the nineteenth century, Johannes Müller, Liebig and Rokitansky founded respectively the sciences of physiology, organic chemistry and pathological anatomy upon the basis of concentrated laboratory effort and gave to these sciences an impetus the result of which we recognize to-day in the importance which they have attained. The main line of advance, however, has been in the past 70 years, and was made possible by the study of cells, through (1) the work of Schleiden on vegetable cells and of Schwann on animal cells thus establishing the cell doctrine; (2) the application of this theory by Virchow to pathology, and (3) Pasteur's conception of the role played by microscopic cells in fermentation and his application of this to the etiology of disease. Out of Pasteur's work grew, the treatment of bacterial diseases by vaccines and antitoxic sera, and the increased knowledge of infectious diseases gained by the study of bacteriology, led to the search for protozoa as causes of disease and the demonstration of the etiological importance of the latter, led, in turn, to the development of Ehrlich's chemotherapy as a means of combating protozoan disease. But while this was the main line of advance we have seen how Pasteur influenced surgery through Lister, and how anesthesia, through the efforts of Morton came also to aid this science. So, likewise, physiological chemistry came into being, indirectly as a result of Liebig's work, but more directly as a result of the needs of physiology for a better understanding of cell composition and enzyme action, and, finally, both physiology and physiological chemistry contributed to the establishment of pharmacology and experimental pathology. Medicine, in the sense of internal medicine, benefited by each and every advance in each and every one of its contributary branches, and, through the application of the principles of physics and chemistry to methods of diagnosis, gained its present large equipment of instruments of precision and means of exact interpretation; surgery in like manner gained the X-ray and many technical and mechanical procedures; and preventive medicine, utilizing the knowledge obtained through bacteriology, protozoology, immunity and chemistry, shares, with the science of engineering, the glory of promoting in greater degree than all other factors the social and industrial welfare of humanity.
The facilities and opportunities possessed by American universities for the continuance of this progress will be the subject of the fifth lecture.
- The Hitchcock lectures, delivered at the University of California, January 23-26, 1912.
- The use of this term is not perhaps above criticism, but its increasing use and need of some comprehensive word to cover the various activities represented by the term "studies in immunity," "serology" which in themselves are not adequate, are given as justification of its use.
- (I.) The arsenic group: arsenious acid, atoxyl, acetylatoxyl, arsenophenylglycin and dioxydiamidoarsenobenzol. (II.) Azo-dyestuffs: trypan-red, trypanblue and trypan-violet. (III-) Basic triphenylmethan dyestuffs: parafuchsin, methyl-violet and pyronin.
- Nagana, surra, sleeping sickness, mal de Caderas, Texas fever, chicken spirillosis, relapsing fever and syphilis.
- These appeared in the following publications: "Instructions for the Chemical Analysis of Organic Bodies," 1837; "Chemistry in its Application to Agriculture and Physiology," 1840; "Animal Chemistry or Organic Chemistry in its Application to Physiology and Pathology," 1842; "Handbook of Organic Analysis," 1853. (Dates taken from early English translations.)
- Dr. Marshall 's notes on the development of physiological chemistry at Tübingen are as follows: "In 1816 Dr. Med. George Kark Ludwig Sigwart at the request of the Medical faculty of the University of Tübingen delivered from time to time lectures on 'Zoochemie,' but notwithstanding that he was made professor extraordinarius in 1818 he was not provided with a laboratory. In 1835 the professor was given the use of quarters in the laboratory for agricultural and technical chemistry which was located in the old Tübingen castle. In 1845 Eugen Schlossberger, a pupil of Liebig and of Heinrich Rose was called to a professorship of physiological chemistry in Tübingen which was the first independent chair of physiological chemistry created at a German university and the laboratory was the first one to be established as a separate institution. From 1861 until 1872 this chair was held by Hoppe-Seyler when in 1872 he resigned to accept a professorship of the same title in the newly revived university at Strassburg. The laboratory in the old castle was occupied until 1885 when it was removed to the new building which had been erected for the subject."