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Home , Antitoxin, Emil von Behring, Robert Koch

668 MARCH 1954 BRITISH 668 MARCH 20, MEDICAL JOURNAL

penetration into the body generally. The hypothesis was EMIL VON BEHRING then advanced that these two bacilli secreted -soluble poisons BORN , 1854 which, being absorbed, acted on the cells of the central nervous system and other organs of the BY body. Loeffler's work had been subsequently confirmed by many Sir ARTHUR S. MacNALTY, K.C.B., M.D., F.R.C.P. observers, but particularly by Roux and Yersin at the F.R.C.S. in a series of three important memoirs Formerly Chief Medical Officer of the Ministry of Health (1888-90). They also announced that they had grown diph- theria bacilli in broth and removed the bacilli by filtration The Army Surgeon through unglazed porcelain; the resulting sterile filtrate on into animals the Emil von Behring, "one of the greatest benefactors of injection produced characteristic symp- toms of ; this soluble poison they termed a humanity" (British Medical Journal, 1929), was the son . of a schoolmaster, who had 11 other children. He was These important results aroused universal interest. born at Hansdorf, Deutsch-Eylau, West , on Loeffler had also been engaged in searching for the hypo- March 15, 1854, the day following the birth of Paul thetical toxin, and in 1890 Brieger and C. Fraenkel pre- Ehrlich. He took his doctor's degree at the University pared a toxic substance from cultures of the diphtheria of in 1878 and bacillus in bouillon, which

" passed the State examina- ...... they called toxalbumin." tion in 1880. Hea ybegan By injections of this tox- albumin into guinea-pigs, his career as a military J--ig Fraenkel established an im- surgeon, serving in the I munity, so that 14 days Army Medical Corps, first later the animals were resist- at Posen, then in 1887 at virulent living cul- Bonn, as staff surgeon, and : *83 | | | ture of C. diphtheriae. These lastly in the same rank in results were published in the 1888 at the Army Medical Berliner klinische Wochen- College, Berlin. His first schrift on December 3, 1890, 4 publishedpapeBr (1887) Sil | 111 F and on the following day, dealt with iodoform as an December 4, there appeared in the Deutsche medicin- antiseptic. ische Wochenschrift Behring xwhile still an army sur- and Kitasato's classical geon Behring was im- paper, entitled "Ueber das pressed by the discoveries Zustandekommen der Diph- in which were therie-Immunitait und der bei revealing the of a Immunitait Thieren." number of diseases, and One week later (December especially by the great 1) Behring, alone, published another work of his compatriot paper, in the same journal, . In the early dealing with against eighties, therefore, he be- diphtheria and enumerating gan a series of investiga- five different methods by tions which were the pre- which this could be obtained. cursor of his main life- These papers announced work. Bacteriologists had the great discovery that an noted already that white animal immunized against rats were immune to anth- tetanus and, diphtheria by graduated rax, while wild rats were injections of killed broth cultures of these bacilli susceptible. Behring took produces in its blood sub- the fresh serum of white __ stances which are capable of rats and tested it on anth- vonI Behring. neutralizing the toxic action rax bacilli in vitro. In a of of these bacilli. It was also short time the bacilli were killed. Nuttall had made shown that an animal previously injected with the serum similar observations on the bactericidal powers of the of such an immunized animal was resistant to an otherwise fresh sera of man and of several animals, and his obs.er-' fatal dose of bacilli or toxin; and, in addition, that an vations, together with Behring's findings, led to the animal when treated with the serum, even if symptoms deyeloped, could be cured. The substance in the serum humoral theory of defence against the ini'asion of of germs immunized animals was given the name of " into '" the animal body. by Behring and Kitasato. As the treatise on diphtheria of the Medical Research Council (1923) states : " In Discovery of Diphtheria Antitoxin these papers we have the details of one of the greatest By 1889 Behring had left the army and had become an discoveries ever made in .... History must assign assistant to Koch at the Institute of Infectious Diseases, unchallenged to E. Behring the merit of the discovery of Berlin, then a stimulating and productive centre of bacterio- antitoxin. It came at the end of a long period of research logical research. In 1884 F. Loeffier had been deeply in which the bactericidal action of the blood had been very immersed in the study of diphtheria and had issued his thoroughly studied." exhaustive work on the bacillus of the disease, which he These experimental results opened the gate of the new identified with the bacillus described by Klebs in the pre- field of serum therapy for mankind. In quick succession ceding year. Kitasato had discovered the bacillus of tetanus. many papers appeared confirming and amplifying Behring's Both diphtheria and tetanus were shown toI be diseases discovery, including further papers by Behring himself and caused by the local multiplication of the organism without by Ehrlich. MARcii20, 1954 EMIL VON BEHRING BRITISH 669 M,s.n~~~~~~~~~~~~~~~~~~~~~~~~cii 20, 1954 EMIL VON BEHRLNG~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~MEDICAL JouRNAL tality from diphtheria in , an annual credit of Treatment of Diphtheria in Mlan 45,000 human lives. For this work Behring shared with The practical application of the discovery to the treatment Roux the 25,000 francs prize of the Paris Academy of of diphtheria in man was advanced by the further work Medicine and the 50,000 francs prize of the Institute of of Behring and Baer and of Behring and Wernicke. The France. In 1901, when he received with Roux the Nobel antitoxic serum was tested in children with favourable Prize for medicine, he delivered an address at Stockholm results. The first child treated by antitoxin was a patient on serum therapy. Orders and distinctions in the years in von Bergmann's clinic in Berlin, the injection being made following 1895 were showered upon him by learned societies by Geissler on Christmas night, 1891. The firm of Meister, -of all European countries. Nor was the prophet without Lucius, and Bruning began to immunize animals in their honour in his own country. In 1895 he received the title factory at Hoechst in 1892. of Medical Privy Councillor and in 1901 a patent of nobility. In 1893 Behring had the title of professor conferred upon him. In this year with Kossel and Heubner he recorded Researches on the first cases in man treated with the new remedy. In 1894 Behring became Professor at Halle, and in 1895 Emile Roux, with his fellow-workers Louis Martin and was appointed to the Chair of Hygiene at the University Yersin, was mainly responsible for bringing diphtheria im- of and Director of the Institute of Hygiene. Ill- munization from the experimental to the practical stage. health compelled him to give up systematic lecturing and Roux and Martin were the first to immunize horses, and teaching, and he gave only an occasional public lecture. were thus enabled to produce antitoxic serum in large After 1901 he turned his attention to the problem of im- quantity. In the hospitals of Paris serum treatment of diph- munization in tuberculosis. His premises were that human theria was established by 1894. In that year Roux was able and bovine tuberculosis were but varieties due to the same to announce in his famous address at the International Con- organism; that in man and animals takes place gress of Hygiene and Demography at Budapest that the case in early life in the alimentary canal and pulmonary tuber- mortality in children suffering from diphtheria in the Paris culosis is a sequel to such intestinal infection ; and that children's hospital had already been reduced from 52 to 25%. few human or bovine subjects escape infection before reach- In England in the summer of 1894 E. W. Goodall first ing adult life. The first two premises were not generally treated by the new method some 20 patients suffering from accepted. He attempted to immunize calves against tuber- diphtheria- with favourable results, in the Eastern Hospital, culosis with an attenuated strain of human tubercle bacilli, Homerton; he used serum supplied to him by Sir Joseph but the results were disappointing. His bovo-vaccine was Lister, who had obtained it from Roux. Goodall stated in largely used in Germany, Russia, Sweden, and America, his book (A Short History of the Epidemic Infectious Dis- and for a time aroused much interest. It has not withstood eases, London, 1934) that in the autumn of the same year the test of time and prolonged experiments. Armand Ruffer prepared antitoxin at the British Institute For the treatment of human beings von Behring prepared of Preventive Medicine, now the Lister Institute, and this a form of , named " tulase," by the action of serum was first used at the Eastern Hospital on October 23, chloral on tubercle bacilli. The exact method of prepara- 1894. It has lately been put on record that Sir Charles tion of tulase was unfortunately kept secret. It was eventu- Sherrington used the first antidiphtheritic serum made in ally found not to be superior to any other form of tuber- this country on October 15, 1894. The serum was pre- culin. He also did experiments on human immunization pared by Ruffer and himself at the Brown Institution. The with killed tubercle bacilli. patient, a boy of 8 years, was regarded as dying from diph- As already mentioned, von Behring believed at first that theria. He recovered. (See Marginalia contributed by Sir human and bovine tubercle bacilli were identical, and, Charles Sherrington to Science, Medicine, and History: though there was a time when he favoured their dual , Essays on the Evolution of Scientific Tlhouighlt and Medical he returned in the end to his original belief. He also Practice written in hlonour of Charles Singer. Oxford considered that tuberculosis was a lifelong affection; and University Press, 1953, Vol. II, 550.). contemporaries often quoted his aphorism that "phthisis is but the end of a lullaby sung at the cradle of the prospective Ehrlich's Standardization consumptive." His experimental work in tuberculosis, In 1895 a control station was set up in Berlin for testing although disappointing, was an introduction to the problem antitoxin; in 1896 this became an institute for serum of immunization against tuberculosis in man and bovines. research and testing, first at Steglitz (Berlin), and from Von Behring was financially interested in the manufacture October 1, 1899, at Frankfurt under the direction of Paul of antitoxic sera by the great commercial firm of Farb- Ehrlich. He produced a quantitative method for determin- werke Hochst, which built and equipped laboratories on a ing the antitoxic value of any sample in units defined in well-planned and extensive scale for him. Here he con- relation to a stable standard of reference ; his method is ducted researches in which were used 7,000,000 oz. of cul- still the most accurate of all such biological titrations, and, tures of tubercle bacilli. He was also interested in another incidentally, he laid down the main principles for all stand- commercial enterprise, the Behringwerke, which manufac- ardizations by the use of biological tests, which subsequently tured his bovine-vaccine. As a consequence of these interests provided a basis for the accurate dosage of many different von Behring rose to affluence and became the owner of a types of new remedies (Dale, 1950). Bv Ehrlich's work a large estate on which grazed herds of cattle, which he also good antitoxin with a precise measurement of its activity used for experimental purposes. was made available to mankind, and antitoxin could be In 1905 he had investigated the collection of milk by given in an adequate dose at the onset of diphtheria. The aseptic methods and its preservation bv formalin and hydro- mortality of the disease, in such cases, fell to insignificant gen peroxide. He was the author of numerous articles on proportions. Ehrlich therefore greatlv extended the prac- the experimental therapeutics of and streptococcal tical application of Behring's discovery to the of diph- , the hygiene of the milk supply, water, and other theria in man. subjects. He also wrote books on blood serum therapy International Recognition (1892), the aetiological treatment of infectious diseases Within a few years the administration of antitoxic serum (1893), the history of diphtheria (1893), and the general to patients suffering from diphtheria became a routine treatment of infectious diseases (1898). method of treatment. In an address, "The Aims and Achievements of Serum Therapy." delivered at the Natural- Discovery of Toxin-Antitoxin ists' Congress in 1895. Behring said: " I have no fear that In the study of diphtheria von Behring had achieved the thought which forms the basis of serum therapy will fame, and in 1913 he introduced his new preparation for ever disappear out of medicine ! " He estimated that anti- protection against the disease. With Wernicke he had toxin treatment produced a reduction of 750, in the mor- shown in 1892 that immunity to diphtheria was produced 670 MARCH 20, 1954 EMIL VON BEHRING BRITISH by a protective dose of antitoxin. Later work by Good- Behring at first attempted to produce a disinfection in the man, Lohr, and others showed that such immunity does not body by a great variety of chemical substances. With persist after two to three weeks from the inoculation. It trichloride of iodine he partially succeeded in curing some appears that Behring and Wernicke discovered in 1898 that cases of experimentally produced diphtheria in animals, and immunity against diphtheria could be produced by doses of his comparison of their blood with normal blood may have neutralized by antitoxin in experimental ani- aided him in the discovery of antitoxin. mals, but it was not until 1913 that. von Behring gave his It is a far better thing to prevent disease than to cure it. " new" preparation to the world. in 1907, Active immunization against disease began with Jenner and as the result of successful experiments upon guinea-pigs, had was applied by Pasteur. Koch and von Behring were un- suggested that a toxin-antitoxin mixture might be used for successful in tuberculosis, but Wright's typhoid vaccine has preventive inoculation in man, but it was left to von Behring helped to abolish as a scourge of armies. The to achieve this. The preparation of his nearly neutral mix- B.C.G. vaccine of Calmette and Guerin, involving the ad- ture of diphtheria toxin and antitoxin was varied from time ministration of a living culture of the tubercle bacillus to time, and gradually rendered less toxic. rendered avirulent, has now become the subject of experi- mental trial in this country. The assessment of the real Active Immunization in Diphtheria value of antibacterial vaccines is very difficult. Von Von Behring's toxin-antitoxin mixture was the forerunner Behring's initiation. of toxin-antitoxin immunization and its of modern prophylaxis in diphtheria, and here again he must later triumphs have already been described in this paper. be acclaimed as a pioneer in immunization. The practical Immunization with tetanus is a more modern in- application on a large scale in New York City was due to stance of successful prophylaxis. Immunization against the work of W. H. Park and to Bela Schick's skin test with virus infections, of-which the most successful is that against a small dose of diphtheria toxin, which gave evidence of yellow fever, is another recent advance, and work is pro- the need of the individual for immunization and of its suc- ceeding on vaccines designed to overcome the viruses of cess when applied. Sheldon Dudley's work and tests on young influenza and of poliomyelitis. Much of this successful naval personnel assisted in establishing the value of the work in the conquest of disease during the present century method in Great Britain. The immunizing reagent (toxin- has followed from von Behring's pioneer researches, and his antitoxin) has been modified in various ways-for example, discovery of diphtheria antitoxin and toxin-antitoxin. Re- the production of toxoid by treating the toxin with formalde- membering the great boon he conferred upon mankind by hyde (toxoid-antitoxin mixture), etc. In Hamilton, Ontario, these discoveries and the way he opened to the prevention the incidence and mortality from diphtheria had shown little of this killing disease of childhood, it is fitting, therefore, change for years up to 1925, when general immunization that the centenary of his birth should be honoured in Great began. Thereafter, both fell so rapidly that there has been Britain. no death from diphtheria since 1930 and no case of the BIBLIOGRAPHY British Medical Journal, 1917, 1, 498. disease since 1933. Similar excellent results have been - 1929, 1, 517. secured in other parts of Canada and in the United States of Dale, H. H. (1950). Fifty Years of Medicine, p. 33. B.M.A., London. Lancet, 1917, 1, 890. America. In this country successive Chief Medical Officers Medical Research Council (Andrewes, F.W., Bulloch. W., et al.) (1923). of the Ministry of Health have advocated artificial im- Diphtheria: Its Bacteriology, Pathology and . H.M.S.O. London. (This contains a bibliography of papers on diphtheria by munization since 1922, but, in spite of official memor- E. von Behring and his collaborators.) anda and the co-operation of a number of medical officers Nature, 1917, 99, 228. of health, both incidence and mortality of diphtheria con- tinued high. The incidence varied between 69,480 cases in The spread of certain diseases from one country, and 1920 to 46,281 in 1940 (England and Wales). At the end even from one continent, to another is facilitated by air of 1940 the Ministry of Health undertook the free pro- travel. Insects such as mosquitoes, flies, fleas, and lice may vision of prophylactics, the cost of which had been borne carry diseases dangerous to man. Perhaps most serious are by local rates. This provision undoubtedly aided the cam- , yellow fever, virus encephalitis, sleeping sickness, paign for immunization, which during the war years and typhus, and plague. According to Dr. P. H. Bonnel, of the subsequently has been vigorously pressed. In 1952 only epidemiological services of World Health Organization, the 376 cases of diphtheria and 32 deaths in England and Wales behaviour of insects in aircraft in flight has been the subject were recorded, as compared with 23,199 cases and 934 deaths of close scientific observation. Such observations have in 1944. shown that altitude and changes in air pressure and tempera- Such are the encouraging sequelae of von Behring's ture during long flights do not permanently affect the activi- pioneer work in diphtheria immunization. ties of the insects. The vibrations in modern aircraft are Von Behring in his later years was subject to severe reduced to a minimum, and insects which penetrate into a periods of mental depression, which the advent of the first plane can live there for as long as they can exist without world war exacerbated. He died at Marburg of an acute nourishment-that is, if they cannot find what they need in attack of pneumonia on March 31, 1917. the aircraft itself. It was noted that certain insects laid their eggs on the outside of aircraft, on the wings, the The Significance of von Behring's Work fuselage, the rudder, and even on the propellers. These In the course of this paper reference has already been eggs were found to be still there at the end of the journey: made to the significance of von Behring's work. In general neither the wind nor the altitude nor yet changes in tempera- terms it can be said that he was one of the founders of ture had affected their capacity for survival. On one single immunology as a science, and that Ehrlich's standardization plane thousands of larvae emerged from the eggs and of diphtheria antitoxin augmented its potentialities. Tetanus swarmed over the surface of the aircraft. Strict surveil- antitoxin, the discovery of von Behring and Kitasato, was lance of aircraft and of aerodromes is therefore absolutely another striking example of passive immunization, and its essential. This passive defence can be effective, however, value has been proved in the prophylactic treatment of the only if it is complemented by more active measures which disease. The specific sera which neutralized the other sporing remove all possibility of transporting live insects in air- anaerobic causing gas gangrene, together with craft. Active control measures consist in spraying aircraft tetanus antitoxin, helped to reduce these deadly complica- with insecticidal aerosols containing pyrethrin or D.D.T., tions of soil-contaminated wounds in two world wars. Anti- but countries vary in their methods and in when " disinsectiza- sera have also been used in dysentery due to the Shiga bacil- tion" is performed. The application to the interior of air- lus, and in the treatment of pneumococcal pneumonia and craft of certain new resinous varnishes in which are incor- cerebrospinal meningitis. The use of all these antibacterial porated residual insecticides is perhaps the best and simplest sera has largely given place to chemotherapy. In 1935 came means of control. This important aspect of international the sulphonamides and later penicillin, , and prevention of disease is one of the subjects dealt with by other . It is of interest here to note that von the WtH.O. committee on international quarantine.