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Tuberculosis
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 Historical Perspective
Nature Medicine Special Web Focus: Tuberculosis (2000)

Robert Koch’s highs and lows in the search for a remedy for tuberculosis

Stefan H.E. Kaufmann

Max-Planck-Institute for Infection Biology

It is generally agreed that tuberculosis would be best controlled by a combination of vaccination and drug therapy. Although we do have an efficacious, if complicated, drug treatment regime, an effective vaccine remains out of reach. One of the first people to envisage a vaccine for the control of tuberculosis was Robert Koch, who discovered the etiologic agent of tuberculosis (Fig. 1). Despite his first reports of a remedy for tuberculosis, studied in the guinea pig model, clinical trials soon demonstrated the ineffectiveness of his therapy. Since then, a victory over tuberculosis has been claimed several times in vain, and the search for an effective vaccine continues. A look back at the discussions about Koch’s therapy at the turn of the last century, therefore, is not only interesting but also provides lessons about how things can go wrong when public and political pressure, as well as the incentives for scientists from the private enterprise, become too strong.

Figure 1. 
Figure 1 thumbnailInvasive lobular carcinoma. Monotonous, nonpolarized, small Robert Koch in 1883.



Use of figure authorized by R. Munch, with support from the German Science Foundation.

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On 24 March 1882, Koch presented his groundbreaking lecture on the etiology of tuberculosis to the Physiological Society of Berlin. The experiments Koch described in his lecture defined tuberculosis as an infectious disease according to the postulates that are now known as the Koch-Henle postulates. Mycobacterium tuberculosis, the causative agent of tuberculosis, is an organism that is particularly difficult to work with, making this lecture meritorious even today. Koch began the lecture with a step-by-step account of his identification of the microbes. Tubercle bacilli are difficult to stain by conventional staining methods. Koch succeeded in staining them by first applying methylene blue and then vesuvin (Bismarck’s brown), resulting in a brown appearance of the host tissue and dark blue staining of the microbes. The methylene blue staining procedure lasted about 1 day at room temperature but, as Koch noted, the time of incubation could be considerably shortened by heating at 40 °C. The consistent identification of microbes in affected tissue fulfilled the first Koch-Henle postulate.

The next step was to isolate the bacilli and culture them in pure form. Here again, Koch had to develop a specific method appropriate for the slow-growing mycobacteria. He used cattle or sheep serum that had been sterilized by treatment at 58 °C for 1 hour on 6 successive days. The serum was then heated to 65 °C for several hours, after which it solidified. Because Koch wanted the material to have a translucent appearance, he took care not to heat it above 65–70°C, this being the temperature at which the solidified serum became opaque. To increase the surface area for bacterial growth, Koch slanted the tubes in which the bacilli were grown. Once he had inoculated the tubes, Koch had the patience to wait. It took 10 days for small dry spots to become visible. The successful isolation and culture of the bacteria fulfilled the second Koch-Henle postulate.

Figure 2 represents a page from Koch’s original manuscript for the lecture, in which he described many cases of spontaneous tuberculosis he had analyzed. These included one case of a tubercle in the brain, two patients with intestinal tuberculosis, three cases of scrofulosis and four cases of joint inflammation caused by tubercle bacilli. Koch then continued with a very detailed description of the many experiments in which he had infected animals with isolated cultures of M. tuberculosis. Successful infection with isolated bacilli fulfilled the third Koch-Henle postulate. Koch summarized this part of his talk as follows: "All these factors together allow me to note that the bacilli present in the tuberculous lesions do not only accompany tuberculosis, but in fact cause it. These bacilli are the true agents of tuberculosis."

Figure 2. 
Figure 2 thumbnailA page from Koch's lecture "The etiology of tuberculosis," delivered on 24 March 1882.
 
Use of figure authorized by R. Munch, with support from the German Science Foundation.



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Koch’s lecture created great interest in the medical community and was published on 10 April 1882, less than 3 weeks afterward, in the Berliner Klinische Wochenschrift (Berlin Clinical Weekly) (Fig. 3). At that time, almost one-third of adult mortality in the capitals of Europe was caused by tuberculosis. For example, in Prussia, the German state where Koch resided, tuberculosis was the cause of 12.26% of all deaths in 1887. In particular, it caused 41.3% of the deaths of people 25–40 years of age. At the conclusion of the lecture, Koch emphasized that tuberculosis could no longer be regarded to be purely a consequence of social conditions. Instead, the public health measures to control the spread of tuberculosis would need to take into account that a contagious agent was involved. As the bacilli survived only in the human or animal hosts but not freely in the environment, Koch’s announcement represented a rather optimistic outlook for the control of the disease.

Figure 3. 
Figure 3 thumbnailA published version of Koch's lecture "The etiology of tuberculosis" in Berliner Klinische Wochenschrift 10 April 1882.



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However, another 8 years passed before Koch announced the means for curing tuberculosis. He did so at the Tenth International Congress of Medicine, which opened in Berlin on 4 August 1890 (Fig. 4). This congress was attended by more than 5,000 participants from 40 different countries. Many famous scientists gave general lectures on the opening day, among them Koch, who gave a keynote lecture on bacteriological research (Fig. 5). Koch’s lecture was fairly general. Only at its very end did he make an exciting announcement: "Guinea pigs, which are known to be highly susceptible to tuberculosis, no longer respond to infection with tubercle bacilli once they had been pretreated with such substances. Moreover, in guinea pigs that suffered from severe tuberculosis, the disease process could be brought to an end without harming the animals. I do not want to draw further conclusions from these experiments, but only to state that the possibility exists to inactivate pathogens in the host without major side effects–a possibility that was thus far considered extremely unlikely."

Figure 4. 
Figure 4 thumbnailCircus Renz in Berlin, where the main symposia of the Tenth International Congress of Medicine took place on 4 August 1890.



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Figure 5. 
Figure 5 thumbnailKoch's lecture on bacteriological research, delivered at the Tenth International Congress of Medicine on 4 August 1890, as published in the Congress Proceedings.



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With these remarks, Koch announced the discovery of a vaccine for both the prevention and therapy of the disease. Not surprisingly, this announcement was received with great excitement not only by the expert audience, but also by the general population. Later that year, on 13 November 1890, a special issue of the Deutsche Medizinische Wochenschrift (German Medical Weekly) entitled "A further report about a remedy against tuberculosis" was published (Fig 6). In this report, Koch related that healthy individuals and patients suffering from diseases other than tuberculosis did not show any reaction to the treatment. Tuberculosis patients, in contrast, typically developed many specific symptoms that began to appear about 4–5 hours after injection and lasted about 15 hours. The symptoms included fever and general malaise. The infected tissue showed rapid signs of swelling and reddening; this reaction then subsided and disappeared. Koch noted that "the way which this process works is not yet fully understood because histological analyses are still not available. But one issue is already clear: the material does not kill the bacilli in the tissue directly, but instead, the tissue containing tubercle bacilli is affected by this treatment."

Figure 6. 
Figure 3 thumbnail"A further report about a remedy against tuberculosis" by Robert Koch, published in Deutsche Medizinische Wochenschrift 13 November 1890.



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This statement shows that Koch considered host mechanisms, rather than a direct action of the bacteria, responsible for this. Koch also described his initial testing of the material on himself. He found that he was far more sensitive to the treatment than were guinea pigs. After he had injected the material into his arm, he suffered a strong malaise, vomiting, fever, shivering and other side effects that lasted a few days. He was forced to state that "one should not conclude an identical behavior in man from animal experiments." This holds true even now, as an ideal animal model for tuberculosis still does not exist. Even though healthy individuals in general reacted more sensitively to tuberculin than guinea pigs, Koch’s response was particularly severe. He probably had developed an immune response to M.tuberculosis during all the years he had been working with this microbe. It is therefore likely that Koch was the first individual to show a positive delayed-type hypersensitivity reaction to tuberculin. In this paper, Koch had already clearly envisaged the diagnostic value of tuberculin: "I think that I do not exaggerate the findings in assuming that the substance will become an indispensable diagnostic measure in the future. It will enable us to diagnose questionable cases of early phthisis even when we fail to detect bacilli..." (Fig. 6).

During this professionally turbulent phase of Koch’s life, he met and fell immediately in love with 17-year-old Hedwig Freiberg, his junior by 30 years (Fig. 7), who later became his wife. When Hedwig learned of Koch’s severe reaction to tuberculin, she immediately volunteered to serve as his ‘guinea pig’ for further tests with the material, and so the appropriate concentrations of tuberculin for humans were determined using this young lady.

Figure 7. 
Figure 3 thumbnailKoch's second wife Hedwig, at the age when she met Robert Koch and served as a test subject for a trial with tuberculin.
 
Use of figure authorized by R. Munch, with support from the German Science Foundation.



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In a further report entitled "A continued report about a remedy against tuberculosis," which appeared in the Deutsche Medizinische Wochenschrift on 15 January 1891, Koch finally described the material: "The substance with which the new treatment against tuberculosis is being performed, is a glycerol extract of pure culture of tubercle bacilli" (Fig. 8).

Figure 8. 
Figure 3 thumbnail"A continued report about a remedy against tuberculosis" by Robert Koch, published in Deutsche Medizinische Wochenschrift 15 January 1891.



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In his last report on this topic, entitled "Further news about tuberculin," published in the Deutsche Medizinische Wochenschrift on 22 October 1891 (Fig. 9), Koch mostly dealt with the preparation and partial purification of tuberculin. This makes it the first description of a partially purified tuberculin (PPD). Koch described a new preparation procedure of tuberculin: the switch from bacterial culture on solid agar plates to liquid broth.

Figure 9. 
Figure 3 thumbnail"Further news about tuberculin" published in Deutsche Medizinische Wochenschrift 22 October 1891.



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Because of the interest it raised, Koch’s lecture at the Tenth International Congress of Medicine was republished in the Berliner Klinische Wochenschrift on 17 November 1890. For the next year or so, a substantial proportion of this journal was dedicated to reports on clinical trials with tuberculin, all of which were completed within the short time span of less than 12 months. Although in the beginning most reports on tuberculin treatment were positive, with time, criticism and negative experiences mounted. By the beginning of 1891, opinion about tuberculin ceased to fluctuate, and deteriorated unequivocally. In February 1891, an official report summarizing all available clinical data about the efficacy of tuberculin was published (Fig. 10). The trial comprised a total of 1,769 tuberculosis patients, and the progress report was compiled at the request of von Gossler, the minister of health. The report concluded (Fig. 11) that in total, 1,061 patients with tuberculosis of internal organs had been treated. Of these, only 1% were cured, 34% showed improvement, 55% showed no improvement and 4% had died. Moreover, 708 patients with tuberculosis of external tissues (including joints and bone) had been treated. Of these, 2% were cured, 54% showed improvement, 42% were unchanged and 1% had died. That is, the results from the treated group were no better than those of the untreated tuberculosis patients. In sum, the outcome of the trials was disastrous, and Koch was criticized for proceeding far too hastily.

Figure 10. 
Figure 3 thumbnailAn official report about the clinical trials on the efficacy of tuberculin, edited by A. Guttstadt, February 1891.



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Figure 11. 
Figure 3 thumbnailSummary of the trials on the efficacy of tuberculin



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What were the motivating forces that drove Koch to proceed so quickly? Originally, Koch had been very hesitant about announcing the new treatment at the Tenth International Congress of Medicine. He considered presentation of his experiments premature, as he had obtained only a few results with guinea pigs. His boss, Minister von Gossler, had been urged by Emperor William II to ensure that something spectacular was presented at the congress. Von Gossler had in turn urged Koch to present some spectacular data. Although in his lecture Koch had clearly stated that he had only done guinea pig experiments and had done no clinical studies, the importance of his talk was very much overrated by the medical community as well as the general public. Medical doctors from all over the world came on a pilgrimage to Berlin, to observe the treatments with their own eyes (Fig. 12). Koch became a public hero. He was offered the 'Grand Cross of the Red Eagle' (Großes Verdienstkreuz) by the Emperor William II as well as the ‘Key to the city of Berlin’ (Ehrenbürgerschaft) by the city government. The emperor invited him to private audiences, and declared that all profits from the discovery belonged to the discoverer, even if the product was produced in a state-owned laboratory. It has been rumored that the Hoechst Company purchased the exclusive rights to manufacture tuberculin for one million gold marks, which was clearly a strong motivating factor for Koch. Another factor was the fact that Koch disliked his current position, which involved teaching duties, as he wanted to concentrate more on laboratory and clinical research. Most importantly, he wanted a new institute that would enable him to carry out the clinical research on his therapy, because he was still convinced of its therapeutic potential. The different issues concerning Koch’s therapy were even discussed by the Prussian Parliament (Fig. 13), which deemed it important that a new ‘Institute for Infectious Diseases’ be built rapidly. The offer of directorship of this new institute, located on the campus of the University Clinics Charitè, was an ideal solution for Koch. The Institute comprised the so-called ‘triangle building’ and the clinical barracks (Fig. 14). The triangle building, which housed the laboratories and offices, already existed but required renovation (Fig. 15). The city of Berlin sponsored the renovation, a project that cost approximately half a million gold marks. The construction of the clinical barracks, comprising 128 beds, was considered ideal, as they could be put into use almost immediately as a provisional facility for the next 15 years at least.

Figure 12. 
Figure 3 thumbnailA contemporary sketch demonstrating the treatment of a tuberculosis patient with tuberculin.



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Figure 13. 
Figure 3 thumbnailMinutes of the session of the Prussian Parliament on tuberculin treatment on 29 November 1890.



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Figure 14. 
Figure 3 thumbnailThe Institute for Infectious Diseases comprising the clinical barracks and triangle building on the Campus of Charit´┐Ż Clinics (Berliner Klinische Wochenschrift, 7 September 1891).



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Figure 15. 
Figure 3 thumbnailThe triangle building of Koch's Institute for Infectious Diseases, which housed the laboratories and offices (Berliner Klinische Wochenschrift, 14 September 1891).



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Although tuberculin had failed as a therapy, it became the most important diagnostic tool for tuberculosis. Koch continued to be a highly productive scientist, and to produce excellent work, in particular on cholera and tropical diseases. At the new Institute for Infectious Diseases, Koch assembled a highly productive team, notably Emil Behring and Shibasaburo Kitasato (the discoverers of antitoxin therapy for diphtheria and tetanus), Paul Ehrlich (who developed the concept of the side-chain theory in immunology and chemotherapy), Richard Pfeiffer (who discovered immune lysis) and August von Wasserman (who developed the diagnosis of syphilis). Two of these scientists later received the Nobel Prize: Behring in 1901, and Ehrlich in 1908. This all helped to fully restore Koch’s reputation, and he himself was awarded the Nobel Prize in 1905 for his work on tuberculosis. Koch’s dream to control tuberculosis, however, was not fulfilled until today. Although drugs for the treatment of tuberculosis and a vaccine for the prevention of childhood tuberculosis have been developed, the disease remains a major health threat for humankind and urgently requires new control measures.

Stefan H.E. Kaufmann
Max-Planck-Institute for Infection Biology
Department of Immunology
Schumannstrasse 21/22
10117 Berlin
Germany
Phone: (+49)30-28460-504/500
Fax: (+49)30-28460-501/503
E-mail: kaufmann@mpiib-berlin.mpg.de
Max-Planck-Institute website: http://mbib-s1.mpiib-berlin.mpg.de


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ISSN: 1078-8956
EISSN: 1546-170X
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