Robert Koch, the Nobel Prize, and the Ongoing Threat of Tuberculosis
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《新英格兰医药杂志》
"During my wandering through medicine, I encountered sites where gold was lying around. It needs a lot of serendipity to distinguish gold from ignobility; this however is not a particular achievement." With these words, spoken on April 12, 1908, at a New York banquet held in his honor by the German Medical Society, German physician and scientist Robert Koch reflected on his life's accomplishments. It is a rather modest statement coming from a man who created a new discipline — medical microbiology — and who was honored, 100 years ago, with the Nobel Prize in Physiology or Medicine.
Although his work on tuberculosis was specified in the Nobel laudation, Koch's achievements in bacteriology were wide-ranging and profound. He discovered the causative agents of consumption, anthrax, wound fever, and cholera1 and developed the methods and conceptual framework that established medical bacteriology as a precise science. He was a mentor to other highly successful medical bacteriologists, including Friedrich Loeffler, who discovered the cause of diphtheria, and Georg Gaffky, who, with Koch, isolated the agent underlying cholera. And he laid the groundwork that facilitated the emergence of the related discipline of immunology.
Robert Koch was born in 1843 in Clausthal, Germany, the son of a mining engineer. In 1862, he entered the University of G?ttingen, where he first studied natural sciences, then medicine. While there, he attended the lectures of the anatomist Jacob Henle, who strongly argued against miasmatic transmission of disease. Henle claimed that germs — originally described in 1860 by Louis Pasteur as the cause of fermentation and putrefaction — were also responsible for a whole group of maladies.
This daring hypothesis must have lit a fire in Koch. After becoming a district practitioner (i.e., a physician who also supervised other health care providers) in Wollstein, he established a small private laboratory at his office. There he began studying anthrax, attempting to elucidate its cause. He identified Bacillus anthracis in specimens obtained from diseased animals, cultured the bacilli in vitro, and successfully infected animals with the agent. He also clarified the life cycle of the organism, which forms spores in hostile environments and rapidly germinates in a living host. In 1876, he published his findings in a paper entitled "The Etiology of Anthrax, Based on the Life History of Bacillus anthracis."1
During the next two years, Koch improved his laboratory techniques. He developed solid-culture media for isolating pure bacterial cultures from single colonies, designed staining procedures to differentiate bacterial pathogens from the surrounding tissue, and refined animal models and the use of microphotography. These pioneering achievements allowed Koch to isolate various bacterial species from wound infections and to describe a range of syndromes, including abscesses, septicemia, necrosis, and fever. His "Investigations of the Etiology of Wound Infections" was published in 1878.1
In 1880, Koch was appointed director of the bacteriological laboratories at the Imperial Health Office in Berlin, and two years later he published "The Etiology of Tuberculosis," in which he clarified the infectious nature of the disease. Although meticulously documented, his findings met with some opposition — because of its chronic nature, tuberculosis was widely believed to be inherited. In particular, Rudolf Virchow, a highly respected pathologist at the Charité Hospital in Berlin, saw tuberculosis in the context of cellular pathology, as the result of malfunctioning host cells with no involvement of foreign invaders.
The need to prove the contagious nature of tuberculosis to his most ardent opponent led Koch to formulate what are now known as Koch's postulates — criteria, based on the hypothesis of Koch's mentor Henle, for establishing causal relationships between parasites and disease. The requirements include the consistent presence, in a unique form and structure, of a microorganism in diseased tissue; the isolation in pure culture of the microbe; and the induction of similar disease in animals by means of the pure culture. These postulates remain central concepts of medical microbiology.
Although Mycobacterium tuberculosis is particularly recalcitrant to microbiologic analysis, Koch succeeded in fulfilling all three postulates. He did so by developing a specific staining-and-destaining method for identifying acid-fast bacilli and designing a special solid-culture medium that permitted the long-term cultivation and subcultivation of the slow-growing microorganisms. He then succeeded in eliciting tuberculosis in various animals by infecting them with isolated cultures.
Koch concluded that "the bacilli present in the tuberculous lesions do not only accompany tuberculosis but rather cause it. These bacilli are the true agents of consumption." His findings led to the implementation of improved hygienic measures, such as the sterilization of bedsheets and patients' clothing, as well as restrictions on spitting in public places. They also cemented Koch's reputation.
In 1883, with Asiatic cholera having spread to Egypt and threatening Europe, Koch led an expedition that included coworkers Gaffky and Bernhard Fischer. In Alexandria, the group soon isolated Vibrio cholerae from patients' stool. When the disease vanished from Egypt more quickly than expected, Koch moved on to India, where cholera was endemic. There, he demonstrated the link between cholera outbreaks and drinking contaminated water. These studies were instrumental in establishing the need for sewage systems in cities and other public health measures and were soon applied toward that end in Berlin. However, it was not until 1884, during a new cholera outbreak in Europe, that Koch succeeded in infecting animals — in this case, guinea pigs — thereby fulfilling the third postulate.
Given Koch's seminal contributions, it was rather surprising that in 1901, the first Nobel Prize in Physiology or Medicine was awarded not to Koch himself but to his former student Emil von Behring, for his work on the treatment of diphtheria and tetanus. One possible explanation is that the Nobel rules required that the award be granted for a discovery made within the preceding year or two and that earlier discoveries could be considered only if their significance had just recently been recognized. Koch's major breakthrough, the identification of the causative agent of tuberculosis, had occurred almost 20 years earlier. But a contributing factor might well have been that despite Koch's other remarkable findings in the last decade of the 19th century (notably, those regarding tropical diseases), he had also stumbled into his most important failure during this period — his claim to have discovered a remedy for tuberculosis.
In 1890 and 1891, Koch had published a series of four papers describing the nature of his treatment — a glycerol extract of pure culture of tubercle bacilli — as well as the reaction of animals infected with M. tuberculosis and the differential responses to tuberculin in healthy and diseased persons.1 Koch noted that the extract "will enable us to diagnose questionable cases of early consumption even when we fail to detect bacilli" — and thus clearly foresaw the diagnostic value of tuberculin, which is still used today in a modified form of purified protein derivative. But his claim to have found a remedy was rapidly disproved when a multicenter clinical trial in Berlin involving more than 1700 patients with tuberculosis showed that tuberculin's therapeutic value was negligible. This failed effort may well have influenced the 1901 Nobel Prize committee.
Yet Koch never abandoned his hope that tuberculin would ultimately cure tuberculosis and never retracted his claim. He would conclude his Nobel lecture by reasserting his optimism about a cure: "The fight has been ignited fully and the enthusiasm for this goal is so broad that I am not afraid that it will cease again. If we continue to work in such a powerful way, victory will be achieved."
Unfortunately, the founder of medical microbiology and the intellectual forerunner of infectious-disease control has not yet been proved right in this regard. A full century after the Nobel Prize was awarded to Koch, tuberculosis remains a major global threat. Each year there are more than 8 million new cases and 2 million deaths from tuberculosis.2 Yet Koch would no doubt find it rewarding that, after a decades-long standstill, renewed interest in tuberculosis has led to clinical trials of several new candidate drugs and vaccines in time for the 100th anniversary of his Nobel Prize.
(Figure)
Timeline Showing Highlights of Robert Koch's Work and the Ongoing Threat Posed by Tuberculosis.
Since the Nobel Prize was awarded to Koch in 1905, several advances have been made against tuberculosis. By 1921, a viable attenuated vaccine had been developed by Albert Calmette and Camille Guérin; it protects against severe forms of tuberculosis in newborns but does not prevent pulmonary tuberculosis in adults. The first tuberculostatic drug was developed by Selman Waksman in 1943, and chemotherapy became possible. But because prolonged treatment with multiple drugs is required, compliance is often incomplete, leading to an increasing incidence of multidrug-resistant disease. In 1998, the genome of Mycobacterium tuberculosis was sequenced, providing the blueprint for the development of an improved vaccine and new drugs.
Source Information
Dr. Kaufmann is the director of the Department of Immunology at the Max Planck Institute for Infection Biology, Berlin.
References
Koch R, Gaffky G, Pfuhl E. Gesammelte Werke von Robert Koch. Leipzig, Germany: Georg Thieme Verlag, 1912.
Kaufmann SHE, McMichael AJ. Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nat Med 2005;11:Suppl:S33-S44.(Stefan H.E. Kaufmann, Ph.)
Although his work on tuberculosis was specified in the Nobel laudation, Koch's achievements in bacteriology were wide-ranging and profound. He discovered the causative agents of consumption, anthrax, wound fever, and cholera1 and developed the methods and conceptual framework that established medical bacteriology as a precise science. He was a mentor to other highly successful medical bacteriologists, including Friedrich Loeffler, who discovered the cause of diphtheria, and Georg Gaffky, who, with Koch, isolated the agent underlying cholera. And he laid the groundwork that facilitated the emergence of the related discipline of immunology.
Robert Koch was born in 1843 in Clausthal, Germany, the son of a mining engineer. In 1862, he entered the University of G?ttingen, where he first studied natural sciences, then medicine. While there, he attended the lectures of the anatomist Jacob Henle, who strongly argued against miasmatic transmission of disease. Henle claimed that germs — originally described in 1860 by Louis Pasteur as the cause of fermentation and putrefaction — were also responsible for a whole group of maladies.
This daring hypothesis must have lit a fire in Koch. After becoming a district practitioner (i.e., a physician who also supervised other health care providers) in Wollstein, he established a small private laboratory at his office. There he began studying anthrax, attempting to elucidate its cause. He identified Bacillus anthracis in specimens obtained from diseased animals, cultured the bacilli in vitro, and successfully infected animals with the agent. He also clarified the life cycle of the organism, which forms spores in hostile environments and rapidly germinates in a living host. In 1876, he published his findings in a paper entitled "The Etiology of Anthrax, Based on the Life History of Bacillus anthracis."1
During the next two years, Koch improved his laboratory techniques. He developed solid-culture media for isolating pure bacterial cultures from single colonies, designed staining procedures to differentiate bacterial pathogens from the surrounding tissue, and refined animal models and the use of microphotography. These pioneering achievements allowed Koch to isolate various bacterial species from wound infections and to describe a range of syndromes, including abscesses, septicemia, necrosis, and fever. His "Investigations of the Etiology of Wound Infections" was published in 1878.1
In 1880, Koch was appointed director of the bacteriological laboratories at the Imperial Health Office in Berlin, and two years later he published "The Etiology of Tuberculosis," in which he clarified the infectious nature of the disease. Although meticulously documented, his findings met with some opposition — because of its chronic nature, tuberculosis was widely believed to be inherited. In particular, Rudolf Virchow, a highly respected pathologist at the Charité Hospital in Berlin, saw tuberculosis in the context of cellular pathology, as the result of malfunctioning host cells with no involvement of foreign invaders.
The need to prove the contagious nature of tuberculosis to his most ardent opponent led Koch to formulate what are now known as Koch's postulates — criteria, based on the hypothesis of Koch's mentor Henle, for establishing causal relationships between parasites and disease. The requirements include the consistent presence, in a unique form and structure, of a microorganism in diseased tissue; the isolation in pure culture of the microbe; and the induction of similar disease in animals by means of the pure culture. These postulates remain central concepts of medical microbiology.
Although Mycobacterium tuberculosis is particularly recalcitrant to microbiologic analysis, Koch succeeded in fulfilling all three postulates. He did so by developing a specific staining-and-destaining method for identifying acid-fast bacilli and designing a special solid-culture medium that permitted the long-term cultivation and subcultivation of the slow-growing microorganisms. He then succeeded in eliciting tuberculosis in various animals by infecting them with isolated cultures.
Koch concluded that "the bacilli present in the tuberculous lesions do not only accompany tuberculosis but rather cause it. These bacilli are the true agents of consumption." His findings led to the implementation of improved hygienic measures, such as the sterilization of bedsheets and patients' clothing, as well as restrictions on spitting in public places. They also cemented Koch's reputation.
In 1883, with Asiatic cholera having spread to Egypt and threatening Europe, Koch led an expedition that included coworkers Gaffky and Bernhard Fischer. In Alexandria, the group soon isolated Vibrio cholerae from patients' stool. When the disease vanished from Egypt more quickly than expected, Koch moved on to India, where cholera was endemic. There, he demonstrated the link between cholera outbreaks and drinking contaminated water. These studies were instrumental in establishing the need for sewage systems in cities and other public health measures and were soon applied toward that end in Berlin. However, it was not until 1884, during a new cholera outbreak in Europe, that Koch succeeded in infecting animals — in this case, guinea pigs — thereby fulfilling the third postulate.
Given Koch's seminal contributions, it was rather surprising that in 1901, the first Nobel Prize in Physiology or Medicine was awarded not to Koch himself but to his former student Emil von Behring, for his work on the treatment of diphtheria and tetanus. One possible explanation is that the Nobel rules required that the award be granted for a discovery made within the preceding year or two and that earlier discoveries could be considered only if their significance had just recently been recognized. Koch's major breakthrough, the identification of the causative agent of tuberculosis, had occurred almost 20 years earlier. But a contributing factor might well have been that despite Koch's other remarkable findings in the last decade of the 19th century (notably, those regarding tropical diseases), he had also stumbled into his most important failure during this period — his claim to have discovered a remedy for tuberculosis.
In 1890 and 1891, Koch had published a series of four papers describing the nature of his treatment — a glycerol extract of pure culture of tubercle bacilli — as well as the reaction of animals infected with M. tuberculosis and the differential responses to tuberculin in healthy and diseased persons.1 Koch noted that the extract "will enable us to diagnose questionable cases of early consumption even when we fail to detect bacilli" — and thus clearly foresaw the diagnostic value of tuberculin, which is still used today in a modified form of purified protein derivative. But his claim to have found a remedy was rapidly disproved when a multicenter clinical trial in Berlin involving more than 1700 patients with tuberculosis showed that tuberculin's therapeutic value was negligible. This failed effort may well have influenced the 1901 Nobel Prize committee.
Yet Koch never abandoned his hope that tuberculin would ultimately cure tuberculosis and never retracted his claim. He would conclude his Nobel lecture by reasserting his optimism about a cure: "The fight has been ignited fully and the enthusiasm for this goal is so broad that I am not afraid that it will cease again. If we continue to work in such a powerful way, victory will be achieved."
Unfortunately, the founder of medical microbiology and the intellectual forerunner of infectious-disease control has not yet been proved right in this regard. A full century after the Nobel Prize was awarded to Koch, tuberculosis remains a major global threat. Each year there are more than 8 million new cases and 2 million deaths from tuberculosis.2 Yet Koch would no doubt find it rewarding that, after a decades-long standstill, renewed interest in tuberculosis has led to clinical trials of several new candidate drugs and vaccines in time for the 100th anniversary of his Nobel Prize.
(Figure)
Timeline Showing Highlights of Robert Koch's Work and the Ongoing Threat Posed by Tuberculosis.
Since the Nobel Prize was awarded to Koch in 1905, several advances have been made against tuberculosis. By 1921, a viable attenuated vaccine had been developed by Albert Calmette and Camille Guérin; it protects against severe forms of tuberculosis in newborns but does not prevent pulmonary tuberculosis in adults. The first tuberculostatic drug was developed by Selman Waksman in 1943, and chemotherapy became possible. But because prolonged treatment with multiple drugs is required, compliance is often incomplete, leading to an increasing incidence of multidrug-resistant disease. In 1998, the genome of Mycobacterium tuberculosis was sequenced, providing the blueprint for the development of an improved vaccine and new drugs.
Source Information
Dr. Kaufmann is the director of the Department of Immunology at the Max Planck Institute for Infection Biology, Berlin.
References
Koch R, Gaffky G, Pfuhl E. Gesammelte Werke von Robert Koch. Leipzig, Germany: Georg Thieme Verlag, 1912.
Kaufmann SHE, McMichael AJ. Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nat Med 2005;11:Suppl:S33-S44.(Stefan H.E. Kaufmann, Ph.)