© 2004 American Thoracic Society
Mycobacterium tuberculosis and the Cause of ConsumptionFrom Discovery to FactPulmonary and Critical Care, University of California San Francisco, San Francisco, California Correspondence and requests for reprints should be addressed to John F. Murray, M.D., F.R.C.P., Box 0841, Pulmonary and Critical Care, University of California, San Francisco, CA 94143-0841. E-mail: johnfmurr{at}aol.com Experts seem to agree that the scourge of tuberculosis, which had been steadily worsening for at least 200 years, climaxed in western Europe around the end of the eighteenth century or the beginning of the nineteenth—in either case while the industrial revolution was in full swing. In the year 1800, according to one model, the mortality rate from tuberculosis peaked at 1,000/100,000 inhabitants (1) and accounted for one of every four deaths recorded in parish registries from England. Similar rates from records kept in New England at the same time attest to the colossal burden of the disease in the United States as well (2). Burgeoning industrialization created the need for a greatly enlarged workforce in manufacturing cities. Hoards of people converged from rural areas, mainly young adults, but including also adolescents and children. Living and working conditions were appalling and consisted, for many people, of overcrowded dwellings and congested factories where sanitation and hygiene were abominable. Malnutrition was epidemic and medical care, if it can be dignified as such, was virtually useless in those rare instances when it was available. No wonder tuberculosis prospered. During the eighteenth and nineteenth centuries, consumption was considered incurable by most people, patients and physicians alike. Not surprisingly, speculation abounded concerning the cause of what was by far the number one killer of family, friends, and neighbors. Different theories were passionately espoused by leading medical authorities of the day. Some experts advocated contagion, others a constitutional hereditary defect, atmospheric imbalances, the depredations of stress, or an inevitable consequence of the degeneration of the human race; even the role of divine retribution was occasionally evoked. The controversy flourished despite the report in 1865 by Jean-Antoine Villemin, a French military surgeon, that he had been able to transmit tuberculosis from humans to rabbits by inoculation, the first clear demonstration of contagion (3); Villemin's observations were confirmed by Edwin Klebs, Julius Cohnheim, and Carl Salomonsen in elegant experiments, but the causative agent remained elusive and skeptics prevailed (for review and references see Reference 4). Not long after, the debate was concluded—once and for all—by one of the most definitive pronouncements in medical history, though by no means all physicians believed it, and there are two accounts of the events surrounding the declaration. MARCH 24, 1882 The popular and presently received version holds that only 36 physician-scientists assembled at the Berlin Physiological Society that decisive night in 1882 (5, 6) to hear a lecture by Robert Koch (Figure 1) entitled simply "Über Tuberkulose" (concerning tuberculosis). Koch was already known to the audience for his important studies on the origin and life cycle of the bacillus that causes anthrax, and rumors circulated that he was going to announce something sensational. He did not disappoint. Paul Ehrlich, who later gained fame and a Nobel Prize for inventing the concept of chemotherapy and for discovering the world's first chemotherapeutic agent, arsphenamine, the "magic bullet" that would cure syphilis, wrote afterward, "This evening remains imprinted on my memory as the most awe-inspiring scientific event I have ever attended" (7).
By all reports, Koch was not a brilliant lecturer and never became a facile public speaker (8); moreover, it was his maiden exposition and his old teacher, Professor Rudolf Virchow, the apotheosis of the then contemporary authoritarian system of German medicine, whose every word was gospel, was said to be among those present. Koch started nervously, fumbling with his notes and peering at them shortsightedly. He began by reminding his audience of something of which they were already well aware (9): "If the number of victims which a disease claims is the measure of its significance, then all diseases, particularly the most dreaded infectious diseases, such as bubonic plague, Asiatic cholera, etc., must rank far behind tuberculosis. Statistics teach that one-seventh of all human beings die of tuberculosis, and that, if one considers only the productive middle-age groups, tuberculosis carries away one-third and often more of these." From then on, the style of Koch's delivery mattered not at all, because slowly and methodically he convinced his spellbound audience that a bacterium, which he had invented a novel way of staining so that it could be seen under a microscope, which he had succeeded for the first time ever in growing on artificial culture medium, and which he had then used to infect laboratory animals and reproduce the identical disorder, caused the most important disease of mankind of all time—tuberculosis. At the end of his lecture, there was no applause; everyone remained silent in stunned appreciation. In the apocryphal version, all eyes turned to the usually outspoken Virchow, "who had dignified the meeting of the Physiological Society by his presence and was second in interest only to the speaker" (5). No stranger to tuberculosis, the professor of professors had formulated his own theory about the genesis of the disease that he had imposed on medical thought for more than 30 years. Not only that, he had preached against germs as a cause of any disease, and he had rebuked Koch earlier when he presented him his findings privately. Virchow must have known that his cherished postulates about the multiple origins of tuberculosis lay in ruins, but he had nothing to say. In one account, Virchow "put on his hat and stormed from the room without speaking a word" (10). The less well known version of the events of March 24th, which is almost certainly the more accurate, attests that about 80 people actually attended the meeting, and the small reading room in which Koch held forth could not possibly have accommodated them all (R. Münch 2000, personal communication). In addition, it is doubtful that Virchow was actually present; he may have been outside the lecture room and went unnoticed among the crowd, but that seems unlikely given his stature. Accounts by two of Koch's major biographers affirm, seemingly unequivocally, that Virchow did not in fact show up. Heymann (11) states that among all the distinguished members of the Berlin medical establishment who gathered that night, "only Virchow" was absent; Henneberg (12) agrees and writes that Virchow was "missing." The next day, many scientists, Virchow definitely among them, went to the Imperial Health Office to view Koch's experimental preparations, which had been moved there to facilitate thorough examination. Part of the myth concerning the supposed enmity between these two venerable giants of medical science was undoubtedly planted by a 1939 German movie about Koch, which placed Virchow near center stage at the seminal Physiological Society meeting (13). In the Nazified cinematic account, Koch was portrayed as a brilliant scientist, a certified hero, and an exemplary doctrinaire German (i.e., would have made a good Nazi); by contrast, Virchow (who had been a contentious liberal member of Bismarck's parliament) was presented as a nonconformist and a narrow-minded old man who clung to obsolete concepts. What is not in doubt is that 17 days later, lightning fast by today's publishing norm, an article by Koch announcing his discovery appeared in an important medical journal (9). The article also included the first enunciation of what we now call Koch's postulates, the principles that guided his discovery and underlay the certainty that Mycobacterium tuberculosis was indeed the cause of tuberculosis: "To prove that tuberculosis...is caused by invasion of bacilli and...the growth and multiplication of the bacilli, it was necessary to isolate the bacilli from the body; to grow them in pure culture...; and, by administering the isolated bacilli to animals, to reproduce the same morbid condition...." Word of Koch's incredible findings spread quickly, although not everyone accepted them. Scientists are born skeptics, rightly so, but sometimes they behave with exasperating stubbornness. Koch knew he would have to struggle hard to have his scientifically rigorous discovery of the tubercle bacillus accepted by an obstinate medical profession. In one account (4) he predicted that it would take "one year" and in another (14) "two generations" for his incontrovertible findings to become certainty. Although general acceptance occurred within a few years, Virchow, who died in 1902, remained skeptical and unconvinced and continued to the end of his days to refer to "the so-called tuberculosis germ" (15). Koch quickly became famous. Kaiser Wilhelm I made him an Imperial Privy Councilor, raised his salary and research support, and provided additional laboratory assistants (4). Koch went on to study malaria, sleeping sickness, and eye infections, and he topped off his post–M. tuberculosis career by discovering Vibrio comma, the bacterial cause of cholera. In 1905 he received the Nobel Prize in Medicine, a well deserved achievement. But there's more to the story. MYCOBACTERIUM TUBERCULOSIS VERSUS MYCOBACTERIUM BOVIS Koch knew, of course, that tuberculosis occurred in cattle, but he believed—incorrectly—that bovine disease posed no threat to humans. He also waffled over the question of whether the mycobacteria that caused tuberculosis in humans and cows were the same or two different species. That debate was firmly settled in 1896 by Theodore Smith (16) who identified morphologic and biochemical differences between the two organisms; but it took a long time, until 1970, before it was officially declared that M. tuberculosis and M. bovis were two distinct species of microorganisms within the M. tuberculosis complex (17). That formal designation, however, did not establish which of the two mycobacteria preceded the other as an animal pathogen and in the evolutionary hierarchy. There was no way to know for sure which species came first until recently because the precise origins of tuberculosis are deeply concealed in antiquity. To begin with, there is persuasive archeologic evidence that the disease was present in humans during the Stone Age. Characteristic abnormalities of the spine, which are almost certainly caused by tuberculosis, have been found in skeletons from the Neolithic period, one dating as early as 5000 B.C. The best and most abundant documentation comes from Egypt, where the climate, burial techniques, and the art of embalming combined to provide well preserved mummies, dozens of which have shown typical (but not pathognomonic) skeletal deformities of tuberculosis (15). In contrast to the considerable number of specimens from the epoch before 1000 B.C. that show presumed tuberculosis involvement of bones, evidence of tuberculosis of the lungs, now by far the most common manifestation of the disease, does not appear until after 1000 B.C. The mounting archeologic information led to the compelling hypothesis that tuberculosis began in the Neolithic period, when the causative microbes spread from wild buffalo to the humans who succeeded in domesticating them. Highly specific molecular typing has revealed evidence of mycobacteria in a now-extinct late-Pleistocene long-horned bison that roamed North America 17,000 years ago, long before the domestication of cattle (18). The facts were also consistent with the belief that the bacterium originally harbored by buffalo—that they transmitted in milk to their human captors—was M. bovis, which, once in human bodies, is more likely to infect bones than lungs. Then, after gaining its Homo sapiens foothold, M. bovis evolved over the subsequent millennia into the closely related but more specialized human aggressor M. tuberculosis (19). Both organisms are certainly capable of causing progressive tuberculosis in humans—and still do so—but M. tuberculosis much more often nowadays than its mycobacterial cousin. The formerly attractive, epidemiology-based theory that M. tuberculosis evolved from M. bovis has been superceded by new gene-based information. Once more we have to acknowledge and abandon a beautiful hypothesis destroyed by a single ugly fact. The (not-so-ugly) fact came to light recently as a result of sophisticated molecular analyses of the genetic composition of 100 strains of members of the M. tuberculosis complex, including isolates of both M. tuberculosis and M. bovis. Now, there is incontrovertible evidence that M. tuberculosis contains genetic elements that are deleted from M. bovis and, therefore, the former must have preceded the latter in the evolutionary hierarchy—not the other way around (20). It seems almost certain that there was a primordial ancestor of today's members of the tuberculosis complex, a sort of ur-tubercle bacillus, perhaps already a human pathogen, that resembles modern M. tuberculosis much more closely than M. bovis, and that M. bovis and its progeny split off later on as the lineage evolved. CONCLUSIONS Having to sit and listen while Koch dismembered his treasured and oft-proclaimed views on both the origins of tuberculosis and the unimportance of germs must have been painful for Virchow, probably the most distinguished physician of the day, if indeed he was actually present that fateful night in March 1882. Even if he did not attend the meeting, which now seems much more likely, there is little doubt that Virchow's eminence and opposition delayed reception of what is undoubtedly one of the masterpieces of scientific investigation and medical exposition. By contrast, contemporary and historical reputations were not at stake over the hypothesis that M. bovis preceded M. tuberculosis in the evolutionary procession of mycobacteria and, therefore, as a paramount pathogen of humans and other animals, an attractive postulate that seemed to fit the then available facts. Lack of professional commitment to the old theory favored its instant replacement by the current one, based—like Koch's proclamation—on new scientific facts. The lessons are obvious: cherished vested interests may prejudice the process of scientific inquiry, and gigantic egos do not give ground easily. I still wonder, though, why there seems to have been so much more tuberculosis of bones than of lungs in distant millennia: was it merely a matter of sampling? Acknowledgments The author gratefully acknowledges the contributions of Dr. Ragnild Münch, Professor Robert Loddenkemper, and Dr. Udo Schagen who provided useful information and references concerning Robert Koch and Rudolph Virchow. FOOTNOTES Conflict of Interest Statement: J.F.M. has no declared conflict of interest. Received in original form December 2, 2003; accepted in final form January 2, 2004 REFERENCES
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