ROBERT KOCH

12 May

In  contrast   to  Louis   Pasteur,   whose  road   to  microbiology   began with  chemistry,  Robert  Koch  (1843–1920) came  to  bacteriology  as a physician,  and  his research  was primarily  motivated  by medical  and methodological  questions.   Lacking  Pasteur’s  flair  for  the  dramatic, Koch’s gift was for attention to detail and simple, but  ingenious  tech- niques that made modern microbiology possible. To his contemporaries, Koch  was ‘‘a man of genius both  as technician  and as bacteriologist.’’ Robert  Koch was the third of 13 children born to Mermann Koch,

a mining administrator, and  his wife Mathilde.  When Koch  began  his medical  studies  at  the  University  of  Go¨ ttingen,  the  faculty  included many eminent scientists, but in the 1860s not even Jacob Henle seemed to have any interest  in the possible relationship  between bacteria  and disease. In 1866, Koch received his doctor’s degree and passed the state medical  examination.  He  spent  several  months   in  Berlin,  observing medical care at the Charite´  hospital  and attending  a course of lectures by Germany’s  most  famous  physician,  Rudolf  Virchow  (1821–1902), the founder  of cellular pathology.  Given  to  romantic  dreams,  despite his rather  phlegmatic  personality,  Koch  originally  hoped  for a career as a ship’s doctor  or military  surgeon,  but  he abandoned this goal in order to become engaged to Emmy Fraatz. His first position  as a medi- cal assistant  at the Hamburg General  Hospital  gave him some practical experience in working with cholera,  a disease he would return  to later. In 1867, after finding another  position and establishing a modest private practice, he married Emmy and appeared  to be doomed to spending his life in rural  isolation  as a general practitioner and district medical offi- cer. A brief interruption occurred  during  the Franco-Prussian War  of

1870 when Koch enlisted in the medical corps. Like many other doctors, Koch  found  that  war  was  indeed  the  ultimate   medical  school.  His experience with typhoid fever and battle wounds would later prove valu- able in his research.

Despite  his  official  duties  and  busy  practice,  Koch  found  time for hobbies such as natural history, archaeology,  photography, and for research  concerning  hygiene,  public  health,  and  bacteriology.  A  trip taken  in 1875 to  attend  medical  meetings  and  visit various  scientific

Robert Koch

laboratories encouraged  his commitment to  scientific research.  Thus, when anthrax  appeared  in his district,  Koch  began  a serious study  of the relationship  between  bacteria  and  disease. Anthrax  is primarily  a disease of sheep and cattle,  but  several forms of the disease can occur in human  beings: severe, localized skin ulcers known as malignant  pus- tules, a dangerous  condition  known  as gastric  anthrax, and  a virulent pneumonia known  as  woolsorter’s  disease.  Proponents of  the  germ theory  were particularly interested  in anthrax  and  the relatively  large bacilli  associated  with  it.  Franz  Pollender  (1800–1879) had  observed bacteria  in the blood  of anthrax  victims as early as 1849, but  he did not  publish  his findings until  1855. Pierre  Rayer  (1793–1867) claimed to have seen the bacillus in the blood  of sheep he had inoculated  with

blood from animals that  had died of anthrax. However, it was Casimir Joseph  Davaine  (1812–1882) who  first  presented  good,  albeit  circum- stantial evidence of a link between the bacillus and the disease. Davaine demonstrated that  inoculations  of blood  from  anthrax  victims trans- mitted the disease to experimental  animals. In 1863, Davaine  published several papers  on the infectivity of the ‘‘filiform bodies’’ that  appeared in  the  blood  of  animals  dying  of  anthrax. Identical  bacilli  could  be found  in the malignant  pustules  of human  victims. These experiments were suggestive but not compelling; Davaine  had not isolated and puri- fied  the  anthrax   bacillus  nor  had  he  satisfied  the  criteria  of  proof suggested by Jacob  Henle.

By 1876, Koch had obtained  cultures of Bacillus anthracis and had

worked  out the life cycle of the bacillus and the natural history  of the disease. Like  Davaine,  Koch  transferred anthrax  from  infected  cattle to rabbits  and  mice. Going  beyond  his predecessors,  Koch  discovered that he could grow anthrax  bacteria  outside the body of living animals. Using  the aqueous  humor  of rabbits  or cattle  as his growth  medium, Koch  was able to establish  and  purify  bacterial  cultures,  which could then  be injected  into  experimental  animals.  These laboratory cultures produced  anthrax  just as if a sample of blood from a naturally  infected farm animal had been used. In order to have fresh anthrax  material con- tinuously  available  and  determine  whether  the  bacilli  would  change after  a  certain  number  of  generations,   Koch  conducted   a  series  of mouse-to-mouse inoculations. Even  after  the  bacilli had  been  passed through  a series of 20 mice, they remained  true to form. These experi- ments  ruled  out  the  possibility  that  some  poison  or  toxin  from  the original  animal  caused  the  disease in the  experimental  animals.  Only an agent  capable  of multiplying  within  the bodies of infected animals could create such a long chain of transmission.

While observing  anthrax  bacilli on  microscope  slides, Koch  saw

thread-like   chains  of  bacteria  become  bead-like  spores.  When  fresh medium  was  added,  the  spores  were  transformed into  active  bacilli, which  began  to  multiply  again.  The  extreme  hardiness  of the  spores explained many of the mysteries surrounding the persistence of anthrax in contaminated pastures.  Because spores were resistant  to harsh  con- ditions,  a carcass  deposited  in a shallow  grave  could  furnish  enough spores to infect other  animals for many years. Thus, an understanding of the natural history  of anthrax  immediately  suggested  measures  for controlling   the   disease   through    proper   disposal   of   contaminated carcasses.

Convinced  that  he had solved the riddle of anthrax, Koch sent an

account   of  his  work  to  Ferdinand  Cohn  (1828–1898), the  eminent botanist  who  was Germany’s  leading  expert  on  bacteriology.  Despite some initial skepticism,  Cohn  invited Koch  to come to the University of Breslau  to  demonstrate his experiments.  Certainly,  Koch  was not

the first amateur  to invade  the academic  community  claiming to have found  a solution  to  the problem  of contagion.  In  this case, however, Cohn  and  his  associates  found  the  experimental  results  and  demon- strations   absolutely   convincing.  Under   Cohn’s  sponsorship,  Koch’s paper  ‘‘The Etiology  of Anthrax, Based on the Life Cycle of Bacillus anthracis’’ was published  in Contributions to Plant  Biology.

On the basis of his work with anthrax, Koch confidently predicted that  bacteriological  science would  lead to  control  over infectious  dis- eases. To overcome the opposition  of conservative physicians and scien- tists, Koch  urged  advocates  of the germ theory  of disease to learn  to cultivate  pure  strains  of  microbes,  abandon careless  and  speculative work, and demonstrate the value of microbiology  in the prevention  or treatment of disease. In  the  long  run,  Koch’s  predictions  were richly validated,  but it was Pasteur  who produced  an anthrax  vaccine to pre- vent the disease in sheep and cattle. Moreover,  Pasteur  explained how earthworms participated in the natural chain of transmission by bring- ing anthrax  spores to the surface of pastures  where they were ingested by grazing animals. Although  quantity  is not necessarily a sign of qual- ity, it is interesting to note that Pasteur  published 31 papers on anthrax to  Koch’s  total  of 2. Such  differences  in approaching a  problem,  as well as achieving  practical  solutions,  aggravated the  conflict  between Koch and Pasteur.  Attacking  Pasteur’s work openly and directly, Koch called the results of his rival into question for his alleged failure to pro- duce  pure  cultures  and  emphasized  the  obvious  and  well-known  fact that Pasteur  was not a physician. Responding  to those who had praised Pasteur as a ‘‘second Jenner,’’ Koch contemptuously noted that Edward Jenner’s work had involved humans,  not sheep.

Establishing  a safe and  effective vaccine for  anthrax  in humans

remained  a problem  into  the twenty-first  century,  although  the possi- bility of the use of anthrax  spores as a terrorist  weapon  gained plausi- bility.  During  the  1990s, anthrax   vaccinations  were blamed  for Gulf War Syndrome among American soldiers who had been subjected to mandatory  vaccinations.   Although   the  effectiveness  of  the  anthrax vaccine was already  controversial, critics argued  that  modifications  of the  vaccine had  been  made  without  sufficient  testing  and  insufficient safeguards  were applied  to production. The dangers  of the large-scale production of weaponized  anthrax  spores were revealed by an anthrax epidemic  that  occurred  in 1979 in Sverdlovsk,  Russia,  near  a  Soviet Biopreparat plant  that  was doing  research  on chemical and  biological weapons. Initially, Soviet officials blamed the outbreak on contaminated meat. Problems with livestock and meat processing had been responsible for many cases of anthrax  in Russian  history.  However,  the 62 deaths that  occurred  during  the 1979 outbreak were clearly due to inhalation anthrax, not  gastric  anthrax. Revelations  about  the nature  and  extent of the Biopreparat program  appeared  in the 1990s.

Having  demonstrated  the  etiology  of  a  specific  disease,  Koch turned to the general problem of wound infection, which the British sur- geon Joseph Lister had begun to master  through  the antiseptic  system. Many  investigators  had  observed  bacteria  in  traumatic infective dis- eases, but  they could  not  determine  whether  bacteria  were nonspecific entities, the cause of disease, or the product  of some pathological  pro- cesses. In part,  Koch’s work on wound infection was meant to support the  concept  that  bacteria  existed  as  distinct,  fixed species. Karl  von Na¨ geli (1817–1891), the  eminent  Swiss botanist, who  holds  a  special place  in  the  history  of  genetics  for  his  failure  to  appreciate  Gregor Mendel’s (1822–1884) theory  of inheritance,  had  attacked  the concept of specific bacterial  species. If bacteria  did not exist as separate  species, it made no sense to say that a specific microbe—such  as Bacillus anthra- cis—caused a specific disease. Many  critics of the doctrine  of specific etiology claimed to have ‘‘seen’’ transformations between various types of bacteria.  Convinced that such observations were invariably the result of sloppy  laboratory techniques,  Koch  realized  that  scientists  needed simple, reliable methods  of establishing  pure cultures and standardized means of preparing  bacteria  for microscopic  examination.

Studies of experimentally  induced  traumatic infective diseases led Koch to believe that  a different microorganism caused each septic con- dition.  He also demonstrated that  bacteria  were not found in the blood or  tissues of healthy  animals.  Unfortunately, the  medical  community misinterpreted Koch’s general proof of the applicability  of germ theory to wound  infection  as a series of laboratory curiosities  involving gan- grene and septicemia in mice. Although Koch excelled in the rigorousness of his techniques, he lacked Pasteur’s flair for choosing and staging dramatic,  attention-getting events. Koch’s colleagues would have been more  impressed  if he had  demonstrated the  relationship  between  his work on sepsis in mice and human  disease. In this case, the disadvan- tages of working  in rural  isolation,  instead  of an urban  medical center with  access to  clinical material  were critical.  However,  Joseph  Lister understood the implications  of Koch’s  work  and  was instrumental in having Koch’s Aetiology of Traumatic  Infective Diseases translated into English.

After years of struggling to pursue  his research while maintaining a private practice, Koch  finally obtained  a position  as head of a newly established  laboratory for  bacteriological   research  with  the  Imperial Health  Office in Berlin.  In  1885, he became  Professor  of Hygiene  at the  University  of Berlin and  Director  of the  University’s  Institute  of Hygiene,  a  title  he  held  until  1891 when  the  Institute  for  Infectious Diseases was created  for him. Despite  his professional  success, Koch’s private  life was evidently quite unsatisfactory until he met 17-year-old Hedwig  Freiberg   and  divorced  his  first  wife.  By  this  time,  Koch’s daughter   Gertrude  had   married   Koch’s  research   associate   Eduard

Pfuhl. The romance between the eminent scientist and the young artist’s model raised a ‘‘moral storm’’ in the medical and scientific community. At the 1892 Congress of German  Physicians there was more excitement about  Koch’s escapades than  the scientific papers. Koch was almost 50 and Hedwig was 20 years old when they married  in 1893.

Frustrated by the skepticism  with which the medical community

viewed germ theory, Koch became convinced that finding reliable meth- ods of obtaining  pure cultures was the key to progress. The animal body might  well be the optimum  apparatus for cultivating  pathogenic  bac- teria, but bacteriologists  had to cultivate pure strains  outside  the body in order  to establish  the role of bacteria  in causing disease. Finding  it impossible  to  construct  a  universal  medium  suitable  for  all bacteria, Koch  sought  a method  that  would  convert  the  usual  nutrient  broths into  a  solid  form  on  which  bacterial  colonies  would  stand  out  like islands,  rather  like the colonies of mold  often  found  on old bread  or

Robert Koch and his second wife

Robert Koch and his second wife in Japanese  costume (1903).

potatoes. Ancient kitchen lore solved this problem when Koch substi- tuted agar-agar, a polysaccharide derived from seaweed that is used in Asian cooking, for gelatin. (Gelatin liquefies at normal body tem- perature, 37 C, and is digested by many bacteria; gels made with agar are inert to bacterial digestion and remain solid up to 45 C.) Use of agar gels to isolate bacterial colonies was called ‘‘Koch’s plate technique.’’ Koch argued that the pure culture was the essential foundation for work on infectious diseases. A special plate for use with agar cultures was invented by Richard Julius Petri (1852–1921), who worked at Koch’s Institute of Hygiene. Thanks to the universal adoption of the Petri dish, Petri’s name is generally more familiar to biology students than that of Robert Koch. Another technical problem addressed by Koch and his associates at the Imperial Health Office was a re-examination of various public health measures, such as disinfection. Microbiology made it pos- sible to understand the difference between disinfection (killing vegetative cells, but not necessarily all spores) and sterilization (completely killing both spores and vegetative cells). In testing the activity of reputed anti- septics, Koch discovered that many old favorites had virtually no disin- fecting powers, whereas other supposedly antiseptic agents inhibited the growth of bacteria but did not kill them. When Lister, Pasteur, and Koch met in London at the Seventh International Medical Congress in 1881, Koch enjoyed the opportunity to demonstrate his plate technique in Lister’s laboratory. Shortly after returning from this triumphant visit, Koch began his work on tubercu- losis. Committing all his energies to the task of identifying the causal agent of tuberculosis and finding a cure for this ubiquitous malady, Koch worked indefatigably in strict secrecy. In March 1882, at a meet- ing of the Berlin Physiological Society, Koch announced his discovery of the tubercle bacillus, Mycobacterium tuberculosis. News of Koch’s discovery caused great excitement throughout the world. British phy- sicist John Tyndall (1820–1893), one of Pasteur’s most dedicated sup- porters, published an English summary of Koch’s paper as a letter to the London Times. A few weeks later Tyndall’s letter was published in the New York Times. News reports and editorials immediately took up the theme that Koch’s discovery would soon lead to a cure for tuberculosis.

During the golden age of bacteriology, Koch reflected, the bac- terial agents of many infectious diseases seemed to fall into the hands of microbiologists ‘‘like ripe apples from a tree,’’ but the tubercle bacil- lus did not fall so easily. Of all the microbes studied by Koch, the tubercle bacillus was the most difficult to identify, isolate, and culture. On appropriate nutrient agar, most bacteria produce large colonies within two days; the tubercle bacillus took two weeks to form visible colonies. In these investigations, superb microbiological technique, special media and staining techniques, and appropriate experimental animals were indispensable. But so too were Koch’s conviction that tuberculosis was a contagious bacterial disease, strong faith that the causative agent could be isolated, and almost infinite patience. The dis- covery of the tubercle bacillus and Koch’s proof that it could be found in diseased tissue swept away the confusion that had so long thwarted efforts to understand tuberculosis in all its many forms. Because M. tuberculosis can attack virtually every part of the body, it produces a bewildering array of clinical patterns known as phthisis, consumption, scrofula, miliary tuberculosis, meningitis, and so forth. Identification of the tubercle bacillus proved that the various forms of tuberculosis were manifestations of the work of a specific pathogen. To understand the profound effect of Koch’s discovery requires an appreciation of the ways in which this disease permeated the fabric of life in the nineteenth century. Tuberculosis was, in terms of the number of victims claimed, more devastating than the most-dreaded epidemic diseases, including smallpox and cholera. Even in the seventeenth cen- tury, Richard Morton (1637–1698), author of Phthisiologia: A Treatise of Consumptions (1694), found it difficult to believe that anyone could reach adulthood without at least a touch of consumption. Well known as the ‘‘captain of the men of death,’’ in the nineteenth century tuberculosis was the cause of about one in seven deaths. Its devastating impact on society was amplified by the fact that tuberculosis was particularly likely to claim victims in their most productive adult years. The tragic deaths of young artists, writers, composers, and musicians supported the myth that tuberculosis was related to artistic genius. Robust artists com- plained that it was fashionable for poets to suffer from consumption and die before reaching the age of 30 years. The brief life of John Keats (1795–1821) reflects the romantic view of tuberculosis and the medical mismanagement that often accelerated the inevitable. Although the poet’s mother and brother had died of tuberculosis, his illness was mis- diagnosed as ‘‘gastric fever’’ and Keats was subjected to a debilitating regimen of bleeding and starvations diets. A definitive diagnosis of pul- monary tuberculosis was finally made at autopsy; the lungs were almost totally destroyed. Victims of most infectious diseases died or recovered too quickly to indulge in the deep, dark meditations of consumptive artists brooding on the slow, but inexorable, progress of their disease. To Austrian novelist Franz Kafka (1883–1924), tuberculosis was not an ordinary disease but the ‘‘germ of death itself.’’ In Romantic imagery, consump- tives were possessed by a nervous force that drove them to artistic accomplishments. However, with the disease running rampant in city slums and impoverished villages, the connection was obviously fortu- itous, not causal. Perhaps the threat of early death, the chronic mild fever, and the opiates taken to control coughing intensified the creative drive of consumptives who were artists and enhanced the allure of tubercular women. Only an ‘‘angel of phthisis’’ fit the Romantic ideal of femininity: young, pale, thin, with eyes bright from fever, discreetly coughing up blood into her lace handkerchief before her inevitable, but redemptive death. As Keats lamented: ‘‘Youth grows pale, and specter thin, and dies.’’ After Koch’s discovery of the tubercle bacillus, the perverted sen- timentalism associated with the disease was gradually superseded by acceptance of the fact that it was more intimately linked to poverty and filth than to genius and art. Worse yet, as Koch noted in his early papers on tuberculosis, the tubercle bacillus was very similar in form, size, and staining properties to the microbe that caused leprosy. Medical thinking about the cause and management of tuberculosis reflected peculiar regional differences. Consumptives from northern climates, seeking a cure in the south, were shocked to find themselves quite unwelcome in sunny Spain and Italy, where people assumed that tuberculosis was contagious. Physicians in northern Europe generally believed in a noncontagious, hereditary ‘‘tubercular diathesis’’ (which essentially means that people who are susceptible to tuberculosis are susceptible to tuberculosis). It was common knowledge that the disease ‘‘ran in families,’’ sometimes for several generations. Moreover, the fact that only certain individuals developed the disease, although almost everyone was exposed to it, was used to argue against contagion.

This is rather like saying that bullets do not kill, because not every soldier on the battlefield was killed by a barrage of bullets. Koch was not the first scientist to argue for the ‘‘unitary theory’’ of tubercular disease, nor even the first to demonstrate that consumption was contagious. William Budd (1811–1880), an English epidemiologist best known for his classic treatise on typhoid fever, argued that the epidemiology of tuberculosis among blacks in England and Africa indicated that it was a contagious disease. The distinguished French physician, Jean Antoine Villemin (1827–1892), attempted to demon- strate the contagiousness of tuberculosis by inoculating rabbits and guinea pigs with sputum and other materials from victims of tubercu- losis. The transmission of human tuberculosis to rabbits allowed Villemin to demonstrate the infectiousness of sputum, blood, and bron- chial secretions. He even argued that tuberculosis in humans was iden- tical to that occurring in cattle. However, Villemin’s work had little immediate impact and attempts by other physicians to repeat his experi- ments were inconclusive. Indeed, Rudolf Virchow argued that pulmo- nary tuberculosis and miliary tuberculosis were different diseases, although Rene´ Lae¨nnec (1781–1826), the inventor of the stethoscope, had shown that tuberculosis caused morbid effects throughout the body. In some individuals, tuberculosis infection resulted in the acute miliary pattern, whereas others exhibited the symptoms of pulmonary tuberculosis. Despite the brilliance of Virchow’s work in cellular pathology, his views on tuberculosis may have been distorted by nationalistic pride and prejudice. Just as Koch belittled French micro- biology, Virchow denigrated the combination of clinical observation and autopsy studies that characterized the work of Rene´ Lae¨nnec and French investigators of pathological anatomy. Of course, Virchow’s resistance was not entirely a matter of nationalism. Even after inspect- ing Koch’s demonstrations, Virchow continued to speak of the ‘‘so- called tubercle bacillus.’’ Having cultured a specific microbe apparently associated with tuberculosis in all its manifestations, Koch provided unequivocal evi- dence that B. tuberculosis was the specific cause of the disease. In doing so, Koch formalized the criteria now known as ‘‘Koch’s Postulates,’’ a series of steps that must be performed in order to prove that a particular microbial agent is the cause of a particular disease. In a general way, these criteria had been suggested previously by Jacob Henle and others, but Koch provided the most rigorous demonstrations of the germ theory of disease. To satisfy Koch’s postulates, the investigator must prove that a specific microorganism is invariably associated with the disease. Combining such observations with evidence that the microbe was not found in healthy individuals or in those suffering from other diseases was suggestive, but not compelling. To establish unequivocal proof, the investigator had to isolate and culture the microbe in the lab- oratory in order to separate it from contaminating tissue and other organisms. After the putative pathogen had been transferred through a series of cultures, it should be inoculated into healthy animals. If pure laboratory cultures induced the disease in experimental animals, the investigator should isolate the microbe from those animals in order to prove that a causal relationship existed between microbe and disease. For many human diseases, such as cholera, typhoid, and leprosy, it was impossible to satisfy Koch’s postulates, because scientists had not found any suitable experimental animal model. To provide unequivocal evidence in such cases would require unethical human experimentation. Koch’s postulates were formulated for studies of infectious disease, but his general approach has been extended to guide studies of other disorders, such as the health hazards posed by asbestos and other chemicals. Even though Koch’s discovery of the tubercle bacillus was not immediately followed by a preventive vaccine or specific therapeutic agent, it stimulated hope that conscientious patients might recover their health through appropriate medical guidance.

Nevertheless, Koch was under considerable pressure to match the achievements of his great French rival. In 1889, after devoting several years to his official duties and travels, Koch began to work in the laboratory again, with great intensity and complete secrecy as to the nature of the experiments that produced such large numbers of dead guinea pigs. One year later, at the Tenth International Congress of Medicine in Berlin, Koch seemingly implied that he had discovered a cure for tuberculosis. A close exami- nation of what Koch actually said should have prevented the excess of hope and the sense of betrayal that followed distorted newspaper accounts of his tentative assessment of the prospects for a cure. In his speech, Koch discussed a substance that arrested the growth of the tubercle bacillus in the test tube and in living bodies. The living bodies, however, were those of guinea pigs, not human beings. This was an important point, because guinea pigs do not acquire tuberculosis nat- urally, although they become infected when properly inoculated. Never- theless, Koch incautiously referred to the agent he had discovered as a remedy. Press reports immediately labeled the mysterious agent ‘‘Koch’s lymph,’’ ‘‘Kochin,’’ or ‘‘Koch’s fluid.’’ Koch called his preparation ‘‘tuberculin.’’ Based on Koch’s preliminary results in guinea pigs, large-scale human trials were obviously premature, but desperate con- sumptives were not willing to wait for controlled clinical tests to validate tuberculin’s promise. Despite the fact that Germany had a law prohibiting ‘‘secret medi- cines,’’ Koch refused to reveal the nature of tuberculin. He did, how- ever, provide the name and address of a doctor who was preparing tuberculin under the direction of Koch’s son-in-law, Eduard Pfuhl. As reported by Sir Arthur Conan Doyle (1859–1930), who came to Berlin to learn about the alleged German remedy, hundreds of thousands of consumptives were begging for treatment. Even Joseph Lister, who brought his niece to Berlin for treatment, had to wait a week before Koch had time to see him. Impressed by the work on tuberculin, as well as the new therapeutic methods for diphtheria and tetanus developed by Emil von Behring (1854–1917) and Shibasaburo Kitasato (1852–1931), Lister complained that German science was far ahead of British science. Within a year, thousands of people had received tuberculin treat- ment, but Koch’s associates had little or no interest in rigorous clinical trials. Tuberculin seemed to help some patients in the early stages of tuberculosis of the skin, bone, or joints, but physicians and patients were often misled by subjective signs of improvement induced by hope rather than specific therapeutic interventions. Unfortunately, in patients with pulmonary tuberculosis, further experience indicated that tuberculin was useless, or even dangerous. For example, Dr. Edward L. Trudeau (1848–1915) who directed an important tuberculosis sanatorium at Saranac Lake, New York, discovered that tuberculin did not provide the miraculous cures that he and his patients had anticipated. Through- out the world, disappointed and disillusioned patients and physicians bitterly condemned Koch and his secret remedy. A study prepared for the German government found remarkably little evidence to justify the claims made for tuberculin.

Nevertheless, anecdotal reports of cures and improvements led government officials to continue support for tuberculin, which was used in prisons and in the army. When Koch finally described the nature and preparation of his remedy, scientists and physicians were surprised to learn that tuberculin was simply a glycerin extract of tubercle bacilli. Critics cynically noted that Koch had revealed the great secret after it had become obvious that tuberculin was worthless. In his own defense, Koch argued that prepar- ing tuberculin was very difficult. Therefore, he had been afraid that doc- tors and quacks all around the world would attempt to prepare and inoculate harmful imitations, causing great damage to patients and to the reputation of German science. As condemnation mounted, Koch undertook a visit to Egypt, leaving his son-in-law in charge of tuberculin and the Institute for Infectious Diseases. After 1896, Koch essentially gave up research on tuberculosis and tuberculin. Turning to the study of tropical diseases, Koch finally realized his old dreams of traveling to exotic locations. Despite his pioneering role in the history of medical microbiology, it was not until 1905 that Koch was awarded a Nobel Prize for his work on tuberculosis and bacteriology. Experience with a wide variety of diseases led Koch to the con- clusion that it was probably impossible to achieve immunity to tubercu- losis by the methods successfully used for other bacterial diseases. Nevertheless, Koch never completely gave up hope that an improved form of tuberculin would serve as an immunizing agent or cure. This dream was never realized, but at least the medical community could agree that tuberculin was a valuable diagnostic aid in the detection of early, asymptomatic tuberculosis. In the heroic tradition of the time, Koch had tested tuberculin on himself. His strong reaction indicated that, like most of his contemporaries, he had not escaped a ‘‘touch of tuberculosis.’’ What Koch had actually stumbled upon was the complex immunological phenomenon later called delayed-type hypersensitivity. Where tuberculosis was considered a shameful disease, an obstacle to marriage, or a condition excluded from life insurance policies, many individuals and their families might not find an accurate diagnosis particularly desirable. Tuberculin was not a cure, but the discovery of the tubercle bacil- lus and tuberculin provided the basic weaponry for a crusade against tuberculosis. The tuberculin test could detect asymptomatic cases of tuberculosis, and microbiology laboratories could help the physician monitor the patient’s status by analyzing throat cultures or sputum samples. The need for caution and for critical clinical trials should have been a major part of the lessons taught by the tuberculin fiasco. Wide- spread support for abandoning the whole apparatus of double-blind clinical trials in the search for AIDS remedies one hundred years later suggests that such lessons are quickly forgotten. AIDS in the 1980s, like tuberculosis in the 1880s, was perceived as a mysterious, dreaded, shameful, and fatal illness. Withholding a drug that might cure, or at least slow, the progress of a fatal illness is, doubtless, a cruel and unethical act. The history of phantom remedies indicates that it is more difficult to come to grips with the pressures that lead to dispensing ineffectual drugs and unjustified optimism when treating a disease with as complex and uncertain a natural history as AIDS or tuberculosis. Expressing the despair caused by tuberculosis, the British writer Charles Dickens (1812–1870) characterized consumption as the disease that medicine never cured and wealth never warded off. Nevertheless, tuberculosis morbidity and mortality rates declined significantly well before the advent of specific antibiotic therapy. Progress in controlling tuberculosis was gradually achieved, as physicians and public health workers assimilated the idea that it was a preventable disease and began to think in terms of a complex web of causation. Detecting early cases and accurately measuring the incidence of infection were made possible by the development of more sensitive tuberculin skin tests and X-ray examinations of the lungs. Even though the tubercle bacillus remained ubiquitous, the incidence of sickness declined with changes in living standards, as more people gained access to fresh air, sunlight, and improved nutrition. Scientists suggested that with biological wisdom directing social and individual behavior, the disease could be eradicated without vaccines. However, medical and public health authorities have rarely reached a workable consensus as to the nature of ‘‘biological wisdom.’’ According to surveys conducted during the 1920s and 1930s, tuberculin skin tests indicated that 50 to 60 percent of undergraduates in northeastern colleges and about 80 percent of students in the south- west were infected. Medical and nursing students had even higher rates of infection. Some schools reported that by graduation all the students were tuberculin positive. At the same time, tuberculosis was declining in the general population.

Because tuberculosis was associated with pov- erty, these findings among the relatively privileged college population were disconcerting. Women’s colleges, in particular, made the preser- vation of student health a top priority. This was essential to counteract the medical warnings about how detrimental education was to female health and development. When marked variations in the virulence of different varieties of tubercle bacilli were discovered, scientists hoped that a particular strain could play the role cowpox served in preventing smallpox. However, evaluating tuberculosis vaccines is very difficult; in some areas, almost everyone has been exposed to the bacillus and many have long-standing, but dormant, infections. The tubercle bacillus can remain dormant in the human host for many years. It effectively evades immune attack and protects itself with a thick coat of complex lipids. The most widely used vaccine against tuberculosis is derived from the live, attenuated strain produced by Albert Le´on Charles Calmette (1863–1933) and co-workers. Since the 1920s, Bacille Calmette-Gue´rin (BCG) has been used as a vaccine against childhood tuberculosis. Despite recurring questions about the safety and efficacy of BCG, preventive vaccination remains the basis of antituberculosis efforts in many developing nations. Recognition of the danger posed by contaminated milk played an important part in efforts to control tuberculosis. Some scientists thought that tuberculosis originated in domesticated cattle and had been transmitted to humans through milk and meat, but the relation- ship between human and bovine tuberculosis became very controversial. In 1901, at the First British Congress of Tuberculosis in London, Koch announced that bovine and human tuberculosis were two distinct dis- eases. Counter to prevailing opinion at the time, Koch declared that humans could not be infected with the bovine tubercle bacillus. This announcement was stunning, not just because it was absolutely wrong, but because in his early work on tuberculosis Koch had said that bovine and human tuberculosis were caused by the same microbe. If true, Koch’s new ideas about bovine tuberculosis had tremendous public health implications. Bacteriologists, therefore, rushed to confirm or dis- prove his proclamation. A British Commission reached the conclusion that bovine tuberculosis was a public health menace, but a German Commission agreed with Koch. Emil von Behring (1854–1917), however, argued that contaminated milk was the major source of in- fection for children. This view was confirmed by American bacte- riologist Theobald Smith (1859–1934). Children between the ages of one and five years of age were particularly susceptible to infection from the ‘‘pale cultures of tuberculosis’’ sold as milk. Smith, therefore, campaigned for the destruction of tuberculous dairy cattle as a neces- sary public health measure. Veterinarians and public health workers tended to emphasize the dangers of bovine tuberculosis to human health. Koch was criticized for his emphasis on pulmonary tuberculosis and his suggestion that bovine tuberculosis was an insignificant issue. American pediatrician Abraham Jacobi said: ‘‘The lives of the thousands of babies in the world are far more important than the reputation of one scientist.’’ Although the vast majority of deaths from tuberculosis were the result of active pulmonary tuberculosis, about 10 percent of the deaths of infants and young children in urban America could be blamed on diseases trans- mitted by milk. Theobald Smith argued that ‘‘the whole machinery of public health’’ was at risk if the battle against contaminated milk and water was undermined by Koch and others. While pursuing his early work under primitive and difficult con- ditions, Koch had been a patient and conscientious worker. After achieving his greatest victories, he seems to have become increasingly opinionated, arrogant, and dogmatic. Many critics pointed to the militaristic and authoritarian environment of German science as a fac- tor. Perhaps even Koch fell victim to the Koch mythology and was swept away by official and public adulation and pressure. When a scien- tist of Koch’s standing was wrong, his oracular pronouncements could endanger the public health. In 1908, the major issue of contention at the International Tuberculosis Congress was the problem of bovine tuberculosis. To the delight of America’s ‘‘anti-pasteurizers,’’ Koch focused on pulmonary tuberculosis. According to Koch, the question of the intestinal infection of children was essentially irrelevant, because pulmonary tuberculosis accounted for 11 out of every 12 deaths from tuberculosis. Whatever the mortality and morbidity rates for the various forms of tuberculosis might have been, ignoring preventable infections caused by contam- inated dairy products revealed a very strange approach to childhood ill- ness. Critics contended that Koch had taken this position to shield the German government and the German meat industry.

When Koch returned to Berlin after the bitter 1908 meeting, he tried to resume his research on tuberculosis, but his health deteriorated rapidly and he died of a heart attack in 1910. Two years later, the Institute for Infectious Diseases was renamed the Robert Koch Institute. Since the time of Hippocrates, consumptives have been subjected to bizarre diets, noxious remedies, and a soothing elixir of ‘‘opium and lies.’’ Probably, the most colorful cure was the ritual of the Royal Touch, performed by kings of England and France from the Middle Ages to the eighteenth century. Because the scrofulous wretches selected for the ceremony received a coin as a souvenir, records of the alms dis- bursed during such rituals provide estimates of the number of touches. Perhaps a few skeptics like Michael Servetus (1511–1553) could see that many were touched and few were cured, but because of the unpredict- able nature of the disease, the Royal Touch might have worked as well as any other remedy. Depending on the shifting tides of medical fashion, physicians have prescribed rest, exercise, starvation diets, rich foods, fresh air, sunshine, tonics, and tranquilizers for their consumptive patients. Many standard remedies were useless, and some, like gold salts, actually exacerbated the illness. Folk remedies for phthisis included wolf’s liver boiled in wine, weasel blood, pigeon dung, and essence of skunk. Eating live snails was said to prevent the disease. Twentieth-century physicians prescribed creosote, digitalis, opium, cod-liver oil, heavy metals, gold salts, and Fowler’s solution (a tonic rich in arsenic). Public and private agencies established tuberculosis dispensaries and sanatoriums. Some physicians prescribed mountain air, hiking, horseback riding, and carefully gradu- ated work programs, whereas others warned that exercise placed too much stress on the lungs. Complete rest for the afflicted lung was pro- duced by artificial pneumothorax or ‘‘collapse therapy.’’ Collapsing the lung by injecting air into the pleural cavity was supposed to rest a tuberculous lung and allow it to heal. Artificial pneumothorax, which had been demonstrated in the 1890s, was widely practiced in the 1930s and 1940s. Injections were repeated at regular intervals until the lung healed or the patient died. During the early decades of the twentieth century, tuberculosis remained the ‘‘captain of the men of death.’’ The work of Koch and the scientific hygiene movement made it possible to believe that tubercu- losis could be controlled, perhaps ultimately eradicated, by new medical techniques, institutions, administrative structures, and the authority of the state. However, twentieth-century campaigns against the disease emphasized individual responsibility while neglecting the deep-seated social and economic problems that forged close links between poverty and tuberculosis. Many physicians ignored the implications of Koch’s work and minimized the role of the microbe and the contagiousness of the disease. Old ideas about the hereditary nature of the disease, or an innate predisposition, were not abandoned. The social and environ- mental factors responsible for the association between poverty and tuberculosis, such as malnutrition, crowding, lack of fresh air and sun- light, were neglected. Victims of the disease were isolated, shunned, and confined in sanatoriums in a manner reminiscent of the medieval leper. The romantic notion of the tuberculosis sanatorium as a peaceful place on a ‘‘Magic Mountain’’ that offered rest, sunshine, nourishing food, and a healing atmosphere has been largely dispelled by further studies of the suffering endured by patients who experienced the iso- lation, rigidity, and degradation characteristic of many of these insti- tutions. In the nineteenth and twentieth centuries, the sanatorium regimen evolved from a benign program of fresh air and rest to more rigid and medicalized programs involving strict prescriptions of gradu- ated work, drug trials, and surgery. The criteria used to measure success were remarkably low, as indicated by claims of success for gold salts in which nine out of 42 patients died.

Many patients were subjected to artificial pneumothorax, although, in some institutions, the mortality rate for this operation was about 50 percent. The analysis of such disappointing results convinced many investigators that it was impos- sible to find a specific chemotherapeutic agent for a disease as intract- able and unpredictable as tuberculosis. For complex reasons that are still the subject of heated debate, by the time effective antibiotics were available, tuberculosis, the ‘‘white plague,’’ was already subsiding. All detailed studies of tuberculosis reveal that a significant decrease in tuberculosis mortality occurred before the introduction of specific antibiotic therapy in 1947. As in the case of leprosy, the history of tuberculosis, when considered in a broad social and global context, reminds us that the pattern of human suffering and death associated with a specific disease cannot be reduced to a description of its microbial agent. The tubercle bacillus did not, however, disappear. Epidemiologists at the Fourth World Congress on tuberculosis (2002) warned that about two billion people were infected with tubercu- losis and that the disease killed about two million people a year. About one thousand cases of tuberculosis were reported in New York City in 2002, but about 5 to 10 percent of New Yorkers tested positive for exposure to the disease. The machinery for dealing with tuberculosis had been essentially dismantled by the time tuberculosis became asso- ciated with AIDS and drug-resistant strains became common. Drug- resistant tuberculosis outbreaks were reported in the 1980s in New York City prisons and shelters. By 1991, 20 percent of those diagnosed with tuberculosis in New York City were resistant to the antibiotics commonly used to treat the disease (rifampin and isoniazid). Case fatality rates for drug-resistant tuberculosis were as high as 40 to 60 percent, which is essentially the same as that for untreated drug-susceptible tuberculosis. Epidemiologists estimated that, on a global basis, about three hundred thousand new cases of drug-resistant tuberculosis oc- curred each year, but reliable data were lacking for many poor countries with high rates of HIV/AIDS. Drug-resistant cases are more common in countries where patients have received inadequate treatment, a situation that favors the development of drug-resistant strains. In some countries, tuberculosis drugs are sold over the counter and often misused. The successful introduction of penicillin during World War II led to hope that other antibiotic agents would be effective against tubercu- losis. Unfortunately, drugs that were effective against experimental tuberculosis in laboratory animals were not necessarily useful in the treatment of the disease in humans. Reports that streptomycin, an anti- biotic discovered by Selman A. Waksman (1888–1973) in 1943, was effective against tuberculosis in guinea pigs were soon followed by evidence of its efficacy in humans. The early, impure preparations of streptomycin, however, caused serious side effects, including deafness. In some trials, only 51 percent of the treated patients improved after six months of treatment. Eventually, para-aminosalicylic acid, isoniazid, rifampin, and other drugs were added to the antituberculosis arsenal. Alone and in various combinations, these chemotherapeutic agents transformed the management and treatment of tuberculosis patients and virtually emptied the sanatoriums. Efforts to evaluate the contri- bution antibiotics made to the decrease in the mortality rate for tubercu- losis are complicated by the fact that BCG vaccine was widely adopted shortly before the introduction of streptomycin. From the public health standpoint, even a partial course of treat- ment is useful in arresting an active tuberculosis infection and breaking the chain of transmission.

A complete cure may, however, take many months. As in the case of leprosy, the long course of treatment is costly and creates ideal conditions for the proliferation of drug-resistant bac- teria. Although tubercle bacilli grow slowly, they are remarkably persistent; bacilli have been cultured from surgical and autopsy specimens immersed in formalin solutions for many years. With proper treatment, however, the disease was entirely curable. By the 1960s, glob- al eradication of tuberculosis was regarded as well within the technical possibilities of medical science. Nevertheless, for complex socioeco- nomic and political reasons, in the 1980s epidemiologists acknowledged that eradication was a very remote possibility. In the United States, for example, public health authorities detected localized increases in the incidence of tuberculosis in areas marked by poverty and HIV/AIDS. Drug-resistant tuberculosis, often associated with AIDS, highlights the vast chasm between what medical science and public health pro- grams expected to achieve and the heavy toll taken by old and new epidemic diseases. By the end of the nineteenth century, microbiology was a well- established discipline that had sprouted several specialized branches. Textbooks, journals, institutes, and courses in microbiology multiplied almost as rapidly as bacteria. In 1879, Pasteur’s associate E´ mile Duclaux (1840–1904) established a course in microbiology at the Sorbonne. Koch introduced a course in medical microbiology at the University of Berlin in 1884. By the 1890s, even American medical schools and agricultural colleges were beginning to include bacteriology in their curricula. Medical microbiology was an important stimulus for the emerging acceptance of the laboratory-based curriculum that the 1910 Flexner Report on medical education in the United States and Canada presented as an absolute necessity. While most physicians and surgeons learned to reconcile medical practice with the germ theory of disease, some continued to challenge germ theory well into the twentieth century. For example, Charles Creighton (1847–1927), British pathologist, epidemiologist, medical historian, and anti-Jennerian, argued that miasmata, climatological disturbances, and soil poisons were the most significant factors in the generation of epidemics. Although Creighton acknowledged the fact that bacteria were associated with some diseases, he did not accept them as causal agents. Many of those who rejected germ theory were actively involved in sanitary or hygienic reform movements, which had signifi- cant successes in improving the health of cities. In practice, an all-out attack on filth, contamination, and pollution may be even more effective in the long-range control of epidemic and endemic diseases than an attack on specific pathogens, because of the general improvements in hygienic conditions. The indomitable Max von Pettenkofer (1818–1901), a man who had little sympathy for the germ theory of disease, established the first Institute of Hygiene. After seriously considering a career in acting, Pettenkofer decided to study physiology, chemistry, and medicine. In 1843, he was awarded his medical degree at Munich. Four years later, he was appointed professor of medicinal chemistry, but in 1878, in honor of his pioneering work on hygiene and epidemiology he became Munich’s first professor of hygiene. Pettenkofer believed that the science of hygiene would reveal the origin of infectious diseases and the most effective means of preventing them. His approach to medicine was sani- tarian or what would now be called environmental medicine. Rejecting the major conclusions drawn by Pasteur, Koch, and other germ hunters, Pettenkofer continued to argue that poisonous miasmata, soil conditions, and climatological disturbances were pri- marily responsible for the generation and dissemination of disease. For example, while minimizing the discovery of the microbe that causes cholera, Pettenkofer developed his own ‘‘ground-water theory’’ of the development of cholera-producing miasmata. On the basis of this theory, he led a very successful campaign for the improvement of Munich’s sewage systems. As a consequence of these sanitary reforms, Munich enjoyed a significant reduction in the burden of intestinal dis- eases.

Challenging Koch’s claim that the causal agent of cholera was the so-called comma bacillus or cholera vibrio, in 1892, in the presence of unimpeachable witnesses, Pettenkofer swallowed a broth culture of cholera vibrios. Later, Pettenkofer confessed that he had experienced some intestinal discomfort, but he refused to diagnose this as cholera. Improvements in water systems and sewers undertaken in response to cholera also diminished the threat of other water-borne diseases, such as typhoid fever. William Budd (1811–1880), author of the classic Typhoid Fever; Its Nature, Mode of Spreading, and Prevention (1873), demonstrated that water contaminated by the excrements of typhoid fever patients transmitted the disease from household to household. Vic- tims of the disease may suffer from fever, rash, headaches, bloating, diarrhea, stupor, delirium, coma, or peritonitis and gastrointestinal hemorrhages. After Salmonella typhi was discovered in the 1880s, Robert Koch proposed practical means of preventing the spread of the disease. The isolation of ‘‘healthy carriers’’ became one of the most controversial aspects of the public health battle against enteric fevers. Mary Mallon (1870?–1938), the woman who became known as ‘‘Typhoid Mary,’’ has been called an icon of public health history. Mallon was an Irish immigrant who supported herself as a cook. Unfortunately, she was also an asymptomatic carrier of S. typhi. Her cooking led to the infection of 47 people and caused three deaths. Pub- lic health authorities were particularly concerned about the role of food-handlers in the transmission of disease. Some typhoid outbreaks were traced to carriers working at dairy farms, a discovery that added to demands for the pasteurization of milk. Mallon was identified as a carrier in 1907, after her employers became ill. New York City public health officials had her confined, but she was released in 1910 and warned against working as a cook. After a typhoid outbreak in 1915, officials discovered Mallon working as a cook at Sloane Maternity Hospital. She was confined again to North Brother Island where she died in 1938. Social historians have attributed Mallon’s draconian treatment to gender, ethnicity, and class, rather than her bacteriological status. Asiatic cholera was apparently unknown to Europeans until the nineteenth century when it escaped its ancestral home in India. European trade, commerce, travel, and military incursions presumably broke down regional barriers that had previously confined cholera to limited areas of India. The disease spread westward, becoming endemic in new areas, and generating major pandemics. Cholera was present in 75 countries and on all continents at the beginning of the twenty-first century. Compared with pandemics of bubonic plague or influenza, cholera generally traveled slowly along major trade routes, until railroads and steamboats expedited the movements of goods, armies, and microbes. Although in terms of total mortality cholera was much less significant than tuberculosis and malaria, cholera became the most feared epidemic disease of the nineteenth century. The terror provoked by cholera played a major role in forcing many cities to deal with water purity and other fundamental public health projects. The onset of symptoms was often sudden and violent, although some patients initially noticed intestinal discomfort, dizziness, and lassi- tude. Many cases began with severe vomiting and diarrhea, thirst, pain- ful cramps, and so forth. The catastrophic loss of body fluids led to the characteristic ‘‘rice water stools’’ that reflected loss of bits of the intes- tinal lining. In a matter of hours, healthy adults could become as desic- cated as ancient mummies. Debilitated survivors experienced muscle cramps, chills or fever, and profound weakness. By the beginning of the twentieth century, Western Europe was essentially free of the disease, but cholera remained a serious public health problem in Russia, the Middle East, Africa, and Asia. Since World War I, cholera outbreaks in the most impoverished areas of the world have claimed the lives of 50 to 60 percent of its victims. Death occurs primarily from dehydration and its complications. Where intra- venous infusion of liquids can be arranged, almost all patients recover, but treatment requires fairly sophisticated medical resources. Victims of severe dehydration cannot ordinarily be restored to normal by means of liquids taken by mouth, because water cannot be absorbed quickly enough to make up for such profound losses. However, where intravenous infusion is not available, oral administration of appropriate solutions of salts and glucose can reduce the mortality rate to about 5 percent. This simple and effective form of treatment provides a remarkable contrast to the methods advocated by many nineteenth-century physicians. With estimates of mortality rates ranging from 30 percent to 80 percent, it is likely that many less serious diarrheal diseases were misdiagnosed as cholera and gave rise to miraculous ‘‘cures.’’ Many doctors urged early and vigorous interventions at the first signs of intes- tinal disturbance. Treatments included bleeding, calomel, opium, laudanum, brandy, naphtha, valerian, phosphorous, and magnesium carbonate or castor oil as gentle laxatives. Warm baths, hot blankets, mustard and linseed poultices, bags of hot salt and bran, and friction and counter-irritants applied to the skin were thought to fight circula- tory collapse and debility. Some doctors favored immersion in ice water, tobacco smoke enemas, and intravenous injections of salt water. Many patients rejected orthodox medicine and turned to Thomsonian herbal remedies, patent medicines, water cure doctors, and homeopaths. Hos- pital doctors who applied the ‘‘numerical method,’’ that is, a statistical analysis of different treatments, began to realize the futility of their rem- edies. Faced with the threat of cholera outbreaks, public health officials warned that only common sense, fresh air, and personal and public cleanliness could ward off the disaster. In some cites, the threat of chol- era provoked such unprecedented fits of cleanliness that residents discov- ered cobblestones emerging from traditionally filth-covered streets. Physicians and public health officials engaged in endless debates about the nature and transmission of cholera. Florence Nightingale (1820–1910) argued that experience in India, where cholera was en- demic, proved that the disease was not communicable from person to person. Doctors who examined the sick or performed autopsies rarely contracted the disease, because they washed their hands afterwards and did not eat in the sickroom. In impoverished households, all mem- bers of the family might have to eat in the sickroom and had little opportunity to wash. The classic epidemiological study of cholera was conducted by the British physician John Snow (1813–1858). Snow argued that the cholera ‘‘poison’’ must be introduced into the alimentary canal via the mouth in food, water, and on contaminated fingers. Direct contact between the sick and new victims was not required, because the disease was trans- mitted by water contaminated with cholera ‘‘evacuations.’’ Some aspects of the story of John Snow and the 1854 Broad Street cholera outbreak have assumed a mythic status in the history of public health, epidemiology, cartography, and medical geography. Snow published his theory that cholera was transmitted through contaminated drinking water in 1849 in a work entitled On the Mode of Communication of Chol- era. A second edition of the book published in 1855 included new inves- tigations and evidence. The discovery of the cholera vibrio is generally associated with Robert Koch and his coworkers in the 1880s, although earlier studies had been carried out by the Italian histologist Filippo Pacini (1812– 1883). Bacteriologists found the cholera vibrio in dirty linens and in water used for drinking, bathing, and washing clothes. After Koch isolated the cholera vibrio, Elie Mechnikoff confidently predicted that ‘‘the fight against cholera will soon result in relegating this disease to the archives of history.’’ Unfortunately, Mechnikoff was too optimistic. The sanitary reforms pioneered in Europe and America have essen- tially precluded the possibility of major, sustained epidemics of cholera in the wealthy, industrialized nations. Cholera has not disappeared; it is only kept in check by modern sanitary control of water and sewage. Sporadic cases have appeared along the Gulf Coast in Texas and Louisiana, but because Americans have become so unfamiliar with cholera, the disease may be mistakenly diagnosed as food poisoning. There are many different strains of cholera vibrios and confusion about the virulence of different strains. Cholera vibrios persist in oceans and brackish water, where they are widely associated with shellfish, crustaceans, and zooplankton. Cholera vibrios have been found in the raw sewage of various towns in Louisiana, and cases of cholera have been traced to the ingestion of raw oysters and steamed crabs. Global climate change might affect the distribution of the cholera vibrio. Changes in ocean temperature affect various blooms of plankton, and blooms precede cholera outbreaks. Cholera remains a danger in many parts of the world. The true extent of the problem is probably unknown because governments prefer to list deaths from cholera as food poisoning, gastroenteritis, intestinal flu, or other euphemisms for ‘‘diarrheal diseases.’’ In the 1990s, signifi- cant outbreaks occurred in South America, primarily in poor, rural areas in Peru. Some cases, however, were associated with foods served in air- planes, proving again that any disease anywhere is just a plane ride away from any other point on the globe. Despite detailed scientific knowledge about the cholera vibrio, its genome, and its toxin, at the end of the twentieth century the disease remained a threat to hundreds of thousands of people in the developing world. As many as three hundred thousand people in developing countries contract cholera every year. In 2002, scientists discovered that cholera vibrios appear to become more infectious as they pass through the human intestinal tract, which complicates attempts to develop a vaccine based on laboratory cultures. Cholera bacteria isolated from the stool of patients in Bangladesh after an epidemic were 10 to 100 times more infectious than laboratory strains when injected into mice. Despite chlorination, the water available in many of the world’s overpopulated cities is probably worse than that studied by John Snow. Microbial contaminants found in water samples taken in Karachi, the capital of Pakistan, in 2004, for example, included campylobacter, E. coli, shigella, giardia, rotovirus, hepatitis A, and hepatitis E. In the 1950s, the population of Karachi was about 435,000; in 2002 there were about 14 million residents. If Pettenkofer could have investigated the status of water-borne diseases in much of the world today, he would claim vindication of the sanitarian doctrine that contamination, poverty, and the lack of hygienic conditions were the most significant factors in generating and disseminating epidemic disease. Nevertheless, despite the ostensible con- flict between Pettenkofer’s miasmatic theory and Koch’s germ theory, both physicians were dedicated to the idea that the scientific study of hygiene would have a great and beneficial impact on the battle against infectious diseases. However, it was the work of Pasteur, Koch, and their disciples, grounded in microbiology, or the ‘‘gospel of the germ’’ that generated interest in public and private hygiene and sanitary reform. Some historians have argued that germ theory and medical microbiology deflected attention from the real socioeconomic roots of disease and reinforced industrial capitalism, racism, and moralistic vic- tim blaming. Certainly, poverty, overcrowding, poor sanitation, and lack of access to medical care are associated with the public and private burden of disease. Microbiologists and epidemiologists note, however, that specific microbes are still necessary factors in the development of specific diseases.

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