Microbe hunting was not uncommon in the ﬁrst-half of the nineteenth century, and Louis Pasteur (1822–1895) was not the ﬁrst to argue that infectious diseases were caused by germs, but his work was of paramount importance in demonstrating the relevance of germ theory to infectious disease, surgery, hospital management, agriculture, and indus- try. Pasteur’s work illuminated many areas of the nineteenth-century science, including stereochemistry, fermentation, biogenesis, the germ theory of disease, immunology, virology, disinfection, sterilization, and the preparation of protective vaccines. Generally, Pasteur and his associates were involved in several research problems simultaneously. The interaction between Pasteur’s many interests makes it impossible to discuss his work as an orderly chronological progression, but this complexity reﬂects his belief that ‘‘the sciences gain by mutual support.’’ His career can also serve as a case study for the interplay between researches devoted to practical problems and so-called pure or basic scientiﬁc knowledge.
As a youth, Pasteur was a diligent student and talented artist, but his high school work in chemistry was rated only mediocre. (Stories about such ludicrous errors in judgment by teachers of the gifted and talented seem to be a required part of the hagiography of great scien- tists, perhaps to give hope to underachieving students and to make teachers more humble.) Pasteur’s ﬁrst attempt at student life in Paris in 1838 led to homesickness so acute that he had to return to his family. Portrait painting during this period seemed to provide a form of therapy and the energy to return to his studies. Eventually, Pasteur decided to abandon art in order to devote all his energies to science. He went on to study chemistry and physics with distinction, but the most important
lesson he learned from his studies at the prestigious E´ cole Normale
Supe´rieure of Paris was a willingness to apply the experimental ap- proaches he had learned in chemistry to a broad range of problems in biology and medicine, areas in which he had no speciﬁc training.
The research problems and methods that Pasteur assimilated as a doctoral student led to studies of many different problems. Nine speciﬁc
Louis Pasteur studying rabies.
aspects of his work were carved into the marble walls of the chapel at the Pasteur Institute in Paris where he was buried: molecular dissym- metry, fermentations, studies of so-called spontaneous generation, stud- ies of wine, diseases of silkworms, studies of beer, contagious diseases, protective vaccines, and the prevention of rabies. Although Pasteur was actually more interested in broad philosophical questions and basic scientiﬁc issues than speciﬁc medical problems, in terms of the history of medicine, he is primarily remembered for the practical aspects of his work that are most directly related to understanding and preventing infectious diseases.
Studies of crystal structure, stereoisomerism, and molecular dis-
symmetry seem remote from medical microbiology, but this work
provided the unifying thread that guided Pasteur through the labyrinth of research. Pasteur discovered that certain organic molecules could exist as mirror images, that is, as right-handed and left-handed versions, rather like gloves or mittens. As Pasteur pursued this remarkable trait from the behavior of crystals to that of microorganisms, he came to see molecular dissymmetry as a fundamental criterion that distinguished the chemical processes of vital phenomena from those of the inanimate world.
Among the aphorisms of Louis Pasteur, the most quoted have to do with the importance of theory and the role of chance in discovery. He insisted that the theoretical was as important as the practical, although he accepted the idea that, for the good of the state, scientiﬁc education should be made relevant to industrial and commercial needs.
‘‘Without theory,’’ Pasteur argued, ‘‘practice is but routine born of habit.’’ When asked the use of a purely scientiﬁc discovery, Pasteur liked to pose the question: ‘‘What is the use of a newborn child?’’ By chance, Pasteur discovered that mold growing in solutions of certain organic chemicals fermented the right-handed form but not the mirror image. In keeping with his conviction that ‘‘in the ﬁeld of observation, chance favors only the mind that is prepared,’’ Pasteur followed the impli- cations of this observation on to fundamental studies of the role of microorganisms in fermentation.
When Pasteur was appointed Professor of Chemistry and Dean
of Sciences at the University of Lille, he was urged to assist local indus- tries. Applying the methodology he had used in his studies of crystals to fermenting vats of beet juice, Pasteur observed microorganisms and optically active products of fermentation. His stereochemical studies led him to the hypothesis that the fermentation process was dependent on living germs or ferments. Previous speculations about the role of yeasts in fermentation had been ridiculed by Justus von Liebig (1803–1873), Jo¨ ns Jacob Berzelius (1779–1848), and Friedrich Wo¨ hler (1800–1882), the most illustrious organic chemists of the period, who argued that fermentation was a purely chemical process and that microorganisms were the product rather than the cause of fermentation. Although today Pasteur is universally known, Liebig has been called the greatest organic chemist of the nineteenth century. Like Pasteur, Liebig was known for his combative personality, quarrelsome nature, pro- ductivity, and his ability to pursue many projects simultaneously.
Further experiments on a variety of fermentations led Pasteur to
the conclusion that all fermentations are caused by speciﬁc, organized ferments. Changes in environment, temperature, acidity, composition of the medium, and various poisons affected different ferments in par- ticular ways. Moreover, Pasteur suggested that living ferments might be the cause of infectious diseases as well as fermentation. Although Joseph Lister’s work on the antiseptic system of surgery owed a great
deal to Pasteur’s fermentation studies, most physicians rejected the idea that the diseases of wine and beer were related to human disease. Never- theless, Pasteur’s fermentation studies made it possible to improve the production of wine, beer, vinegar, and so forth. Establishing controlled conditions for fermentation, partial sterilization (pasteurization), and the preparation of pure inocula were developments that were immedi- ately applicable to many industrial problems of substantial economic importance.
Studies of fermentation led Pasteur to a declaration of war on the ancient doctrine of spontaneous generation. Friends warned him against being drawn into a contest that could not be won, for one can- not prove a universal negative. That is, one cannot prove that spon- taneous generation never occurred, never occurs, or never will occur. Certainly, Pasteur did not enter the battle with an open mind. Although his private notebooks reveal that he was fascinated by the doctrine, in public he was passionately dedicated to destroying advocates of the doctrine of spontaneous generation and their allies in the medical pro- fession. Building on an experimental approach that can be traced back to Francesco Redi’s (1626–1698) studies of the alleged spontaneous generation of ﬂies in rotting meat, Pasteur set out to prove that microbes do not spontaneously arise in properly sterilized media and that all the so-called evidence in support of the contrary proposition was the result of careless technique and experimental artifacts.
Philosophical arguments about the origin of life, materialism and
atheism, or religion and spiritualism were irrelevant to the daily con- cerns of wine-makers and surgeons. The practical point established in the context of the spontaneous generation controversy was that, under present conditions, fermentation, putrefaction, infection, and epidemic diseases were caused by speciﬁc microbes found in the air and on sur- faces, including instruments, bandages, sponges, and the hands of the surgeon. The germ-carrying capacity of air could be measured by suck- ing air through cotton ﬁlters to trap the germ-laden dust particles. The numbers and kinds of germs in the air depended on many environmen- tal factors; for example, the germ content of hospital air was quite high compared with that of mountain air.
One of Pasteur’s simplest and most convincing experiments involved the use of specially constructed swan-neck ﬂasks. When liquids were properly sterilized in ﬂasks with long necks drawn out into an S-shaped curve under a ﬂame, the medium remained sterile even though ordinary air could enter the ﬂask. Critics could not argue that some mysterious life force had been tortured out of the medium, because if the ﬂask was tipped so that sterile medium mixed with the germ-laden dust particles trapped in the bend of the swan neck, the medium was soon teeming with microbial life. Although almost all kinds of media could be sterilized by fairly simple means, certain apparent exceptions
were eventually traced to the existence of heat-resistant spores that gave rise to microbes under appropriate conditions. Convinced that a revo- lution in medicine would only become possible when the defenders of spontaneous generation were totally defeated, Pasteur and his disciples created the sterile techniques that made modern microbiology and sur- gery possible. Despite the apparent futility of jousting with the advo- cates of spontaneous generation, Pasteur warned that the development of rational methods for the prevention and treatment of disease depended on annihilating the erroneous doctrine of spontaneous generation.
Well aware of the skepticism with which the conservative medical
profession regarded his theories, Pasteur was apparently reluctant to begin a direct assault on the diseases of higher animals. However, in
1865, at the request of his friend Jean Baptiste Dumas (1800–1884) and the Minister of Agriculture, Pasteur became involved in studies of silkworm diseases. By 1870, Pasteur had demonstrated the existence of two microbial diseases in silkworms. The condition that was threat- ening the silkworm industry of France, however, was the result of com- plex interactions among environmental factors, nutritional deﬁciencies, and microbes. Research on silkworms provided a transition between Pasteur’s studies of fermentation and his studies of the microbial agents that cause anthrax, chicken cholera, swine erysipelas, puerperal fever, cholera, and rabies. As Pasteur became more conﬁdent of the general applicability of the germ theory of disease, he acquired collaborators with the skills that made it possible to carry out experiments on higher animals and even human patients. Contrary to the Pasteur mythology, not all of these studies were successful. For example, his studies of a microbe found in victims of childbed fever led him to warn hospital per- sonnel that they carried the microbe from infected women to healthy women, but, like Oliver Wendell Holmes and Ignaz Philipp Semmelweis, he failed to convince physicians of the need to change their approach to obstetrics and gynecology. Indeed, an outraged opponent challenged Pasteur to a duel for this assault on the honor of the medical profession. Such violent and personal animosity was not characteristic of the entire medical and public health community. Many of France’s statistically based hygienists, for example, enthusiastically accepted Pasteur’s work as an asset to their own public health reform campaigns. Although some French physicians resisted Pasteur’s ideas because they anticipated a new form of preventive medicine that would threaten the profession and practice of medicine, by about 1895 this opposition was essentially disarmed by the prospects of powerful new therapeutic tools that strengthened the medical profession. Ultimately, of course, Pasteur and the research institute dedicated to him became icons of French science. According to Nobel Laureate Franc¸oise Jacob (1920–), when a Cabinet minister suggested making some changes to the Colle`ge de France, General de Gaulle (1890–1970) retorted: ‘‘There are three things in
France that are inviolable: the Colle`ge de France, the Pasteur Institute, and the Eiffel Tower.’’
Rabies, a rare but fatal human disease, and its invisible microbe
provided Pasteur’s most famous triumph. In his development of a pro- tective vaccine against rabies, Pasteur provided ample proof of his con- tention that microbiology was a demonstration of how the role of the
‘‘inﬁnitely small in nature is inﬁnitely great.’’ The ﬁrst step in all his previous studies of speciﬁc diseases had been to ﬁnd the microbe, but all efforts to identify the causative agent for rabies proved futile. At a time when scientists were just beginning to formulate the technical and theoretical problems of immunization, Pasteur was able to make the intellectual leap of developing a vaccine against an invisible virus. During this period, the term virus was traditionally used in a nonspeciﬁc sense in referring to an unknown disease-causing agent or poison. In terms of modern virology, rabies is an acute fatal encephalitis caused by neurotropic viruses in the genus Lyssavirus, family Rhabdoviridae. The majority of rabies cases are caused by bites by rabid mammals. After an incubation period of several weeks to months, the virus makes its way to the central nervous system where it replicates. Rabies virus can then be disseminated to the salivary glands and other organs via the nerves. Modern medicine has provided an unanticipated mechanism for the transmission of rabies from person to person. Three people died of rabies in 2004 after receiving infected organs (lungs, kidneys, liver) from the same donor. The donor had shown no symptoms of rabies before his death from a brain hemorrhage. Previous reports indicate that at least eight people have contracted the rabies virus through cornea transplants.
Given the difﬁculties involved in pursuing this project, Pasteur’s
decision to study a disease as rare as rabies when there were so many common diseases that might have been easier to work with seems puzzling. Several answers have been offered. Perhaps it really was the haunting memory of the howls of the mad wolf that had invaded Arbois when Pasteur was a boy and the screams of its victims as their wounds were cauterized. Alternatively, the choice may have reﬂected Pasteur’s ambition and his ﬂair for the dramatic. However, Pasteur had done enough to achieve immortality before embarking on what was obviously a dangerous project, for research on rabies must begin with one of the most feared of all creatures, the mad dog.
Another factor inﬂuencing Pasteur’s choice may have been the ten-
sion between his condemnation of experimentation on human beings and his desire to prevent human disease. Human experimentation, Pasteur believed, was not only immoral, but also criminal. Moreover, his entry into the study of human diseases was apparently inhibited by a deep antipathy for vivisection and his ambivalence towards physicians. To reconcile these conﬂicts, Pasteur needed a disease shared by humans
and animals that was invariably fatal so that an experimental treatment could not make the outcome any worse. Whatever the motive might have been, Pasteur had chosen well; the success of his quest for a rabies vaccine was greeted throughout the world as the greatest achievement of microbiological science. (Those old enough to remember the fear aroused by polio might reﬂect upon the similar outbursts of joy, hope, and gratitude that greeted Jonas Salk (1914–1995) and the polio vaccine in the 1950s.) The real Pasteur, a great scientist who certainly had his faults and failures, all but disappeared under the weight of myth, romanticism, and adoration. Venerated by the public as genius, hero, and saint, Pasteur, or the mythic Pasteur, became the target of late twentieth-century historians of science.
The difﬁculty of predicting the outcome of the bite of a rabid
animal is a complicating factor in assessing Pasteur’s rabies vaccine. That is, rabies was invariably fatal if contracted, but not all encounters with mad dogs result in human rabies; and not all ‘‘mad dogs’’ are actu- ally rabid. Moreover, the incubation period for rabies is so variable that in some cases the association between bite and disease was difﬁcult to assess. The English surgeon John Hunter (1728–1793) noted a report of a dog that allegedly bit 21 people. None of these people received any medical attention, but only one became ill. If all of them had been treated, the attending doctors would have claimed 20 cures. Neverthe- less, physicians were unlikely to forego treatment, even if their remedies did more harm than good. For example, the distinguished medieval physician Arnau de Villanova (c. 1235–1311) believed that wounds resulting from the bites of mad dogs should not be allowed to heal. Leeches, cupping vessels, and noxious dressings should be applied to the open wound for at least 40 days. The notion that like cures like was the basis for remedies containing either the worms found under a mad dog’s tongue or the heart of a hound. According to Anglo-Saxon folklore, even mad dogs had medical virtues. Mixing a powder made from the head of a mad dog with wine was said to produce a cure for scrof- ula (a form of tuberculosis that affects the lymph nodes of the neck).
In order to isolate the rabies virus and prepare a vaccine, Pasteur needed a laboratory culture of the causative agent. Obviously, it was difﬁcult to ﬁnd rabid dogs on a routine basis and even harder to secure their cooperation. Not surprisingly, kennels for rabid dogs were as welcome in any neighborhood as an AIDS clinic in the 1980s or a toxic waste dump. A reliable and relatively safe system of transmitting rabies, which involved trephining experimental animals and inocula- ting infectious material through the dura mater, was used to study the disease in rabbits and other animals. Rabies was transmitted from rabbit to rabbit so that ‘‘ﬁxed virus’’ with a reproducible degree of virulence and a shortened incubation period was always available. Finally, Pasteur and his colleagues discovered that when the isolated
spinal cord of a rabid animal was subjected to increasing periods of air-drying, the rabies virus became progressively weaker. To test the use of the air-dried material as a preventive vaccine, dogs were inocu- lated daily with suspensions of increasingly virulent preparations of spinal cord. At the end of this procedure, dogs were resistant to rabies even if the most virulent preparations were inoculated directly into the brain. By 1885, Pasteur was satisﬁed that he could reliably induce immunity to rabies in dogs.
The question of the safety and effectiveness of this vaccine in human beings could not be avoided once the results on dogs became known. Protecting people by immunizing all the dogs in France was surely an impossible task; moreover, wild animals served as an inﬁnite reservoir of disease. Obviously, rabies vaccine was not a candidate for mass immunizations because human rabies was too rare a condition to justify a dangerous series of painful injections. However, Pasteur’s vaccine was the only hope against the pain, suffering, and death that were inevitable for those who contracted the disease. On July 6, 1885, nine-year-old Joseph Meister was brought to Pasteur’s laboratory. He had sustained at least 14 wounds, some very deep, when attacked by a mad dog two days before. Physicians who examined the boy did not doubt that he would contract rabies and that death was inevitable. After consultation with colleagues at the Academy of Medicine, Pasteur initiated the immunization procedure. Despite the discomfort entailed by the long course of injections, Joseph made a complete recovery. The next well-known patient was a 15-year-old boy who had been sav- agely bitten by a rabid dog six days before treatment began. News of the apparently successful use of Pasteur’s vaccine created both bitter criti- cism and excessive hope. Pasteur was attacked by physicians, veterinari- ans, antivivisectionists, and antivaccinators, while terriﬁed victims of the bites of rabid (or presumably rabid) animals besieged his laboratory.
The uncertainties inherent in the course of human rabies and the crudeness of the vaccine led to tragic failures and successes. Successful immunization depends on how soon the inoculations are begun and the individual’s reaction to the vaccine. A certain number of deaths due to reactions to the vaccine were inevitable. Critics could always charge that success measured only by the failure of patients to die of rabies was meaningless. When some patients developed paralysis, Pasteur’s critics called him an assassin and charged him with infecting human beings with ‘‘laboratory rabies.’’ However, when victims of dog bites compared the risks of the Pasteur treatment to rabies, thousands decided that the vaccine was a great victory in the battle between science and disease and chose the vaccine. Throughout the world, people echoed Joseph Lister’s tribute to Louis Pasteur: ‘‘Truly there does not exist in the whole world a person to whom medical science owes more than to you.’’ Perhaps Pasteur’s German counterpart Robert Koch would have quarreled with
that assessment. The hostility between Koch and Pasteur was due, at least in part, to nationalistic rivalries inﬂamed by the Franco-Prussian War, but there were also major differences in their goals, objectives, scientiﬁc style, and personalities.
Pasteur’s account of Joseph Meister’s treatment was presented to the Academy of Science of Paris, in October 1885. Newspapers and journals quickly disseminated news of the rabies vaccine and generated interest in the germ theory of disease and expectations of imminent cures for other deadly diseases. Victims of bites by rabid dogs and wolves were soon appealing to Pasteur for treatment. For example, when a rabid dog bit seven dogs and six children in Newark, New Jersey, the boys were sent to France, where they received the Pasteur vaccine. When the boys returned, they were widely exhibited, which cre- ated additional interest in Pasteur’s work and his germ theory of dis- ease. During the twentieth century, efforts to prevent rabies in the United States were largely directed at domestic animals, which repre- sented most reported cases before 1960. Because of the success of such campaigns, by 2000, only 10 percent of rabies incidents were attributed to domestic animals. Rabies-related human deaths dropped from more than one hundred a year in the early 1900s to about two a year. However, about 40,000 people in the United States are treated for rabies exposure annually, primarily because of contact with rabid raccoons, coyotes, and bats. Federal and state ofﬁcials have attempted to eradicate raccoon rabies by dropping bait containing oral rabies vaccine from aircraft. Switzerland and France used oral vaccine to become rabies-free. Statistically, however, rabid bats pose a greater danger than raccoons.
In public, Pasteur insisted on a rational scientiﬁc method, but in private he pursued a more empirical approach, often guided by theories that might be considered irrational. His colleague, the clinician Emile Roux, urged more caution and was critical of Pasteur’s approach to human experimentation. Some historians of science have depicted Pasteur as ‘‘authoritarian, politically reactionary, self-deceiving, overly concerned with priority and credit, ungenerous to his assistants, ruthless with his adversaries, and recklessly overconﬁdent in putting human patients at risk.’’ However, other scholars and scientists argue that Pasteur took calculated risks that were appropriate to the information available to him and the dangers that his human subjects were already facing. Pasteur was a public ﬁgure and a scientist and he was very adept at attracting attention and converting people to his views. Pasteur apparently chose to conceal ambivalent or unfavorable aspects of his work on rabies and anthrax. At least two patients had been inoculated with rabies vaccine before Joseph Meister, but the results were con- sidered inconclusive and they were not published. Not surprisingly, Pasteur’s critics called his rabies vaccine dangerous and his defenders insisted on the relative safety of the vaccine in the face of a deadly
disease. Pasteur’s advocates emphasized the fact that there are unknown risks inherent in all medical therapies and known risks inherent in the diseases that scientists selected for their research. Historians of science have also subjected Pasteur’s work on vaccines to scathing criticism, but, it should be noted, many of the difﬁculties and uncertainties that Pasteur and his contemporaries faced in attempting to develop safe and effective vaccines remain unresolved.