He was born in 1822 to a father who was a provincial tanner of animal hides—a bitterly nostalgic veteran of the Napoleonic Wars who would pin his Legion of Honor ribbon to his spotless frock coat for his regular solitary Sunday stroll through town and field—and to an imaginative, enthusiastic mother from a large family of warmhearted gardeners. Their snug little home above the tannery in Arbois was thick with the fetid smell of wool grease. Still, Louis Pasteur’s rustic boyhood was a happy one. He enjoyed fishing, sledding, and the company of his three sisters. An eager but undistinguished student, he was noticed primarily for his artistic abilities. While some of the locally distinguished acquaintances who sat for portraits with the young Pasteur supposed he might someday have a modestly bright future in painting, his father’s ambition was that Louis would eventually achieve the respectable station of secondary-school instructor.
Pasteur was not quite nine years old when his quiet village childhood was punctuated by a disturbing drama. After hearing reports of a rabid wolf marauding through the region of Arbois, furiously biting man and beast, Pasteur and his friends witnessed one victim being brought to the blacksmith’s shop for treatment. The sight of a red-hot iron cauterizing the man’s still-frothy wounds made a lasting impression on the young Pasteur. So did the hydrophobic deaths soon afterward of eight of his fellow Arboisians, who had suffered the wolf’s bites on their hands and heads.
As a university student in Paris, Pasteur was exposed to the great scientific minds of his day, and his own gift for original research finally surfaced. Following completion of his master’s degree at the École Normale Supérieure, Pasteur chose not to return to the provinces as a schoolteacher and instead took a position in the laboratory of the famous chemist Jérôme Balard. He defended theses in physics as well as chemistry and after one year’s time made his first report to the French Académie des Sciences on the relationship between various crystalline forms of particular chemical substances and the rotational polarization of light—a paper that elegantly unified much of the contemporary research into molecular physics and chemistry.
Pasteur was appointed a professor of chemistry at the University of Strasbourg, where he underwent two important transformations. First, almost immediately upon meeting Marie Laurent, the gentle, patient daughter of the university provost, Louis Pasteur began a campaign to win her hand that would soon seal his fate as a dutiful family man. Second, while he continued to make discoveries in the laboratory concerning the physical and chemical character of crystalline substances, Pasteur increasingly concerned himself with scientific problems that had direct practical applications, such as the process for industrial production of racemic acid crystals and, later—as the dean of the faculty of science at Lille—the fermentation of beetroot alcohol. Pasteur saw himself as performing science for the people: the French people in particular. Before long he would likewise be known as the people’s scientist.
In 1857, Pasteur returned to the École Normale in Paris. Here his ongoing discoveries in the fermentation and spoilage of wine, which he established to be microbiological processes, led to studies that exploded the stubborn myth of spontaneous generation and notably led to the development of new preservation methods for perishables. Pasteurization was born and would change forever the handling of food and drink. Pasteur immediately and doggedly began to explore the relationship between the putrefaction of foodstuffs and the necrosis of diseased tissues. As his research interests evolved from physics and chemistry to microbiology and medicine, the general populace became increasingly interested in his work. Indeed, the emperor and empress themselves began to pay keen attention, and Pasteur, for his part, quickly learned how to transform public interest in his research into material support for the glassware, incubators, laboratory bench space, animals, and capable assistants his ongoing endeavors would require.
Many scientists would train and toil by Pasteur’s side, but the flinty young physician Emile Roux contributed more than any other to Pasteur’s researches into animal and human disease processes. Roux’s medical training had been temporarily disrupted when he, in a fit of anger at the director of the Val-de-Grâce Army Medical School for slighting the serious scientific effort he was expending on his student dissertation on rabies, insulted his superior and was consequently imprisoned and then expelled. As a medical graduate, Roux monastically devoted himself to the systematic study of microbes and immunity in the Pasteur laboratory at the École Normale (and later at the Institut Pasteur). In this role, he was often a thorn in the side of his master, pitting his own methodologies against Pasteur’s, always urging the elder scientist toward greater extremes of scientific rigor. “This Roux is really a pain,” Pasteur complained. “If you listened to him, he would stop you in everything you are trying to accomplish.” Still, the collaboration between the two men, which lasted from 1878, when Pasteur began to concentrate on contagious diseases, until Pasteur’s death in 1895, was an extraordinarily productive one.
Throughout his career, Pasteur was known for his diligence and tenacity: he would approach every research question with an exhaustive, meticulous zeal. Since he often took on problems of particular controversy in his own lifetime, his rigor was never wasted, as he was constantly under attack. The French scientists of the nineteenth century were not content to air their disagreements in sternly worded missives placed in relevant academic journals, as is standard today. Rather, they confronted one another face-to-face before their esteemed colleagues at the Académie des Sciences, the Académie Nationale de Médecine, or even the venerated Académie Française. Pasteur’s fastidious methodology was matched by his aggressive rhetorical manner, a combination that frequently allowed him to make a great show of toppling his rivals’ scientific theories in public—indeed, to terrific applause. These performances were a particular source of satisfaction for Pasteur.
Pasteur professed a belief in research and experiment as a means to end human misery. It was a goal both lofty and earnest. He advised his younger scientific colleagues, “Live in the serene peace of laboratories and libraries. Say to yourselves…, What have I done for my country? Until the time comes when you may have the immense happiness of thinking that you have contributed in some way to the progress and to the good of humanity.” Pasteur’s love for children, in particular, and passion for preserving them against the morbid threat of infectious disease were to become famous. “When I see a child,” said Pasteur, “he inspires me with two feelings: tenderness for what he is now, respect for what he may become hereafter.” Much of Pasteur’s medical research focused on diseases that were particularly associated with childhood illness. Pasteur himself had lost three children to disease: two young daughters to typhoid and another to cancer. Following the death of the third daughter, Cecile, he wrote to a colleague, “I am now wholly wrapped up in my studies, which alone take my thoughts from my deep sorrow.”
Pasteur felt his calling as a scientist was ultimately to spare life and alleviate suffering, and as the secrets of microbiology revealed themselves to him over the course of his career, his conscience guided him toward new humane applications. Early in his career, he painstakingly tested and vigorously defended techniques to control microbial contamination—not just of food and drink but also of surgical wounds—and in doing so saved countless lives around the world. But as his restless mind turned toward other diseases, contagions first of France’s livestock and then of its countrymen, Pasteur began to think of a more fundamental means of preventing the morbidity and mortality caused by infection. Vaccines took hold of his imagination.
Vaccination is the induction of immunity to a disease in an otherwise vulnerable individual, accomplished through intentional exposure to some less virulent form of the disease. The practice began with variolation against smallpox infection, originating in Asia more than a millennium before Pasteur. The procedure consisted of taking a small amount of the pus from an active smallpox lesion and introducing it into a small surgical incision or directly into the nose of a patient with no history of the disease. The resulting infection was milder and less disfiguring than natural smallpox, leading to a case fatality rate of only 1 to 2 percent, as opposed to 30 percent with a natural infection. Variolation was popularized in western Europe during the early eighteenth century by England’s Lady Mary Wortley Montagu. After witnessing its successful practice during her husband’s term as British ambassador to the Ottoman Empire, Lady Montagu insisted that her three-year-old daughter be variolated a few years later when a smallpox outbreak threatened England. Much interest was generated in the British court, and within a year the Prince of Wales’s daughters Amelia and Caroline had been variolated as well. The practice immediately became widespread throughout Britain but had yet to overcome several decades of resistance in France. Only after the unexpected death of Louis XV from smallpox in 1774 did variolation become common among the French.
Since variolation was neither affordable nor accessible to the lower classes, it was never taken up generally as a preventative. Instead, large-scale vaccination efforts were set up only after an epidemic was in progress, limiting the ability of variolation to make a broad impact against smallpox. The physicians who carried out these procedures had no genuine scientific knowledge of why they were effective; it would be more than a century before Pasteur would popularize the germ theory and establish microbiology and immunology as fundamental medical sciences. Many physicians of the eighteenth century believed, for example, that variolation was most survivable when combined with fasting, bleeding, and mercurial purges.
One British country physician, still stricken by the memory of the noxious variolation protocol he himself underwent as a child, was motivated to find a way to diminish danger and discomfort to the patient without compromising protection against the dreaded smallpox. And so Edward Jenner set out to test the folk belief that those who handle cattle from a young age, and thus have the opportunity to be exposed to cowpox, or vaccinia, before they encounter smallpox, are protected from smallpox infection. Once this hypothesis was confirmed, he demonstrated that vaccinia could be intentionally inoculated into a naive human, conferring similar protection. His simple experiments on his neighbors and family members sufficed to convince the world that rather than being variolated with potentially deadly active smallpox, one could be inoculated with a much less virulent disease associated with altogether different species and thereby be protected from the graver infection. This humane innovation was quickly taken up around the globe; more than 100,000 were vaccinated before ten years had passed, and Jenner became an international celebrity. Immediately upon the creation of vaccine came the birth of the antivaccine movement, scientists and laypeople who claimed (much as in our present day) that vaccine was “poison.” But its use became more and more widespread, even compulsory in many places, as the decades wore on and vaccine production became standardized and improved. Altogether, it would take less than two centuries for Jenner’s vaccine to eradicate the scourge of smallpox from the earth.
Louis Pasteur favored preventative strategies against infection, and he was a great admirer of Jenner and the principle of vaccination. By the time Pasteur began his own work on communicable diseases, Jenner’s legacy was firmly established, if still not well understood. The Académie Nationale de Médecine recommended general vaccination but was still struggling to differentiate the agent of the vaccine from that of smallpox itself. Pasteur’s interest extended well beyond smallpox. He was determined to figure out the general method for immunizing patients against all of the different pathogenic microbes being cultivated in his laboratory.
Chicken cholera was the first disease to yield its secrets to the Pasteur research team. This bacterial disease of fowl was rampant in France during the 1870s, bringing misfortune to poultry farmers across the countryside. According to one of Pasteur’s assistants, Émile Duclaux, the breakthrough was made after the culturing of microbes was interrupted for the summer holiday. When the new academic year commenced, it was noted that the bacteria that had been set aside no longer transmitted the disease.* The formerly deadly germs produced no grave effect on experimentally infected healthy chickens. Intrigued, Pasteur took these same chickens and submitted them to a second experiment, alongside chickens that had never received inoculations. He infected both groups of animals with very fresh chicken cholera isolates, of determinately high virulence, and monitored them closely for ill effect. Shortly, Pasteur was able to observe that the birds exposed originally to the aged bacteria resisted infection with the virulent strain, too, while the naive chickens succumbed.
The significance of this finding was not lost on Pasteur. Here was induced immunity from a mortal disease—not happened upon fortuitously in the cowshed like Jenner’s, but experimentally produced in the laboratory! If chicken lives could be spared through inoculation of laboratory-attenuated microbes, it did not require much imagination on Pasteur’s part for him to suppose his method may have potential for saving human lives as well. As a nod to Jenner, Pasteur referred to his method of chicken-cholera immunization as a “vaccine.”
Pasteur’s new vaccine soon attracted naysayers on several fronts: those who fought against all science based upon the germ theory; the anti-vaccinists (who had already honed their rhetoric against the Jennerian vaccine); and those scientific rivals who would have invented the chicken-cholera vaccine themselves if their own methodology had been more sound. Pasteur was in the midst of preparing his findings for the Académie Nationale de Médecine when his arguments with his rivals in that body became so heated that he received an invitation to duel from the aging surgeon Jules Guérin. (The sixty-year-old, hemiplegic Pasteur was delicately extricated from the challenge by friends in the Académie.)
To test the broader utility of his method, Pasteur turned his attention to a second veterinary disease, one with greater economic importance for French and European agriculture: anthrax. While capable, in rare instances, of dealing a farmer or veterinarian a grisly death, anthrax was most feared across rural Europe for its ability to depopulate a prosperous farm, leaving behind an indefinitely contaminated field. Spurred on by Robert Koch’s pioneering paper, Pasteur set out to attenuate the isolated anthrax bacillus in a similar manner as he had done with chicken cholera. He was soon successful: after achieving partial success with heat deactivation, the Pasteur team ultimately found that temperamental anthrax was best attenuated chemically, with carbolic acid treatment.* In the end, the pathogen proved no less amenable to laboratory domestication than chicken cholera had.
The furor among France’s scientists and medical men created by Pasteur’s announcement of the anthrax vaccine was so intense, so fevered, as to demand some public proof of his claims. The influential veterinarian Hippolyte Rossignol accused Pasteur of “microbiolatry” in an editorial in his Veterinary Press. He invited Pasteur to perform a public demonstration on Rossignol’s own Pouilly le Fort farm in the pastoral Brie region east of Paris. Pasteur accepted the challenge, eager for a means of advancing his doctrine of vaccination. He devised a simple experimental protocol: twenty-five sheep would be vaccinated against anthrax, fifty including these would be infected, an additional ten would serve as untreated controls. All sixty would be monitored for subsequent ill health. The demonstration, carried out during May 1881, was witnessed in its various stages by a large rabble of farmers, physicians, pharmacists, newspapermen, and, especially, veterinarians—many of whom remained as skeptical of Pasteur’s vaccine as they were of the germ theory that gave birth to it. Far away from the pasture where the vaccine trial took place, some of Europe’s most ardent germ theory supporters, Robert Koch and his assistants, suspicious that Pasteur’s strong public assertions regarding microbial attenuation rested on as-yet-unstable science, voiced their stern disbelief as well.†
Great excitement was focused on the final stage of the trial, when the vaccinated and unvaccinated groups would both be injected with virulent anthrax. At the last-minute insistence of one of the more passionately skeptical veterinary observers, a triple dose of live anthrax was administered to each of the experimental animals. Pasteur himself vigorously shook the vial of anthrax prior to each inoculation, in order to prevent uneven distribution of the virulent principle. Other veterinary spectators demanded that the injections proceed with careful alternation between vaccinated and unvaccinated subjects. Pasteur assented indifferently to the various dictates of the veterinary crowd, never backing down from his assertion that “[t]he twenty-five unvaccinated sheep will perish; the twenty-five vaccinated ones will survive.”
Pasteur projected complete confidence but was privately anguished as he waited to learn the fate of the herd. As the hours ticked by and the only news from Rossignol’s farm was of a sick ewe from the vaccinated group, Pasteur’s resolve began to waver. But two days after the inoculation, all twenty-five of the unvaccinated sheep were dead, while all of the vaccinated sheep had survived. “As M. Pasteur foretold at two o’clock 23 sheep were dead,” the Times of London observed. “Two more died an hour later. The sheep which had been vaccinated frolicked and gave signs of perfect health. Farmers now know that a perfect prevention exists against anthrax.”
Pasteur was roundly congratulated, especially by France’s veterinarians, who had become his newest allies—allies who would prove extremely useful as his research progressed into the most fearsome disease known to that profession.
From anthrax, Pasteur turned his attention next to another veterinary disease, but one with widely understood consequences for people. Rabies, and its associated illness in humans, hydrophobia, did not claim so many French lives as others did. That said, it had a prominent place in the French imagination. For each one of the few hundred deaths from rabies registered each year in France, there were several bitten Frenchmen—or, more frequently, French children—who, along with their loved ones, spent many months in the agony of uncertainty: Would the wound lead to a grisly death from hydrophobia? In Pasteur’s youth, when his own village had been terrorized by the rabid wolf, the danger was viscerally understood. But even as the scientist aged, the debate about whether rabies was a contagion or a spontaneous occurrence raged on among France’s prominent biologists, physicians, and veterinarians.
Pasteur’s collaborator Roux believed that Pasteur selected rabies as a subject for research as a calculated bit of stagecraft, so that his ideas about vaccination would attract maximum public interest. “This malady is one of those that cause the smallest number of victims among humans,” Roux later wrote. “If Pasteur chose it as an object of study, it was above all because the rabies virus has always been regarded as the most subtle and the most mysterious of all, and also because to everyone’s mind rabies is the most frightening and dreaded malady…. He thought that to solve the problem of rabies would be a blessing for humanity and a brilliant triumph for his doctrines.”
The Pasteur laboratory received its first mad dogs from M. J. Bourrel, the former army veterinarian whose 1874 survey had found the anti-contagionists ascendant. Bourrel had been studying rabies for some years without penetrating very deeply into its mysteries. He had, however, localized its contagious principle to the rabid animal’s saliva; given this fact, he recommended the precautionary measure of filing down the teeth of all dogs at large, so that should they become infected, they might not be able to penetrate skin and transmit the deadly agent. Bourrel could provide no better preventative than this, as his search for a rabies cure had led nowhere. He wrote in 1874 that his efforts in the laboratory had shown only that rabies is “impenetrable to science until now.” In the summer of 1880, while assisting him in the laboratory, Bourrel’s own nephew suffered the bite of a rabid dog and died following several days of torturous agony.
In December of that year, Bourrel provided the Pasteurians with two terrifying specimens of canine rabies for study. The first suffered from dumb, or paralytic, rabies. Its mute affliction was wretched to witness: a paralyzed, slack jaw, failing to support a limp, foam-covered tongue, and, above this, eyes full of “wistful anguish.” The second dog, a victim of the more common furious form of the disease, terrorized the laboratory, menacing the scientists with its enraged, bloodshot gaze, its unpredictable lunges and fits, and its unforgettably mournful, hallucinatory howls.
During the same month, a doctor named Odilon Lannelongue contacted Pasteur about a five-year-old patient, bitten on the face one month prior to hospitalization, now racked by all the classic symptoms of rabies: restlessness, convulsions, aggression, hydrophobia. The child suffered mightily for fewer than twenty-four hours in the hospital and then died, his mouth full of the viscous mucus he had been unable to swallow. Within four hours after the child’s death, Pasteur collected a sample of the mucus. Upon his return to the laboratory, he inoculated some of the diluted mucus into a group of rabbits—a procedure, published more than a decade earlier by the veterinarian Pierre Victor Galtier, proven to determine whether rabies was present in the saliva of suspect dogs. But the rabbits inoculated with the child’s mucus surprised Pasteur, and contradicted precedent, by dying too quickly: they died in only thirty-six hours, when it should have taken weeks. Rabbits inoculated with saliva from those dead rabbits died nearly as rapidly. Moreover, the rabbits died of apparent respiratory failure, not neurological disease as would be typical of rabies. Dr. Lannelongue and his colleague Dr. Maurice Raynaud, after repeating the experiment themselves, eagerly announced proof that the child had died of rabies. If they were correct, this also would represent the first documented case of human-to-animal transmission of the disease.
Pasteur did not commit himself. He cultured a figure-eight-shaped microbe from the blood of the dead rabbits in veal broth and tested its virulence in more rabbits and also in dogs. Again, it swiftly dispatched its recipients. With further investigation, Pasteur and his assistants found that they could isolate and culture this organism from patients who were hospitalized with illnesses completely different from rabies—even from healthy adults. Pasteur named the microbe pneumococcus and declared that he was “absolutely ignorant of any connection that there may be between this new disease and hydrophobia.”
Critics seized on this as evidence of the slipperiness of germ theory. Pasteur claims to be working on one disease, they sneered, but instead is working on another. To this notion Pasteur responded indignantly, “This is indeed a new disease produced by a new microbe; neither the microbe nor the disease has been described before. This tenacity in research, Monsieur, is the honor of our work, and it was because we, my collaborators and myself, pursued these experimental combinations that we were able to demonstrate that the new disease existed in the buccal mucus of children who had died of the same disease as well as in the saliva of perfectly healthy persons. It was then, and only then, that I had the right to assert that the new disease had no relation with rabies.”
If rabies was not pneumococcus, then what was it, exactly? Despite a thorough investigation using all the tools of the Pasteur laboratory, no combination of methods and media available to Pasteur and his assistants would yield a microbial cause for rabies. Even as Pasteur’s team discovered that the infectious principle for rabies resided in the central nervous system as well as in the salivary glands, they failed to culture a pathogen from either location. Thanks largely to the work of Pasteur himself, it was by this time a basic tenet of medical science that infectious diseases are caused by specific demonstrable microorganisms. Robert Koch’s famous “postulates,” first articulated in 1880, had made clear the relationship between microorganisms and disease, defining a disease-causing microbe as one that appears exclusively in diseased individuals; that can be isolated and cultured from a diseased host; that will cause disease when next introduced into a susceptible host; and that can be subsequently recovered from the experimental host and shown to be identical in culture to the microbe originally isolated. For rabies, not a single one of these conditions had been met. Koch’s precepts have often been summed up with the phrase “one disease, one microbe,” and Pasteur concurred with this view, but his vision saw a third term in this equation: one vaccine. He believed that every disease-causing microbe, once isolated, could be attenuated so as to safely confer immunity on a potential host. But it was hard to see how this equation could hold true unless a pathogen could be isolated, identified, trapped under glass, and then tamed.
Pasteur referred to the unseen—and apparently unseeable—agent of rabies as a virus. As his biographer Patrice Debré observed a century later, the word “virus” had until that point been associated with a darkly mysterious etiology: with miasmas, with poisons, with plagues. Rabies behaved as though it were a microbic contagion, and so Pasteur maintained absolute faith that it was one, even though he could neither culture it in broth nor observe it under the light microscope. The word “virus” conveyed his uncertainty of rabies’ specific form and characteristics. It was not until 1898 that a “virus” was scientifically defined as a microbe that is invisible under the light microscope and can pass through a filter designed to trap bacteria; it was not until 1903 that it was experimentally demonstrated that the agent of rabies fit squarely within this category.
Despite the confounding invisibility of rabies, despite the fact that it seemed to violate the scientific principles of the day to do so (principles that Pasteur himself had played no small part in establishing), Pasteur persevered in his work on a vaccine. His intellectual flexibility in the face of unexpected results allowed him to conclude early on that trying to cultivate the agent of rabies using existing laboratory methods would be fruitless. Instead, he nimbly refocused his attention and that of his assistants on inducing immunity, in animals and eventually humans, to what would remain an obscure, intangible foe.
Bourrel’s two rabid dogs were part of a surge of rabies cases in Paris during 1880, and so the Pasteur laboratory would have no trouble obtaining infectious material. They got it from kennels of the national veterinary school at Maisons-Alfort and from private veterinary offices around the city. Because rabies could not be cultured on a plate or in a vial, it had to be maintained in living tissue. In the 1880s, this meant within the corporeal cells of a living afflicted animal. The maintenance of rabid animals within the modest rooms and basement of the Pasteur laboratory was discomforting to the personnel. There was the ever-present risk of contracting rabies—either directly from the jaws of the animal, or at the bench top, where infected tissues and sharp instruments could combine to do harm. Meanwhile, the researchers were forced to weather the public fury of the antivivisectionists, who denounced their work as senseless torture of innocent creatures.
In order to create and test a vaccine against rabies, the Pasteur team first had to develop a strain of rabies that behaved more reliably than the natural infection. Early studies relied on the crude method of one animal biting another, followed by an anxious wait over weeks or longer to see whether infection had been transmitted. The Pasteurians developed a preference for inoculating their subjects, rather than exposing them to the competing risks that accompanied the bite from a rabid dog: trauma, sepsis, fright. However, this technique involved the dangerous collection of rabid saliva from a raging animal. Pasteur’s son-in-law, René Vallery-Radot, recalled one such dramatic scene:
“We absolutely have to inoculate the rabbits with this slaver,” said M. Pasteur. Two helpers took a cord with a slip knot and threw it at the dog as one throws a lasso. The dog was caught and pulled to the edge of the cage. They seized it and tied its jaws together. The dog, choking with rage, its eyes bloodshot, and its body racked by furious spasms, was stretched out on a table while M. Pasteur, bending a finger’s length away over this foaming head, aspirated a few drops of slaver through a thin tube. It was…at the sight of this awesome tête-à-tête that I saw M. Pasteur at his greatest.
Such exertions would soon prove unnecessary. Careful experiments showed that rabies could be as readily communicated with material from the affected animal’s brain stem as with its saliva. “The seat of the rabic virus,” wrote Pasteur, “is therefore not in the saliva only: the brain contains it to a degree of virulence at least equal to that of the saliva of rabid animals.” Whether the Pasteurians were inoculating nervous tissue or slaver, uncertainty during a prolonged incubation period remained a problem, as not all animals would manifest signs of rabies following inoculation and the interval before onset of signs was still quite variable. “It is torture for the experimenter to be condemned to wait for months on end for the result of an experiment,” lamented Pasteur.
The Pasteur team soon found it was able to improve the infection rate and shorten the incubation period by administering chloroform anesthesia to the recipient animal, trepanning a hole in its skull, and then inoculating the rabid nervous tissue directly onto the dura mater, the connective tissue that covers the brain. Pasteur, disturbed by the invasive nature of this procedure, initially resisted the widespread implementation. But he was soon reassured by the vigorous, happy appearance of his laboratory’s first subject dog, only one day post-trepanation. The method was perhaps more stressful for the experimenters themselves, as remembered by Emile Roux’s niece:
[Roux], [Charles] Chamberland, and [Louis] Thuillier bent down around a table. A large dog was tied down on it, its muscles contracted and its fangs bared…. If the animal, despite all the precautions, had caused them to make a false move, if one of them had cut himself with his scalpel, and if a small piece of the rabid spinal cord had penetrated into the cut, there would have been weeks and weeks filled with the anguished question: will he or will he not come down with rabies?…They were no longer just “researchers” absorbed in the meticulous work of their laboratory; they were pioneers, adventurers of science.
Using the trepanation technique, Pasteur’s assistants successfully transmitted rabies to the healthy animal in every case attempted. Signs of disease were apparent in the inoculated animal in less than two weeks—a significantly shorter time than with natural infection—and death concluded within a month. As canine rabies was thereby passed to a rabbit, and from one rabbit to another rabbit, and from that rabbit to still another rabbit, and so on in successive passages, the incubation period became reliably shorter. Once twenty-one passages had been made, brain to brain, one rabbit to another, the incubation period had decreased to eight days. Here it became fixed and constant, so that subsequent passages in rabbits produced no further change.
Shortened incubation period is associated with increased virulence. The enhanced virulence of rabies following intracranial serial passage in the rabbit was plainly observable when the virus was inoculated back into a canine host: dogs infected with the rabbit virus were even more catastrophically affected than those afflicted with natural strains. Through persistent repetition, Pasteur could now induce a consistently deadly version of the volatile virus at will. Even if he could not culture it in a tube like a bacterium, or coax it to shine in the eyepiece of his light microscope like a spore, the rabies virus was now finally under his control.
The next step would be attenuation: the deliberate weakening of the virus in order to induce immunity without causing disease. From the beginning, Pasteur had sought a strain with a sure and fast-acting immunity that could be applied after exposure to rabies had already occurred. Much more challenging to achieve than the already-established method of prophylaxis, the vaccine strain would race to establish immunity against a natural rabies infection as it made its murderous way from bite wound to brain. If the infection inhabited the brain before protective immunity had taken hold, the patient’s death from rabies would be as certain as ever. But Pasteur hoped that an extremely robust yet attenuated rabies vaccine would provoke a sufficiently quick, vigorous immune response to interrupt the progress of the infection and spare the brain—indeed would drive the virus from the body altogether. The postexposure application of a paradoxically “weak strong” rabies vaccine strain would require innovation beyond Jennerian-Pasteurian vaccine principles. In fact, it would necessitate the creation of an entirely new branch of science: immunology.
Pasteur would create his highly immunogenic but determinately safe rabies vaccine strain through a two-stage process: a first stage that would carefully hone the virulence of the virus, and a second that would deliberately blunt it. The second stage, like the first stage, relied on the ingenious manipulation of postmortem nervous tissue from rabid animals. It also, like the first stage, was directly carried out by Pasteur’s most trusted assistants: Chamberland, Thuillier, Adrien Loir, and, especially, Roux. Roux, in fact, probably invented the Pasteurian method of attenuating the most dangerous strains of rabies by aging the dissected spinal cords of rabbits that had succumbed to the virus in specialized flasks for desiccation (although Pasteur himself would take much of the credit for this). As they had done with so many other methodologies devised in the Pasteur laboratory, the research team perfected and verified this protocol through numerous repetitions. Soon they had gone on to demonstrate the powerful effectiveness of their attenuated-virulent strain as a vaccine—both as a prophylaxis against future exposure to rabies in dogs and, ultimately, as a postexposure immunization therapy that would prevent rabies in dogs already exposed to the deadly virus.
In September 1884, Pasteur received a letter from the emperor of Brazil, inquiring when a vaccine would become available for human victims of a rabid bite. He replied:
Until now I have not dared to attempt anything on men, in spite of my own confidence in the result and the numerous opportunities afforded to me since my last reading at the Academy of Sciences. I fear too much that a failure might compromise the future, and I want first to accumulate successful cases in animals. Things in that direction are going very well indeed; I have already several examples of dogs made refractory after a rabietic bite. I take two dogs, cause them both to be bitten by a mad dog; I vaccinate the one and leave the other without any treatment: the latter dies and the first remains perfectly well.
But even when I shall have multiplied examples of the prophylaxis of rabies in dogs, I think my hand will tremble when I go on to Mankind.
It was only six months later, in March 1885, that Pasteur wrote in a letter to his friend Jules Vercel, “I have not yet dared to treat human beings after bites from rabid dogs; but the time is not far off, and I am much inclined to begin with myself—inoculating myself with rabies, and then arresting the consequences; for I am beginning to feel very sure of my results.”
Perhaps he continued to weigh the possibility, but Pasteur never did submit himself to this terrifying trial of his own vaccine. It was never necessary, as there were always unfortunate dog-bite victims whose physicians and families would offer them up for experimentation. Pasteur’s notes indicate that he allowed himself to be persuaded more than once to administer a vaccine to humans already in the throes of hydrophobia. These patients received no benefit from vaccination, as the natural virus had already infected their brains at the time of inoculation. Pasteur drew the necessary scientific conclusions and then made sure that these false starts were never publicized. He continued to believe that under the right circumstances the rabies vaccine would succeed, and he was determined that the vaccine’s public debut in humans would be nothing less than triumphant—providing the world with a broadly persuasive argument for the lifesaving potential of vaccines.
It was the destiny of Joseph Meister, a boy of nine, to provide Pasteur with a sufficiently compelling experimental case to deploy his fledgling vaccine. While walking alone to school on the outskirts of his small Alsatian village, Meister was viciously attacked by a grocer’s dog. The animal knocked him to the ground and tore at his flesh while he cowered, holding his hands over his face in vain. By the time a nearby bricklayer reached the scene and fended off the dog with two iron bars, Meister had suffered fourteen penetrating wounds to his thighs, legs, and hand. Later that day, after cauterizing the bite wounds with carbolic acid, Meister’s local physician sent the boy to distant Paris for consultation with the famous Louis Pasteur.
Pasteur proceeded cautiously. He was touched by his initial meeting with the stricken boy and his mother but did not agree to treat Meister until he had conferred with Alfred Vulpian, one of France’s most respected physicians and a member of the government’s official Commission on Rabies, and Jacques-Joseph Grancher, the head of the pediatric clinic at the Paris Children’s Hospital. The two esteemed medical men agreed that experimental treatment with Pasteur’s vaccine would offer Meister his best hope for survival given the extremely grave nature and severity of his wounds. Vulpian and Grancher provided not only an ethical sounding board for Pasteur but also very necessary practical assistance as he proceeded with his trial. Louis Pasteur had never been trained as a doctor, did not have a medical license, and so was prohibited from holding the syringe as it administered the first modern laboratory vaccine for humans, even though he himself had overseen every aspect of its creation.
Meister received his first injection immediately. “On 6 July, at eight o’clock in the evening, sixty hours after the bites of 4 July, and in the presence of Drs. Vulpian and Grancher, we inoculated into a fold of skin over young Meister’s right hypochondrium half a Pravaz syringe of the spinal cord from a rabbit dead of rabies on 21 June; the cord had since then—that is, for fifteen days—been kept in a flask of dry air,” recorded Pasteur in his laboratory notebook. The full, ten-day treatment would consist of thirteen inoculations, all delivering postmortem spinal tissue from a rabid rabbit. Each successive injection would contain a section of cord that had been exposed to air for a shorter time than the one before it, so that as the series proceeded, the vaccine would become less attenuated.
Throughout treatment, Meister and his mother were housed adjacent to Pasteur’s lab at Collège Rollin. While Meister made himself happily at home among the laboratory chickens, rabbits, guinea pigs, and mice, Pasteur’s dauntless confidence in the rabies vaccine wavered as the inoculations he dispensed became more and more virulent. “My dear children,” began a letter from Mme Pasteur, “your father has had another bad night; he is dreading the last inoculations on the child. And yet there can be no drawing back now! The boy continues in perfect health.”
On July 16, at eleven o’clock in the morning, Meister received his final inoculation. This preparation contained the most virulent tissue of all: rabid spinal cord from a dog that had been infected with a strain of rabies virus maximally strengthened by serial passage in the rabbit and harvested only one day prior to injection. Such a dangerous inoculation would provide a convincing test of Meister’s immunity: a naive recipient of this shot would be expected to show signs of rabies within several days. Pasteur’s son-in-law describes the fateful occasion as tense:
Cured from his wounds, delighted with all he saw, gaily running about as if he had been in his own Alsatian farm, little Meister, whose blue eyes now showed neither fear nor shyness, merrily received the last inoculation; in the evening, after claiming a kiss from “dear Monsieur Pasteur,” as he called him, he went to bed and slept peacefully. Pasteur spent a terrible night of insomnia; in those slow dark hours of night when all vision is distorted, Pasteur, losing sight of the accumulation of experiments which guaranteed his success, imagined that the little boy would die.
Shortly afterward, Pasteur left Paris for a much-needed rest and relied upon frequent updates from the physicians still monitoring Meister to reassure him of his successful treatment. On August 3, Pasteur wrote to his son from Arbois, “Very good news last night of the bitten lad. I am looking forward with great hopes to the time when I can draw a conclusion. It will be thirty-one days tomorrow since he was bitten.”
As more weeks passed and Meister remained free from rabies symptoms, Pasteur began to share the news of his success with close associates. One of these, Léon Say, leaked the story to the Journal des Débats, and soon the world began tentatively cheering the news. After Pasteur returned to Paris in the early fall of 1885, he made a statement to the Académie des Sciences describing the treatment received by Meister. More than three months had passed since the child suffered his terrifying bite wounds, and still he appeared healthy. The details of the case were outlined for the academy. Dr. Vulpian rose first to respond:
Hydrophobia, that dread disease against which all therapeutic measures had hitherto failed, has at last found a remedy. M. Pasteur, who has been preceded by no one on this path, has been led by a series of investigations unceasingly carried on for several years, to create a method of treatment by means of which the development of hydrophobia can infallibly be prevented in a patient recently bitten by a rabid dog. I say infallibly, because, after what I have seen at M. Pasteur’s laboratory, I do not doubt the constant success of this treatment when it is put into full practice a few days only after a rabic bite.
It is now necessary to see about organizing an installation for the treatment of hydrophobia by M. Pasteur’s method. Every person bitten by a rabid dog must be given the opportunity of benefiting from this great discovery, which will seal the fame of our illustrious colleague and bring glory to our whole country.
Pasteur’s modest laboratory at the École Normale was immediately transformed into a clinic and dispensary. People terrified of rabies arrived in droves to receive inoculations. By December, eighty courses of treatment had been completed or were in progress in Pasteur’s bustling lab on the rue d’Ulm.
Every morning, Pasteur’s assistant Eugène Viala meticulously prepared inoculations for the day’s vaccinations. From rows of desiccating flasks, Viala selected and sectioned pieces of aged rabbit spinal cord. The pieces then were isolated in sterilized vials according to the number of days since postmortem harvest and suspended in a few drops of veal broth to create an inoculant. Pasteur supervised Viala’s work closely and saw that, for every patient, an appropriately attenuated inoculation was prepared specifically for each given day of treatment.
At eleven o’clock, Pasteur’s study was opened to patients. For each, the date and circumstances of the bite, along with the veterinarian’s certificate, were entered into the register alongside the name of the victim. Pasteur stood attentively alongside the pediatrician Jacques-Joseph Grancher as he made each injection according to protocol. The patients and their families were free to ask questions of the celebrated scientist responsible for the vaccine, but these were often redirected to Grancher: Pasteur would never hesitate to gently remind his visitors that he was trained as a chemist, not as a physician. Pasteur’s son-in-law recalls that “he had a kind word for every one, often substantial help for the very poor. The children interested him the most; whether severely bitten or frightened at the inoculation, he dried their tears and consoled them.”
In December 1885, a telegram arrived at the rue d’Ulm announcing that four children from New Jersey, bitten by rabid dogs, were en route to Paris to receive Pasteur’s now internationally famous cure. Money for their passage had been raised through a public subscription organized in the New York Herald. The published appeal, written by the well-known Newark physician Dr. William O’Gorman, read:
I have such confidence in the preventive forces of inoculation by mitigated virus that were it my misfortune to be bitten by a rabid dog, I would board the first Atlantic steamer, go straight to Paris and, full of hope, place myself immediately in the hands of Pasteur…. If the parents be poor, I appeal to the medical profession and to the humane of all classes to help send these poor children where there is almost a certainty of prevention and cure. Let us prove to the world that we are intelligent enough to appreciate the advance of science and liberal and humane enough to help those who cannot help themselves.
Contributors to the subscription included Andrew Carnegie and the former secretary of state Frederick Frelinghuysen, along with neighbors and friends from the children’s Newark neighborhood, whose nickels, dimes, and dollars within twenty-four hours had amassed to a thousand dollars. The four boys quickly embarked for Paris, accompanied by a doctor and by the mother of the youngest among them. That boy, only five years old, reportedly exclaimed upon experiencing the trifling sting of his first injection, “Is this all we have come such a long journey for?” As their treatment proceeded, the story was raptly followed by the New York press—whose articles were subsequently reprinted in newspapers across the nation. As much as 10 percent of the Herald was devoted to rabies while the children were under Pasteur’s care. All of America waited breathlessly for news of the boys’ cure.
When the healthy, vaccinated boys stepped off the boat from Paris several weeks later, they were celebrities in New York and across the nation. For months afterward, the four of them were trotted out in theaters and dime museums, from the Bowery in Manhattan to the heartland of America. For ten cents, the curious could witness with his or her own eyes the ongoing health and vigor of the treated boys, and even question them about their experience in Pasteur’s laboratory. Around the United States and around the world, the media of the day continued to dwell on the particulars of Pasteur’s rabies treatment as experienced by the four young Americans. Many newspapers also went out of their way to explain Pasteur’s laboratory-based scientific research that gave rise to the vaccine.
According to the historian Bert Hansen, the popular sensation caused by the Newark boys receiving Pasteur’s cure led to a profound change in the way Americans thought about science and medicine. “It reversed the assumption that older doctors and older medicines were better than new ones,” explains Hansen. “It created a new expectation that medicine can and should change, that progress is to be expected, that the new advances would come from laboratory experiments on animals, and that specific injections would be a major tool of the new medicine.” The public, led by journalists and public officials, now waited breathlessly for the arrival of new medical breakthroughs and greeted these with ready fanaticism. Some, in the decade or so following Pasteur’s rabies vaccine, would prove to be worthy—like diphtheria antitoxin and diagnostic X-rays—while others would fall flat, such as Koch’s tuberculin treatment for consumption. Meanwhile, the global medical establishment was forced to adapt to the popular view. In the French journal Concours Médical, one Dr. Jeanne editorialized in 1895:
From the heights of our settled situations, we should no longer laugh at bacilli and culture media. Those who cultivate them already deserve our respect for the services that they have given mankind; for us, the old guard of the medical profession, they must also inspire salutary fear and a determination to be useful. We must march with the times. The coming century will see the blossoming of a new medicine: let us devote what is left of this century to studying it.
Let us go back to school and prepare the ground for an evolution, if we are to avoid a revolution.
Before the four children had even begun the return voyage from Paris, enthusiastic groups of physicians in New York, Newark, and St. Louis had initiated steps to bring Pasteur’s cure to the United States. Pasteur made it known that he would welcome American scientists, along with those from all corners of the globe, to study his methods in his laboratory. By the year 1900, there would be at least six clinics devoted to administering rabies vaccines in the United States.
Back in Paris, having assembled enough cases to demonstrate a statistical difference in survival between those vaccinated and those not, Pasteur set his sights on creating an institution that could meet the growing demand for his rabies treatment, as well as provide a home for the ongoing scientific research that might lead to even more cures. Although fervently proud of his contribution to the glory of France, he wanted this establishment to remain independent of the government. On announcing a fund-raising campaign in 1887, Pasteur immediately began to receive donations from all around the world. From the editor of the Herald, to the tsar of Russia, to little Joseph Meister in Alsace, donors gave generously to the cause. But much was needed in order to endow Pasteur’s grand vision. Around Paris, Pasteur became a philanthropic fixture, regularly appearing at charity balls, bazaars, and banquets—and in the drawing rooms of wealthy Parisians, discreetly soliciting financial contributions. His personal contribution of 100,000 francs made Pasteur himself one of the largest single donors to his own cause. On November 14, 1888, the Institut Pasteur was formally inaugurated.
The Institut Pasteur would serve as the flagship for the growing syndicate of Pasteur Institutes worldwide. According to its official statute, registered in 1887, the institute’s purposes were “(1) the treatment of rabies according to the method developed by M. Pasteur; (2) the study of virulent and contagious diseases.” Unofficially, the Institut Pasteur was intended to foster science that would not only protect human lives and livelihoods but also engender profitable applications to support the institute’s self-perpetuation and growth. The modern buildings, erected according to Pasteur’s specifications on an expansive property in the then-suburban Parisian plain of Grenelle, would house laboratories, kennels, libraries, and Pasteur’s own comfortably appointed residence. Its opening ceremony was attended by the president of the French Republic; ambassadors from Turkey, Italy, and Brazil; the most esteemed French scientists of the day; and a robust international press corps, who would ensure that the triumphant opening remained prominent in newspapers worldwide for several days.
Even as Pasteur was seeing his doctrines grandly institutionalized, in Paris and around the globe, he was constantly under attack from scientific detractors. Foreign microbiologists, especially those in Germany and Italy, claimed that they could not reproduce his rabies vaccine results. Physicians at home and abroad insisted that the improvements in survival from rabies due to being vaccinated were insignificant. Scientific journalists, who had risen to prominence in Europe during the latter half of the nineteenth century because of the popularization of intellectual issues, for the most part supported Pasteur, but those who chose to make their careers questioning the contemporary scientific orthodoxy missed no opportunity to chip away at Pasteurian principles. Each time the vaccine failed to save a life, even if it was simply because the treatment was delivered too late in the course of disease, the case would occasion a whole new trial of Pasteur’s methods in the dock of a skeptical press. Numerous publications gave column space to Pasteur’s scientific rivals, further fanning controversy. Some writers emphasized alternatives to Pasteurian treatment. Others expressed a nostalgic view that traditional methods were better or even argued that Pasteur’s vaccine was somehow derivative of historical therapies.
If Pasteur’s contemporary popularity and eventual historical legacy did not suffer, it is because he never gave anyone else the last word about his research and its fruits. Each and every hostile article, whether published in an academic journal or in a popular magazine, would receive an aggressively didactic response from the man himself. To a Naples newspaper, Pasteur wrote about one of his rivals, “Dr. von Frisch…has not succeeded, I am sorry to say. But I can counter his trials with positive results that will overthrow any negative facts he claims to have obtained.” To his family, Pasteur remarked in frustration, “How difficult it is to obtain the triumph of truth! Opposition is a useful stimulant, but bad faith is such a pitiable thing. How is it that they are not struck with the results shown by statistics?”
Pasteur would die at home on September 28, 1895. His health, during the years leading up to his demise, had been undermined by a series of strokes, as well as by the confining fatigue of congestive heart failure. His last years were spent in somewhat diminished productivity at the institute, as described by Mme Pasteur in 1893: “Pasteur continues to be fairly well, but he must resign himself to put aside all work that is in any way strenuous. He takes much interest in the work of others. He still enjoys going to the Academies.”
The “work of others” was Pasteur’s principal source of pride in those final years, especially as those other scientists were frequently men he had trained himself at the École Normale Supérieure or who had learned their discipline at the Institut Pasteur. “Our only consolation, as we feel our own strength failing us, is to feel that we may help those who come after us to do more and to do better than ourselves, fixing their eyes as they can on the great horizons of which we only had a glimpse,” pronounced Pasteur, with characteristic gallantry. Many of the Pasteurians would eventually be remembered for their own contributions to science and medicine—though acknowledgment of their individual achievements would not generally be realized until after Pasteur’s day-to-day involvement in laboratory activities had decreased.
Emile Roux, Pasteur’s closest collaborator during the creation of vaccines against fowl cholera and anthrax, and who had been so instrumental in devising an attenuation method for the rabies virus, would go on to develop serum therapy against diphtheria toxin. Élie Metchnikoff, a Russian biologist who had trained in Germany with Koch, would help, during his time at the Institut Pasteur, to lay the scientific foundations of immunology by describing the mechanisms of cellular immunity. Albert Calmette, after establishing a Pasteur Institute in Saigon, would build on the antitoxin research of Roux and develop antivenom serum therapy for snakebites. Later, at a Pasteur Institute he had founded in Lille, Calmette would join Jules Guérin, another Pasteur disciple, in his work on tuberculosis; together they would identify the famous BCG (Bacillus Calmette-Guérin), a strain of bovine TB that functioned as a human vaccine. Alexandre Yersin, a Swiss physician who was working under Roux when the Institut Pasteur was inaugurated, went on to spend his most productive years in Indochina. When a plague outbreak threatened Hong Kong in 1894, Yersin quickly established a field laboratory in the afflicted city and within days had discovered the plague bacillus. He furthermore determined that the dead rats littering Hong Kong were the origin of the deadly epidemic and quickly developed and began production of a lifesaving serum therapy against plague. Charles Nicolle, who met Pasteur only once, worked under Roux and Metchnikoff, then later at the Pasteur Institute in Tunis. He determined that typhus was spread by the human louse and that leishmaniasis was transmitted from dogs to humans by the bite of the sand fly. Jules Bordet, who worked in Metchnikoff’s laboratory from 1894 to 1901, made great progress in the field of immunology, particularly concerning humoral immunity, and he discovered the bacillus responsible for whooping cough after creating a Pasteur Institute in Belgium. Together, these early Pasteurians would further the laboratory-based approach to medical problems favored by their master and would carry his doctrines linking science, medicine, and public health to all the corners of the earth.
Pasteur’s remains were interred not in the Panthéon but instead, according to his family’s wishes, in a specially appointed crypt beneath the Institut Pasteur. There, fifteen years later, his wife, Marie, would be laid to rest also. Mosaics depicting Pasteur’s research triumphs watched over the tombs—and so did Joseph Meister, who, years after being the first to be vaccinated successfully against the horror of rabies, became the concierge of the institute. When the Nazis, on occupying Paris, attempted to visit the Pasteur crypt in 1940, Meister bravely refused to unlock the gate for them. Soon after this discouraging event, he took his own life.
Then, as now, Pasteurian science remained very much alive. Soldiers at the front in that war, on both sides of the battle, were protected from disease with Pasteurian vaccines, treated for illness with Pasteurian sero-therapies, and benefited from hygienic first aid and surgical techniques based on Pasteurian asepsis. As remains the case today, there were then still scientists ready to argue against Pasteurian principles—but history would take little note. Indeed, though many miraculous cures lay in the future, no figure in medicine since has ever enjoyed the heroic status conferred upon Louis Pasteur, conqueror of rabies.
* Duclaux’s account was supported by the biography written by Pasteur’s son-in-law, René Vallery-Radot, but some modern scholars dispute it. In 1985, based on a thorough study of Pasteur’s notebooks, the French historian Antonio Cadeddu asserted an alternate history: Pasteur’s collaborator Roux determined the method for attenuation of chicken cholera through prolonged, deliberate laboratory experiment—without the knowledge of Pasteur.
* The superior technique of carbolic acid attenuation was devised by the veterinary researcher Henri Toussaint and perfected by Pasteur’s assistants, Roux and Charles Chamberland, after Pasteur had already announced the creation of attenuated anthrax using temperature manipulation.
† The Koch group, which relied on different culture methods than did the Pasteur laboratory, doubted the particulars of Pasteur’s thermal method of attenuation.