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  The next twenty years would revolutionize medicine further still, and once again Pasteur would be at the revolution’s red-hot center, establishing the critical connection between fermentation, putrefaction, and disease.

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  As early as 1857, Pasteur had disputed Liebig’s position that putrefaction was the cause of fermentation and contagious disease—that both were, in some sense, a result of rot. The leap was to invert Liebig’s logic. When Pasteur had examined the diseased silkworms in Lille, and the ailing wine grapes he had studied in Arbois, what he saw in the microscope looked exactly like fermentation. Since he knew that fermentation was caused by microorganisms like yeasts and even smaller living things, fermentation and disease must have a common, microbial cause.

  Pasteur wasn’t the only one to arrive at this hypothesis.

  The Frenchman’s first notable breakthrough, in the revolutionary year of 1848, was the discovery that two molecules can be made up of the same ingredients but structurally be mirror images of one another. One of the by-products of wine fermentation, tartaric acid, which is composed of four carbon atoms, six hydrogen, and six oxygen, is a “right-handed” molecule: Light passing through it is bent in a right-handed direction. Racemic acid, on the other hand, has the same formula—C4H6O6—but rotates light in both directions: It is, in formal terms, both dextrorotatory and levororotatory. This discovery was important enough on its own terms, as any high school chemistry student who has struggled with the concept of stereochemistry can testify. Rotating the lens of history on Pasteur reveals his only serious rival for the title of “Father of the Germ Theory of Disease” (also “Father of Microbiology”) was Robert Koch: his chiral double.

  Koch was born in 1843 in the town of Claustal in the Kingdom of Hanover, one of the principalities that preceded the creation of the modern German state. Like Pasteur, he was a beneficiary of an entire nation’s newfound enthusiasm for technical education, even more profound in the Germanophile world than in France. This was especially true in medical education; every major hospital in the patchwork of German-speaking states had been aligned with a university since the late eighteenth century, when Joseph Andreas von Stifft opened the Vienna Allgemeine Krankenhaus as part of the University of Vienna. In 1844, a year after the birth of Koch, Carl von Rokitansky succeeded Stifft, and the “Vienna School of Medicine” linked examination of living patients with the results of autopsies performed on the same patient. By separating clinical medicine from pathology—before Rokitansky the same doctors had been responsible for both—and documenting more than sixty thousand autopsies, they built a huge diagnostic database that could be validated by postmortem studies.

  Credit: National Institutes of Health/National Library of Medicine

  Robert Koch, 1843–1910

  As a result of the German-speaking world’s embrace of scientific education, especially in medicine, Koch attended at least as rigorous a secondary school and university as Pasteur, where, again like Pasteur, he acquired both a medical degree and a mentor who planted the seed for his future researches. For Koch, that mentor was Jacob Henle, professor of anatomy at the University of Göttingen, who had been an advocate for the idea of infection by living organisms since the 1840s.

  Both Pasteur and Koch were gifted experimentalists, happiest working in laboratories.

  Pasteur came to the experiments that would revolutionize medicine by a relatively roundabout route: first studying the basic chemistry of organic molecules, then the phenomenon of industrial fermentation. Koch did so more directly. As medical officer for the Rhineland town of Wöllstein, he began studying a disease then decimating herds of farm animals in his rural district.

  Anthrax was and remains a deadly disease both to all sorts of herbivorous animals who contract it while grazing, and (rarely) to carnivores who get it secondhand from their prey. Every year of the nineteenth century, it killed hundreds of thousands of European cows, goats, and sheep. It was also a feared killer of the humans who acquired it indirectly from infected animals they handled as herders or ranchers; a particularly deadly form is known as “wool-sorter’s disease,” for obvious reasons. For both animals and human victims, anthrax kills in a gruesome fashion: Lethal toxins* cause severe breathing problems, the painful tissue swelling known as edema, and eventually death. Koch was determined to learn the disease’s secrets. What caused it? How was it transmitted from sick to healthy organisms? Most important: Could it be prevented or cured?

  Even by the standards of the day, Koch’s lab equipment was notably primitive; he inoculated twenty generations of lab mice with fluids taken from the spleens of dead cows and sheep, using slivers of wood. It was an object lesson in the importance of rigorous technique rather than sophisticated tools. Koch’s wood slivers established that the blood of infected animals remained contagious even after the host’s death. They showed him that it wasn’t the blood itself, but something within the blood, that carried the disease. In order to find it, he needed a pure sample of the contagious element. Once again working with homemade equipment, he isolated and purified the element and caused it to multiply in a distinctive environment: the watery substance taken from inside the eye of an uninfected ox, where he cultivated pure cultures of it. When he injected the cultured fluid into healthy animals, they contracted anthrax.

  He had his pathogen. The country doctor had forged, for the first time, a link between a distinct microorganism and a single disease. And he had something more, something that explained how grazing animals contracted the disease that he was able to grow only in very specific conditions. When unable to grow, anthrax produces spores that allow it to survive in the absence of food, a host, or even oxygen (in, for example, the well-ploughed soil of Wöllstein). When conditions improve—after they enter either the digestive or respiratory system of some unlucky bovine—they germinate and start multiplying again. Soon enough, the toxins that cause the disease reach deadly levels.

  This was big enough news that it attracted the attention of Ferdinand Julius Cohn, a professor of botany at the University of Breslau, and, perhaps most notably, the scientist who had, in 1872, named an entirely new class of living thing: bacteria (from baktron, the Greek word for “staff”). By then, the complicity of the tiny organisms that Leeuwenhoek had called animalcules in both fermentation and disease was starting to become doctrine. Awareness of the existence of a connection between disease and bacteria didn’t, however, tell much about the microorganism’s pervasiveness, the mechanism by which they killed, or even how long they had existed.

  One reason for the nineteenth century’s ignorance about the age of bacteria was a comparable deficiency in knowledge about the age of the earth itself. Until the beginning of the twentieth century, the oldest estimates for the planet’s origins were those of William Thomson, Lord Kelvin, who had used the equations of thermodynamics to calculate that the earth was approximately twenty million years old. This was a massive problem for advocates of Darwinian evolution, including Darwin himself, who was “greatly troubled” by it, since a mere twenty million years were insufficient for anything like the known diversity of life on earth.

  Current estimates of the age of the planet, roughly 4.6 billion years, solve that problem. For most of that unimaginably long time, bacteria were the dominant form of life on earth. By some estimates, they still are. Recognizable bacterial life—single celled, with a full suite of metabolic tools, but without a nucleus—first appeared about 3 billion years ago, and were the only form of life on earth until about 570 million years ago. They remain by far the most numerous. A single gram of topsoil can contain more than forty million bacteria; an ounce of seawater thirty million. Overall, the mass of the earth’s 5 x 1030 bacteria may well exceed that of all the plants and animals combined.

  Until the middle of the twentieth century, bacteria were a puzzle for taxonomists, who had spent centuries assuming that all living things were either plants or animals. It
wasn’t until the 1930s that a French marine biologist named Edouard Chatton came up with a different, and more accurate, bifurcation of the living world, dividing it between organisms that possess, and those that lack, a cellular nucleus, the “kernel of life.” The Greek word for “kernel,” karys, gave Chatton his naming convention: Bacteria are prokaryotes (in French, procariotique); virtually everything else, from Pasteur’s yeasts to a blue whale, is a eukaryote.* Bacteria live everywhere from Arctic glaciers to superheated vents in the ocean floor to mammalian digestive systems. They have been around so long—the number of generations that separate the first bacteria from the ones that probably gave George Washington his sore throat is about 3 x 1011, roughly six orders of magnitude greater than the number of generations separating the general from the first yeasts—that they have become past masters of evolutionary innovation. Bacteria, which reproduce as frequently as three times an hour, can mutate into entirely new versions of themselves in what is, to every other organism on the planet, a figurative blink of an eye. And, perhaps most relevant for a history of disease, they can feed themselves on everything from sunlight, to chemicals so toxic that they are used to clean the undersides of ships, to, well, us. In the words of one twentieth-century biologist, “It is not surprising that microbes now find us so attractive. Because the carbon-hydrogen compounds of all organisms are already in an ordered state, the human body is a desirable food source for these tiny life forms.”

  Though its age and extent was unknown to Cohn, he did know that the microorganism that Koch had found was part of this bacterial universe. He published Koch’s work in his journal, Beiträge zur Biologie der Pflanzen—in English, Contributions on Plant Biology—in 1876. The discovery immediately turned Koch into one of Europe’s best-known life scientists. Which brought him to the attention of an even more famous one: Louis Pasteur.

  In 1877, Pasteur took it upon himself to resolve what remained of the debate about the causes of anthrax. The bacteria isolated by Koch were still thought to be, in the words of at least one biologist, “neither the cause nor necessary effect of splenic fever [i.e., anthrax]” since exposure to oxygen destroyed them, but material containing the dead organisms still caused anthrax. Pasteur wasn’t convinced. He repeated the same process used by Koch: successive dilution—essentially taking a few drops from a flask in which he grew anthrax, diluting it in a new flask, over and over, until there was no doubt that every other potentially contagious element had disappeared—then injecting the pure culture into host animals, who reliably contracted the disease. The endospores discovered by Koch were the reason that seemingly dead bacteria remained carriers of disease: Anthrax cells weren’t killed by oxygen, but simply became dormant inside the walls of a spore. The groundbreaking understanding of anthrax—a combination of Koch’s spores and Pasteur’s dilutions—was the first to link the German physician with the French chemist. It would not be the last.

  The next step for Pasteur was the transformation of his experimental results into a practical therapy. A hundred years before, the English physician Edward Jenner had demonstrated that exposing healthy subjects to fluid taken from (relatively benign) cowpox lesions conferred immunity to smallpox. Pasteur himself had discovered that injecting hens with cultures containing chicken cholera that had lost virulence offered the same protection against that disease. Why not anthrax? The key, as always in vaccination, was to find a version of the disease-causing agent that was weakened enough that exposure to it was unlikely to cause the disease itself. In 1881, Pasteur and several of his colleagues, including Charles Chamberland and Emile Roux, used a variety of methods, such as exposure to acids or to different levels of heat, to reduce the disease-causing powers of the bacterium, though not without complications. Pasteur’s absolute belief in his irreplaceable gifts had by then taken the form of insufferable arrogance; in 1878, he had attacked the brilliant physiologist Claude Bernard, who questioned the argument that fermentation required living organisms, as a near-blind, publicity-seeking fraud.* And so, naturally, when the veterinarian Jean-Joseph Henri Toussaint successfully attenuated the anthrax bacterium first, Pasteur was furious. So much so that when his team discovered a procedure that weakened the bacteria sufficiently to make a practical vaccine using Bernard’s technique—potassium dichromate, an oxidant—he claimed to have done so by using oxygen alone in order to avoid sharing credit.

  His tactics worked, both as a disease preventative and as a public relations coup. On May 5, 1881, at the French village of Pouilly-le-Fort, fifty sheep and ten cows were divided into a control group and an experimental one, with the latter receiving the vaccination, and all subsequently exposed to anthrax bacilli. A month later, all the unvaccinated animals in the control group had died; none of the vaccinated ones had even contracted the disease. Anthrax had been defeated by Louis Pasteur. Already France’s favorite scientific hero, he was now mentioned in the same breath as Lavoisier and Blaise Pascal.

  Germany reacted less enthusiastically. After attending Pasteur’s 1882 presentation to the Fourth International Congress for Hygiene, Robert Koch wrote a ten-thousand-word-long screed, of which the following offers a taste:

  Pasteur began with impure material, and it is questionable whether inoculations with such material could cause the disease in question. But Pasteur made the results of his experiment even more dubious by inoculating, instead of an animal known to be susceptible to the disease, the first species that came along—the rabbit. . . . Pasteur follows the tactic of communicating only favorable aspects of his experiments, and of ignoring even decisive unfavorable results. Such behavior may be appropriate for commercial advertising, but in science it must be totally rejected. At the beginning of his Geneva lecture, Pasteur placed the words “Nous avons tous une passion supérieure, la passion de vérité.” [“We have no passion greater than the passion for truth.”] Pasteur’s tactics cannot be reconciled with these words. His behavior is simply inexplicable. . . .

  Koch’s report was nothing less than a declaration of war, one that would last until Pasteur’s death in 1895 (some would say, ending not even then). By 1880, Koch had moved to a much-improved lab at the Imperial Health Bureau in Berlin, from which discoveries continued to appear on what seemed to be a monthly basis. Having learned, by hard trial and error, that growing bacteria in nutrient-rich liquids like beef broth was a losing game—colonies of different sorts mixed together far too easily—he discovered that he could grow pure strains on potato slices, and later on what is still the standard growth medium for bacterial cultures, the seaweed-based jelly known as agar. His assistant, Julius Richard Petri, designed and built the eponymous dishes on which agar compounds would host microbial colonies. In 1882, Koch discovered the bacterium that caused tuberculosis, an achievement that his colleague Friedrich Löffler called a “world-shaking event” that transformed Koch “overnight into the most successful researcher of all times.”* In 1885 he discovered and identified the bacterium responsible for cholera.

  Nor did he limit himself to experimental work in his Berlin lab; Koch formulated criteria for managing cholera epidemics, and created, with Löffler, what became known as the “four postulates” of pathology, a diagnostic tool that would link a single pathogen to a single disease. The postulates themselves were plausible and useful. The first states that a pathogen must be found in all organisms that are a disease’s victims, but not in any healthy organisms. The second, that the microorganism must be isolated from a diseased organism and multiply in a culture like agar. The third postulate held that a cultured microbe must continue to cause disease in a healthy host. Finally, the fourth required that the reisolated microbe would be the same as the original one.*

  It seemed at the time to scientists throughout Europe that it was Pasteur’s unwillingness to use the postulates as a diagnostic tool that caused so much of Koch’s hostility. No doubt it was a contributing factor. Another was more basic: Koch was German, Pasteur French. And neither had forgotten the
year 1870.

  In July 1870, the French parlement, in support of Pasteur’s patron, the Emperor Napoleon III, voted to declare war on Prussia. They had been maneuvered into doing so by Prussia’s prime minister, Otto von Bismarck, whose North German Confederation swiftly and decisively destroyed the French armies in the east, captured the emperor, besieged Paris, accepted France’s surrender, and proclaimed a new German Empire under the Prussian king, all in less than a year. This upset the balance of power that had been obtained in Europe after the defeat of Bonaparte, but not as much as it upset Louis Pasteur, whose reaction was the opposite of moderate: “Every one of my works to my dying day will bear the epigraph: Hatred to Prussia. Vengeance. Vengeance.” That Koch was German—Hanoverian, not Prussian, not that it mattered—didn’t escape Pasteur’s notice. Nor the fact that Koch had served as a military surgeon during the war.

  So it went, then, for the remainder of the two men’s lives: two brilliant experimentalists revolutionizing the practice of biology and medicine, each with a résumé listing a dozen achievements, any one of which would have bought them scientific immortality, each honored in every way that their nations could honor them. And, as if to underline the mirror-image metaphor, each was retrospectively dogged by accusations of what might kindly be called embellishment.

  For Robert Koch, the moment of overreach wouldn’t come until 1890, when, working at Berlin’s Imperial Health Bureau, he announced the discovery of a new therapeutic technique for tuberculosis, an extract of the tubercle bacillus that he named “tuberculin.” By then, Koch’s reputation was sufficiently great that his word was sufficient grounds for widespread acceptance; a cure for one of the most dangerous diseases known was at hand, and it was used as a treatment over the course of the next eleven years. That it took so long before tuberculin’s therapeutic uselessness was discovered is partly because the subjects on whom it was used were already so sick that frequent failure was expected, even forgiven. Koch himself was not so easily forgiven. He had kept his formulation a secret, which was damning enough, but his reason was worse: He had made no secret of his intention of profiting by it, and was therefore unwilling to share potentially valuable trade intelligence with other scientists. Moreover, when he was finally forced, by reports that the substance was actually harmful (as it turned out, the bacteria, even in glycerin, produced the equivalent of an allergic reaction),* it became clear that Koch had only the sketchiest idea of its ingredients, nor could he provide the guinea pigs that he had supposedly cured with it. It took until the end of Koch’s life for his reputation to recover from the scandal, a testimony both to the limitations of the vaccine approach itself—as we shall see, attacking and defeating infectious disease is a very different process than defending against it—and to the pressures of scientific discovery.