The Remedy

by Thomas Goetz

  The problem was that there were no consistent standards of evidence and proof—the essential tools for modern science. Today, of course, there are rigorous standards for performing valid research, an accepted and universal experimental protocol. There are clear steps for designing a medical experiment, such as the double-blind, randomized clinical trial, where neither the study subjects nor the researchers know who is getting which therapy, and with the subjects assigned their path randomly, so as not to introduce bias into the experiment. There are schools of epidemiology and biostatistics and quantitative analysis where researchers spend years learning how to conduct a valid scientific experiment. There are accepted procedures for analyzing the data collected, with confidence intervals, p-values, and widely accepted thresholds for statistical significance—a measure by which a researcher can say, “We have learned something new here.”

  Today’s scientists take for granted that if they follow generally accepted processes of reliability (following best practices for experiment design), reproducibility (the ability of other scientists to repeat the experiment and produce similar results), and presentation of evidence (disclosing enough data so a reader can assess the evidence independently), their work will be taken as scientifically valid. Any scientist working today takes as a given that there are explicit boxes to check and a clear process for checking them.

  But Koch and his contemporaries had no such standards. The scientific method then was a hodgepodge of practices, with no uniform protocols for posing a hypothesis, conducting an experiment, analyzing evidence, and presenting results. There were techniques, to be sure, but there were as yet no standards—and between the two lies the great chasm separating antiquated science from modern research.

  This isn’t to say there wasn’t a gesture toward such universal rules. The scientific method available to Koch and others then can be traced back to Francis Bacon, in 1620, when he proposed a method for establishing causation through inductive reasoning. Not long after, Descartes, in the 1640s, advanced the cause of empiricism, the idea that science must be tested against observations. But neither provided explicit frameworks for how to design an experiment, let alone one for medicine. It wasn’t until 1865, when the French physiologist Claude Bernard wrote “An Introduction to the Study of Experimental Medicine,” that the first true effort to institute a formal process for gathering and assessing evidence appeared.

  Amid such ambiguity, Robert Koch arrived on the scene. Koch’s greatest virtue, it turned out, was to overinvestigate a problem, exhausting every possible argument opposed to his conclusions with a barrage of meticulously collected evidence. His lack of affiliation also proved an advantage, since he was subject to no particular procedural dogma. Elsewhere, every school pursued its own version of a scientific method, determined and governed by the laboratory chief: Cohn had his approach in Breslau (his insistence on a control group for Koch’s anthrax experiment, for instance, would have been an unnecessary step to many), Virchow his in Berlin (he had little patience for theories without evidence, deeming Darwin’s notions of evolution outside the scope of provable knowledge), Pasteur yet another approach in Paris, and so on. One researcher assessing the field in 1877 put it this way: “The various researchers have become embroiled in such contradictions that a survey of the studies in this field does not yield a single uncontested advance.” He added: “There is something depressing in this admission for one who is searching for the truth.”

  Amid these competing protocols, Koch approached the problem of wound infections. Using rabbits and mice, he set out to study five different types of infections: gangrene, septicemia, pyemia (abscesses due to infection), erysipelas (a skin infection), and sepsis. His experiments went on for about nine months, a remarkably brief period by today’s standards. But even in this short time, he was able to assemble enough evidence to clearly demonstrate that he had discovered something new. This was evident in the very title of his report: “The Etiology of Wound Infections.” Though this title seems benign, or even generically scientific, etiology (meaning the cause of disease) was a bold term to use. Considering how the cause of wound infections had bewildered medicine for centuries and frustrated the greatest scientists of the age, and considering how little was known about the etiology of any disease whatsoever, this constituted a succinct and swaggering proclamation. He had established causality once again.

  It wasn’t a boast or hyperbole. Koch took the term seriously, and his paper proposed two essential conditions for establishing proper etiology. First, he maintained that the bacteria would have to be evident in all cases of a disease. “In order to prove that bacteria are the cause of traumatic infective diseases,” he wrote, “it would be absolutely necessary to show that bacteria are present without exception and that their number and distribution are such that the symptoms of the disease are fully explained.” His second condition was that the observed bacteria had to be distinct from one disease to another (a clear response to Klebs’s failure to distinguish among Microsporum septicum a few years earlier). “The morphological characteristics of the bacteria found in pyemia, diphtheria, smallpox, and cholera are so similar that it is indeed easy to mistake them for identical forms,” he wrote (though he mistakenly included smallpox, which is caused by a virus, not bacteria). “But this would mean that one could not assign any specific importance to these organisms. In this case they would be parasites of the diseases, not their cause.”

  The bacteria Koch had found were, foremost, the two great villains of infection, Streptococcus and Staphylococcus. Koch isn’t generally credited with their discovery, in part because, though he had isolated both bacteria and identified them as agents of disease, even including images of the microbes in his paper, he curiously didn’t venture to name the organisms he had found. Naming rights aside, Koch’s triumph here was larger than planting the flag of discovery on another microbe. Instead, his work on wound infections accomplished something even more enduring, in two related respects. First, he demonstrated unambiguously that specific bacteria cause specific infections. Second, he stipulated a set of threshold protocols for proving causation, standards that could be used by others to make their own demonstrations of causation.

  These protocols, known as Koch’s postulates, are perhaps what Koch is best known for today. Though they wouldn’t be presented formally as the postulates until 1884, they make their first appearance in his report on wound infections. They can be summarized as follows:

  1.The infectious agent must be present in every case of the disease.

  2.The infectious agent must be extracted from a diseased individual, isolated from all other microorganisms, and grown independently in laboratory culture.

  3.The infectious agent must create the same disease when introduced into a healthy test individual.

  4.The supposed infectious agent must be extracted from the test individual and shown to be the same microorganism.

  In these principles, Koch was building on the twin pillars of German science, or Wissenschaft: Vollständigkeit, or completeness, and Nachvollziehbarkeit, clarity of methods and results (what is today known as reproducibility). He was, in other words, advancing a process for creating legitimate science, a framework for bacteriology that would, once and for all, allow it to emerge as a recognized and valid explanation for the cause of disease. This framework pertained to more than bacteriology; it also offered a template for all modern medical science and indeed all scientific investigation.

  Koch’s process—isolating a bacterium from a diseased organism, growing it, introducing it into a healthy organism, and then establishing disease once more—came as close as science could to affirming causation. This is no small feat; science today still grapples with the difference between correlation and causation, and Koch’s postulates, in slightly revised form, continue to be used as criteria for valid research. The mantra of “correlation is not causation” is so pervasive in modern science as to be a cliché, b
ut it is nonetheless commonly overlooked, as overeager researchers (or overeager chroniclers of research) make a wishful leap from a correlation between a disease and an agent and an actual causative relationship. Koch had laid the groundwork for a more rigorous science, one that could withstand the doubts, distractions, and obfuscation of his contemporaries.

  The work on wound infections, though less celebrated than his work on anthrax or his later research on tuberculosis, would mark Koch’s first demonstration of his greater scientific capacity: not just as a hunter of microbes, but as a pioneer of science. It would also be his last significant research in Wöllstein. By now, it had been more than three years since his work on anthrax. He was no longer practicing in isolation from true scientists. Through persistence, diligence, and skill (with some luck along the way), he had established himself in the vanguard of European bacteriology. He was now in regular correspondence with Cohn and Cohnheim; no longer following in Klebs’s footsteps anonymously, he was now regularly corresponding with him and publicly debating him. Cohnheim invited Koch to give a lecture on his work in Kassel, and in 1879, Cohn put his name forward to join the University of Breslau. Koch was elated—this was the escape he’d been pining for—but there were no funds available for the position, and the appointment fell through. Koch remained in Wöllstein, increasingly frustrated, ready to jump at anything that offered a way out.

  Then, in 1880, the director of the German Imperial Health Office, Heinrich Struck, made an argument to the kaiser that Germany’s future depended on its scientific leadership. Chief among these sciences was bacteriology, which not only was germane to issues of public health, but seemed essential to combating disease in the colonial lands that Germany had assembled in Africa and Indonesia. Struck called for a new institute devoted to bacteriological research, to be based in Berlin, and he already had a lab director in mind: Robert Koch.

  In early July 1880, the kaiser agreed; Struck could have his laboratory. On Wednesday, July 7, Struck sent Koch a telegram officially offering him the position. It was a terse dispatch that cut to the chase, asking when Koch could report for his new assignment. He would have to end his practice, move his wife and daughter, and find somewhere to stay in Berlin.

  Koch replied at once: “I will be at your disposal in Berlin on 10 July.”

  The tenth was just three days away, and a Saturday. He wasn’t even going to take the weekend off.

  CHAPTER 3

  1878 • The Rivalry

  Louis Pasteur, in 1878

  On April 30, 1878, a few steps away from the Seine in Paris, a man entered the grand courtyard of the Académie Nationale de Médecine. His closely cropped beard had gone white, and he walked with a limp, his left side dragging slightly, the result of a stroke nine years earlier, which made him seem much older than his fifty-five years. Slowly, carefully, the man climbed the stairs to the Session Room. This was Louis Pasteur, and he was on his way to tell the French medical establishment something few of them wished to hear.

  Pasteur took the post behind the speaker’s desk at the front of the chamber, a massive marble statue of Hippocrates hulking behind him. Before him were the two hundred physicians and surgeons of the academy, the most respected medical men in France. Though Pasteur belonged to the academy, he was not one of them. His training was in chemistry, and though his career was already marked by great discoveries, he was a newcomer to medicine. Many in the audience considered him an interloper. When he’d applied to the academy a few years earlier, in 1873, he’d just barely gained admission, squeaking by on a vote of 41 to 38.

  Even those who voted for Pasteur’s membership in the academy felt that his place was to bolster their work; instead, he quickly began challenging it. His speech of April 30, entitled “Germ Theory and Its Applications to Medicine and Surgery,” would be the most provocative yet. This day, Pasteur would do nothing less than scold French medicine for putting its citizens at risk, and then school them in how they might rebuild the integrity of their profession.

  Pasteur began by appealing to the academy’s members as scientists. Germs, he acknowledged, were a novel idea. But science, Pasteur insisted, was a sublime process, perfectly suited to transform the unknown into the known.

  If it is terrifying to think that life may be at the mercy of the multiplication of those infinitesimally small creatures, it is also consoling to hope that Science will not always remain powerless before such enemies. . . . All is dark, obscure and open to dispute when the cause of the phenomena is not known; all is light when it is grasped.

  And then he took the impudent liberty of putting himself in the surgeon’s place:

  If I had the honor of being a surgeon, convinced as I am of the dangers caused by the germs of microbes scattered on the surface of every object, particularly in the hospitals, not only would I use absolutely clean instruments, but, after cleansing my hands with the greatest care . . . I would only make use of charpie, bandages, and sponges which had previously been raised to a heat of 130°C to 150°C.

  Pasteur continued in this way for some time, explaining in detail the precautions that surgeons should take, immediately, if they wanted to improve their patients’ chances of avoiding infection and surviving surgery. When he finished, the audience applauded politely, but the consternation in the room was palpable. Some were outraged, some were convinced, and yet all of them understood that, after Pasteur’s remarks, medicine could no longer be the same. He had issued, in effect, a declaration of war against those who clung to ideas such as spontaneous generation or miasma. He had infiltrated their ranks, and now he seemed dedicated to changing their profession.

  Pasteur, of course, knew what he was doing. His animus toward germs, and toward those who would deny their existence, was deeply personal. “Do you know why it is so important to me to fight and defeat you?” Pasteur wrote to a proponent of spontaneous generation a few months before his “Germ Theory” speech. “It is because you are one of the main adherents to a medical doctrine that I consider extremely harmful to the art of healing.” Even for Pasteur, who’d made his career by battling the dragons of conventional wisdom, this was unusually blunt.

  Pasteur’s disdain wasn’t just philosophical. He also abhored germs in a literal sense. In fact, he may have been history’s first germophobe: He was compulsive about washing his hands, leaving his work repeatedly throughout the day to roll up his sleeves and lather up. This wasn’t tidiness; as his nephew described later, Pasteur was convinced that shaking hands was dangerous.

  If by chance a stranger had come to call on him in the laboratory, particularly if it was a physician, and if he had been unable to avoid this time-honored gesture of courtesy, he gave me a slight sign that I knew well, pointing towards the sink with his head, which meant that I was to go to open the spigot.

  The particular antipathy toward shaking hands with a medical man was telling. Those who were best served by the germ theory were also, regrettably, often the same ones who were most responsible for spreading the most dangerous germs of all—which is what compelled Pasteur to give his speech that day: Physicians were the problem, but they were also the solution. To stop them from spreading germs, Pasteur needed to convince them that there were germs.

  Though we can’t be sure when or how, sometime around his “Germ Theory” speech, Pasteur heard about Koch’s breakthrough work on anthrax. Somehow, from out of nowhere, this unknown young doc-tor in eastern Germany had isolated the anthrax bacterium and pro-ven, decisively, that it could be not only drawn from a diseased animal but also cultured and then inserted into another animal, which would then develop the disease. It was a remarkable feat of science, beautiful in its thoroughness, and it would have given great comfort to any champion of the germ theory. If the doubters wanted proof, here were heaps of it.

  If only he hadn’t been German. The thought must have crossed Pasteur’s mind, for like Koch, Pasteur was very much a patriot. During the Franco-Prussian
War, after German forces bombed Paris, Pasteur angrily returned an honorary degree he had received a few years earlier from the University of Bonn, Germany. “I obey a call of conscience in requesting you to erase my name from the archives of your faculty,” Pasteur wrote, “and to take back this diploma as a sign of indignation which the barbarity and hypocrisy instills in a French scientist from those who, to satisfy a criminal need, insist on the massacre of two great nations.”

  Pasteur would bear a grudge for the rest of his life. As he once wrote to a friend after the German victory at Metz (where Koch served at the German field hospital), “each of my studies, to my dying day, will bear the epigraph: ‘Hatred of Prussia, vengeance, vengeance!’” Sometimes this retribution took absurd form, as when he created a recipe for a special lager that, he believed, was far better than anything coming out of Munich or Berlin. He called it “Bière de la Revanche Nationale” or “the Beer of Revenge.”

  As word of Koch’s discoveries began to spread, he began to be mentioned alongside Pasteur. This surely caught Pasteur’s attention, especially when those reports cast Koch as not just a peer of Pasteur’s but perhaps his successor, a younger scientist who had taken the Frenchman’s broadly suggestive work and made it specifically relevant to medicine. The English physicist and essayist John Tyndall spotted this connection right away, making it in an 1876 speech on the germ theory—just months after Koch’s anthrax publication: “The very first step toward the extirpation of those contagia is the knowledge of their nature; and the knowledge brought to us by Dr. Koch will render as certain the stamping out of splenic fever as the stoppage of the plague of pébrine by the researches of Pasteur” (pébrine being a disease that Pasteur had diagnosed in silkworms).