The Remedy

by Thomas Goetz

  The microscope was one of several technological instruments to reach medicine in the nineteenth century. The stethoscope, which allowed physicians to hear inside the chest, was the first; a version was invented in 1816. It was followed, in 1851, by the ophthalmoscope, which made it possible for the first time to see inside the human eye, creating the modern specialty of ophthalmology. Other scopes, all invented around the same time, had a similar impact: the otoscope for the ears; the endoscope for the gut. Each of these scopes made it possible for the physician to see inside the patient, to push past the limitations of the patient’s physiology and the physician’s senses. (They were all upstaged by the discovery of X-rays in 1895, by Wilhelm Roentgen, which radically altered the physician’s perception of the patient.) When the stethoscope was perfected into its now-iconic form and function in the 1850s, for instance, it made it possible for a physician to hear a patient’s lungs and heart, connecting various sounds inside with various symptoms on the outside. It became especially indispensable as a tool for the diagnosis and assessment of tuberculosis.

  All these scopes would be described today as disruptive technologies: They rattled the status quo of nineteenth-century clinical care, in particular the physician. Most were suspicious of the new tools, which seemed to encroach on their authority. This distrust was nicely captured by Dr. Oliver Wendell Holmes, in his day the most respected physician in the United States, and a respected poet. In a bit of verse called “The Stethoscope Song,” published in 1848, Dr. Holmes lampooned a wet-behind-the-ears doctor enthralled by his fancy new stethoscope, which leads him to mistake a buzzing fly for a patient’s heartbeat.

  In truth, the arrival of the scopes marked a significant shift toward the scientific practice of medicine and away from the inherited art of medicine. “Learn to see microscopically,” the German pathologist Rudolf Virchow often said, imploring his students at the University of Berlin to master the craft of close observation and analysis. Virchow, the most celebrated physician of the day, was a fierce advocate for the widespread adoption of microscopy in medicine. It was a lesson that Robert Koch would take to heart, to the eventual chagrin even of the great Virchow.

  • • •

  BY 1873, KOCH’S PRACTICE WAS FLOURISHING. HE TREATED ringworm and dysentery, whooping cough and colic, and aches and infections and attended births and deaths. During spare hours, he would go down to the lakes and bottle up some water samples. Back home, he’d examine them under his microscope, noting the microorganisms he observed. And on idle afternoons, he and his friend the baron would pack up shovels and trowels and visit nearby prehistoric settlements, digging into ancient Teutonic graves.

  On one such excursion, Koch discovered a trove of ancient relics. Knowing that Rudolf Virchow shared his interest in archaeology, Koch sent a note inviting him to Wöllstein to see the find. They spent a pleasant morning inspecting the dig, and Virchow arranged for some of the artifacts to be displayed in Berlin.

  In Berlin, Virchow ran the new Institute of Pathology at the Charité, the illustrious medical center. There, he devised his cell theory of disease, which argued that all cells come from preexisting cells, refuting the false notion of spontaneous generation of disease. Unfortunately, Virchow proposed a new fallacy: that the body generated its own disease. “Disease is nothing but life under altered conditions,” he stated. He believed that epidemic disease was inextricably social, and advocated hygienic measures decades before they became commonplace.

  The German word for science is Wissenschaft, which literally means creating systematic knowledge; it requires an application of a method, a process. In the nineteenth century, Wissenschaft became the official ideology of German universities, an institutional demand upon every student and professor that they pursue their research with rigor, thoroughness, and care. Virchow especially thrilled to this larger task. “Die Medicin ist eine sociale Wissenschaft,” he wrote, meaning that medicine had the potential for profound social impact. “We shall soon perceive that observation and experiments only have a permanent value,” he wrote in 1847. “Then, not as the outgrowth of personal enthusiasm, but as the result of the labors of many close investigators, pathological physiology will find its sphere. It will prove the fortress of scientific medicine, the outworks of which are pathological anatomy and clinical research.”

  Virchow was his own finest example: He published thousands of scientific papers during his fifty-year career, covering everything from a taxonomy of parasites to a catalog of the shapes of the heads of German schoolboys, from leprosy in Norway to swamp diseases in ancient Troy. It’s hard to overstate the shadow Virchow cast over German medicine; he appeared to have taken it, single-handedly, and thrust it into modernity. In the 1870s, three decades after his first calls for scientific medicine, Virchow wrote that “it is no longer necessary today to write that scientific medicine is also the best foundation for medical practice,” though he evidently felt compelled to write it nonetheless. “Even the external character of medical practice has changed in the last thirty years. Scientific methods have been everywhere introduced into practice.”

  As a student, Koch arrived at Göttingen just as Virchow’s call to arms was beginning to seem self-evident. With the diligent example of teachers such as Henle, Koch would have been indoctrinated with this sense of history and opportunity. But where Virchow looked in his scope and could see only cells of human origin, Henle saw microbes.

  Like the proverbial blind men touching the elephant, both Virchow and Henle were partly right and partly wrong. Virchow’s dogmatism for cell theory helped push medicine toward science and away from humoral theory; in his way he was as much a radical as Koch would become. For his part, Henle was correct to put faith in microscopy (in what could be seen) and to evangelize against miasma and for germs. He was undoubtedly on the right path when he suggested that “before microscopic forms can be regarded as the cause of contagion in men, they must be constantly found in the contagious material; they must be isolated from it and their strength tested.” The statement would become the blueprint for Koch’s career.

  • • •

  WÖLLSTEIN IS JUST 230 KILOMETERS, OR 140 MILES, FROM BERLIN. But in the 1870s, 230 kilometers might as well have been 230,000. If Koch yearned for better prospects, there seemed no way to leave Wöllstein. He had a solid practice, and his patients admired him. Given his meager background, he had indeed arrived. Except that he had arrived in Wöllstein, such as it was.

  So rather than look to Berlin, Koch looked to Wöllstein. In 1873, just as he began to grow bored of looking at pond water under his scope, a new opportunity to test his science emerged. Sheep in the area had begun to die. Then a few local farmers and sheep shearers began to get sick as well. This happened from time to time in such a place, an outbreak of a malady known as woolsorter’s disease. It was also called anthrax.

  Historically, anthrax was a common, and devastating, part of agriculture. Farmers called it the “black bane” and could only watch as the disease ran its course from symptoms to death in a matter of hours. An infected animal would slow down, drift back from the herd, and soon fall to the ground. Blood would stream from the mouth and nose. And just like that, the animal would be dead. Inside the swollen cadaver, the organs would be awash in a dark fluid, and the spleen, in particular, would be distended.

  In humans, anthrax on the skin was unmistakable: Boils with a dark, almost black, center of necrotic flesh would break out on the hands and arms, and red streaks would spread up and down the affected limb. It is an ugly, disfiguring infection, and before the discovery of antibiotics, it would prove fatal in about 15 percent of cases.

  Anthrax is an ancient disease; biblical scholars have suggested that it was the fifth plague on Egypt. “Behold, the hand of the Lord is upon thy cattle which is in the field, upon the horses, upon the asses, upon the camels, upon the oxen, and upon the sheep,” the King James Bible describes. “There shall be a very grievous murrain.�
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  For farmers in any era, the disease spelled disaster. But in the late nineteenth century, when the cattle, wool, and leather industries had become integral components of a booming European economy, the disease was especially unwelcome. In 1870 in Russia, where the disease was known as the “Siberian pest,” an outbreak in Novograd killed 56,000 cattle and 528 people. Anthrax was endemic in Italy; in the ten years from 1880 to 1890 there were more than 24,000 reported human cases, with nearly 6,000 fatalities.

  The cause was a great mystery. A French veterinarian suggested that anthrax in sheep was brought about by an excess of blood circulating in the vessels, due to too much feeding. Others believed the disease was in fact poisoning by a toxic plant, though which plant could never be determined. Others simply thought that the fields themselves were cursed.

  When the Wöllstein outbreak took hold in late 1873 and began spreading to humans as well as sheep, Koch probably used the available folk remedies: poultices of cow manure or tree bark, leaves, and even roasted onion. He may have treated some wounds with surgery, excising the diseased flesh or cauterizing it with a hot iron or acid. From time to time, though, he would take the blood from a recently stricken animal and put it under his microscope. On April 12, 1874, he described what he saw in his notebook. There were spores, some of which grew into chains of rods—these must be bacteria, he wrote, using the term that the German zoologist Christian Gottfried Ehrenberg had coined in 1838 to describe tiny rod-shaped organisms. “The bacteria swell up, become shinier, thicker, and much longer,” he observed.

  Koch wasn’t the first scientist to look at the strange, dark blood of a dead animal through a microscope and observe these bacteria. Anthrax, as it happens, is a particularly large bacterium, easy to see under a scope. In 1850 the French physicians Casamir Davaine and Pierre Rayer observed “little, threadlike motionless bodies” in the blood of sheep that had died of anthrax. Though he couldn’t determine whether these bodies were living or dead, Davaine went on to show that the blood of one animal with the disease could infect another, and he conjectured that these “bacteridia” were the cause of the disease. The German physician Aloys Pollender recorded a similar observation in 1855 and in his report likewise speculated about bacteria’s link to disease. “Whether they are the infectious material itself or simply the bearers of it, or, perhaps, have no connection with it at all?”

  This, of course, was the essential question. Did these microbes cause disease or were they caused by it? Or were they mere bystanders? It’s the question that made Klebs’s battlefield research so suggestive but ultimately unconvincing. As one surgeon said in reaction to Klebs’s work, “My heart says ‘yes’ to bacteria, but my reason says ‘wait, wait.’” It was a true mystery of cause and effect, and dozens of scientists, with better resources and training than Koch, had failed to solve it. Why should Koch, sitting in his kitchen in Wöllstein, be any different?

  That summer, the anthrax outbreak seemed to wane. As the months passed, Koch fell back into his routine practice—but his passion for the microscopic world only grew. Emma had saved enough money to buy another, better microscope, which Koch would use long into the night, examining blood from the animals out back, even bits of tissue from his patients.

  A year went by, and Koch went back to his practice. Then, a few days before Christmas 1875, a local police officer came across a dead animal near town. The beast’s blood was dark and thick, a sure sign of anthrax. Fearing another outbreak, the officer took the dead animal to Dr. Koch, who extracted some blood and placed it under his microscope. Sure enough, it was teeming with the bacteria he had noted eighteen months before. He found himself in just the same place, facing just the same question: Were these bacteria the cause of disease or the result? Once again, Koch considered the question, mulling it over.

  Then he began an experiment.

  CHAPTER 2

  1875 • The Germ Theory

  Sketch by Robert Koch of Bacillus anthracis, from his 1876 paper

  Koch’s first experiment, on the evening of December 23, 1875, was remarkably simple: He went outside to his garden, pulled a healthy rabbit out of its cage, and brought it back to his makeshift laboratory downstairs. He drew a sample of the animal’s blood and examined it under his microscope, making sure it was clear of the bacteria he’d seen earlier in dead animals. Then he took some blood from the corpse the police officer had brought over and injected it into the ear of the rabbit.

  Koch spent the following day tending to a full office of patients, and that evening, when he looked in the cage, the rabbit was dead. He removed its ear, cut off some tissue, and examined it under the microscope. The bacteria were there, “in moderate numbers,” Koch observed in his notebook.

  The next day was Christmas. Wöllstein was quiet as families celebrated the holiday at home. On Strasse am weissen Berge, Emma was preparing a holiday dinner upstairs, with Gertrud nearby. Downstairs, Koch was oblivious to the occasion. With no patients to attend to, he’d spent all day on his research. He removed some other tissue from the dead rabbit and found that it had even more bacteria than the day before; clearly these germs were reproducing. It wasn’t quite cause and effect, but the creatures were thriving. In his notebook, he planned a series of experiments that he hoped would link the bacteria to the disease.

  The following day, the patients returned. But Koch’s evenings were spent in the quiet laboratory. He injected one healthy mouse with blood from one that had been sick. When the new one died, he injected its blood into another mouse, and so on and so on, until twenty mice had passed along both the bacteria and the disease. “In all the animals the results were the same,” he wrote in his notebook, keeping assiduous track of every step. “The spleen was markedly swollen in appearance and contained a large number of transparent rods which were very similar in appearance.”

  Koch knew it wasn’t enough just to inject animals with infected blood. Davaine had followed that path in his experiments a few years before and had still failed to prove his case. Koch would have to go further. He would have to conduct a series of experiments that, with each step, established a chain of evidence that irrefutably connected the bacterium with the disease.

  This began, Koch realized, with Henle’s directive: to create a culture of the bacteria. Only by growing the microbes in something other than a living animal could he be certain his experiment was not polluted by something undetectable in the animal. The tricky part here was finding a medium for the growth. Many before had tried to nudge the anthrax bacteria to grow outside an animal, but they had failed.

  Koch’s solution was ingenious: the hanging drop. First, he took a cattle eye he’d procured from the local slaughterhouse, and drained the fluid, known as aqueous humor. In this fluid he placed a sample of spleen from a mouse that had died of anthrax. Then he placed a drop of the fluid on a thin slide, and fit this slide over a thicker slide into which he’d carved a small concave well. He lined the slides with petroleum jelly and pressed them together, forming a sealed environ-ment for the drop of fluid, which hung in the chamber. He put the slides under his microscope and had a look.

  For an hour, then two, nothing happened. The spleen tissue seemed to sit, inert, in the cattle-eye humor. Then, suddenly, the sticks of bacteria began to divide and grow. After a few hours, the whole drop was filled with microbes. They were clearly alive, and they were clearly growing in this novel medium. The chain of evidence was falling into place, and Koch’s notebooks grew thick with drawings of Bacillus anthracis, the whorls of filaments covering the pages.

  As Koch’s experiments went on, his backyard menagerie began to thin out; his daughter, Gertrud, grew concerned that she was losing all her pets. He needed a new pool of animals to experiment upon. Koch and Emma set live mousetraps in the horse barn behind their house. They caught a bounty and stuffed them into tall glass jars with some holes poked in the lid for air. When he needed an animal, he’d pull one out,
tail first, using an old bullet extractor he’d saved from the war. After the mouse had died, ostensibly from the microbes, Koch would dissect it, searching for the bacteria—and then dispose of the cadaver by burning it in the oven. Later, he found a more dependable source of animals, after a friend sent Gertrud some white mice as pets. The animals began reproducing rapidly, and Koch began using the extra supply in his lab. These became one of his most iconic contributions to science: the white lab mouse.

  By this point, Koch needed some dedicated space for his experiments. He took a heavy brown curtain and hung it across the ceiling of his examination room, dividing it in two: one side was for patients, and the other served as his laboratory. As soon as he was done seeing patients, he would cross behind the curtain and turn to his experiments, staying up long into the night. Working without electricity, he struggled to maintain the right temperature to grow his cultures. Soon he devised a layered element of sand, paper, and glass that he could place over a low flame. The technique maintained the culture at a steady ninety degrees Fahrenheit—an ideal climate for home-brewed anthrax. In this way, his one experiment contained a multitude of smaller experiments, a pyramid of challenges Koch had to solve one by one in order to work toward the larger question of causality.

  He began to buy more equipment: a new, more powerful microscope; a spectroscope; and a microtome (an instrument for cutting small tissue samples). He began to skirt appointments and beg off house calls in town in order to do one more experiment, to check one more mouse spleen under the microscope. Emma found herself running interference for her distracted husband. “It was my job to find out first how sick a patient really was,” she explained to her father, “and to send away those who didn’t really need medical attention. In that way, Robert could often remain for hours at his work.”