The Remedy

by Thomas Goetz

  The only question was, which of the two men would the world believe?

  Part III

  CHAPTER 8

  1891 • The Fall of Dr. Koch

  Robert Koch and his second wife, Hedwig, in 1908

  All across Berlin, the letters began to pile up. Koch’s announce-ment of his remedy had directed doctors who wished to make their own investigations to his colleague Dr. Libbertz. And so, every day, the postman would arrive at Libbertz’s office and drop a knee-high pile of letters upon the floor, each message a plea for some small amount of the remedy. When word got out that the Berlin clinic of Dr. Georg Cornet had some stock, the letters arrived there as well. “There was no stopping [them],” Cornet observed. “Like a growing avalanche, letters and telegrams from all countries and in every language reached Koch and were passed on to me, and within a few days my correspondence also numbered in the hundreds.”

  The appeals came from physicians hoping to secure some lymph for their patients; from hospitals and sanitariums hoping to provide some last treatment in their wards; and mostly, from the patients who had been struck by the disease. They were all desperate for what might be the only chance for survival.

  Actual doses of the remedy, meanwhile, were scarce, almost mythic. The production process was slow, and since the substance was a secret, only Drs. Koch and Libbertz knew how to manufacture it. Libbertz’s supplies were soon gone, and he expected it would be months before there was enough supply again to meet the demand.

  But that demand was unquenchable—it comprised, after all, a quarter of all humanity or more. These were millions of people who had little hope, until Koch had offered a bit more. So they sent letters, hoping that theirs might land somewhere and earn enough notice, enough sympathy, to merit a dose of Koch’s remedy. Their stories were both uniquely and uniformly tragic. Charles Pratt lived in Minneapolis, Minnesota, when his daughter developed TB. In search of a cure, the family subsequently sold their home and moved to consumptive colonies in Phoenix, then Tucson, their savings dwindling with each passing day. By the time word of Koch’s cure reached the western United States, the Pratt family was living in a tent in Idaho at 3,500 feet. But the disease wouldn’t release its grasp on the girl. “Is there any place in the world where the Koch method of treatment by inoculation is so successfully tried, as to make it worthwhile to go there?” the desperate father wrote to a Philadelphia physician who he had heard was influential. “Pardon this from a stranger.”

  • • •

  FROM PARIS, PASTEUR SENT A TELEGRAM CONGRATULATING KOCH for his efforts. Even the French press joined in the acclaim: “All the world rejoices in the humanitarian significance of Koch’s discovery,” one Paris reporter offered. In the meantime, Koch dispatched his assistants throughout Europe to conduct public demonstrations of the remedy, including in London, Edinburgh, and Paris.

  The acclaim, though, was tempered by concerns that Koch had been uncharacteristically secretive about his remedy. He, of all people, should be keen to divulge it, in the interest of science. After all, as The Review of Reviews noted in an introduction to Conan Doyle’s essay, “according to the rule of the profession, no cures wrought by secret remedies can ever be examined into. All dealers in secret remedies are quacks. But Dr. Koch, as far as the retention of the secret of his remedy goes, is as much a quack as Sequah or Count Mattei.” Sequah and Count Mattei were the two most notorious quacks of the day, and ordinarily they would be held up as Koch’s opposite. Clearly, his reputation was on the line: What, exactly, was in this lymph? Why, people wanted to know, was this a secret remedy? Why wouldn’t he share his discovery with the world, as he had every time before? What was Koch afraid of?

  Today, the gold standard for medical research is the randomized clinical trial, or RCT. A group of patients, all suffering from a condition, are randomly divided into two groups: One is the case group, which will receive the treatment (typically a drug), and the other is the control group, which will receive a benign placebo (typically a sugar pill). The experiment must be double-blind, meaning neither the patient nor the investigators know which patients are receiving which treatment. (The results are monitored by a lab assistant, not the principal investigators.) In this way, wishful thinking on the part of both the study subjects and the researchers is minimized.

  The basic structure for a clinical trial dates back to British naval surgeon James Lind, who wanted to examine whether citrus fruits helped sailors avoid scurvy, the nasty wasting away of connective tissue caused by a deficiency of vitamin C. Though lemons and limes had occasionally been thought effective against the disease, that knowledge was anecdotal. In 1747, Lind set about to test the theory rigorously. He divided twelve scurvy-afflicted sailors into six groups of two. He gave them the same diet, but each pair received a different supplement: cider, sulfuric acid, vinegar, seawater, barley water, or oranges and lemons. After less than a week, the duo getting the fruit had recovered, while the others were still suffering. Lind published his results in 1753, though it would take fifty years (and the deaths of thousands more sailors) before his results were put into practice.

  The experimental method got another boost in the 1830s, when French physician Pierre Louis took the then-radical position of urging his colleagues to forsake their subjective assessments and instead apply statistical rigor to their experiments. “Let those who engage hereafter in the study of therapeutics . . . demonstrate, rigorously, the . . . degree of influence of any therapeutic agent on the duration, progress, and termination of a particular disease.” (Louis would mentor Oliver Wendell Holmes when he studied in Paris.)

  Despite these pioneers, the standard protocols for the RCT were developed surprisingly recently, in the 1940s and ’50s, by the British epidemiologists Arthur Bradford Hill and his colleague Archie Cochrane. Cochrane’s passion for the RCT is legendary: “Randomize, always randomize!” he would implore his students in Cardiff, where he taught at the Welsh National School of Medicine. Cochrane, who developed his methods as a German prisoner of war in the 1940s, was certain that if investigators knew which groups were getting which treatment, bias would inevitably slip into the analysis and destroy the credibility of an experiment. The magic of randomization is that it greatly reduces methodological biases, and it makes room for statistics. Statistical analysis is the lifeblood of contemporary science. It provides the foundation for evaluating the validity of an experiment’s results and a common language for other scientists to pursue their own analogous experiments.

  Study design is just one of the formalities we now take for granted in modern medical research. The second is experimental oversight, specifically an ethical review to assess whether the research itself is within the bounds of accepted values. Today, every experiment involving human subjects must be approved and monitored by an institutional review board, or IRB, an independent ethical committee with a mandate to ensure that all human subjects are both informed of possible risks and protected from any physical or psychological harm. In the United States, IRBs are run in close affiliation with major research institutions; IRBs are also regulated by the Food and Drug Administration.

  None of this existed in Koch’s day. The experiments involving tuberculin were, by today’s standards, reckless, disorganized, and conducted with scant regard for individual human life. Shipments of tuberculin were sent all over Europe, their destinations determined as much by personal connections as by need or scientific bona fides. Within weeks of the November demonstration, tuberculin experiments were under way in several academic clinics in Berlin and around Europe, and in private clinics and sanatoriums around Europe and the United States. Those with enough resources procured their own supplies, and soon private individuals were conducting their own regimens. Koch appears to have personally selected some physicians to receive a supply of tuberculin, enough for a demonstration of its potency, but not enough to conduct a thorough assessment of its efficacy. These experiments were more spectac
le than science, and some physicians began criticizing the whole thing as so much sensationalism. An anonymous letter to The Lancet made the point:

  Day after day the gaping multitude were informed how Dr. This and Dr. That, having received a sample of the precious fluid, had proceeded to inject it in the presence of a circle of admiring and envious confreres. The ceremonial, which might have been the performance of a sacred rite rather than the administration in minimal doses of hypodermic injections of a secret remedy was . . . chronicled with as much detail as a fashionable wedding or a public funeral.

  Even when there was enough supply to afford a true experiment, there was no such thing as a standard protocol. Each facility followed its own interpretation of Koch’s rather imprecise descriptions of proper dilution and dosage. In practice, dosages varied widely, as did the frequency and timing of injections; physicians seemed to be calibrating these factors by gut instinct, depending on the severity of a patient’s symptoms. Some gave patients a course of six doses of seven milligrams each; others gave more than twenty doses of twenty or more milligrams each. Even how to administer the dose varied; Koch suggested an injection in the back, between the scapulae, but others tried injections in the arms and legs. Record keeping was haphazard at best, with most clinics noting how symptoms progressed hour by hour, but with descriptions and terminology at the discretion of the note taker. (The patient’s name, age, and occupation were routinely disclosed in full, while the physician was identified only by his initials.) In some hospitals, the injections were performed almost ceremoniously. When a shipment of the remedy arrived at a hospital in Greifswald, a town on Germany’s north coast, for instance, the whole staff turned out for the occasion. “Against a background of laurel bushes, doctors, nurses and patients in snowy-white garments and the chief in his black cutaway were lined up: Address by the internist, injections for a chosen group of patients, thundering hurrahs for Robert Koch.”

  In terms of patient response, the reactions varied widely. Some people seemed to improve almost instantaneously, such as a woman suffering from tuberculosis in her throat. After three injections, she appeared entirely cured. Others seemed only to get worse from the moment of the initial reaction, their temperature spiking and their experiencing frequent nausea and vomiting. Injections were given to patients almost randomly, for various reasons: to severely consumptive patients near death, to test the degree of their fevers; and to those suffering from nonconsumptive diseases as well, such as syphilis or meningitis, just to see how they reacted. The remedy was given to men and women; to children of eleven, six, and two and a half years old; and even to newborns, despite von Bergmann’s declaration that he “considered the use of Koch’s medication in children under the age of 10 extremely dangerous.”

  Inevitably, patients began to die in the throes of fever, their limbs thrashing violently, in what would today be recognized as shock. Worryingly, this sometimes happened even to patients whose phthisis had seemed to be in remission. Undoubtedly, some died because the general rule was to increase the dose gradually, even if low doses provoked severe reactions. In the thrall surrounding the treatment, though, these unfortunates were quickly dismissed as having been beyond help to begin with.

  In all, it was an uncontrolled, absolutely chaotic process, closer to anarchy than experimentation. But the enthusiasm for a cure was such that a sense of euphoria overtook even those who should have been immune, including Lord Lister. In late 1890 he visited Berlin with his niece, who had a case of consumption. Though Koch greatly admired Lister, it would be a week before he could see him and arrange for treatment. Upon his return to London, in an address at King’s College Hospital, Lister gave the remedy his full endorsement. “The effects . . . are simply astounding,” he said, comparing the effect to Pasteur’s anthrax vaccine. Lister even endorsed the secrecy of the cure. Even now, weeks into an experiment being conducted upon thousands of individuals across the globe, nobody outside Koch’s lab knew what was being injected into so many people. “By publishing now the precise mode of preparing this material, he might do immense harm instead of good,” Lister suggested. Whatever it might be, Koch’s secret remedy seemed to be the cure that so many had yearned for.

  • • •

  ON NOVEMBER 22 (THE SAME DAY CONAN DOYLE’S PIECE APPEARED in The Review of Reviews), the German emperor bestowed upon Koch the Grand Cross of the Order of the Red Eagle, the government’s highest decoration, typically reserved for military heroes or royalty. In part this was payback. A few months earlier, the emperor had urged Koch’s patron, Minister Heinrich von Gossler, to have something spectacular on tap for the International Medical Congress that took place in Berlin in August; von Gossler had asked Koch to deliver something appropriate. He had clearly exceeded expectations.

  As he watched Pasteur gain acclaim and honor in France, Koch had expected the same of his country. On October 31, when the human experiments were still in their early stages but before he had publicly disclosed the research, Koch made a formal request: He wanted a new institute dedicated to the production and study of tuberculin, with himself as its director.

  He was keenly aware of the prospect of financial gain from his discovery. In his proposal, he suggested that, for six years, he be the sole beneficiary of tuberculin sales; the rights would thereafter be transferred to the German government. The money involved was not trifling: At a daily production of five hundred doses, a conservative estimate, Koch calculated that his new institute would earn 4.5 million marks a year on tuberculin. Thanks to the constant supply of people with tuberculosis, he noted, there would be a guaranteed long-term demand.

  In early November, Koch and German officials reached an agree-ment: Koch would run an institute with two purposes: first, for clinical testing of tuberculin, and second, as a laboratory for medical research. He would get his monopoly.

  No official announcement was made, but rumors soon began to spread. A London paper reported that Gerson von Bleichröder, von Bismarck’s private banker, had agreed to contribute one million marks for Koch’s new clinic; this was reputed to be matched by another million from the German government. Others began to speculate how much Koch would be personally profiting from the remedy. By December, his institute deal had become an outright controversy, verging on scandal. With the remedy itself still unproven, the German chancellor exercised his privilege to veto the deal, explaining it would be unseemly for Koch to be perceived as exploiting his remedy for personal gain. The negotiations were put on hold until “public opinion has a clearer idea as to the value of the medication.”

  Koch’s continued secrecy about the actual composition of the therapy was particularly vexing. In a rare interview with the press, he offered the reason for his secrecy. He was concerned, he said, that if he disclosed the formula before his testing was complete,

  thousands of medical men, from Moscow to Buenos Aires, would tomorrow be engaged in concocting it, and injecting it for that matter. Is it far-fetched, then, for me to suppose, as I do, that more than half of these gentlemen are incompetent . . . ? Then these experiments might cause incalculable harm to thousands of innocent patients, and at the same time bring into discredit a system of treatment which, I believe, will prove a boon to mankind.

  But physicians were growing suspicious. Koch’s reputation had protected him so far, but as the experiments continued and expanded, more medical men began to openly voice their concerns. A Berlin colleague of Koch’s, Ernst von Leyden, noted in late November that “the clinician finds himself in a peculiar position. We have received from the hands of a scientist of genius a medication for our use, yet we have no information about its nature; save for some vague conjectures, it is shrouded in mystery.” In December, a doctor from Heidelberg wrote of “the unease that creeps up on every physician when he has to operate with a secret nostrum.” Indeed, it’s a remarkable testimony to Koch’s reputation that so many physicians injected it into their patients, and that so many people from
around the world continued to flock for a dose of his treatment, without the least sort of understanding of what it might be.

  • • •

  BY YEAR’S END, THE DATA HAD STARTED TO COME IN. IT DID NOT look good for Koch. At least sixty-nine scientific papers appeared on tuberculin, mostly case studies. The Prussian government gathered the evidence into a summary report. In these, some 2,172 people had been injected with tuberculin, receiving a total of 17,500 doses. These patients suffered from every manifestation of the disease, from pulmonary phthisis to lupus and scrofula. The results were ambiguous at best: Of 242 patients with pulmonary TB treated with tuberculin, 9 appeared to have been cured, and 131 seemed improved. Of 444 advanced cases treated, there had been just 1 cure and 68 more or less improved. In 188 cases of lupus treated, 7 had considerably improved, 31 had improved, and 30 had died. Overall, just 28 cases could be declared as cures, with nearly 2,000 uncertain or unimproved cases. These were not the results of a successful trial by any means.

  That January, even as the experiments continued around the world, the Berlin Medical Society decided that, given the gravity of the disease and the controversy over Koch’s cure, some sort of public assessment was in order. The society began a three-month-long debate on tuberculin, with all the Berlin clinicians who were testing it in attendance. Koch himself never appeared; he was, he said, too busy in his laboratory conducting research.