The Demon Under the Microscope, page 17
There was more good news. Bayer slowly, conservatively began letting Streptozon out for tests in human patients. Today the testing of new medicines in humans—clinical testing, as it is called—is a highly organized process with established ethics, regulations guiding the informed consent of patients, and detailed safety guidelines. In 1933, it was a far more haphazard business. It was still common for physicians or chemists who found a new medicine to test it first on themselves, on colleagues, even family members. As drugs became more powerful, so did side effects—and so did concerns about trying new chemicals on humans before they were proved safe. Bayer and other European chemical firms often went to Africa to do large-scale human tests. In Britain they used soldiers. In the United States, tests were done on prisoners and inmates in mental institutions.
None of these things were done with Streptozon. Instead the drug was leaked to hospitals quietly, on a case-by-case basis. Domagk talked about it to physicians he knew in the area around the Elberfeld plant, who in turn told others. Within a few weeks of the Christmas patent, word began to spread about a new drug that might cure strep diseases. Domagk started receiving letters from physicians begging to try it in patients dying of strep and other diseases. He personally distributed samples to a few nearby hospitals.
The first tests of Streptozon in humans were more humanitarian gestures than carefully run experiments. A young Düsseldorf physician named Förster in early 1933 was about to lose a ten-year-old boy to advanced blood poisoning when he heard about Streptozon from an older physician in his hospital, who had heard about it from his friend Heinrich Hörlein. It was not a strep disease—it was staph blood poisoning—but it was a hopeless case, the boy would likely be dead within a few days, Streptozon had some limited effect against staph, so why not? No one knew what a proper dose should be. Förster treated the boy like a very large mouse, extrapolating an effective dose from what had worked in a certain-weight animal up to the weight of the child. He gave the boy a red tablet to swallow, then crushed another half tablet in water, the particles refusing to dissolve but small enough to swallow easily, and had him gulp that. No one knew what to expect. Within a few hours, the boy’s skin turned bright red. Förster gave him another half tablet. The next day the boy’s temperature started to come down. After three days and a total of just four tablets of Streptozon, the infection, to everyone’s surprise, seemed to have disappeared. The red-stained skin faded. The boy appeared to be totally cured. Förster reported the case to a meeting of dermatologists in May 1933—the first public announcement of Streptozon’s effects in a human—setting off another round of requests for samples.
Domagk provided Streptozon to one of his friends, Philipp Klee, the head of internal medicine in the nearest large hospital, in the newly created town of Wuppertal (an amalgamation of several older villages, including Elberfeld). Domagk and Klee had similar temperaments, both reserved, sensitive, careful, and intellectual. They even looked alike, with high foreheads, upright bearing, receding hairlines, and piercing blue eyes. They shared an interest in art as well. Domagk had long appreciated modern painting, and Klee had married a Budapest artist, Flora Palyi. It did not matter much to either of them that she was Jewish.
Klee tried Domagk’s new medicine on an eighteen-year-old girl who had entered his hospital with a severe strep throat infection. The bacteria were invading her body, creating abscesses behind her tonsils, threatening to get into her blood. Her temperature shot up, and her white blood cell count skyrocketed. The usual therapy, opening and draining the abscesses, helped for a while, but the girl relapsed. Her temperature rose again; a blood clot formed in her jugular vein (one of the ways the body tries to stop a blood infection); she was shivering and drenched in sweat. Then her kidneys started to shut down, and she stopped urinating. She was about to die. With nothing to lose, Klee dosed her with Streptozon. The next day her temperature fell to normal. Her kidneys restarted, and she began urinating “copious amounts,” Klee reported. She was kept under observation and given continuing doses of Streptozon. A few weeks later, they could find no trace of strep in her system, and she was discharged. Klee got more of the drug from Domagk and began using Streptozon on patients suffering from a variety of infections, inflamed tonsils, boils and abscesses, fevers following septic abortions and childbirth. Not all of his attempts resulted in a cure. But most of them did. “The results were indeed miraculous,” a medical historian wrote later. “To the properly skeptical and meticulous Philipp Klee, who had seen so very many of his patients die from exactly the same infections, this was the most wonderful experience of his life.”
The word spread, and the requests for Streptozon grew to a steady stream. In Düsseldorf a senior physician in the skin department named Schreus—the same friend of Hörlein’s who had gotten the drug to Förster—tried it against two of the worst infectious diseases in hospitals, erysipelas and cellulitis, as well as strep-caused joint infections and rheumatic fever. Again there were cures in most cases. He did find that the new drug had little effect on strep infections of the heart and was unable to reverse the most advanced cases of infection in older patients, after the circulatory system had begun collapsing or if their fevers rose too high. Overall it worked best against strep, as expected, and sometimes, although less often, against Staphylococcus infections. In younger patients, especially, its effects were incredible. Side effects were limited to some nausea.
The cases were individual, the amounts of drug used variable, the results communicated, if at all, in small meetings or in relatively obscure German medical journals. As Hörlein wished, the news about Bayer’s new miracle drug remained contained and muted while his team continued to work. By the summer of 1933, Streptozon had been shown to be both effective and safe in animal tests and in at least a few humans. By the summer of 1934, the drug had been tried on a growing number of patients and was available to a handful of German physicians for testing in both tablet form and as an injectable solution. But in late 1934, fully two years after the initial patent had been filed for Kl-730, there had still been no widespread release of the medicine, no articles from the Bayer team relating their success published in any scientific journals, no reports of the animal tests, no general public announcement from Bayer that the company had discovered the world’s first antibacterial medicine, a safe, effective compound capable of saving hundreds of thousands, perhaps millions, of lives each year. Bayer continued releasing other drugs—an injectable liver extract, a new antiepilepsy medication, an improved successor to Atebrin—in addition to pushing forward research into synthetic rubber and synthetic fibers. But the company kept curiously quiet about Streptozon.
Hörlein said later, when asked about the long delay, that within Bayer there was a level of disbelief that had to be overcome; extraordinary care, he said, had been taken in testing and retesting before making announcements because, in effect, Streptozon was too good to be true. The impression he gave was that skeptics within the company needed to be convinced by repeated and confirmed proof of the drug’s power, especially concerning safety, before they would risk the firm’s reputation by announcing it to the world. Hörlein’s excuse is plausible, but more than one observer has pointed out that in fact Bayer did not seem to put much effort into testing the medicine’s safety through extensive human trials, instead letting the drug trickle out on a case-by-case basis, lessening the chances of definitive large-scale experiments in human subjects that would have convinced the skeptics.
Another reason for the delay might have been that Bayer was hoping for something better. Mietzsch and Klarer’s continued tinkering with azo dyes hinted at new forms that might be effective against gonorrhea, staph, and tuberculosis. As long as their work remained secret, Bayer would maintain its position as the only place in the world doing research on sulfa-containing azo dyes. Publicizing Streptozon threatened to draw the attention of the rest of the world’s drug firms, possible poachers on Bayer’s preserve. There was no way to protect the area forever, because their work already showed that any number of azo-dye derivatives could be active as medicines; Bayer could not patent them all. But delaying publicity about Streptozon gave Bayer time to find and patent the best of them. It was all right for Domagk to pass the drug out to a few of his medical friends for emergencies, and it was necessary to get at least some clinical backing for the eventual marketing effort, but there was no hurry. As long as the patent they had filed back in 1932 was still under review pending final approval, it would not be made public. They had time.
They could not keep it secret forever, though. Physicians using the drug were talking too much. As far away as England, by 1934, a few physicians and chemists knew that, as one put it, “something was brewing in the Rhineland.” On December 13, 1934, Bayer’s patent for Kl-730 was granted and entered into public record. Anyone who wanted to know how to make Streptozon, at least in vague terms, could now look it up. Publication of the patent seemed to push Bayer into finally releasing the drug widely.
It now had a new name, thanks to the advertising and marketing offices at Bayer. The most recent clinical tests had shown that the drug sometimes worked against staph and gonnorhea infections, and a new name was needed that was not limited to strep. The name they chose, Prontosil, also hinted at the fact that it worked quickly.
Then, two years after the fact, Domagk finally began writing his first article on the discovery. It was a strange piece of work. In it Domagk described only one of his scores of animal experiments, a test his lab had done on Kl-730 and strep just before Christmas 1932. He did not mention anything about the other eight azo dyes tested at the same time against the same germ, all of which gave equally dramatic results. He did not note any of the results in rabbits or give detailed information about the medicine’s effects against any bacteria other than strep. Still, because of its importance in announcing the scientific methods used to find the world’s first widely effective antibacterial chemotherapy, it has become a classic of medical history. “It is currently the general opinion that only protozoal infections can be attacked by chemotherapeutic means,” Domagk began, and went on to review the many failures in the search for ways to attack bacteria, the chemicals that had proved ineffective or too toxic, before running through his results from December. The paper, “A Contribution to the Chemotherapy of Bacterial Infection,” appeared—in conjunction with papers from Klee and others that detailed a few clinical successes—in a leading German medical journal in February 1935.
It was then generally ignored.
Part of the problem was the limited scope of Domagk’s paper—one experiment only—and the too-perfect results he got, every control animal dead, every test animal healthy, which raised the natural skepticism of physicians. The results came from an industrial lab, which in itself was suspect. There was no explanation given for the two-year-plus delay between the date of the experiment and the date of publication. There was no indication of how the drug might achieve its surprising effects. There was the puzzling fact that the medicine did not work in the test tube. As Domagk noted in his paper, “Whether Prontosil acts directly or indirectly against the pathogen in the body cannot be decided as yet. It is remarkable that in vitro it shows no noticeable effect against Streptococci or Staphylococci. It exerts a true chemotherapeutic effect only in the living animal.” Then there was Domagk’s tone, oddly restrained, mentioning the shortfalls of the drug in treating anything other than strep and calling for “close cooperation” between physicians and bacteriologists to identify the source of infection, a manner of writing described by one historian as “extremely conservative as to conclusions.”
A single, suspiciously good animal experiment, a number of significant questions, and a handful of anecdotal reports of human cures were not the stuff of wild enthusiasm. No wonder the paper was greeted with what appeared to be a collective yawn.
It was not, however, totally without effect. The German journal in which it appeared was respected and widely read, so many people saw the paper even if few were enthusiastic about it. Its publication seemed to open the door for more clinical reports, which now began showing up regularly in medical journals: Dr. Gmelin in Essen cured blood poisoning in children with Prontosil; Dr. Veil in Jena reported positive results treating rheumatism; Dr. Anselm in a women’s clinic, cures for patients with childbed fever. Physicians were getting good results in Dortmund, Frankfurt, Cologne, Göttingen, Munich, and Berlin. Veterinarians began reporting success in treating livestock. Bayer finally began rolling Prontosil out into the marketplace, relatively slowly at first, in Germany, then throughout Europe. Instead of requests for samples, Domagk now received correspondence from German physicians asking for advice on proper dosages and target diseases.
The grand dream of an effective antibacterial chemical—history’s first—was about to be realized. Despite all the worries, skepticism, and disbelief, it appeared that Prontosil really cured human disease. A nontoxic internal disinfectant exquisitely targeted to bacteria, Ehrlich’s long-sought Zauberkugeln, had finally been found. Panacea, after thousands of years of failed attempts, had finally awakened.
CHAPTER TWELVE
ON OCTOBER 3, 1935, Heinrich Hörlein delivered a lecture to the prestigious Royal Society of Medicine in London on the chemotherapy of infectious diseases caused by protozoa and bacteria. The talk was heard by many of the leading health experts in the United Kingdom. The news of more human cures in Germany was beginning to draw attention in other European nations, and Hörlein used his Royal Society appearance both to inform the curious and to rouse enthusiasm for the new drug Prontosil among practicing physicians. He reviewed Domagk’s results, published in a German journal eight months earlier but still news to many in the audience, stressed that the new azo dyes were “remarkable for their non-toxicity,” and made certain that the British physicians in the audience knew that the Germans had seen “remarkable effects” using Prontosil in a number of streptococcal infections, where “in many cases it has proved a lifesaving agent.” He noted as well that the drug was almost entirely strep-specific, having little effect on other bacterial infections—with the sole exception of a limited benefit against staph.
Sir Henry Hallet Dale, first director of England’s National Institute for Medical Research, was impressed. He already knew more than most Englishmen about Prontosil. He had been introduced to the drug back when it was still called Streptozon, well before Domagk’s first paper appeared. On a visit to Elberfeld in 1933 or 1934, he saw for himself the enormous effort German industry was putting into pharmaceutical research and heard about the dye-medicine that could cure strep infections in mice. Immediately after Domagk’s article appeared in February 1935, Sir Henry asked for samples. He knew that the clinical results reported in Germany were inadequate—too few patients, no proper controls—and he wanted to get the drug to a British researcher for more thorough testing. The best man for studying a new drug for strep infections, he thought, would be Colebrook, leader of the investigations into childbed fever at Queen Charlotte’s.
Sir Henry was a forward-looking man. He believed that medicine was finally about to take its place as a science as much as an art. This new, modern medicine, armed with the latest and most powerful tools from biology, chemistry and physics, X-ray machines, centrifuges, chromatography, immunological techniques, research into the molecules of life, controlled experimentation—the methods and approaches of the established “hard” sciences—was going to usher humanity into a golden age of health. These were the tools Sir Henry had used while researching nerve conduction, and they had worked. Now there was talk of a Nobel Prize for his research. Sir Henry’s technological optimism was positively German, confirmed, perhaps, during the months he had spent as a young man in Ehrlich’s lab, a wonderful introduction to dyes and medicine. Sir Henry had seen the future unfold when he saw Ehrlich’s methylene blue bringing to light the fine pattern of nerve cells under a microscope. He still kept up with the latest news from Germany.
After reading Domagk’s article, he quickly wrote Bayer. “Colebrook is interested to try a new preparation issued by the Bayer Products Company called ‘Prontosil’; and I wrote to Dr. Hörlein, of Elberfeld, to obtain some,” Sir Henry told a colleague. “He replies that they will be delighted to supply all that is required.”
Delighted, perhaps, but not swift. The remainder of March passed, then April, May, the rest of the spring, and a good part of the summer of 1935 before Colebrook finally got the promised Prontosil tablets plus a supply of the deep red liquid that the Germans were still distributing under the old name “Streptozon solubile.” Colebrook’s coworker Ronnie Hare thought that the Germans seemed “less than willing” to let Colebrook have the Prontosil, a delay that Bayer’s representative in England blamed on a “hitch in the supply.” The reasons were not important. After his failure to save any new mothers in the Isolation Block with arsenicals, Colebrook was simply happy to begin testing the promising new drug. He, too, had seen Domagk’s paper and the accompanying clinical reports as soon as they appeared—and like many readers was unimpressed. The human tests were too sketchy to be convincing. Domagk’s own findings were both too much and too little: those suspiciously perfect results, yet in only a single mouse test; no references to similar basic research; no ideas on how this medicine picked strep to attack; no idea of how or why the drug worked. Prontosil looked like, as Hare put it, “another of those damned compounds from Germany with a trade name and of unknown composition that are no use anyway.”
But Colebrook was willing to try. It was, after all, reportedly nontoxic, so why not? He got his first batch of Prontosil on July 18, 1935, and immediately started work on strep infections in mice, seeing if he could replicate Domagk’s initial findings. What he saw made no sense when put up against the German reports. The new drug did not seem to cure strep infections at all. The mice he treated with Prontosil died almost as fast as those he did not. Three months later, after Hörlein’s Royal Society speech, Colebrook was still struggling to get some positive results.
