The Demon Under the Microscope, page 11
That was Roehl’s next target. Before he could zero in on it, however, he had to find a suitable test animal. The malaria parasite, so lethal in man, could not be grown reliably in standard lab animals like mice or rabbits, but Roehl found that he could grow a closely related parasite in birds. He began to use canaries as his test animal for drug screening. Soon the Bayer animal facilities were full of canary cages. With a test animal in place, Roehl began following a trail that had started with Ehrlich’s observation that his favorite blue dye, methylene blue, had shown a mild effect against the malaria parasite. Impressed by the Germanin success, the Bayer management team rewarded Roehl with expanded facilities for the antimalarial hunt. He was still part of a team, however, a central cog in a well-organized medical-research machine that now included another physician and two newly hired chemists, all dedicated to finding synthetic medicines. He no longer had to bother the dye chemists at Leverkusen to get his goods. Roehl’s job was to suggest fruitful starting points (like methylene blue), then allow the chemists to tinker with the starter molecules, adding an atom or a side group here, subtracting one there, creating variations. The new chemicals were delivered to Roehl, who was in charge of testing and retesting them in test tubes and animals, throwing out those that did nothing and requesting new variations on those that had any sort of effect. If one variation worked better than another, the team asked why: What did this or that variation do to improve the effect? Then they would try more variations around the same theme, looking for something with a stronger effect. A team effort at this scale was something new in drug research—particularly in German research, where the tradition was to center a laboratory around a single brilliant, autocratic scientist (an Ehrlich, say). Hörlein’s Bayer model was both larger and more decentralized. Roehl made suggestions, but he did not tell the chemists how to do their work. The chemists did not tell Roehl how to test. All results were sent up the line to administration for review and analysis. The Germans sometimes called it an American-style laboratory.
The size of the team, including all the assistants, animal keepers, and administrative support, translated into the ability to quickly screen hundreds of chemicals for medicinal abilities. Promising compounds now could be tested on several diseases at the same time: In the search that yielded Germanin, hundreds of chemicals were also tested on syphilis, in hopes of finding a replacement for the Salvarsan medicines (none was found). For every promising chemical, scores of others showed no effect whatsoever.
When the methylene blue trail played out, all those variations leading to another dead end, the Bayer researchers changed their focus to quinine. Chemical after chemical, all variations on the quinine pattern, were tested on cage after cage of canaries. It was years before Roehl’s research group finally came up with something that worked: a synthetic chemical thirty times more effective against malaria than any other they had tested—and much more effective, gram for gram, than natural quinine itself. The Bayer team was not set up to test new drugs on humans, so they sent their find to the Institute for Tropical Diseases in Hamburg, where physicians determined that it worked well in malaria patients, especially when boosted with a dose of natural quinine. Field tests in malaria-infested areas followed; these were successful as well. In 1927, Bayer started marketing the drug under the trade name Plasmochin in Germany (Plasmoquine in the English-speaking world).
It was not perfect. There were side effects—side effects of some sort or another were now expected in all new drugs—and the chemical worked at only one stage during the complicated reproduction cycle of the malaria parasite, which meant that timing became critical for effective treatment. But, used correctly, it could cure. The world’s first successful synthetic antimalarial, Plasmoquine broke the monopoly of the Dutch and South American growers. Bayer began marketing it aggressively, and money started to roll in. The company planned more expansion, new laboratories, a bigger drug-research program. Roehl was put in charge of parasitic (or, as they were also known, tropical) diseases, the area in which he had so much success. He never found a successful antibacterial chemical. Parasites and bacteria were far different organisms, so a completely new effort was planned to complement Roehl’s tropical-disease unit, a group devoted to bacterial diseases only. In 1927, Domagk was hired to head it.
Domagk owed a great deal to Roehl. His first laboratory was a few rooms carved from Roehl’s bustling operation, above a glassware storeroom. He saw how Roehl’s system worked, how he ran his tests, how he correlated his results. Domagk inherited both Roehl’s successful methods and a piece of the company support that started flowing to new-drug development thanks to the sales of Roehl’s Germanin and Plasmoquine.
Still, it was not easy. There was Bayer Elberfeld itself, an aging factory along the Wupper River, in which Domagk now worked. Elberfeld had the brick-and-smokestacks look of the nineteenth century. It was vaporous, dark, and the river, in 1927 when the Domagks arrived, was foul-smelling from decades of chemical pollution. The factory huddled along the banks in a particularly steep part of the valley, a space so narrow that a suspension railway was built to freight in workers; it screeched and clanked all day long. Gerhard and Gertrude had grown up in the open fields and fresh winds of the lake country of the Brandenburg March. They hated the darkness, the smell, and the constriction. The people were different, too: The Domagks found that here in the Rhineland people did not seem as friendly as they had at home; they sometimes got the impression that the locals looked down on them.
It was not a good start, especially coupled with his small rooms above the storage area and the small amount of help he was given to start with, one technical assistant and two boys to wash glassware. Hörlein told him that the new laboratory was on the drawing board and would be completed soon. There would be more room and more help. He just needed to be patient.
Then tragedy struck. In 1929, Roehl, Bayer’s drug-development star, a new Ehrlich well on his way to his own Nobel Prize, was hard at work finding an improved new version of his antimalarial. He was traveling in Egypt when he noticed a boil on his neck while he was shaving. As it turned out, the boil was infected with Streptococcus, the same germ that Sir Almroth Wright had identified as the most important cause of wound infections. The strep broke out of the boil and moved into his bloodstream. Roehl knew the physician’s nomenclature for his condition: bacterial septicemia, an infection of the blood. This was a bacterial infection. There was no cure. Domagk had been looking for an antibacterial medicine for two years but had not yet found one. A few days later, Roehl was dead. He was forty-eight years old.
DOMAGK’S RESPONSE was to throw himself into his work. He was in a hurry to find cures, to ease suffering, and to make his name, but Hörlein took a longer view. When it came to industrial research, Hörlein was both a visionary and an optimist. By the time he hired Domagk, he knew that most researchers had given up on Ehrlich’s magic bullets, convinced after years of fruitless searching that synthetic medicines were little more than a dream, one of Dr. Phantasmus’s fantasies. In the two decades since Salvarsan, all the excitement had yielded only Germanin and Plasmoquine, which were effective (although, like Salvarsan, with occasionally severe side effects), but only against tropical diseases, parasitic illnesses that mattered most to relatively poor people halfway around the world. In Europe and North America, Bayer’s major markets, most of the important infectious diseases were bacterial: pneumonia and tuberculosis, meningitis and blood infections, diphtheria and cholera. Chemical firms kept coming up with medicines they claimed would work, but none did. Ehrlich, it appeared, had been very, very lucky.
Hörlein was more patient than that. He wanted solid breakthroughs. He figured the search would take years. And he expected hundreds of failures along the way. But he had faith. One success against bacteria, just one, could open an entire field, lead them to a host of patentable drugs. IG Farben would reap enormous profits. Hörlein, with one foot in the research labs, the other in corporate boardrooms, approached the idea of synthetic medicines not from the standpoint of a single discipline—bacteriology, say, or chemistry, or pathology—but as the manager of an integrated business, able to devote enormous resources and the talents of many researchers to the quest. He kept his workers enthused and his bosses happy, led cheers when things looked hopeless and ensured a steady flow of money. As a former dye chemist, he also knew that the ways they had used to find new dyes—by taking a core compound and altering the bits around it—was the same as the process for finding new medicines. His team had proved the point with Germanin and Plasmoquine. This was Hörlein’s greatest strength: the ability to build teams and systems, to ramp up the search for medicines, to expand drug research from the lab of a single scientist to an efficiently organized industrial process with carefully chosen specialists guided by a coordinated strategy.
Hörlein was also proudly German, and enthusiastic about the ways his company’s success added to his nation’s reputation. “Every Aspirin tablet or Salvarsan ampoule used in the most distant countries bears witness to the high position of German science and technology,” he said in 1927. But his rhetoric belied the postwar realities: The demand for dyes had declined; international conflict had invigorated competing chemical industries in other nations; German pride had been wounded; the German economy was still in disarray. Hörlein believed, as did Duisberg, that one way to return Germany to the forefront was to find wonder medicines. IG Farben was ready to gamble. The giant firm had fat profits and massive reserves; money was available for big new investments. Synthetic gasoline was one of them. Synthetic rubber was another. And now, under Hörlein’s guidance, synthetic medicine was given its chance.
In 1927, the funds Hörlein needed to expand the program began flowing. He designed his organization, hired Domagk, brought in new chemists, expanded the test-animal operation, broke apart old research teams, and built new ones. The former bacteriological laboratory was dissolved. A new pharmacologist was hired. Domagk’s antibacterial-medicine program was launched. He started building new facilities, the most modern pharmaceutical laboratories in the world, the best equipped, the largest. The old Elberfeld chemical-research laboratories designed by Duisberg himself in the previous century—a warren of tiny lab spaces off a central corridor that the workers called “the Stables”—were kept as well, and there, up in the attic, was Workroom 4, a legendary lab space for chemists lit by skylights set in a low roof. Workroom 4 was old and somewhat cramped. It was unbearable in the summer, when the heat got so bad that the diethyl ether sometimes boiled in its bottles. But it was a badge of honor to work there. It was in Workroom 4 that chemists had created Germanin and Plasmoquine. It was a lucky place to work. And it was here that chemists started the flow of chemicals to be sent to Domagk for testing, in hopes of finding the next miracle: a drug that would stop bacteria.
HÖRLEIN’S PLAN for Domagk’s new laboratory was a single three-story building divided into thirds, one end for biochemical research, the middle for tropical diseases, and the last third devoted to Domagk’s research. Roehl’s death had been a setback, but Bayer was bigger than any individual scientist. When Roehl died, the basic plan was retained, with a successor hired to take on the tropical-disease effort.
Domagk was happy. He adapted Roehl’s (and Ehrlich’s) system, overseeing the testing of compounds provided to him by chemists. Bayer had a crew of them in the Stables making chemicals for both Domagk’s antibacterial effort and for the tropical-disease program. For maximum efficiency many of the same chemicals would be tested at the same time in both places. Soon Domagk was receiving new compounds from a half dozen chemists, the chemists pumping them out, Domagk testing them. They were relatively independent operations at Bayer. Only one of the chemists up in Workroom 4 was assigned specifically to Domagk. But one, as it turned out, was all he needed.
Josef Klarer was reputed to be something of a genius. Tall and handsome, a few years younger than Domagk, hired as part of the same 1927 expansion, Klarer had received his doctorate summa cum laude in Munich under the tutelage of Hans Fischer, himself a Nobel laureate. Observers had called Klarer’s thesis on dye structures “sensational.” He seemed destined for a stellar career in academia but had, it was said, turned down a professorship to come to Bayer. He was brilliant but also, as brilliant people often are, slightly unstable. Some chemists were theoretical, carefully thinking through structures, but clumsy in the lab; Klarer by contrast was a natural hands-on scientist with an inborn genius for lab work, a Mozart at the bench. Many chemists worked slowly and deliberately; Klarer was spontaneous and fast. He worked without any apparent plan, and he made it look easy. Yet there was something manic about him. At Bayer he could be found toiling fiercely at all hours. He ate irregularly, then disappeared for days at a time. He avoided talking with people and seemed gruff and touchy when forced into conversation. In the absence of communication, his coworkers gossiped: Klarer never slept; he had been severely wounded in the war; he had undergone a long convalescence (these last two were true). Most of his colleagues left him alone. The tradition at Bayer in any case was for chemists to work on their own, reporting up the ladder, not across the aisle to other chemists. It was a style suited to industrial secrecy. And it suited Klarer. The company appreciated his talents, so they allowed him to set his own work schedule, looked the other way when he took off, let him work all night when he needed to. Klarer made new molecules at a fantastic rate and sent them to Domagk for testing. He was the most productive chemist the company had. No one else could come close to his output.
The only person who could be even loosely be called Klarer’s “friend” was Fritz Mietzsch, another Bayer chemist. They made an unlikely pair. Mietzsch, who had come to the company a few years earlier to work with Roehl, was a model of organization, a reserved man, a neat dresser who kept regular hours, a meticulous planner who outlined each coming week’s work schedule in advance. Mietzsch was polite, quiet, scholarly, and respectful of authority. He never raised his voice. Mietzsch “kept his distance,” as one writer put it, “which was also a characteristic trait of Domagk’s.” Klarer worked primarily for Domagk, Mietzsch for the tropical-disease unit, but their lab benches were close to each other, and he and Klarer bonded somehow, the older man appreciating Klarer’s peculiar genius, the younger man turning to Mietzsch—himself a talented chemist, better grounded than Klarer in traditional techniques—when he ran into problems. There was a sense of the older chemist’s keeping an eye on the mercurial younger man. That would become important later.
For now they worked quietly in Workroom 4, tracing the patterns of atoms, unlocking the structures of chemicals, finding ways to take them apart and re-form them, altering them slightly, creating new compounds, hoping that one would become Bayer’s next miracle medicine.
CHAPTER EIGHT
DOMAGK COULD NOT TRY Klarer’s chemicals against every kind of bacteria. There were too many that could cause disease—scores of major infections, hundreds of minor conditions. So for testing purposes he used a panel that included some of the most common and deadly: tuberculosis, pneumonia, Staphylococcus, E. coli, and the germ that killed Roehl: Streptococcus pyogenes.
Strep might seem an odd choice today when the only strep disease most people ever experience is a bad sore throat. In the 1920s, however, it was one of the most feared killers on earth. No one was safe from strep.
In the summer of 1924, a skinny, gawky teenage boy loped across the South Lawn of the White House with a tennis racket in his hand. He looked frail, but when he played tennis, he gave it everything he had. On this particular afternoon, he wished he’d worn socks under his sneakers. When he got back to his room after playing, he found a blister on his big toe, which he treated with iodine and forgot.
Two days later Calvin Coolidge Jr., son of the president of the United States, started to feel weak and feverish. He felt pain in his legs. He went to bed. When the White House physician, Admiral Joel Boone, examined the boy, he found the foot with the blister inflamed and tender. Boone cleaned the foot, bandaged it, and ordered a regimen of bed rest and regular changes of antiseptic dressings. When President Coolidge heard that his son was ill, he became unusually concerned. Calvin Jr. was his favorite, his youngest. Some historians later pointed out that the boy’s face resembled that of the president’s beloved mother, who had died young. Boone told the president and the First Lady not to be too concerned: The foot was infected, but with proper care healthy young men could shake off an infection like this within a week or two. He would keep a close eye on Calvin Jr.
The next day the boy’s stiffness and pain were worse. Boone was a decisive physician—he had won a Medal of Honor in France during World War I—and he was not one to spend much time playing wait-and-see. He drew blood samples and drove them personally to Walter Reed Hospital. When he saw the results, his concern increased. It looked as if the boy’s blood was infected with a particularly bad germ, a fast grower that was famous for spreading quickly through the body, shedding poison as it went. It looked like Streptococcus pyogenes, the main culprit in wound infections during World War I. Boone started moving quickly. When he got back to the White House, he found Calvin Jr.’s temperature soaring. He did what he could, eased the pain, cleaned the area, changed the dressings, and hoped the boy’s immune response would kick in soon. That night he again consulted with the president and the First Lady. The next day, July 4, the president’s birthday, the boy was worse. The planned festivities were toned down. Guests left the White House. The boy’s room was turned into a hospital ward. Every medical expert on blood infections in the area was called in. The physicians tried everything they could to stop the infection, which was now moving up the boy’s leg.
