The Drug Hunters Read online

  By the 1830s, a new subdiscipline of chemistry had emerged known as synthetic chemistry. Synthetic chemists were able to combine simple chemical elements together into more complex compounds, like fastening together increasingly elaborate Tinker Toys. And the first businesses to harness synthetic chemistry for big profits were the dye companies.

  In 1856, an English teenager named William Henry Perkin, the son of a carpenter, was experimenting with the nascent techniques of synthetic chemistry in his small apartment—not much different than a high school student playing with a home chemistry kit today. While attempting to synthesize quinine, he serendipitously noticed that one of the resulting chemicals was a bright purplish color that readily dyed silk. He dubbed the never-before-seen color “aniline purple,” but the French would eventually rename it mauve. It was the world’s first synthetic dye. In a matter of years, mauve launched a massive international synthetic dye industry.

  For the first time, instead of relying on expensive plants or animals to produce natural dyes, companies could create fabric dyes by mixing chemicals in a lab. Even better, dye companies quickly discovered that by tweaking the chemical formula of one color they could easily get another color, offering up a seemingly boundless kaleidoscope of unimagined hues. Simply adding a couple atoms onto a molecule of red dye produced spectacular new shades of indigo, crimson, or violet. Since synthetic dyes could be manufactured in factories using highly efficient and scalable processes, they cost significantly less than traditional vegetable dyes. Fashion was transformed forever. For the first time, the middle class and even people of low means could afford garments bedecked with vivid, attractive colors. Everyone could dress like royalty.

  Although the first synthetic dye was discovered in London by Perkin, nineteenth-century Germany possessed a muscular capitalist culture and a sophisticated scientific community, including many of the world’s top researchers and institutions in the rapidly growing field of chemistry. As a result, the German dye industry quickly rose to global prominence as purveyors of quality synthetic dyes. (By 1913, Germany was exporting 135,000 tons of dye; Britain exported 5,000 tons.) And, finally, we can return to the Rhine. Most of the German dye factories sprang up along the Rhine because of its proximity to major European cities and because the river allowed for easy transport of both raw supplies and completed products across Germany, central Europe, northern Europe, and the rest of the world through the river’s egress into the North Sea.

  The Rhine dye companies not only became the world leaders of synthetic dye production, they also became the undisputed masters of synthetic chemistry, their cutting-edge research funded by profits from a public hungry for color. One of the most successful of these companies was Friedrich Bayer and Company. By the early 1880s they were selling hundreds of dyes to fabric manufacturers, but their executives had begun to look for new types of products that could leverage their growing expertise in synthetic chemistry. One of these Bayer executives, Carl Duisberg, set his sights on medicine.

  Duisberg joined Friedrich Bayer and Company in 1883 with a doctorate in chemistry. As part of his military service in Munich, he had previously worked in the laboratory of Adolf von Baeyer, a famous German chemist who later won the Nobel Prize for synthesizing the color indigo (Baeyer was unrelated to Bayer company founder Friedrich Bayer.) Duisberg had been hired by the Management Board Chairman of Bayer, who was searching for young gifted chemists who could “make inventions” using synthetic chemistry that Bayer could convert into lucrative products. In 1888, Duisberg established the Bayer Pharmaceutical Research Group with a mandate to invent new medicines.

  For centuries, all drug hunters—including physician-botanists, physician-alchemists, and industrial formulators—took it as a given that drugs could only be discovered, like a vein of gold or a hot spring, rather than crafted through human ingenuity, like a steam engine or a typewriter. The notion that it might be possible to engineer a drug to fight a particular malady required an enormous shift in perspective, and the first step in this shift was propelled by the newfound power and precision of synthetic chemistry.

  Up until this point, all the industrial pharmaceutical companies (such as Squibb) were focused on using chemistry to manufacture known drugs more efficiently and consistently. But Duisberg didn’t just want to improve the manufacture of existing drugs—he wanted to create drugs that had never existed before. The basic model of the synthetic dye business was to start with some molecules known to produce pretty colors and chemically tweak them to make even prettier colors. Duisberg asked, Why not do the same thing with medicines? Start with a good drug and chemically tweak it until it became an even better drug. One of Bayer’s first candidates for this speculative tweaking was a commonplace drug known as salicylic acid.

  Salicylates had been used for thousands of years to reduce fever, pain, and inflammation, and, like most drugs up that point, they were extracted from the library of botany. Salicylic acid was derived from vascular plants, large plants and trees such as the willow tree with nutrient-conduction systems that function like the circulatory system in animals. (Ironically, the fact that an extract from the willow tree cured fever seemed to fulfill a common principle in medieval drug hunting known as homeopathy. According to homeopathy, the cure for any given disease was found in the same place where the disease was contracted. For example, since swamps often produced fever, it was believed that the cure for these fevers would also be found in swamps. Since the willow tree was native to marshy terrain, the fact that a willow extract cured fever made a kind of sense to many eighteenth-century apothecaries.) The key ingredient from these vascular plant extracts remained unknown until 1838, when the Italian chemist Raffaele Piria developed a method for obtaining a more potent form of the willow extract, which he named salicylic acid after the Latin word for the willow tree, salix. Another chemist soon discovered that the active component in extracts from the meadowsweet, another vascular plant, was the same salicylic acid identified by Piria.

  As physicians became increasingly aware of the benefits of salicylate medicines and improved the effectiveness of dosing, the use of these drugs accelerated through the middle of the nineteenth century until salicylics became a standard component of every physician’s medicine bag. Even so, salicylic acid produced highly unpleasant side effects, particularly gastric irritation, tinnitus, and nausea. If Duisberg could find a way to reduce the side effects of salicylic acid while retaining its anti-inflammatory properties, then Bayer would have a chance to improve the drug—and make a fortune. All it needed, Duisberg hoped, was the right chemical tweak.

  Even in this earliest of incarnations, the rudimentary Bayer drug development group was quite similar to the drug development teams found in Big Pharma today. There was a chemistry team composed of chemists who synthesized the compounds, and a pharmacology team composed of biologists who tested the compounds in animals and—if the animal tests were promising—in humans. Duisberg hired two lieutenants to run the salicylic tweaking efforts, Arthur Eichengrün to head the chemistry research and Heinrich Dreser to head the pharmacology research.

  In general, organic compounds produced by plants are extremely complex and difficult to manipulate in a laboratory. It was Duisberg’s good fortune, however, that the salicylates were unusually good candidates for tweaking, for they are rather simple molecules that are easier to manipulate than most plant compounds. In the mid-1890s, Eichengrün, the head chemist, became interested in acetyl groups, small molecules with two carbon atoms that could be attached to many plant compounds, including the salicylics. In August of 1897, Eichengrün instructed Felix Hoffman, a junior chemist in his department, to add acetyl groups to two prominent plant-derived drugs, morphine and salicylic acid. Hoffman added an acetyl group to morphine (derived from poppy flowers) and created a new synthetic compound called diacetylmorphine. He also added an acetyl group to salicylic acid (derived from meadowsweet) and created a new synthetic compound called acetylsalicylic acid.

 
These two new drug candidates, diacetylmorphine and acetylsalicylic acid, were sent to Dreser (the head pharmacologist) for evaluation on animals and humans. Both synthetic compounds passed Dreser’s initial animal trials. But Dreser feared that he did not have a large enough budget to pursue a complete evaluation for both compounds. He believed that, given his limited resources, he could pick only one drug to develop. But which one?

  My first boss in the pharma industry taught me that the most difficult and important decision in drug hunting is the decision to “fish or cut bait”—whether to continue investing resources in the pursuit of a potential drug or cut your losses and move on. These decisions are always based on inadequate information, so scientists often end up chasing after bad drugs instead of good, commercial ones. The frequency of the wrong decision to continue fishing helps explain why 50 to 75 percent of all clinical trials fail.

  On the other hand, the mistaken choice to “cut bait” occurs even more frequently. When I was at Squibb I was trying to develop an alternate version of an existing antibiotic that was effective but somewhat toxic. I believed our initial work showed significant promise, but research management overruled me and shut us down before we could start our clinical trials. They decided to cut bait. Our competitor, Lilly, was trying to develop a similar antibiotic, but unlike Squibb, they decided to keep fishing. Their antibiotic eventually received FDA approval and is currently generating over $1 billion in annual sales.

  Back to Dreser, head of pharmacological research at Bayer. With regard to diacetylmorphine and acetylsalicylic acid, he felt he needed to keep fishing with one of them and cut bait with the other. Dreser was more concerned about spending resources on acetylsalicylic acid because of salicylic acid’s reputation for weakening the heart, which he feared would remain a side effect in the tweaked version. He judged that the morphine tweak was the more promising candidate and redirected all of his efforts into the development of diacetylmorphine, which Dreser renamed “Heroin.”

  Eichengrün (Bayer’s head chemist) arrived at the opposite judgment. He felt that if there were only resources to pursue a single compound they should keep fishing with acetylsalicylic acid, since there would be almost unlimited applications for an effective remedy that reduced fever and relieved pain. He did not have any hard evidence showing that the salicylic acid tweak would not produce side effects, however. In order to demonstrate that acetylsalicylic acid was safe and effective, he needed data from human trials—and Dreser was blocking any further clinical trials on the drug. Eichengrün knew he could appeal to their shared boss, Duisberg, but Eichengrün also knew that Duisberg held Dreser in high esteem. Not only that, in the team-focused culture of German business, it would have been highly unlikely that Duisberg would override the judgment of a man he had just put in charge of Bayer’s biological research. Even today, German drug companies abhor loose cannons and lone wolves. Eichengrün felt the pressure to toe the company line, but since he was convinced that the commercial potential of acetylsalicylic acid was simply too great to ignore he did something that daring drug hunters have always done—he went behind management’s back.

  Eichengrün approached a friend and colleague named Felix Goldmann, Bayer’s representative in Berlin, and quietly arranged for low-profile human trials of acetylsalicylic acid in Germany’s capital. This was truly the very dawn of human drug trials, so modern ethical concepts like informed consent had not yet been conceived, let alone implemented. Berlin doctors (and dentists) simply took the unidentified compound that Goldmann handed them and fed it to their patients. One dentist tested Eichengrün’s compound on a patient with a toothache and reported that a few minutes later, “He jumped up saying the toothache was completely gone.” Since fast-acting anti-inflammatory drugs did not exist in any form, both Eichengrün and the dentist regarded the patient’s speedy relief as near-miraculous. Further tests of acetylsalicylic acid on other patients were also highly encouraging: subjects reported relief from pain, fever, and inflammation, and—crucially—they did not report gastrointestinal distress or other notable side effects.

  Eichengrün shared his surreptitiously obtained findings with Dreser. Dreser was unimpressed. After reading Eichengrün’s clinical reports on acetylsalicylic acid, Dreser wrote, “This is the usual loud-mouthing of Berlin—the product has no value.” He firmly believed that Heroin represented the future of the company. Duisberg finally intervened in the dispute between his two top lieutenants. He reviewed Eichengrün’s Berlin data, overturned Dreser, and authorized the full clinical testing of acetylsalicylic acid on humans—alongside the full clinical testing of Heroin.

  Both synthetic drugs passed human trials with flying colors and Bayer prepared to sell them to the public. In 1899, Bayer selected the commercial name for acetylsalicylic acid: Aspirin. The name is derived from the a in acetyl, plus the Latin name for the meadowsweet plant (Spirea ulmaria), and the standard drug suffix -in, which was believed to make the name easier to pronounce across European languages. Bayer also made sure that the generic term for Aspirin was as difficult to pronounce as possible: monoacetic acid ester of salicylic acid.

  But Bayer ran into an unexpected and discouraging wrinkle. Since other researchers had previously reported the synthesis of acetylsalicylic acid, Bayer’s application for a patent in Germany was rejected. Just as Robert Talbor tried to suppress competition from other chinchona bark peddlers in the 1600s by claiming that his Pyretologia drug contained secret ingredients, Bayer pushed its convoluted name for the generic version of Aspirin to help discourage physicians from prescribing the generic version instead of Bayer’s brand—the company hoped doctors would be reluctant to instruct their patients, “Take two monoacetic acid esters of salicylic acid and call me in the morning.”

  Even though it did not have an exclusive patent on the drug in Germany (Bayer did get one in the United States), it launched a very heavy marketing push, and Aspirin soon became the first blockbuster drug of the Age of Synthetic Chemistry. It was far superior to the old salicylate drugs derived from plant extracts. Aspirin performed just as well but exhibited markedly reduced side effects. Its global popularity grew still further when it became a standard treatment during the Spanish flu pandemic of 1918. After Bayer’s American patent on Aspirin expired in 1917, there was an explosion of aspirin generics and knock-offs, but as you know from any visit to your local CVS or Walgreens, Bayer’s formulation of Aspirin has remained a steady seller, one of a small handful of nineteenth-century drugs that have survived unchanged into the twenty-first century.

  Today, more than 70 million pounds of aspirin are sold each year, about the weight of a small aircraft carrier. The use of the drug has slowly decreased over time because of competition from several other over-the-counter analgesics, especially Tylenol, Advil, and Motrin. Aspirin remains unique among its competitors, however, because it also thins the blood by reducing the aggregation of platelets, so it still maintains enviable sales as a heart medication.

  Today, if you turn to any account of the origin of Aspirin in a contemporary textbook or history of medicine, you will almost always find that Eichengrün’s name is curiously absent, even though he was single-handedly responsible for pushing Bayer to make the drug. Instead, Eichengrün’s junior chemist Felix Hoffman is typically celebrated as the drug’s inventor. According to the standard narrative, Hoffman developed Aspirin to help his father, who was suffering from the side effects of the sodium salicylate he took for his rheumatism. In truth, Hoffman was a very minor character in the story of Aspirin, someone who simply obeyed Eichengrün‘s request to add an acetyl group to salicylic acid without even knowing exactly why he was synthesizing the compound. So how did the popular account come to vary so widely from the truth? You can blame the Nazis.

  Bayer did not publish the story of the discovery of Aspirin until the early 1930s. This delay was due in large part to Bayer’s head biologist, Dreser. He never forgave Bayer’s head chemist, Eichengrün, for going behind his back to test Aspirin
, and when he reported the company’s scientific findings to help publicize the new drug, Dreser spitefully omitted any mention of Eichengrün at all. When Bayer finally published its public account of the discovery of Aspirin nearly fifty years after Eichengrün successfully guided it through, the headache remedy had become something of a national treasure. Unfortunately for Eichengrün, the Nazis had gained power in Germany, which meant that national treasures had to conform to Aryan ideals.

  Even though Eichengrün by this time had become a prominent industrialist running his own chemical company, he was also a Jew. He was eventually interned at the concentration camp in Theresienstadt, where he languished until his liberation by the Soviet Army. When Bayer published its official story of Aspirin’s discovery, the company prudently overlooked the fact that a Jew had been the driving force behind the drug and instead assigned credit to Hoffman, an acceptably Aryan German. During the Nazi era, the Hall of Honor in the chemistry section of the German Museum in Munich featured a showcase filled with white crystals and emblazoned with the declaration, “Aspirin: inventors Dreser and Hoffmann.”

  After the war, the octogenarian Eichengrün published several accounts of the true story, supporting his version with original documents. For his part, Hoffman never publicly took credit for Aspirin and never disputed Eichengrün’s accounts. Nevertheless, the Nazi-influenced story of Aspirin’s discovery had become too entrenched within the history of chemistry, and Eichengrün’s efforts at setting the record straight were mostly ignored.