The Drug Hunters Read online

  In many ways, the false history of Aspirin is an apt metaphor for the gap between the public’s perception of how drugs are discovered and the far-grittier reality. In the sanitized version, Felix Hoffman invented a new drug to help his ailing father, and his brilliant discovery was quickly recognized by Bayer, who immediately shared it with the world. In reality, a vindictive middle-manager preferred the commercial prospects of Heroin over Aspirin, and he did everything he could to shut Aspirin down. Meanwhile, Aspirin’s inventor came up with a clandestine scheme to obtain data on the drug (a scheme that would be considered highly unethical by today’s standards) in order to go over his colleague’s head and persuade senior management to back Aspirin. Then, even after Aspirin was launched, it turned out the drug was not actually a new invention at all, since Aspirin had already been synthesized by several other chemists. Despite a gush of generic competitors, Bayer still managed to squeeze blockbuster profits from its synthetic compound through savvy marketing—and then laundered the story of the drug’s discovery to conform with the anti-Semitic politics of early twentieth-century Germany.

  That is the real story behind the brand-name drug that has sold more units than any other in history—the drug that inaugurated the hunt through a new and untapped library of molecules, the library of synthetic medicine.

  5

  The Magic Bullet

  We Figure Out How Drugs Actually Work

  Early depiction of syphilis

  “Corpora non agunt nisi ligata. (A substance is not effective unless it is linked to another.)”

  —Paul Ehrlich, 1914

  In the waning years of the fifteenth century, a new epidemic swept through Europe like a foul wind. The disease first made itself known as angry red ulcers blooming upon the skin. Rather disconcertingly, these cankers usually started on the genitals. Before long, the patient would develop a scarlet-pink rash on his chest, back, arms, and legs. A fever, accompanied by a headache and sore throat, came next. The afflicted would lose weight, then lose hair. But then, after a few weeks of steadily worsening health, the symptoms would abruptly subside. Did the body fight off the infection? No. The reprieve represented false hope.

  It was not the end of the storm, but the quiet eye at the center of a biological hurricane. After a short period of time the disease surged back in horrible fashion. Hundreds of tumorous balls burst forth from the skin, red and misshapen, making the victim resemble some fairytale demon. Eventually the disease attacked the heart, nervous system, and brain, often producing total dementia. And then—sometimes after a few years, sometimes a few decades—respite usually came at last, in the form of death.

  The first well-documented outbreak of the disease in Europe occurred in 1494 among French troops besieging Naples. The Italians called it “the French disease.” The French, on the other hand, called it “the Italian disease.” Today we call it syphilis. Since syphilis is easily confused with other diseases (it is often called the “great imitator”), its precise origins are still debated. One prominent theory holds that when Columbus and other early European explorers introduced the scourge of smallpox to the aboriginal peoples of the New World, they simultaneously carried syphilis back to Europe; the Italian outbreak occurred shortly after Columbus returned from his first voyage. What is known for certain is that syphilis was one of the most feared and infectious diseases in Europe from the 1500s through the early twentieth century.

  The Spanish physician Ruy Diaz de Isla wrote in 1539 that more than a million Europeans were infected with the ghastly syndrome. Treatment options ranged from poor to useless, such as gum of the guaiacum tree (useless), wild pansy (useless), and mercury, the best of the bad. Mercury had some ameliorative effect on the disease because of its toxicity to the syphilis pathogen. Unfortunately, mercury is quite toxic to humans, too. Nevertheless, since the compound was the only meaningful therapy for the disease, its use fostered the saying, “A night in the arms of Venus leads to a lifetime on Mercury.”

  When syphilis began ravaging Europe, nobody knew how to treat it, because nobody had the faintest idea what caused it—or any disease, for that matter. Until the mid-nineteenth century, the leading hypothesis about the origins of common scourges like typhoid fever, cholera, bubonic plague, and syphilis was known as miasma theory. Miasma theory held that disease was caused by a noxious form of “bad air.” This pestilent miasma presumably emanated from decomposing organic matter as a toxic mist filled with rotten particles. People were not infectious, according to the theory; rather, disease emanated from a place that gave rise to infectious vapors, identifiable by their putrid aroma. Since hospitals, by definition, were clean places that lacked any source of miasma, hospitalized patients were believed to be free from the risk of new infection.

  The miasma theory was challenged in 1847 by Ignaz Semmelweis, a Hungarian obstetrician who worked at the Vienna General Hospital. He frequently treated women with puerperal fever, also called childbed fever. The disease often developed into puerperal sepsis, a serious blood infection that was sometimes fatal. We now know that this disease is caused by a bacterial infection contracted by women during childbirth, but in the nineteenth century doctors were baffled by its persistent presence in maternity wards.

  Semmelweis wondered why so many new mothers were getting sick. He noticed that many women who delivered their babies at the hospital with the aid of doctors and medical students soon died of puerperal fever. On the other hand, there were no deaths among women who gave birth when they were solely attended by midwives. This was a strange enigma that defied easy explanation, but Semmelweis offered up a bold hypothesis.

  He noticed that physicians and medical students often came to the obstetric wards directly after conducting an autopsy. He speculated that there was some kind of contagion present in the autopsy material that was transmitting puerperal fever to the women. To test this radical theory of direct physical contamination, Semmelweis ordered the doctors in his maternity ward to scrub their hands with lime before examining pregnant women. No longer were physicians handling dead flesh, then moments later touching women’s private parts with unwashed hands. It was a success. After Semmelweis’s experiment, childbirth mortality plummeted from 18 percent to 2 percent.

  Semmelweis’s improvements in physician hygiene seemed to disprove miasma theory, pointing to a new way to think about disease. Unfortunately, Semmelweis and his theories were soundly rejected by the Viennese medical establishment. In 1861, Semmelweis published a book to defend his views, Die Ätiologie der Begriff und die Prophylaxis des Kindbettfiebers (The Etiology, Concept, and Prophylaxis of Childbed Fever). The book was mostly ignored, though it was occasionally ridiculed by more distinguished physicians who believed that Semmelweis was a bush-league dilettante.

  The professional humiliation that Semmelweis endured reminds me of something that happened at a prestigious academic biology conference I attended on Long Island. The conference mostly focused on DNA, and one young postdoc gave a talk about how the extremely long strands of human DNA (they are almost ten feet long, despite being only two nanometers wide) could be squeezed into the tiny space of a microscopic cell nucleus. The young man lacked confidence and his presentation was uneven, but his findings, we know today, were essentially correct.

  Suddenly, in the middle of the postdoc’s talk, Francis Crick walked to the front of the stage. Crick was one of the discoverers of the structure of DNA and is one of the most famous biologists in the world. Crick stood directly in front of the lecture podium facing the young man. Their noses were only about a foot apart. Despite becoming unnerved by this bizarre display by one of the legends of science, the postdoc somehow managed to hurry through the rest his talk. As soon as he stopped speaking, Crick spoke up.

  “Are you quite finished?”

  The young man nodded. Crick slowly turned to face the audience and declared, “I do not know about anyone else, but this is about all the amateurism I am willing to stomach at this meeting.” I imagine that Semme
lweis must have felt just as humiliated as that aspiring young biologist.

  Frustrated by his colleagues’ dismissal of his ideas, Semmelweis began to decry obstetricians as thoughtless murderers. They shrugged him off. Doctors continued to insert their fingers into decomposing corpses and then casually use the same digits to deliver babies. Semmelweis began to drink heavily and soon became an embarrassment to his hospital and his family. In 1865, he was duped into entering an insane asylum, where he was locked up. He tried to escape but was severely beaten by guards. Two weeks later, he perished from his wounds. Such was the tragic life of the man who discovered the role of germs in creating infection.

  Though several people over the centuries had proposed some version of the notion that disease was caused by direct physical contamination, clear and conclusive proof of the existence of contagious pathogens finally arrived in the 1860s through the work of the famed French biologist Louis Pasteur. Pasteur conducted experiments to disprove miasma theory and also to disprove spontaneous generation, the widely held notion that new life could erupt forth from inert matter. Imagine, for instance, you were gazing into your mobile device when tiny creatures suddenly came writhing out of your screen—nineteenth-century biologists believed this kind of occurrence was possible due to spontaneous generation.

  Pasteur demonstrated that the generation of new life required exposure to specific types of particles in the air—and, crucially, he showed that these peculiar particles were already alive. Disease, in other words, was caused by organisms too tiny to see—micro-organisms. Scientists had known about the existence of microorganisms since the 1600s, but the nineteenth-century medical establishment could not imagine how something so tiny and insignificant could possibly sicken—let alone extinguish—a healthy human being.

  Once Pasteur revealed that vanishingly small organisms caused some of the most terrible diseases known to humankind, everyone wanted a look at them. Unluckily for would-be germ-gazers, the cells of infectious bacteria and fungi (not to mention the cells of animals and plants) are largely translucent. If you stick a cell on a slide and peer at it through a microscope, you will see vague and indistinct contours that are difficult to resolve. The reason is that there is no contrast—no way to sharply distinguish the structures of the cell from its background.

  A solution arrived in the mid-nineteenth century with the invention of synthetic dyes. Dye manufacturers were like the aerospace industry of the nineteenth century, producing a variety of useful spinoff products as they developed the high-tech products for their core market. Microbiologists began to test off-the-shelf fabric dyes to see if they might also be useful for staining cells. One man who was captivated by synthetic dyes’ potential for improving the study of germs was a German scientist by the name of Paul Ehrlich.

  Ehrlich’s cousin Karl Weigert was a prominent cell biologist and histologist (someone who studies the structure of living tissue). Between 1874 and 1898, Weigert published a series of papers on the use of synthetic dyes to stain bacteria. (Even today, scientists still use the “Weigert stain” to view neurons.) Weigert’s work led to the rapid adoption of a set of synthetic dyes for studying animal cells and microorganisms known as “aniline dyes.” These dyes were based upon the aniline molecule, an organic compound that smells like rotten fish.

  Ehrlich followed in his cousin’s footsteps and began using aniline dyes to stain animal tissues in medical school in Leipzig. He obtained his medical degree in 1878, but he was never considered a particularly promising student. His professors believed his obsession with tissue staining was a pointless distraction that was preventing him from developing more useful skills. When one of Ehrlich’s professors introduced Ehrlich to Robert Koch, an eminent physician regarded as the father of bacteriology for his pioneering research on infectious diseases, the professor told Koch, “That is little Ehrlich. He is very good at staining, but he will never pass his examinations.” In fact, there was nothing in Ehrlich’s early career to suggest that he would eventually become involved in drug hunting, let alone become one of the most influential drug hunters of all time.

  Early on, Ehrlich became fascinated by the peculiar fact that some dyes would stain parts of a certain type of cell (such as the cell wall or chloroplast components in plant cells), while failing to stain any part of other types of cells (such as animal cells). In other words, each dye seemed to have its own biological target that it would adhere to. One day he was struck by a provocative idea: What if a dye that targeted parts of a certain kind of pathogen was also toxic to that pathogen? If so, it might be possible to kill the pathogen without harming the host. Ehrlich called this notion of pathogen-targeting toxins Zauberkugeln—“magic bullets.”

  In 1891, Ehrlich commenced his search for a dye that would selectively target the protozoan that causes malaria … and kill it. After testing dozens of dyes, he observed that one particular dye known as methylene blue stained the parasite but did not stain human tissue. Even more promising, the dye appeared to have some toxicity to the malaria pathogen. He began testing methylene blue on several malaria patients and soon reported that he had cured two of them. The world’s first fully engineered drug was a bright, vibrant dye the color of cobalt.

  Ehrlich admitted that quinine remained a much more effective and reliable treatment for malaria, but he had proven that his notion of a magic bullet was not mere theory—it actually worked in practice. All that was needed was the right kind of dye. He was given an appointment at the Institute for Infectious Diseases in Berlin, where he set up one of the first successful models of a drug research lab. His lab included an organic chemist who developed new drug candidates (that is, new synthetic dyes), a microbiologist who tested the effects of drug candidates on pathogens (this was Ehrlich’s role), and an animal biologist who tested the effects of drug candidates on animals and—if the animal tests were successful—on humans.

  Ehrlich’s three-unit team studied the staining and toxicity of hundreds of synthetic dyes on pathogenic protozoa, infectious single-cell microorganisms that are more similar to mammal cells than bacteria. Though they found many dyes that selectively targeted germs, none of them impaired the protozoa’s activity until they stumbled upon trypan red. This dye stained a parasite in mice known as Trypanosoma equinum—and killed it. Ehrlich’s initial rush of excitement was short-lived, however. The trypanosome pathogens rapidly developed resistance to trypan red, rendering it useless as a cure.

  After a seemingly interminable string of failures, Ehrlich realized he might need to modify his magic bullet theory. Perhaps it was simply too difficult to find a double-duty dye that both targeted a pathogen and slayed it. Instead, why not take a toxin that was already known to kill a pathogen, and use chemical synthesis to mount the toxin onto a dye known to target the pathogen, producing a kind of “toxic warhead”? Even if the toxin was harmful to humans, by attaching it to a dye that targeted a particular germ it could act like a guided missile, delivering its destructive payload directly to the germ.

  Ehrlich launched his new toxic warhead approach to drug hunting by using arsenic as the payload. A French scientist named Antoine Béchamp had previously shown it was possible to attach a molecule of arsenic to a molecule of dye, creating a new compound called atoxyl. Atoxyl was highly toxic to humans, but Ehrlich wondered if he could synthesize a variant of atoxyl that would be safe in humans but lethal to germs. Ehrlich knew that atoxyl stained Trypanosoma cruzi, a parasite causing a nervous system disease known as trypanosomiasis, so for his first round of arsenic experiments Ehrlich chose to target T. cruzi. His team began creating hundreds of variants of atoxyl and testing them on mice infected with the parasite, but all of these synthetic warheads either failed to kill the trypanosomiasis, or if they did succeed, they killed the host, too.

  Frustrated, Ehrlich switched diseases. In 1905, a zoologist working with a dermatologist identified the pathogen that causes syphilis, a spirochete bacterium known as Treponema pallidum. Ehrlich believed there was a biolo
gical similarity between spirochetes and trypanosomes, even though we now know that there is virtually no structural or genetic similarity at all. Nevertheless, motivated by this erroneous assumption, Ehrlich applied his atoxyl toxic warheads to syphilis.

  His team synthesized more than nine hundred arsenic-loaded dyes and tested them on rabbits infected with syphilis. Each compound was a failure. As the team began to think about switching tactics once again, in 1907, Ehrlich’s animal biologist noticed that one of the compounds seemed to be killing the bacterium without killing its hosts. The compound was labeled “606” because it was the sixth compound in the sixth test group. When Ehrlich reported on the success of 606 in the New England Journal of Medicine in 1911, he named it “arsphenamine.” Clinical studies soon demonstrated that arsphenamine was an effective and safe treatment for syphilis in humans. It was, at last, a bona fide magic bullet.

  Ehrlich teamed up with the German company Hoechst AG—a company that had provided him with many dyes over the years—to manufacture arsphenamine for commercial use. It was marketed to the public in 1910 under the trade name Salvarsan with the tagline, “The arsenic that saves.”

  Ehrlich’s toxic warhead was the first reliable and effective treatment for a contagious disease. Put simply, it was the world’s very first cure. But that was not the only reason that the discovery of Salvarsan represented an extraordinary moment in the history of medicine, and indeed, in the history of humankind. Never before had someone thought up a novel way to create a completely unprecedented kind of drug—and then gone out and actually made it. Salvarsan was not a better-engineered knockoff of an existing drug, like Squibb’s ether, or a minor tweak of an existing drug, like Aspirin. Instead, it was the product of a wholly original conception: find a dye that stains a pathogen, then find a pathogen-killing toxin that will attach to the dye.