The Drug Hunters Read online

  Almost overnight, Salvarsan became both famous and notorious. It actually eliminated a disease once and for all, instead of merely mitigating its symptoms. At the same time, since the disease in question was a sexually transmitted infection associated with promiscuity and prostitutes, the number 606 quickly became the butt of innumerable off-color jokes, similar to the number 69 today. Many telephone exchanges even dropped the 606 code because of its newfound sexual connotations.

  Isak Dinesen, the author of the memoir Out of Africa, was one of the first people to be treated with Salvarsan. A Danish aristocrat whose real name was Baroness Karen von Blixen-Finecke, Dinesen managed a coffee plantation in Kenya for most of her adult life. According to her memoir, her husband was a serial philanderer who infected her with syphilis. After realizing she had contracted the embarrassing and deadly disease, Dinesen returned to Denmark for many long months of treatment with Salvarsan. Although her physicians eventually declared that she was cured, she remained dubious, probably due in part to the fact that no disease—including syphilis—had ever been curable before. Though extensive tests failed to reveal any evidence of syphilis remaining in her system, for the rest of her life she remained convinced that she was still afflicted. Even so, her exquisite writing suggests that she suffered neither from the mental degeneration characteristic of advanced syphilis nor from cerebral damage due to excessive Salvarsan treatments. Ehrlich’s magic bullet enabled Dinesen to become one of the finer literary voices of the twentieth century.

  The enormous success of his drug made Ehrlich a public hero. Whenever he was congratulated for his achievement, however, he modestly replied: “For seven years of misfortune I had one moment of good luck.” If he had correctly understood that the syphilis pathogen and the Trypanosoma pathogen were vastly different microorganisms, he probably would have never tried his toxic warhead on the Italian disease. The German-born Ehrlich concluded from his experience that a drug hunter needed what he called “the four G’s”: Geld (money), Geduld (patience), Geschick (ingenuity), and perhaps most importantly, Glück (luck). His formula was extremely prescient, since money, patience, ingenuity, and a heaping dose of serendipity remain essential ingredients for drug discovery to this very day.

  Ehrlich’s method for developing Salvarsan established a completely new vision of what a drug actually was, a conception so strange and radical that the scientific community initially rejected it. Between 1895 and 1930 there were four competing theories of how drugs worked: the “physical theory,” the “physicochemical theory,” the “Arndt–Schulz Law,” and the “Weber–Fechner Law.” All four of these theories were utterly wrong. The physical theory held that the surface tension of the cells in a given tissue dictated what kinds of drugs affected that tissue. The physicochemical theory was a variant of physical theory, arguing that drugs worked by altering the surface tension of cells. The Arndt–Schulz Law postulated that drugs affected the body according to the following formulation: “weak stimuli excite, medium stimuli partially inhibit, and strong stimuli produce complete inhibition.” Needless to say, this wooly-headed hypothesis had little connection with biochemical reality. Finally, the Weber–Fechner Law hypothesized a logarithmic relationship between the size of a drug’s dose and the size of its effect, an idea rather incongruously drawn from a theory of human perception. None of these theories was remotely accurate, and worse, none of them provided any guidance on how drugs could be improved or how new drugs might be discovered.

  But Ehrlich developed a new way of thinking about drugs that he succinctly summarized in the Latin phrase Corpora non agunt nisi ligata—“a substance is not effective unless it is linked to another.” He called this new conceptual framework “side-chain theory,” a conception that grew out of Ehrlich’s understanding of the human immune system. He correctly hypothesized that a person’s immunity to a disease was based on the reaction of special substances in a person’s blood serum to the toxic compounds in a pathogen. He called these substances “side-chains,” though today we call them “antibodies,” and we call the toxic compounds that the antibodies react to “antigens.”

  Ehrlich argued that a particular antibody binds to a particular toxin in a lock-and-key fashion and that this selective chemical binding triggered the immune system to eliminate the pathogen, a theory that we now know to be accurate. He extended the same lock-and-key thinking to drugs, believing that there was a specific molecular site on a pathogen or on a human cell (the “receptor”) that reacted with a specific part of a drug, thereby producing its effect. This is known today as “receptor theory.”

  Ehrlich’s novel conception of drug action was based on his discovery that chemical dyes only stained particular parts of cells, and his receptor theory now serves as the foundation for modern pharmacology. But in 1897, when Ehrlich first proposed receptor theory, he could not provide any direct evidence for the existence of receptors, which he claimed were too small to be visible under existing microscopes. Not surprisingly, other scientists regarded his idea of invisible antibody receptors as squatting somewhere between pseudoscientific and preposterous.

  A group of scientists at the prestigious Pasteur Institute in Paris helped lead the opposition against receptor theory. For ten years, the Pasteur scientists conducted experiments on blood proteins that they contended disproved receptor theory. Ehrlich performed the exact same experiments and obtained similar results, but argued that they actually validated his theory. Since the details of these experiments were very complicated and involved sophisticated scientific reasoning, most scientists simply tended to believe the more straightforward arguments coming from the highly regarded Pasteur Institute.

  Feeling increasingly aggrieved, Ehrlich became an obsessive and bristly defender of his ideas, sorting all of his colleagues into “friends” or “enemies” depending on their view of receptor theory. In 1902, for instance, he wrote to William Henry Welch: “I was most delighted to recognize you as one of the warmest friends of the theory, but even more that you could achieve such new and fundamental insights with its help.” In contrast, he wrote to a pharmacologist in Halle, Germany, “that every impartial person reading the literature has to count you as an absolute opponent.”

  One of the most formidable opponents of receptor theory was Max von Gruber, a famous professor of hygiene at the University of Munich. Nobody else possessed the same ability to infuriate Ehrlich. While Gruber acknowledged Ehrlrich’s contributions to the nascent field of immunology, he published several papers that attacked Ehrlich’s receptor theory of drugs as purely speculative, burdened by “a nearly total lack of evidence.” Gruber’s concerns were rather reasonable given the inability of scientists at the time to identify any drug receptors in the human body. Nevertheless, Ehrlich castigated the hygienist’s criticisms as “stupid” and “negligible.” On one occasion, Ehrlich was evicted from a train because of his loud complaints about Gruber. The more level-headed Gruber responded by writing, “I only reproach Ehrlich for permitting too much fantasy in his theories while accepting too little criticism.”

  Though Ehrlich’s theory was ultimately proven correct, it took almost a century before the underlying details of receptor theory were fully understood. When I first studied pharmacology in the 1970s, the definition of a receptor was still tautological: the “adrenaline receptor” was the thing that bound to adrenaline. I had previously studied biochemistry and molecular biology, well-developed fields where scientists knew with tremendous precision the intimate details of the molecules they were manipulating. Biochemists could usually specify exactly how one compound would interact with another compound. In comparison, pharmacologists usually possessed only a shockingly vague idea of how their drugs worked. For example, the receptor that aspirin acted upon had just been identified a few years before I started my pharmacology studies, more than seventy years after aspirin was first used to treat patients.

  We now know that most receptors within the human body are protein-based molecular switches that
turn cellular processes on or off by reacting to hormones in the body. For example, there are a number of distinct adrenaline receptors in the human body, including the beta-2 receptor, a protein present in smooth muscle cells that reacts with adrenaline to produce muscle relaxation. Once scientists identified the beta-2 receptor as an adrenaline receptor, drug hunters began to search for medications that activated them. One of the best-known drugs to come out of this search was albuterol, used as an inhaler by asthmatic patients. Albuterol opens up a person’s air passages by relaxing the smooth muscle cells in the lungs, improving breathing and preventing or mitigating an asthma attack.

  Though most scientists were skeptical of Ehrlich’s theory of how drugs worked, there was no denying the astonishing effectiveness of Salvarsan—or Ehrlich’s wholly original method of engineering Salvarsan by attaching a germ-killing compound to a molecule of dye. It was the culmination of the Age of Synthetic Chemistry, the first proven method for creating drugs from scratch rather than discovering drugs in the library of plants or by tweaking existing drugs.

  You might imagine that Ehrlich’s ingenious cure for syphilis ushered in a golden age of drug hunting as pharma scientists around the world engineered their own magic bullets. You might, but you would be wrong.

  6

  Medicine That Kills

  The Tragic Birth of Drug Regulation

  The first drug application submitted to the FDA

  “We have been supplying a legitimate professional demand and not once could have foreseen the unlooked-for results. I do not feel that there was any responsibility on our part.”

  —Samuel Evans Massengill, 1937

  Ehrlich’s discovery of Salvarsan in 1909 established a rational and methodical approach to drug hunting. It showed that it was possible to design and synthesize a new drug from scratch by thoughtfully applying one’s knowledge of chemistry and biology. Salvarsan also served as a drug hunting milestone in another important respect. The compound 606 was the first successful antibiotic. When Ehrlich loaded an arsenic warhead onto a khaki-colored dye, there was no reliable, effective cure for an infectious disease. Physicians could sometimes ameliorate the symptoms of various afflictions, but they possessed no confident remedy. After Ehrlich, everything changed. Salvarsan provided doctors with an unprecedented weapon that actually destroyed the source of a disease, the syphilis bacteria.

  Even so, Salvarsan had considerable shortcomings. The drug needed to be dosed with exceptional care. If too little was administered, the syphilis bacterium would not die. If too much was administered, the patient could die. And the drug was not effective at all if the syphilis had already progressed to an advanced state. But the drug’s chief limitation was the fact that it worked only on a single disease—syphilis.

  Today, we enjoy the benefits of many “broad-spectrum antibiotics” such as penicillins and fluoroquinolones, drugs that fight a wide range of infectious pathogens. But Salvarsan was a “narrow-spectrum antibiotic”—a one-hit wonder. At the time of Ehrlich’s great discovery, there was not yet a clear notion that it might be possible to develop drugs that attacked multiple types of infections. Instead, the focus was on discovering any new cure, whether it turned out to be a silver bullet or a silver shotgun blast. Inspired by Ehrlich, a new generation of drug hunters was spurred to search for other synthetic anti-infectives. The largest pharmaceutical laboratories of the early twentieth century put their top researchers to work screening for bacteria-killing dyes, especially the German companies on the Rhine. The rush for synthetic cures began with great enthusiasm, with many chemists predicting a golden age of drug discovery.

  This glow of optimism gradually darkened. After twenty years of well-funded drug hunting, not a single new antibiotic had been found. By the early 1930s, it was beginning to appear as if Ehrlich had been indescribably lucky in his discovery of a synthetic Vindication. Scientists were beginning to suggest that Salvarsan was one-of-a-kind. Then, in 1935, Bayer AG—a corporate descendant of the chemical company that created Aspirin—finally struck gold. Bayer AG had assembled yet another research team in 1932 to try to crack the riddle of making a general-purpose antibiotic from an aniline dye. The team had tested out several thousands of dyes on several thousands of mice, and none showed promise. Then, one day, they tested a bright red dye. It killed several different kinds of infectious bacteria. Bayer dubbed their new drug Prontosil.

  Prontosil was the first broad-spectrum antibiotic. It cured a variety of maladies caused by streptococci bacteria, including blood infections, skin infections, and childbed fever. However, there was something quite perplexing about the drug. It worked only on living animals or living people. The drug failed to kill bacteria growing in test tubes. This presented a new mystery for Bayer AG: Why did Prontosil extirpate pathogens in the body but fail to dispatch the same pathogens when they were outside of the body?

  This pharmacological riddle was finally solved by a Pasteur Institute research group, who discovered that when Prontosil was metabolized in the liver, it was broken down into several smaller compounds. One of these compounds was a colorless molecule known as sulfanilamide. The Pasteur Institute scientists showed that the large Prontosil molecule itself had no effect at all on bacteria. Instead, it was the much smaller sulfanilamide molecule that was the true antibiotic. It wiped out bacteria inhabiting both living creatures and Petri dishes. The reason Prontosil failed to destroy bacteria outside of the body was that it had not been broken down into its active component.

  Bayer’s great triumph—the creation of the first broad-spectrum antibiotic—was based on a false premise, the idea that a toxic dye was selectively targeting bacteria, the way Salvarsan did. Instead, it turned out to be pure biochemical chance that the mammalian physiology transformed the red Prontosil dye into an entirely new compound that cured infections. While this discovery was scientifically embarrassing to Bayer, financially it was devastating. Sulfanilamide was a familiar compound that had been used by chemists for decades and thus could not be patented. The day after the Pasteur Institute published their findings about sulfanilamide in 1936, chemical manufacturers around the world woke up to discover there was a miracle drug that anyone could legally make and sell.

  Within a few years, hundreds of companies were churning out their own idiosyncratic versions of sulfanilamide, launching an international “sulfa craze.” One of the myriad new formulations of sulfa was Elixir Sulfanilamide, produced by the Tennessee pharmaceutical manufacturer S. E. Massengill Company. The company had been founded in Bristol, Tennessee, in 1898 by one Samuel Evans Massengill, a graduate of the University of Nashville Medical School. His firm had manufactured everything from analgesics to ointments before trying to cash in on the sulfa craze, usually marketing Massengill’s products with names that were variants of his own, such as Anagill, Dermagill, Giagill, Resagill, and Salogill.

  Massengill’s sulfanilamide preparation was simple. Sulfanila-mide was dissolved in diethylene glycol, then raspberry flavoring was swirled in. This preparation was formulated by the chief pharmacologist at S. E. Massengill, a man named Harold Watkins. Though Watkins was a trained chemist, his training had apparently not led him to the awareness that the sweet-tasting diethylene glycol was a strong poison. (Today, diethylene glycol is used in brake fluid and wallpaper stripper.)

  Animal testing was already fairly widespread in the pharmaceutical industry by the 1930s, but in his rush to get Elixir Sulfanilamide to the market Watkins did not bother to test his formulation on any living creature. There was nothing illegal about this seemingly egregious oversight—there were no laws requiring any testing before selling a drug to the public. Though the Food and Drug Administration had been established by Congress in 1906, the agency was largely toothless. Its main purpose was to ban adulterated or mislabeled products rather than enforce safety.

  Elixir Sulfanilamide went on sale in drugstores around the country in September of 1937. The Reverend James Edward Byrd of Mount Olive, Mississippi, was one of the
first customers to buy a bottle. Byrd was a sixty-five-year-old Baptist preacher and the long-serving secretary of Mississippi’s Baptist Sunday School. On October 11, he had consulted his good friend Dr. Archibald Calhoun about his cystitis, a painful infection of the urinary tract. Calhoun prescribed sulfanilamide, which remains a safe and highly effective treatment for cystitis. Byrd went to his local pharmacist, who fulfilled his doctor’s prescription with a bottle of S. E. Massengill’s Elixir Sulfanilamide. (Dr. Calhoun also prescribed the Elixir for five other people.)

  After taking the prescribed dose, Byrd departed for a series of clergy meetings in Knoxville. The next day Byrd “felt a constant urge to urinate,” but found it “difficult to start the stream and very little was voided.” A few days later, as he continued to have difficulty passing water, Byrd was admitted to the Knoxville hospital. He was diagnosed with catastrophic kidney failure. The staff administered intravenous saline and glucose in an emergency attempt at stimulating his renal function, to no avail. The reverend’s wife, Leona, and his two sons were at his side as he died an excruciating death.

  Two doctors from the University of Chicago published a paper in the Journal of the American Medical Association that concluded that Byrd’s demise had been due to diethylene glycol, a compound known to devastate kidneys. Byrd’s physician, Calhoun, become despondent. He wrote a letter to President Franklin D. Roosevelt:

  Any doctor who has practiced more than a quarter of a century has seen his share of death. But to realize that six human beings, all of them my patients, one of them my best friend, are dead because they took medicine that I prescribed for them innocently, and to realize that that medicine which I had used for years in such cases suddenly had become a deadly poison in its newest and most modern form, as recommended by a great and reputable pharmaceutical firm in Tennessee: well, that realization has given me such days and nights of mental and spiritual agony as I did not believe a human being could undergo and survive.