The Drug Hunters Read online

  Finally, Cyanamid decided to find out why the FDA was wrapping us up in so much red tape. It was my former colleague. He was using his new job at the FDA to hinder our drug hunting efforts. This was not technically illegal—he was not fabricating his objections and roadblocks out of the air; he was merely seeking out any flaw in our submissions, no matter how irrelevant or miniscule, and then declaring that this flaw required a comprehensive (and costly) correction. No doubt it was spiteful and vindictive. Even so, all we could do was hope that our tormentor would find some reason to get angry at his bosses at the FDA and, with luck, resign from there, too.

  Today, the FDA remains our country’s greatest protection against another Elixir Sulfanilamide disaster. But this protection comes with a very significant cost. About two weeks after September 11, 2001, I had to fly from New Jersey to Boston, a common route for me. When I arrived at Newark Airport it was quiet, deserted, and downright eerie. My flight—usually oversold with more than a hundred passengers jostling to get on—had only two dozen passengers. I sank into an aisle seat, and a woman sat down across the aisle from me. A minute later a swarthy man with a full dark beard started trudging down the plane toward us. The woman grabbed my hand and in a shaky, frightened voice whispered, “Oh my god …”

  Nothing happened, of course. Though the man appeared Middle Eastern, he could have been from many other places and was probably just as anxious about the flight as the rest of us. In such an environment of fear and paranoia, everyone was grateful for the establishment of the TSA, and in the early years after 9/11 we welcomed the reassuring presence of TSA officers in the airports.

  But these days, of course, everyone has complaints about the TSA. We have to empty our pockets, remove our shoes, pull off our belts, and haul out our laptops every time we travel. We can no longer carry on beverages or even bring common toiletries like shampoo, toothpaste, or shaving cream, except in miniaturized versions that we always seem to forget. Security queues get ever longer and slower, and we occasionally miss flights because of the prolonged time it takes to reach our gate.

  Just as protecting society from terrorism requires a constant rebalancing of safety with individual freedoms and costs (for example in the form of higher taxes or airline fees to pay for the expanded security), protecting society from dangerous drugs requires a constant rebalancing of safety with costs and the delay of vital drugs from reaching the clinic.

  7

  The Official Manual of Drug Hunting

  Pharmacology Becomes a Science

  A snake oil salesman

  “When I was at Yale, the Harvard and Yale students used to argue as to which school had the worst course in pharmacology.”

  —Dr. Louis S. Goodman, author of The Pharmacological Basis of Therapeutics

  During the second half of the nineteenth century, thousands of Chinese workers surged into the United States to build the transcontinental railroad. These immigrants brought with them one of their favorite folk remedies, a greasy extract from the mildly venomous Chinese mud snake. The Chinese laborers rubbed this liniment on their joints to relieve pain from arthritis and bursitis. Many entrepreneurs observed the popularity of the exotic salve among the Asian emigrés and got to wondering whether they might produce their own American version of snake oil.

  One of these gumptious capitalists was a man who came to be known as the Rattlesnake King. Clark Stanley, a cowboy, claimed that Hopi medicine men had revealed to him the wondrous power of prairie rattlesnake oil. He peddled his own snake oil concoction at the 1893 World’s Exposition in Chicago. His method of promotion demonstrated his understanding of the value of showmanship when hawking a new pharmaceutical product. In front of a rapt audience of potential customers, Stanley reached his hand into a wriggling sack and plucked out a long rattlesnake showing its fangs. He deftly slit it open with a knife and eviscerated it before plunging the serpent into boiling water. As the fat rose to the top of the cauldron, the Rattlesnake King skimmed it off and scooped it into a clear four-inch-tall bottle. Clark Stanley’s Snake Oil was snapped up by his enthralled spectators.

  In truth, Stanley’s Snake Oil usually contained no snake oil whatsoever, rattlesnake or otherwise. Instead, the bottles contained a mixture of mineral oil, beef fat, red pepper, and a dollop of turpentine to give the brew a medicinal smell. Even though Stanley’s customers were buying a completely bogus product, it hardly mattered: whether authentic or ersatz, snake oil in all its varieties is therapeutically worthless.

  Nearly a half century after Stanley’s Snake Oil was marketed to a gullible public at the World’s Exposition, the 1937 Elixir Sulfanilamide disaster highlighted the dangers of unregulated medicine, signaling the end of more than fifty years of a Wild West, anything-goes approach to selling drugs in the United States. Yet, even though the elixir deaths marked a momentous shift in society’s attitude toward the government’s involvement in the pharmaceutical industry, embodied in a much more powerful and active FDA, it did not alter one of the most troubling facts about drug hunting: There was still no coherent science of pharmacology.

  As the 1940s dawned, even though consumers were demanding that the government do a better job of monitoring the development of new medicines, there was very little hard science that could be relied upon to guide the FDA’s oversight. Not only did the vast majority of medical schools in the 1940s lack a pharmacology department, most did not even offer a pharmacology course. One reason was that there were simply no fundamental philosophical tenets or organizing causal principles in drug science, in the same way that aeronautical science, for example, was organized around the four force vectors of flight, which enabled a practitioner to accurately predict the amount of lift that would be produced by any given wing design. Instead, pharmacology was a chaotic grab bag of ideas from microbiology, physiology, chemistry, and biochemistry, as well as an incoherent casserole of clinical observations about the effects of drugs in various circumstances.

  Because of rampant confusion between fact and falsehood in the field of drug development, most physicians thought it pointless to try to teach medical students any principles of pharmacology—after all, with so much confusion, there was as much chance of teaching something wrong as there was of teaching something helpful. Instead, students learned about the nature of drugs directly from the doctors on their own training wards; these were older physicians who simply shared their own experiences with various medications. Thus, guidelines about which drugs to use in which circumstances were highly personal lore handed down from mentor to apprentice, just as it was during the era of medieval apothecaries. It was simply not possible to learn about drugs from books or the scientific literature.

  The story of how drug hunting, drug testing, and drug administration finally became a legitimate if unique science originates with two young men at Yale. In the late 1930s, Alfred Gilman and Louis Goodman were newly appointed assistant professors in the Yale Medical School Department of Pharmacology, one of the few such departments in the country, where they were assigned the unenviable task of teaching pharmacology to the medical students. One of the biggest problems that this pair of instructors had to confront was the absence of any useful pharmacology textbook. All the existing textbooks were poorly written or hopelessly outdated; most suffered from both of these shortcomings.

  So Gilman and Goodman decided to team up and write their own book. Just as Cordus did five centuries earlier when he penned his groundbreaking opus Dispensatorium, the two young scientists set out to create nothing less than a comprehensive compendium of everything that was known about drugs. And, like Cordus, they took a pragmatic and evidence-focused approach to their project, relying on data from published studies rather than oral lore. But they went further than Cordus ever could have, by drawing upon other medical sciences in a highly original attempt at placing what little was known about drugs within the larger framework of what was known about human physiology, pathology, and the principles of treatment. One of their boldest decisions
was to structure their book around pharmacodynamics, a nascent field that studied the relationships between the dose of a drug and its physiological effects. Today, pharmacodynamics is a central concept of modern pharmacology, but in the 1930s many of Goodman and Gilman’s colleagues believed the field offered little of value. However, Goodman and Gilman wanted to gather together in a single place everything factual and proven that was known about medicines.

  Not surprisingly, the textbook proved to be a mammoth undertaking. It quickly began to swallow up all of the young collaborators’ time, making it difficult for them to focus on teaching and impeding their ability to do research. This made the book a highly risky venture. Goodman and Gilman’s academic careers—including their prospects of getting tenure—were based on publishing original research, not writing a new student textbook. But they pressed on, accumulating an ever more elaborate pharmacopeia—and sending the book’s word count higher and higher.

  The Drug Hunters, the book before you, contains about 75,000 words. The King James Bible, containing the holy documents of two religions, is 783,137 words. But when the publisher, Macmillan, finally received Goodman and Gilman’s completed manuscript, the editor was shocked to see it contained more than a million words.

  Macmillan immediately lobbied to reduce the length of the manuscript. The authors refused to cut a single sentence. They believed they had compiled the first comprehensive scientific survey of the science of drugs. Quite reluctantly, Macmillan eventually agreed to publish an uncut edition of The Pharmacological Basis of Therapeutics in 1941, but priced the 1,200-page book at $12.50 (about $185.00 in today’s money), which was more than 50 percent higher than most medical textbooks of the era. The dubious publisher expected few sales at this outrageous price point, and printed only 3,000 copies. They promised the authors a bonus case of Scotch if the first printing sold out in four years.

  Goodman and Gilman got their Scotch, and it took only six weeks. The first edition of the textbook went on to sell more than 86,000 copies. The Pharmacological Basis of Therapeutics was instantly embraced by the pharma community as its unifying bible. It contained detailed, evidence-grounded information about every known drug, and more than that, it was the first time that this information was organized around guiding scientific principles that attempted to draw a sense of deeper order from the cacophony of knowledge. For the first time, if you wanted to confidently learn about a particular drug—or if you wanted to teach yourself the entire science of drugs—all you needed to do was delve into Goodman and Gilman. In fact, if the book had any meaningful shortcoming, it was its extreme scholarliness, which often made it a difficult read for the medical students for whom it was originally intended.

  As they were publishing their book, Goodman and Gilman went to work for the military as part of America’s war effort during World War II, where they implemented a rational approach to drug hunting by incorporating the ideas they had laid out in The Pharmacological Basis of Therapeutics. The United States Army contracted Yale University to develop antidotes for Germany’s toxic gas weapons, including organophosphate and nitrogen mustard. Gilman and Goodman were put in charge of this countermeasures project, and during their research they observed that nitrogen mustard was cytotoxic, meaning the gas destroyed human cells, especially the fast-growing cells in bone marrow, the digestive tract, and lymphatic tissue. The two young scientists wondered if nitrogen mustard might be repurposed as a lymphoma cancer treatment, targeting the fast-growing lymphoid tumor cells without killing healthy cells.

  At the time, the only treatments for cancer of any kind were surgery and radiation therapy. Goodman and Gilman tested nitrogen mustard on a lymphoma-afflicted mouse. Its tumors diminished rapidly. Next, they tested the mustard on a patient in the terminal stage of lymphosarcoma, when radiation therapy no longer worked. The response was dramatic: within two days the patient’s tumors had softened; within four days, the tumors were no longer palpable; a few days after that, the tumors had vanished. Goodman and Gilman had invented the very first form of chemotherapy for cancer, an impressive product of rational drug hunting.

  Louis Goodman was also interested in drugs that affected the nervous system. One of these was curare, an extract of the bark of a flowering plant that twined around tropical trees. European explorers of the upper Amazon river basin reported that the indigenous peoples hunted their prey using arrows or blowgun darts dipped in curare. (The word curare comes from the Carib word uireary, which means “to kill birds.”) The drug leads to the paralysis of the respiratory muscles and, eventually, asphyxiation. Interestingly, curare is harmless if swallowed, because the compound cannot pass through the lining of the digestive tract into the blood; as a result, South American tribespeople were able to safely eat their curare-poisoned game. Until the 1940s, curare was largely an exotic curiosity in medical circles, but Goodman wondered whether curare could be used as a surgical anesthetic.

  Any surgical anesthetic must possess two properties: (1) it must produce unconsciousness and (2) it must block pain. To determine whether curare fulfilled these requirements, Goodman persuaded the chairman of the Utah Medical School Department of Anesthesiology to allow Goodman to inject him with curare and watch what happened. After giving his elder colleague a heavy dose of the drug, Goodman’s team proceeded to jab his skin with pins. They also monitored the anesthesiologist’s consciousness via a prearranged method of communicating through eye blinks.

  Unfortunately, the anesthesiologist blinked his eyes in response to questions, demonstrating that he was fully conscious and violating requirement number one. Even worse, he still felt pain. He mentally recoiled from every prick of the needle, violating requirement number two. In fact, the curare did not alter his consciousness at all; it merely prevented his muscles from moving. Indeed, the dose was too high, and 30 minutes after receiving the injection he stopped breathing. Goodman’s drug hunting experiment would have resulted in the death of the chairman of anesthesiology, but fortunately Goodman was able to ventilate the anesthesiologist’s lungs using a rubber bag until the drug wore off. This time, Goodman’s attempt at establishing a new therapeutic use for an interesting compound ended in failure, but once again the experience proved to him that it was possible to evaluate potential new drugs in a systematic, logical manner.

  Today, Goodman and Gilman’s tome is longer than ever, but—now in its twelfth edition—The Pharmacological Basis of Therapeutics remains the preeminent pharmacology textbook for twenty-first-century medical students and the bible for all drug hunters. It may also be the only textbook to inspire a child’s name. Alfred Gilman named his son “Alfred Goodman Gilman,” after the two authors of the history-making book. The pharmacology-tinged name does not appear to have been a handicap; young Goodman Gilman went on to become a professor at the University of Texas Southwestern in Dallas and in 1994 won the Nobel Prize in Medicine for his own drug-hunting research on G-protein coupled receptors, a major class of drug targets.

  With the 1941 publication of The Pharmacological Basis of Therapeutics, drug hunters finally possessed a coherent framework for a science of drugs. Now all they had to do was use it to find new medicines.

  8

  Beyond Salvarsan

  The Library of Dirty Medicine

  The library of dirt

  “The earth will open and bring forth salvation.”

  —Isaiah 45:8

  As the world’s first bona fide cure for an infectious disease, Paul Ehrlich’s syphilis-slaying Salvarsan was hailed as a “miracle drug.” There was just one problem. Syphilis was the only disease it cured.

  At first, Ehrlich had hoped that his magic bullet might kill other infectious bacteria, too, but experiments in the 1910s showed that the drug had no effect against any pathogen other than the syphilis Treponeme bacterium. Other bacteria-based diseases like tuberculosis, tetanus, anthrax, whooping cough, gonorrhea, diphtheria, typhoid fever, strep throat, rheumatic fever, and staph infections all remained untreatable and potent
ially fatal. Salvarsan was available during World War I, but it was useless to prevent deaths from bacterial infection, which comprised about one third of all the soldiers’ deaths.

  In 1928, a microbiologist at St. Mary’s Hospital in London was studying Staphylococcus aureus, a type of bacterium that usually lives quietly and harmlessly on our skin. But if it somehow manages to leak into our bloodstream, watch out. The resulting infection can be as mild as impetigo, a skin disease that produces little blisters or sores on children, but other staph infections can be life-threatening, such as septicemia (blood poisoning) or toxic shock syndrome, a disease so lethal that it can turn a healthy person into a corpse in a matter of hours. This microbiologist was studying staphylococcus cells using the agar plating technique, which means that the bacteria are grown on a dish of nutrients (the agar). The solid surface of the agar plate allows researchers to examine visible colonies of bacteria spread out on the dish instead of peering into the murky stew of a bacteria-saturated test tube.

  One day, the microbiologist came into the lab and found something strange. The scientist’s name was Alexander Fleming, and you probably know the story of what happened next. According to legend, Fleming left the window to the laboratory open, and when he examined his agar plate he discovered there was fungus growing in it, presumably fungus that had floated in through the window. (I have always doubted this account. I frequently work in laboratories with the windows closed—or without any windows at all—and I often end up with contaminated plates. Fungus spores are always lurking in the air.) Though we don’t know exactly where the fungus really came from, Fleming was sure about one thing—the staphylococcus colonies were not growing anywhere near the invading legion of fungus. Fleming guessed that the fungus was producing a substance that was toxic to the staph bacteria. He began to wonder: could this mysterious substance be the basis for another miracle drug?