The Drug Hunters Read online

  As word of the breakthrough spread, ether was rapidly adopted as an essential component of every major surgery, creating an ever-increasing demand for the compound. There was one big obstacle to filling this demand, however. Ether was quite tricky to make. It required advanced chemistry techniques that lay well outside the expertise of the apothecary.

  Since ancient times, apothecaries were the place to go to obtain remedies. The apothecary was typically a small, local shop or stand run by a single proprietor. In the seventeenth century, apothecaries in Europe were the first to become formally organized. In London, the Worshipful Society of Apothecaries was granted a royal charter by King James I in 1617 as a professional organization focusing on the formulation of medicines. Medicines were not their only product, however. Apothecaries also sold spices, perfumes, honey, dyes, saltpeter (an ingredient in both medicine and gunpowder), camphor, gum benjamin (a wood resin used as incense, flavoring, and medicine), frankincense, aniseed, capers, and molasses as well as items that seem more suitable for a witch’s cauldron than a physician’s cabinet: hearts of stags, frog spawn, crayfish eyes, bulls’ penises, the flesh of vipers, swallow nests, and the oil of foxes. In Romeo and Juliet, Shakespeare famously describes an apothecary’s shop in Renaissance Italy:

  And in his needy shop a tortoise hung,

  An Alligator stuff’d and other skins

  Of ill-shaped fishes; and about his shelves

  A beggarly account of empty boxes.

  By the seventeenth century, the apothecary had become increasingly specialized in the art of making drugs, and a would-be apothecary required a long and arduous period of apprenticeship before becoming a credentialed professional. Apprenticeships lasted seven years, and apprentices were required to participate in frequent “herbarizing” expeditions, gathering botanical samples in the wild in order to gain sufficient familiarity with medicinal plants. To become an apprentice, one had to demonstrate knowledge of Latin, the international language of pharmacology, and in England a successful candidate had to satisfy the Society of Apothecaries that “he had knowledge and Election of Simples [plants or herbs used for medicinal purposes] and was able to prepare, dispense, handle, commix and compound medicines.” Distinctly absent from the training of an apothecary was any education in the young but rapidly expanding field of chemistry.

  At the time of Morton’s public demonstration of ether, American apothecaries operated small retail shops that served their local community. Drugs were prepared by the apothecaries according to their own individual interpretation of common recipes, many of which dated back to Cordus’s three-hundred-year-old Dispensatorium. Thus, a formulation of opium you bought from a pharmacist in New York could differ greatly from a formulation of opium purchased from a pharmacist in South Carolina. On top of this already-significant variability in the composition of basic drugs, ether was particularly difficult to synthesize, for it required intricate knowledge of organic chemistry and chemical purification procedures that were well beyond the means of most apothecaries. As a result, surgeons found that they needed to procure ether from the nascent industry of chemical suppliers rather than risk the wildly unpredictable (and frequently unavailable) versions of ether offered by apothecaries.

  Unfortunately, surgeons soon learned that the ether from chemical suppliers was not very reliable either. A batch bought from a chemical supplier one day might have a totally different purity than a batch bought from the same supplier a month later. Even worse, there were vast differences between the ether offered by different suppliers, with the most incompetently concocted versions failing at their most important task—putting patients to sleep. This lack of consistency made it very difficult to know how much ether to administer to ensure patients stayed unconscious without actually halting their respiration and killing them. Surgeons needed a standardized formulation of ether they could trust.

  The demand for standardized products was felt across many industries at the dawn of the Industrial Age in the mid-nineteenth century. Before the invention of electricity, the entire nation was illuminated by kerosene lamps. The largest and most successful corporation in the history of the world, Standard Oil, attained success because it was the very first company to standardize its preparation of kerosene—hence the company’s name. If you bought a gallon of Standard Oil’s kerosene in California, it was exactly the same as a gallon of Standard Oil’s kerosene purchased in New York. Rockefeller used standardization to outcompete hundreds of other local kerosene manufacturers and eventually establish a monopoly of the entire energy market, all because he offered a reliable, consistent product that customers could count on.

  As the demand for ether skyrocketed in the 1850s, apothecaries were simply not equipped to provide the kind of mass-produced standardized ether products that hospitals and surgeons hungered for. But like Rockefeller when he figured out how to standardize kerosene, another enterprising man from humble beginnings established an entire industry by figuring out how to standardize ether.

  Edward Robinson Squibb was born a Quaker in Wilmington, Delaware in 1819. Squibb graduated from Jefferson Medical College in Philadelphia, Pennsylvania in 1845 at the age of twenty-six, just one year prior to Morton’s ether demonstration, then joined the U.S. Navy as a ship’s physician. Squibb spent four years with the Atlantic and Mediterranean squadrons, where he became increasingly concerned about the Navy’s poor treatment of the men under his care. He published critical accounts describing inadequate diet, frequent floggings, and—most significantly—the poor quality of the medicine dispensed aboard Navy ships.

  Squibb’s grievances reached the Navy’s Bureau of Medicine and Surgery. They responded to his complaints by ordering him to establish a Naval Laboratory in the Brooklyn Navy shipyard with a mission of producing high-quality drugs. One of his first tasks was to evaluate the myriad brands of ether. Squibb took a six-month leave to attend refresher courses at Jefferson Medical School, where he studied chemical synthesis techniques in order to better understand the manufacture and evaluation of ether. When he returned to the Naval Laboratory, Squibb tested the different commercial formulations of ether and found them to be fantastically variable in purity. He decided to develop a method for producing ether of a consistent quality and quickly discovered what a technical challenge it truly was.

  Ether is highly flammable and highly explosive, but the process for synthesizing ether requires both heat and flame. During one of Squibb’s early experiments, an explosion burned off both of his eyelids, and for the rest of his life he had to place a dark cloth over his eyes at night in order to sleep. But in 1854, the persistent physician-chemist achieved a manufacturing breakthrough. He dramatically improved the process of ether production by replacing the open flame with steam passing through a coil.

  When budget cuts forced the Brooklyn Naval Laboratory to close in 1857, Squibb decided to start his own company around his new method. He founded the first American pharmaceutical manufacturing factory at a site adjacent to the Brooklyn Navy Yard and named his new company E. R. Squibb and Sons. The American Civil War created enormous demand for medical supplies, and Squibb’s contacts in the Navy put him in an excellent position to secure military contracts. The physical location of the company was also favorable; Squibb could simply walk across the street to the Navy Yard to negotiate contracts, then drive a wagon across the same street to deliver the purchased products.

  When the war ended, Squibb’s success continued to grow. The company’s reputation for producing trustworthy, standardized medicines led to high national demand for Squibb products. This consistency is embodied in Squibb’s original logo, used all the way into the 1980s when the company was acquired by Bristol-Myers. The logo comprised a marble pediment emblazoned with the word “reliability,” supported by three columns with the words “uniformity,” “purity,” and “efficacy.”

  Consider how different Squibb’s business model was from that of our own pharmaceutical industry. Squibb did not offer original or uniqu
e drugs. Instead, it outcompeted other suppliers by manufacturing more consistent drugs. Today, drug makers do not compete on reliability or consistency, since modern consumers presume that any drug they find on the shelf is going to be perfectly standardized. (Can you imagine a customer’s puzzled reaction to a television ad that proudly attested, “Every bottle of Tylenol is the same!”?) During the Age of Plants, the drug-making industry was like community theater, each apothecary serving his local neighborhood by formulating drugs according to his own personal tastes and inclinations. But now Squibb began making the pharmaceutical equivalent of the Hollywood blockbuster—formulaic, big-budget productions marketed to the entire world. Big Pharma was born.

  A little more than a century after Squibb began producing ether, I landed my first industrial R&D job with E. R. Squibb and Sons. Although unrecognizable as the company whose Brooklyn factory had once been the site of violent ether explosions—the modern-day Squibb had acquired perfume and candy businesses, among many others—it had nevertheless managed to preserve much of its founder’s abiding philosophy regarding which employees were most important. E. R. Squibb, a physician himself, believed that the physicians and biologists should direct the development of new medicine formulations, while the chemists should merely serve a supporting role.

  I did not fully appreciate Squibb’s medicine-first culture until I had worked for two other pharmaceutical companies. One of these was Cyanamid, which at its heart was a chemical company rather than a medicine company. American Cyanamid was originally founded in 1907 to produce a basic fertilizer ingredient known as calcium cyanamid, then grew by looking for new ways to exploit its newfound expertise in chemistry. Shulton, its consumer division, developed cleaning and grooming products, such as Old Spice aftershave, Breck shampoo, Pine-Sol cleaner, and Combat roach traps. Its agricultural division made chemical pesticides. Its chemicals division made industrial chemicals. In every division, including its pharmaceutical division, Lederle, chemicals and chemistry came first. It was a professional shock to me as a molecular biologist when I was demoted, in a sense, from the “A” team at Squibb to the “B” team at American Cyanamid.

  But I received an even more important lesson about the influence of a business’s attitude toward its drug hunters when I unexpectedly started working for American Home Products (AHP) in the late 1990s. I abruptly became an AHP employee after it bought the pharma company where I was initially employed. AHP was a financially driven holding company, which meant that the people running AHP would buy any company in any industry if they thought they could somehow squeeze a few drops of profit out of it. If AHP had the choice between earning $10.00 an hour for shoveling manure or $9.99 an hour for sniffing flowers, they would not hesitate an instant before picking up the shovel. As with most holding companies, there was little apparent rhyme or reason to its esoteric collection of businesses; AHP sold everything from perfumes to sauce pans to Chef Boyardee to vitamins and medicines. And because all AHP executives were directed to focus on the bottom line, any capital expenditure within any division of AHP—even for sums as little as $5,000—had to be reviewed by the corporate finance committee and approved by the CEO, Jack Stafford.

  Drug discovery requires a sustained effort that usually takes more than a decade to produce a useful medicine. A corporate focus on short-term profits often has a stifling effect on pharmacological research. Many of my fellow drug hunters at AHP tried to work around the restrictive constraints of the company’s capital expenditure policy, most commonly by gaming the system. Pharma scientists would grossly overstate their budgetary needs so that they would have enough funds to continue their research when the inevitable cost cuts came down. My own strategy—at least, at first—was to try to reason with AHP executives and explain how difficult it was to find new drugs when the financial decisions were always made for near-term impact instead of long-term value. Gradually, I realized that there was little hope of changing the minds of managers who were immersed in a corporate culture based on immediate financial calculations rather than one based on the patient and deliberate development of new medicines. While I was working there, I don’t think AHP developed a single drug that made a meaningful difference to patients or to medical practice.

  It is worth taking a moment to retrace the unlikely path that led to the establishment of the pharmaceutical industry in America, which today includes corporate cultures that are distinctly hostile toward the risk-laden realities of modern drug hunting. Ether was discovered during the very height of pseudoscientific alchemy by a physician-botanist who suggested it be used to treat coughs. Three centuries later, in the early 1800s, it was prescribed for an unwieldy hodgepodge of ailments, though we now know that it is worthless as a treatment for most, if not all, of these maladies. Then, in an attempt to impress his snooty in-laws, a dentist decided to try using this party drug to painlessly remove a patient’s tooth and ended up transforming surgery from a shriek-filled horror show to a calm and meticulous craft. And yet, though it revolutionized surgery, ether would not have revolutionized the pharmaceutical industry if it had been easy to make. Since ether required expansive and expensive technologies to produce a standardized compound, it led drug-making out of the apothecary shop and into the factory.

  Squibb’s success served notice that it was possible to manufacture important drugs on a massive scale. The Age of Industrial Formulation was not about inventing new drugs—it was about finding new formulations for existing drugs that could leverage the rapidly growing young science of chemistry and the new manufacturing techniques of industrial factories to produce standardized drugs on a massive scale. Drug hunters from this era, like Squibb, rummaged through the library of industrial formulations for new recipes for established drugs with a pre-existing market. Some other industrialized formulations included chloroform, morphine, quinine, ergot, jalap (a cathartic that accelerates defecation), ignatia (believed to be a kind of antidepressant), conium (used to treat trembling and palsy), guarana (used like caffeine), erythroxylon (fluid extract of cocaine), and alum (used to constrict tissue, reduce bleeding, or sometimes to induce vomiting).

  But this focus on improving the manufacture of existing drugs would soon change. A very different breed of drug hunter arose who searched for their Vindications in the vast new library of molecules known as synthetic chemistry.

  4

  Indigo, Crimson, and Violet

  The Library of Synthetic Medicine

  The original bottle of Bayer Aspirin

  “The product has no value.”

  —Heinrich Dreser, director of Bayer Pharmaceutical Research, on aspirin, 1897

  If this evening you went looking for the pharmaceutical industries of Switzerland and Germany, you would find their largest and most venerable companies along a single river, the Rhine. The headquarters of Novartis, Bayer, Merck KGaA, Hoffmann-La Roche, Boehringer Ingelheim, and Hoechst all sprawl along the banks of a waterway that flows through the heart of Germany on its windy way to the North Sea. In the 1990s, I learned the reason for this geographic convergence of European drug makers.

  I was negotiating a collaboration with Bayer that would permit Bayer to conduct biological tests on the chemical library from my own company, Cyanamid. Basically, that meant the Germans would be permitted to use our vast collection of molecules in their own drug hunting projects. During my visit, my hosts took me on a tour of Bayer’s archives. I held the original handwritten notebooks of August Kekulé, one of the most famous chemists in history, best known for discovering the hexagonal structure of benzene. After winding up our meetings, my chauffeur drove me back to my hotel on the outskirts of Frankfurt. He took the autobahn. While the driver was rocketing along at speeds approaching 130 miles per hour, I did my best to put nagging questions of air bag reliability out of my mind. I noticed that our route was following the Rhine, and in the hope of stifling my fear with conversation I asked my host how Europe’s most enduring drug firms all came to be concentrated along a single ri
ver. The reason, my German colleague informed me, has everything to do with the invention of colors like naphthol yellow, croceine orange, and methyl violet.

  For thousands of years, humans colored their fabrics using dyes made from plants and animals. The most vibrant colors, like Tyrian purple (made from predatory sea snails) and crimson (made from scale insects), could be so costly that fabrics stained with these shades often became status symbols reserved for aristocrats and royalty. But in the early nineteenth century, the British scientist John Dalton proposed the theory of the atom, which held that there was a set of indivisible chemical elements that combined with each other according to strict mathematical laws. Dalton’s atomic theory galvanized the fast-growing field of chemistry by providing a rational framework for understanding the individual components of any given chemical. After Dalton, scientists realized that every compound was composed of a specific set of molecules.

  Using this new way of thinking, drug hunters could finally unravel the key constituents of many ancient medications and determine the precise purity of any given formulation. Before scientific chemistry, the true substance of flowers, trees, and plants was both unfathomable and indistinguishable. Many scientists speculated that there was some kind of mystical élan vital—the force of life—that infused plants with a kind of botanical soul. There were no principles that could explain why one particular flower was poison and another palliative. Though apothecaries had always possessed many recipes for preparing drugs from plants, they usually lacked any understanding of what the active agent actually was in any given preparation. But once it was grounded in atomic theory, chemistry finally provided a set of practical tools for determining which molecules a drug was actually made of—and which of these molecules were active. Soon chemistry was able to do even better.