The Drug Hunters Read online

  These botanical opiates were always second-rate toxins, however. They alter the behavior of beetles and grubs, sure—but other plants assemble far more efficacious toxins, like strychnine, a poison that induces muscular convulsions and, eventually, asphyxiation. Nevertheless, opiate “toxins” were good enough to protect the poppy from chewing, gnawing bugs to enable the plant to survive all the way into the twenty-first century.

  Meanwhile, as poppies were evolving opiates as a way of impairing hostile insects that were sensitive to the toxins, mammals were simultaneously evolving pain-blocking receptors in neurons along a completely independent evolutionary pathway—receptors that by happenstance respond to opiate compounds. Thus, the botanical-chemical system that produces opiates in poppies has absolutely nothing in common with the system that responds to opiates in mammals. In terms of naked statistical probabilities, it is extraordinarily unlikely that a molecular configuration that evolved in plants as a crude insect repellent would also evolve in the sophisticated brains of mammals as a pain-mediator—but, somehow, Mother Nature twice pulled the same chemical volume from the pharmaceutical library of Babel for two disparate missions.

  Once our fun-loving Neolithic ancestors stumbled upon the agreeable effects of the milky poppy sap, they began selecting the seeds from those plants that produced the most euphoric intoxication. And today, after many thousands of years of human-guided selection, modern poppy varieties are turbo-charged opiate factories compared to the original species our forebears discovered on the steppes of Central Asia. Studies have shown that even a few generations of selective breeding can dramatically boost the potency of pharmaceutically active compounds in plants. Marijuana is one example. The psychoactive kick of contemporary cannabis plants has been amped up to seven times the potency of the pot smoked at the Woodstock festival in 1969, as measured by the levels of the active ingredient, THC.

  The randomness of opium’s effect on our brain is underscored by the fact that virtually every compound found in plants has no beneficial effect whatsoever when ingested by humans. Instead, if you swallow a randomly selected leaf or root or berry, most of the time you will get sick. Only about 5 percent of the 300,000 known species of flora are edible. Seventy-five percent of the world’s food is generated from twelve species of plants and five species of animals. Yet, prehistoric drug hunters discovered a Vindication in the form of a mind-bending botanical narcotic that became the all-time best-selling medicine in the history of our species. In 2011, more than 130 million prescriptions were written for Vicodin alone, a generic opioid drug derived from codeine, the most prescriptions for any drug that year.

  Despite the immense commercial success of opiates, the possibility of even greater profits dangles before any drug hunter who might discover a synthetic improvement over Mother Nature’s opiates. The ideal painkiller would be: (1) non-addictive, (2) non-sedating, and (3) able to relieve even the most excruciating pain. While opiates are the most high-impact pain relievers available, they are both psychologically and physiologically addictive, they induce drowsiness and constipation, and at not particularly high doses they can halt breathing, causing death. In comparison, NSAID (nonsteroidal anti-inflammatory) pain relievers like aspirin and ibuprofen are neither addictive nor sedating and have virtually zero risk of causing death—an improvement, to be sure, but they do not help with severe or excruciating pain.

  When I worked for Wyeth, we had a research group devoted to the development of better pain relievers, a quest shared by all Big Pharma companies. Most of these pain projects focus on blocking some type of ion channel in neurons involved with the transmission of painful stimuli. One of the most interesting lines of inquiry at Wyeth originated with a group of fascinating and ill-fated patients who suffer from an extremely rare condition known as congenital insensitivity to pain (CIP). This condition is caused by mutations in a gene that encodes a voltage-gated sodium channel in neurons known as Nav1.7. Without this ion channel, people cannot feel pain. This might seem like something wonderful, but without the sensation of pain people often injure themselves performing mundane activities, like putting their hands in boiling water or dropping a brick on their foot—acts that feel little different than resting their head on a pillow. In developing countries, people with CIP generally do not long survive, though in the West they can often survive into adulthood if their families have the resources to protect them from inadvertent injury 24/7.

  At Wyeth, we realized that if we could somehow mimic the effects of the Nav1.7 ion channel mutation, then we might be able to engineer a drug that could overcome any level of pain, no matter how debilitating. Like everything in drug hunting, this is easier said than done. The painkiller group at Wyeth devoted thousands of man-hours and millions of dollars to the project. Decades later, the Nav1.7 ion channel project has still not produced a single FDA-approved drug, and the dream of a non-addictive, non-sedating, intense-pain-relieving medication remains just that—a wistful dream. As I write this, the best analgesic is still the oldest analgesic.

  The existence of high-performance painkillers in the poppy is the result of pure, naked chance, but even the most ardently science-minded of observers cannot help but feel there is something cosmically appropriate in the fact that the most effective mollifier of human agony is found beneath the velvety petals of a cheerful little flower.

  2

  Countess Chinchón’s Cure

  The Library of Botanical Medicine

  The library of plants

  “The plant is hot and has extreme curative healing power…. A drink mixed of freshly pressed plant juice with honey and wine fights melancholy, clears the eyesight, strengthens heart and lungs, warms the stomach, cleans the gut, and moves the bowels regularly.”

  —Hildegard von Bingen on absinthe, in Physica, c. 1125 AD

  There have always been two distinct breeds of physicians. The practitioners, such as primary care doctors and brain surgeons, focus on providing effective care to their patients. The researchers, in contrast, seek out new medical discoveries that may benefit many. These days, the most prevalent form of the medical researcher is the physician–molecular biologist, typically an MD-PhD hunting for new cures within genomic science. But from the Renaissance back into the murky depths of antiquity the most common type of medical researcher was the physician-botanist. Why? Because virtually all new drugs were found within the chlorophyll kingdom of plants.

  Pharmacology was essentially a specialized branch of botany for the first ten thousand years of human civilization. We might call this era of drug hunting the Age of Plants. All the variegated specimens of the vegetative world—flowers, roots, seeds, bark, sap, moss, seaweed—were considered God’s own pharmacopeia, to be harvested and husked and milled and boiled into beneficial tonics. (Indeed, the English word “drug” comes from an ancient French word, “drogue,” which referred to dried herbs.) The discovery of new balms required expertise in both human disease and plant lore, and thus nearly every pharmaceutical revelation from the dawn of history until the eighteenth century was perpetrated by a physician-botanist. Perhaps the most esteemed of these early botanical drug hunters was a German prodigy by the name of Valerius Cordus.

  Born in Hesse, Germany, in 1515, Cordus was the son of a physician and the nephew of an apothecary. His uncle took the young Cordus on drug-hunting expeditions in the wilds of northern Germany, where they gathered up medicinal plants, and then revealed to him the arcane methods for distilling their horticultural bounty into potions and ointments. Cordus came of age during a time when most apothecaries had an alchemical bent, when elixirs for enchanted romance were just as common as powders for crotch rash. But from the moment he started university in the scholarly city of Wittenberg, Cordus exhibited no interest in superstition or interpretative divination. Instead, he insisted that the apothecary craft should consist solely of careful observation and verifiable results.

  While still a graduate student, Cordus began delivering sophisticated lectures on a
famed ancient Greek apothecary named Dioscorides, a physician-botanist who lived around 50 AD who penned a five-volume encyclopedia about herbal medicine known as De Materia Medica. This hefty pharmacopeia detailed everything that was known in the ancient world about medicinal substances. It described nearly one thousand different drugs. Dioscorides’s tome had served as Europe’s Physician’s Desk Reference for more than fifteen hundred years, an astonishing run that did not rest on the accuracy or clarity of the De Materia Medica but rather on the fact that no serious effort was made to improve upon it.

  Cordus’s lectures on Dioscorides were so highly regarded that even professors attended them—a rarity at the time and even more impressive considering that Cordus was barely out of his teens. Though Cordus praised De Materia Medica, he also suggested that it was high time for Europeans to break from the stodgy old antiquarians and develop their own modern manual of medicines. To fulfill this new mission, Cordus devoted himself to two tasks after he left the university. He searched the world for new plants that could be the source of new drugs. And he began writing a new pharmacopeia based on evidence rather than tradition.

  In 1543, at the youthful age of twenty-eight, he published the Dispensatorium. This landmark opus was the first major pharmacological document to exclude all reference to the supernatural and mystical, focusing exclusively on empirical knowledge about the properties and preparations of plants. It listed more than 225 medicinal plants, including myrrh, crocus, cinnamon, piperis, absinthe, gum Arabic, calamus, camphor, cardamom, cucumeris, citrulli, margaritarum, roses, anise, and balsam. Because of its careful observations on such a wide variety of flora, the Dispensatorium’s contribution to scientific botany became just as important as its contribution to scientific pharmacology. Cordus’s radical new pharmacopeia became the most widely used apothecary manual for the next century.

  But Cordus was not satisfied with documenting all that was already known about drugs. He was obsessed with discovering new ones, too. Influenced by his childhood expeditions with his uncle, he voyaged to exotic and obscure locales in the hope of unearthing new plants to add to his growing compendium of medicines. He also began experimenting with chemistry, a fledgling field that was still closer kin to occult alchemy than verifiable science. Once again, Cordus distinguished himself through meticulous observation, recording only those results that could be replicated.

  As a drug hunter, Cordus mostly scavenged through the library of plants for his Vindications. But he was also a formulator, attempting to contrive new versions of drugs using techniques from the nascent field of scientific chemistry. Cordus’s greatest success was a medicine that is still in use today in a handful of developing nations—ether. While Cordus was not the first person to discover ether, which he referred to as “sulphur” or “vitriol,” there is no question that Cordus was the first to provide a reliable account of its synthesis from sulfuric acid and grain alcohol. He systematically described the chemical properties of both “sour oil of vitriol” and “sweet oil of vitriol” (the latter of which eventually became modern ether), including its high volatility and its unfortunate tendency to blow up in a fiery explosion. Like all of his research, however, his investigation of ether was ultimately directed towards the therapeutic. He wrote detailed reports of the medicinal applications of oleum dulce vitrioli, including its promotion of mucus secretions and its amelioration of hacking coughs. We will return to ether in the next chapter, where we will see how the drug was almost single-handedly responsible for the establishment of the modern pharmaceutical industry.

  So what was life like for a Renaissance drug hunter? Sadly, it could be tragic and short. In the summer of 1544, Cordus ventured into the mosquito-infested swamps of Florence and Pisa, boldly prospecting for new botanical varietals in the sludge. After returning to Rome with his harvest, he was stricken with malaria and perished—a victim of his own drug-hunting ambitions. He was twenty-nine years old. At the time of his death, he had directly contributed to the foundations of no less than three fields of science: botany, chemistry, and pharmacology. His epitaph reads: “Valerius Cordus, while still a youth, explained to men the working of Nature and the powers of plants.”

  As Europeans began to colonize the New World in the wake of Columbus’s voyages of exploration, botanical drug hunters extended their quest for exotic plant tinctures to the uncharted lands on the far side of the world. One of the most important discoveries was the bark of a tree found in the western jungles of Bolivia and Peru, a tree we now call chinchona. The aboriginal Quechua people brewed its bark into an earthy, bitter tea they imbibed to prevent malaria. The Spanish conquistadors quickly adopted the wondrous bark as their own; one Augustinian monk named Calancha wrote in 1633: “A tree grows which they call ‘the fever tree’ in the country of Loxa, whose bark, of the color of cinnamon, made into a powder amounting to the weight of two small silver coins and given as a beverage, cures the fevers and tertians; it has produced miraculous results in Lima.”

  In the fifteenth century, tertian was a term used to describe a fever that was intermittent, rising and falling—the type most commonly seen in malaria. The reason that fevers come and go in individuals suffering from malaria is because the parasite that causes the disease replicates in synchronized waves inside the host’s red blood cells. After a round of replication concludes, the red blood cells burst open, and all the parasites simultaneously dash out to invade new blood cells. This process induces fever when chemical fragments from the burst cells enter the bloodstream (they are toxic products from the degradation of hemoglobin). Once the parasites successfully penetrate a new population of red blood cells, the fever resolves, and a new cycle of infection commences.

  One story holds that chinchona bark was used to treat Countess Anna del Chinchón, the wife of the viceroy to Peru, in 1638. (The genus of plants that produce quinine were named in her honor by Carl Linnaeus, the “father of modern taxonomy,” since he believed she was among the first Europeans cured by the bark.) Her supposedly miraculous recovery led to the introduction of chinchona into Spain in 1639 as a malaria treatment, and for years the bark was called “los Polvos de al Condesa”—the Countess’s Powder. It is true that the viceroy did bring a large quantity of chinchona to Spain, but what is not clear is whether his wife was ever treated with “los Polvos de al Condesa” or if the epithet was merely a marketing ploy invented by the viceroy to help promote the sales of his ample stash of bark.

  The Jesuit missionaries in South America quickly established themselves as the main importers and distributors of chinchona in Europe, where it was often called “Jesuit’s bark.” It soon became one of the most valuable commodities shipped from Peru to the Old World. This New World drug, however, was not without its controversies.

  Traditional physicians of the era, known as Dogmatists, did not believe in the bark’s powers of healing because it did not conform to the teachings of the ancient physician Galen and his theory of the four bodily humors, which held that malaria should be cured through purges (usually a forceful evacuation of the bowels). The Dogmatists were opposed by the Empirics, early rationalists who believed that medical remedies should be sought out through observation and experimentation. This debate raged across Europe for decades and produced a storm of claims and counterclaims about the American bark. Many charlatans and hucksters took advantage of this climate of pharmaceutical uncertainty, the most famous of whom was an English apothecary named Robert Talbor.

  Talbor promoted his own remedy for malaria. In 1672, he published “Pyretologia, A Rational Account of the Cause and Cure of Agues,” a compact volume which—although scientific in appearance—was basically a marketing brochure touting his wonder drug. Though he described the method of administering Pyretologia in great detail, all he reported of its composition was that it was “a preparation of four vegetables, whereof two are foreign and the other domestick.” As he hawked his own remedy, he vociferously warned against the use of chinchona bark:

  And le
t me advise the world beware of all palliative Cures and especially that known by the name of Jesuits’ Powder, as it is given by unskillful hands for I have seen dangerous effects follow the taking of the Medicine uncorrected and unprepared.

  Talbor was a man motivated by lucre. When physicians solicited him for a more complete account of his mystery balm, Talbor wrote that prior to revealing its ingredients he deserved to be compensated for his efforts:

  I intend hereafter to publish a larger, and fuller account of my particular method, and medicine, not being willing to conceal such useful remedies from the world any longer, than till I have made some little advantage myself, repay that charge and trouble I have at in the search and study of so great and unheard of secrets.

  He eventually earned the payoff he was looking for by curing the son of Louis XIV using Pyretologia. The French Sun King rewarded Talbor with “3,000 gold crowns and a lifetime pension.” Nevertheless, even though Talbor was frequently called upon to disclose the ingredients of his remedy, he never divulged his secret recipe. A year after Talbor’s death, several apothecaries finally identified the key component of Pyretologia: the bark of the chinchona tree.

  Two more centuries passed before the active chemical in chinchona was finally isolated in 1820 by two French apothecaries, who dubbed it quinine. The compound had a transformative impact on human civilization. It opened up malaria-ridden lands across the globe to Western colonization, including huge swaths of South America, North America, Africa, and the Indian subcontinent that were previously too dangerous to inhabit. European colonists’ frequent consumption of quinine also gave rise to a new alcoholic cocktail that remains popular to this day—the gin and tonic. The typical nineteenth-century imperial British bureaucrat, reclining on a veranda wreathed with mosquito nets in some remote outpost of the British Empire, ordered gin and tonics from his native servants that he sipped as he enjoyed the setting sun. The tonic water contained the quinine, but its bitter taste was difficult to get down, so gin was added to mask the flavor. (If adding hefty swigs of strong grain alcohol was considered an improvement, you can probably guess just how unpleasant quinine actually tastes.) In addition, quinine has poor solubility in water, so mixing it with alcohol made it easier to dissolve the medicine.