The Drug Hunters

The Improbable Quest to Discover New Medicines

Donald R. Kirsch, Ogi Ogas

• Publisher: Arcade
• Year: 2016
• ISBN:
  9781628727197
• Topic: History
• Subtopic: Science History
• Index: History

The surprising, behind-the-scenes story of how our medicines are discovered, told by a veteran drug hunter. The search to find medicines is as old as disease, which is to say as old as the human race. Through serendipity— by chewing, brewing, and snorting—some Neolithic souls discovered opium, alcohol, snakeroot, juniper, frankincense, and other helpful substances. Ötzi the Iceman, the five-thousand-year-old hunter frozen in the Italian Alps, was found to have whipworms in his intestines and Bronze-age medicine, a worm-killing birch fungus, knotted to his leggings. Nowadays, Big Pharma conglomerates spend billions of dollars on state-of the art laboratories staffed by PhDs to discover blockbuster drugs. Yet, despite our best efforts to engineer cures, luck, trial-and-error, risk, and ingenuity are still fundamental to medical discovery. The Drug Hunters is a colorful, fact-filled narrative history of the search for new medicines from our Neolithic forebears to the professionals of today, and from quinine and aspirin to Viagra, Prozac, and Lipitor. The chapters offer a lively tour of how new drugs are actually found, the discovery strategies, the mistakes, and the rare successes. Dr. Donald R. Kirsch infuses the book with his own expertise and experiences from thirty-five years of drug hunting, whether searching for life-saving molecules in mudflats by Chesapeake Bay or as a chief science officer and research group leader at major pharmaceutical companies.

1	So Easy a Caveman Can Do It The Unlikely Origins of Drug Hunting

A field of poppies

“Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.”

—Thomas Sydenham, seventeenth-century English physician

Our prehistoric forebears harbored an extravagant menagerie of supernatural beliefs. They believed it was possible to prepare potions from flowers that would hide you from the spears of your enemies. They thought snorting pulverized twigs would bestow the power to hear your neighbor’s thoughts. They also believed, with equal improbability, that foul-smelling concoctions brewed from tangly roots would cure disease.

Today, we find the suggestion that a chemical might endow you with invisibility or telepathy to be preposterous. On the other hand, we do not bat an eyelash at the prospect of finding healing salves within the natural world—in fact, we take Mother Nature’s bountiful pharmacopeia for granted. Yet why should the notion of botanical cures be any less outrageous than the notion of botanical telepathy? If you think about it for a moment, why in the world would the juice of a pungent bark found in mucky swamplands hold the power to relieve arthritis or promote digestion or lower blood pressure in Homo sapiens?

Certainly if one imagines that all the world was created for the express benefit of humankind, with all the flora and fauna of the Earth designed by a munificent deity to nourish our divinely ordained species, then we might believe it was God’s will for the sap of the willow tree to assuage headaches and the leaves of the foxglove plant to relieve heart ailments. However, if we believe in the principles of evolutionary biology, then it is far more surprising—mystifying, even—that so many compounds produced in non-human species have a salubrious effect on our own kind.

We cannot be certain that the impulse that drove the earliest humans to rifle through the leafy shelves of Mother Nature for new medicines was the same one that drove them to seek out invincibility powders and clairvoyance potions, but we do know that even the most primitive of human beings somehow plucked out effective drugs, like Ötzi’s parasite-slaying fungus.

It is not too hard to imagine that a plant substance might kill a parasite or even a bacterium; after all, many creatures produce toxins to defend themselves against infestation. But what about a plant that assuages our pain or ameliorates our acne? Or, even more peculiar, a plant that improves our mood or expands our consciousness? It is difficult for our modern minds, used to the overflowing aisles of candy-colored pills and syrups at the local Walgreens, to appreciate just how unlikely and bizarre organic drugs truly are—but what if I told you that there was a bush whose berries, when eaten, would enable you to breathe underwater? There’s not, of course, but we should feel equal skepticism and astonishment regarding the fact that the plant kingdom produces compounds that benefit our animal bodies in ways that have absolutely nothing to do with the way the compounds operate in plants.

Somehow, natural remedies were exhumed and harnessed by our prehistoric progenitors, even as their understanding was laced with myth and magic. Remarkably, some of these Stone Age drugs have stood the test of time and remain in widespread use today. Opium is one. Tracing the history of opium, one of humankind’s most ancient medications, will illustrate just how perplexing the existence of naturally occurring drugs really is, while also serving as a useful introduction to our species’s venerable quest for medicine.

If we relegate alcohol to the status of a beverage, then the oldest known medicine is something that you and I and almost every person in Western civilization has imbibed at some point in our lives—the tincture of the poppy. Percocet, morphine, codeine, oxycodone, and (of course) heroin are all derived from Papaver somniferum, a wild plant with attractively colored flowers common to Asia Minor. Opium is the active ingredient of the poppy, and one reason the drug has been used for so long is because opium is incredibly easy to prepare: the immature fruit of the poppy plant is scratched so that sap oozes out, the sap is collected, dried, and ground into a powder—and voilà, pure opium.

Opium was used by the Sumerians as early as 3400 BC, who referred to it as Hul Gil, the “joy plant.” The Sumerians passed along their knowledge of the joyful effects of the poppy to the Assyrians, who passed it on to the Babylonians, who passed it to the Egyptians. The first-known reference to poppy juice appears in the writings of the Greek philosopher Theophrastus in the third century BC; the word opium comes from the ancient Greek word for “juice,” opion. Later, Arabian traders introduced opium to Asia, where it was used in the treatment of dysentery, an often-fatal disease characterized by explosive diarrhea; in addition to its narcotic effects, opium is also highly constipating.

One major limitation of opiates as a medication is their poor solubility in water. After four thousand years of repeating the same simple water-based preparation of opium, many physicians in the Middle Ages attempted to develop a more effective formulation. These men represented one of the earliest breeds of drug hunters, the “formulator”—someone who tried to figure out a new way to prepare a known medicine. These formulators relied upon crude knowledge of prescientific chemistry, the pseudoscience of alchemy, or indiscriminate experimentation to develop new mixtures that often contained as many non-active compounds as active agents.

Paracelsus, a sixteenth-century botanist–physician, was one of the most talented of the formulator drug hunters. He devised a novel preparation of opium by dissolving it in alcohol. The preparation came to be known as laudanum, though Paracelsus himself was so enamored of its powers that he referred to it as the “stone of immortality.” His alcohol-based version of opium came close to pharmaceutical immortality, as it was still being used late into the twentieth century.

Another alcohol-based opiate mixture is known as paregoric. First formulated in the eighteenth century by Le Mort, a chemistry professor at the University of Leiden, paregoric is familiar to readers of Victorian novels because their heroines were frequently dosed with paregoric to calm frazzled nerves after some social drama, such as rejection by the handsome young baron. The word paregoric, in fact, comes from the Greek term for “soothing.”

Dover’s Powder, another eighteenth-century opium preparation, was invented by Thomas Dover in 1732. While scientists know Thomas Dover as an early pharmacologist, he became famous to the public through his other adventures. After studying medicine at Cambridge University, Dover settled in the English port city of Bristol and at the age of fifty joined a privateering venture to the South Seas. In 1709, the expedition landed on a deserted island off the coast of Chile—except Dover and his party discovered that the island was not deserted after all. It was inhabited by Alexander Selkirk, the sole survivor of a shipwreck from four years earlier. Upon Selkirk’s return to England, he became a celebrity, and his dramatic story inspired Daniel Defoe to write Robinson Crusoe. Upon Dover’s own return to England, however, he invented Dover’s Powder, coarse off-white granules containing equal quantities of opium and ipecac, an ingredient once found in cough syrup. His newly acquired fame as Selkirk’s rescuer surely did him no harm in marketing his new remedy.

Opium itself is actually a complex mixture of many different active compounds, such as the phenanthrenes (which includes familiar analgesics like morphine and codeine) and the benzylisoquinolines (which includes papaverine, a drug used as a treatment for vasospasm). An opium formulation prepared using the ancient water-dissolving recipe, for instance, contains about 10 percent morphine, .5 percent codeine, and .2 percent thebaine (an opioid that is not itself clinically useful but is the starting point for synthesizing other opioids such as oxycodone). In 1826, a young German pharmacist named Friedrich Sertürner became the first researcher to isolate one of the pure active components of opium. He named the chemical “morphine” after Morpheus, the Greek god of dreams, ushering in the modern era of opiates—and the modern era of opiate abuse.

Commercial production of Sertürner’s morphine commenced in 1827 at the Engel-Apotheke (“Angel Pharmacy”) in Darmstadt, Germany. The Engel-Apotheke was owned by Emanuel Merck, a descendent of Friedrich Jacob Merck, who founded the German apothecary in 1668. Engel-Apotheke expanded rapidly and eventually became the pharmaceutical company Merck, its rapid growth driven by the strength of its morphine sales. Merck first marketed morphine to the general public as a superior alternative to opium, and soon morphine addiction became even more common than opium addiction.

In 1897, researchers at Bayer Company in Germany used the new science of synthetic chemistry to create a novel chemical variation of morphine that they dubbed “heroin” because it was expected to have heroic effects in treating disease. We now know there is no disease for which heroin is an effective treatment, let alone a heroic one, though Bayer initially marketed heroin directly to the public as a cough suppressant and, absurdly, as a “non-addictive cure for morphine addiction.” One nineteenth-century Sears Roebuck catalog peddled a handy heroin kit: one syringe, two needles, two vials of Bayer heroin, and a carrying case—all for the bargain price of $1.50.

It was eventually discovered that the human body metabolizes heroin into several smaller compounds, including morphine, revealing that heroin was not a cure for morphine addiction—it served as a straight substitute for morphine. Yet even though heroin is broken down into morphine, there are important differences between the two compounds. Heroin produces greater psychological stimulation and a much more intense euphoria compared with morphine, and consequently is far more addictive. The morphine addict takes his drug to prevent the appearance of withdrawal symptoms. The heroin habitué, in contrast, takes his drug in order to attain an exulting, blissful high that makes everything bad disappear—at least, until the drug wears off, when everything bad comes rushing back worse than ever. When it became clear that Bayer had actually exacerbated opiate addiction, the company was savaged in the press, marking one of the first public-relations disasters for the modern pharmaceutical industry.

For centuries, exactly how the opiates produced their pain-relieving effects was a great scientific conundrum. Clearly, the poppy had not been guided by the hand of evolution to suppress human coughing or create human addicts. Even in the 1970s, when neuroscience research began to take off, it remained an inscrutable mystery why a Central Asian herbaceous plant held such rapturous power over our brain. Finally, two groups of scientists working independently at the University of Aberdeen in Scotland and Johns Hopkins University in Baltimore solved the neurochemical riddle in 1975.

They discovered that opiates act on specialized receptors in neurons known as endorphin receptors. Eric Simon, one of the discoverers of these receptors, coined the term “endorphin” as an abbreviation of “endogenous morphine,” meaning, “morphine produced naturally in the body.” Endorphins are naturally occurring hormones produced by the pituitary gland and hypothalamus that produce feelings of well-being and reduce painful sensations. These hormones produce their effects by binding to the endorphin receptors. Humans have nine different types of endorphin receptors, and each opium compound has a distinctive pattern of engaging these nine receptors. This unique pattern of receptor activation determines the characteristic physiological effects of each compound—euphoria, analgesia, sedation, constipation, and so on. When the opiate compound binds with a particular endorphin receptor, the receptor sends a signal into the neuron commanding it to produce other molecular compounds that in turn trigger circuits in the brain that generate the feelings of euphoria and analgesia.

Even when the operation of the opiates on the human nervous system was finally explained, the age-old question remained: why in the world are these brain-jiggering compounds manufactured within a flower? Scientists now have a pretty good answer. Over the eons, most plants have evolved various toxins to protect themselves from being eaten by insects and animals. In response, animals and insects counter-evolved ways to protect themselves from these toxins, such as by degrading them with liver enzymes or developing a blood–brain barrier to prevent toxins from entering their central nervous system. Plant compounds are the product of a relentless arms race between the vegetable and animal kingdoms, a biological death match still ongoing. Scientists speculate that the poppy plant’s biochemical pathway for opiate production initially evolved to make neurotoxins that fended off insects.

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 ...