The Drug Hunters Read online

  Quinine was one of the last great drugs to be discovered during the Age of Plants. The Spanish physician-botanist Nicolas Monardes published a lengthy treatise in 1574—translated into English as The three books of joyfull newes out of the newe founde worlde—that describes more than one hundred other New World plants that could be used as medicine. This list included curare, coca (cocaine, used by the indigenes for treating hematomas and eventually prescribed by European doctors for a variety of ailments), cacao (chocolate, used for treating depression and exhaustion), sassafras (used as a very ineffective treatment for fevers, including syphilis), arbor vitae (the “tree of life,” used to treat scurvy), tobacco (used to treat a variety of maladies), snakeroot, smilax, maiden hair fern, rose mallow, guaiacum (for the pox), various purgative nuts, oil from the fig tree of hell (a purgative), ipecacuanha (another purgative), canafistula, estoraque, (American) balsam (used to treat many ailments), and white jalap. Out of this list, the only plants still used in scientific medicine today are quinine, curare (as a paralytic in certain forms of surgery), and ipecacuanha (to induce vomiting). Chocolate, of course, is sometimes considered an aphrodisiacal drug—and is sometimes used for self-medicating during depression—but is no longer found on the pharmacist’s shelf.

  In many ways, Valerius Cordus’s short life marked one of the most momentous turning points in the quest for medicine, since his career embodied the transition from searching through the library of plants to searching through the next major pharmaceutical library, the library of synthetic chemistry. His tragic death from overzealous prowling in the boggy wilderness signaled the end of the most enduring era of drug hunting.

  Today it is exceedingly rare to discover new medicines from plants, because the world’s botanical largess has been so exhaustively harvested, husked, and scrutinized. In the 1990s, for example, I was working for the pharma company Cyanamid when our drug development team decided to forage through exotic foliage around the world in the hope of exhuming some new horticultural medicines. This would have required us to work with an expert botanist, but by the late twentieth century botany had devolved into a minor scientific discipline that was no longer pursued with much vigor by American universities. Consequently, we could not find anyone with the knowledge and interest to assist us with the project. (It might seem strange that scientific expertise could be so easily lost, but the diminishment of previously robust fields happens all the time. When I was a graduate student at Princeton, a scientist visited our biology department requesting access to our collection of bivalves, mollusks with two shells like clams and oysters. Nobody knew anything about the collection. The department chairman made some inquiries and learned from the staff that, during a remodeling effort ten years before, one of the workers discovered a bunch of seashells and threw them out. There was no outcry at the time, because there was no longer any professional interest in mollusks. It turned out that the Princeton bivalve collection had been considered one of the best in North America.)

  Since we could not track down a suitable botanist in the United States, we established a collaboration with the Institute of Cell Biology and Genetic Engineering in Kiev, Ukraine, which still had a very active program of botanical research. On our behalf, the institute sent botanical expeditions to remote regions across the globe, including the former Soviet Union (Ukraine, Russia, Kazakhstan, Azerbaijan, Kyrgyzstan, Uzbekistan), South America, Africa (Namibia, South Africa, Ghana), and Asia (China and Papua-New Guinea). The Kiev botanists collected some fifteen thousand species of plants. Despite this impressive haul of obscure herbs, shrubs, and flowers, the Cyanamid team failed to find a single new useful compound. After millennia of human exploitation, the library of plants might just be emptied of its Vindications.

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  Standard Oil and Standard Ether

  The Library of Industrial Medicine

  An early pharmaceutical factory

  “I have seen something today that will go around the world.”

  Dr. Henry J. Bigelow, 1846

  Though the Age of Plants was the longest and most prolific era of drug hunting, botany was becoming overshadowed in the earliest years of the Renaissance by the rise of alchemy, which might be more accurately described as the rise of pre-scientific chemistry. The most noble—and, potentially, the most lucrative—aspiration for any medieval alchemist was the “philosopher’s stone,” the term of art for any method of transforming a base element, like lead, into a precious metal, like gold. One typical formulation can be found in an alchemical manuscript discovered in a Jewish synagogue in Old Cairo dating from the twelfth century: “Combine mercury, horse manure, pearl, white alum, sulfur, clay mixed with hair and a couple of eggs and you will obtain good silver, God willing.” Today, we know that the most crucial step of this recipe—“God willing”—requires either nuclear fission or nuclear fusion, technologies unavailable in a culture that had no conception of the atom. Horse manure, on the other hand, remains a common ingredient of misconceptions to this very day.

  Any discipline that relies on the agglomeration of dung and divine intervention is unlikely to produce useful innovations, and for many uneventful centuries from the 1100s through the 1600s the alchemical drug hunters offered precious little in the way of practical advances in pharmacology, though they added a great many drug formulations that were barely useful at best, and lethal at worst. Valerius Cordus finally shrugged off the hazy bonds of the occult in favor of scientific observation. His reliable recipe for “the oil of vitriol” proved to be far more transformative than the misbegotten quest for the philosopher’s stone.

  The Swiss-German alchemical formulator Paracelsus, a contemporary of Cordus, wrote that ether would put chickens to sleep for “a moderate time” without hurting them, though Paracelsus failed to consider using it to put humans to sleep. Likewise, though Cordus patiently recorded several medicinal uses for ether based on his thoughtful experimentation, there is no record that he was aware of its effects as an anesthetic. Cordus’s formulation of ether remained a standard if minor part of the physician’s pharmacopeia for the next three centuries, used as a chemical solvent and as a (presumably extremely ineffective) treatment for headaches, vertigo, epilepsy, palsy, hysteria, rheumatism, and many other diseases. But even the most forward-thinking physicians of the early nineteenth century exhibited no greater imagination than the medieval apothecaries regarding the oil of vitriol’s uses.

  In 1812, one recommended use for ether appeared on the very first page of the very first volume of the New England Journal of Medicine. Dr. John Warren, one of the founders of Harvard Medical School and one of the most prominent physicians of the time, wrote an article on the treatment of angina, a painful condition that feels like your chest is being squeezed. Today we know angina is caused by insufficient supply of oxygen to the heart, but since Warren lacked adequate knowledge of the disease he offered up a rather dubious catalog of putative treatments: bathing the feet in warm water, bleeding, nitrate of silver, fetid gums, tobacco smoking, opium, and, finally, ether.

  Not only was ether recommended as an angina treatment, by 1830 it was best known to the public as a recreational intoxicant at giggly parties known as “ether frolics,” where wealthy straitlaced Victorians huffed the vapors of the oil of vitriol and proceeded to flop around, stumble into the furniture, or pass out entirely. Ether was also prescribed then as an antiseptic, a cleansing solvent, an expectorant in cough medicines, a carminative (that is, an anti-flatulent), and—rather improbably—a stimulant in cases of fainting, where it was sometimes combined with the far more efficacious aromatic spirits of ammonia. There was one medical use, however, for which ether had never been prescribed in all its years of existence.

  Surgery was uncommon prior to the middle of the nineteenth century. For one thing, surgery was very dangerous. Infection was an almost-inevitable consequence of any surgical procedure, and these infections were often lethal. Aseptic techniques were not practiced at all prior to the establishment of t
he germ theory of disease in the late nineteenth century. Worse, knowledge of disease pathways was either rudimentary or entirely nonexistent, and as a result there was no consistent scientific rationale for surgical intervention. Finally, surgery was conducted without any anesthesia, and as a result, was agonizingly, excruciatingly, soul-wrenchingly painful.

  It’s hard for us to imagine what surgery must have been like before the use of anesthesia, though we can get some idea from George Wilson, a prominent professor of medicine who had had his foot amputated in 1843 and described the unspeakable awfulness of the procedure:

  The horror of great darkness, and the sense of desertion by God and man, bordering close on despair, which swept through my mind and overwhelmed my heart, I can never forget, however gladly I would do so. During the operation, in spite of the pain it occasioned, my senses were preternaturally acute, as I have been told they generally are in patients in such circumstances. I still recall with unwelcome vividness the spreading out of the instruments: the twisting of the tourniquet: the first incision: the fingering of the sawed bone: the sponge pressed on the flap: the tying of the blood vessels: the stitching of the skin: the bloody dismembered limb lying on the floor.

  In the first half of the nineteenth century, surgery was an emergency procedure—the amputation of a limb to prevent fatal gangrene, the drainage of an infected abscess, or a cystotomy for an excruciating bladder stone (one of the few maladies considered more painful than the surgery itself). Fine dissection and careful technique were simply not possible because patients twisted and contorted in pain under the surgeon’s blade. The best strategy for a successful operation was speed. The faster the procedure was completed, the less the excruciating pain, and the less convulsive the patient.

  Spectators in early nineteenth-century operating galleries pulled out their pocket watches to time the pace of surgical procedures. Dr. Robert Liston, for instance, a Scottish surgeon who practiced at University College Hospital in London, was famed for the swiftness of his technique. Once, in his haste to amputate a leg, he sliced off the patient’s testicles as well. During another brisk amputation of a leg, Liston managed to spare the patient’s testicles—but accidentally removed two of his young assistant’s fingers. Both patient and assistant eventually died of gangrene, while a spectator watching the same operation died of shock upon seeing Liston’s whirling blade slash through his coat, believing that he had just been fatally stabbed. Such were the dangers of surgery in the pre-anesthetic era.

  Given the pressing need to relieve surgical pain, physicians experimented with many potential anesthetics. Alcohol, hashish, and opium were all sampled and found wanting. Though they dulled the senses somewhat, they proved to be inadequate for the kind of agony induced by a knife cutting through deep muscles. Physical methods, such as packing a limb in ice or rendering it numb with a tourniquet, were also insufficient to the task. Pain always seared through. Some bolder surgeons went so far as to produce unconsciousness in their patients through strangulation or a severe blow to the head, though most physicians expressed doubts that the benefits of these procedures outweighed their disadvantages. Nineteenth-century surgeons were trained to expect surgery to be a bloody affair, full of writhing and screams, a task that must be completed as hastily as possible. That might be why it took a non-surgeon to imagine the possibility of surgery without pain—a Boston dentist by the name of William T. G. Morton.

  In 1843, at age twenty-four, Morton married Elizabeth Whitman, the niece of a former congressman. Elizabeth’s prominent and patrician parents objected to Morton’s profession. At the time, a dentist was regarded as little better than a barber. The Whitmans agreed to allow their daughter to marry Morton only after he promised to study the far more respectable profession of medicine.

  In the autumn of 1844, Morton dutifully enrolled in Harvard Medical School, where he attended the chemistry lectures of Dr. Charles T. Jackson. Jackson was well acquainted with the pharmacological properties of ether, including its anesthetic qualities, but even though he was a bright working physician he apparently never gave serious consideration to the possibility that ether could be applied during surgery. Morton learned about ether during one of Jackson’s lectures and, intrigued by its unparalleled ability to put people to sleep, he experimented with the drug on his pet dog, writing:

  In the spring of 1846, I tried an experiment upon a water spaniel, inserting his head in a jar having sulphuric ether at the bottom…. After breathing the vapor for some time, the dog completely wilted down in my hands. I then removed the jar. In about three minutes he aroused, yelled loudly, and sprung some ten feet, into a pond of water.

  Morton also tested ether on a hen and some goldfish. They, too, softly succumbed. Emboldened by these successes, Morton inhaled the sweet-smelling vapor himself. He passed out, then recovered fully without any noticeable ill effects. Morton finally felt it was time to try it on an actual patient. Morton performed the world’s first painless dental extraction in his Boston office, removing an ulcerous tooth from a grateful merchant who history records as Mr. Eben Frost:

  Toward evening, a man … came in, suffering great pain and wishing to have a tooth extracted. He was afraid of the operation and asked if he could be mesmerized. I told him I had something better, and saturating my handkerchief, gave it to him to inhale. He became unconscious almost immediately. It was dark, and Dr. Hayden held the lamp, while I extracted a firmly rooted bicuspid tooth. There was not much alteration in the pulse, and no relaxation of the muscles. He recovered in a minute, and knew nothing of what had been done to him.

  On October 1, 1846, the Boston Daily Journal published an account of Morton’s curious experimental procedure. The story made its way to Henry Bigelow, a junior surgeon affiliated with Harvard Medical School. Intrigued, Bigelow convinced the eminent head surgeon of Massachusetts General Hospital to stage a public test of Morton’s purported anesthetic procedure. This was the big time. It was the nineteenth-century medical equivalent to landing a spot on American Idol. Mass General was one of the most respected hospitals in the country, and its head surgeon, sixty-eight-year-old John Collins Warren, had a national reputation. Warren had previously served as the dean of the Harvard Medical School, an institution his father helped found, and helped establish the New England Journal of Medicine.

  With the stakes suddenly so high, Morton knew he would be taking a huge risk. It was one thing to fool around with ether in the relative obscurity of a dental office. After all, nobody expected very much from the uncouth and unruly pseudo-profession of dentistry. It was quite another thing to test the drug’s performance during life-risking surgery in front of the Brahmin cream of the medical establishment. More than fifty skeptical spectators, including many of America’s top surgeons, gathered in the Mass General operating theater on October 16, 1846. Some were genuinely curious about ether’s effects. Most, though, expected to watch the public exposure of a charlatan.

  The patient, one Edward Gilbert Abbott, suffered from a large tumor bulging out of his neck. Its removal would be a harrowing and excruciating experience—at least, that was how it usually went. Two strong orderlies stood nearby, ready to assume their usual role of holding down a flailing, shrieking patient. But would this time be different?

  As the audience watched from the high tiers of seats, the patient was rolled into the operating theater. Warren stood by, waiting. The clock ticked past the appointed time for the commencement of the surgery, but Morton did not appear. Warren turned to the gallery. “As Dr. Morton has not arrived, I presume that he is otherwise engaged.” The patient gritted his teeth. The surgeon lifted his scalpel.

  Suddenly, Morton strode into the theater. There was good reason for his delay. Since nobody had ever before administered ether during surgery, there was no mechanism for delivering ether vapor in a controlled fashion. Morton had been busy constructing an ingenious apparatus: a round-bottomed chemistry flask that contained sponges soaked in ether. Two ports were attached to the fl
ask with brass fittings, and, via a clever system of leather flaps, air was drawn from one aperture over the ether-soaked sponges and inhaled through the other.

  Warren stepped back and said, “Well, sir, your patient is ready.” Surrounded by a silent and largely unsympathetic gallery, Morton went to work administering the ether from his newly contrived glasswork. The patient breathed a few slow breaths of the vapor and his eyes gently shut. Morton turned to the surgeon. “Dr. Warren, your patient is ready.”

  The operation began. As the scalpel sliced deep into his neck, the patient showed no reaction. Even so, the slow heaving of his chest demonstrated he was clearly alive and breathing. The audience gaped in awe. Today, we take the existence of anesthesia for granted, but imagine just how wizardly this must have seemed to a physician at the time—there was some magical substance that somehow completely shut the mind off from all awareness, yet left the body’s physiological operations unaffected. It was a moment as revolutionary to medicine as the discovery of gunpowder was to warfare or the invention of powered flight was to transportation. When the operation was completed, Dr. Warren turned to the audience and announced, “Gentlemen, this is no humbug.”