Patents & Potions Introduction We live today in a world of drugs. Drugs for pain, drugs for disease, drugs for allergies, drugs for pleasure, and drugs for mental health. Drugs that have been rationally designed; drugs that have been synthesized in the factory or purified from nature. Drugs fermented and drugs engineered. Drugs that have been clinically tested. Drugs that, for the most part, actually do what they are supposed to. Effectively. Safely. By no means was it always so. Before the end of the 19th century, medicines were concocted with a mixture of empiricism and prayer. Trial and error, inherited lore, or mystical theories were the basis of the world’s pharmacopoeias. The technology of making drugs was crude at best: Tinctures, poultices, soups, and teas were made with water- or alcohol-based extracts of freshly ground or dried herbs or animal products such as bone, fat, or even pearls, and sometimes from minerals best left in the ground—mercury among the favored. The difference between a poison and a medicine was a hazy differentiation at best: In the 16th century, Paracelsus declared that the only difference between a medicine and a poison was in the dose. All medicines were toxic. It was cure or kill. “Rational treatments” and “rational drug design” of the era were based on either the doctrine of humors (a pseudoastrological form of alchemical medicine oriented to the fluids of the body: blood, phlegm and black and yellow bile) or the doctrine of signatures. (If a plant looks like a particular body part, it must be designed by nature to influence that part. Lungwort, for example, was considered good for lung complaints by theorists of the time because of its lobe-shaped leaves.) Neither theory, as might be expected, guaranteed much chance of a cure. Doctors and medicines were popular, despite their failures. As pointed out by noted medical historian Charles E.Rosenberg, a good bedside manner and a dose of something soothing (or even nasty) reassured the patient that something was being done, that the disease was not being ignored. Blood and mercury By the first part of the 19th century, the roots of modern pharmacy had taken hold with a wave of heroic medicine. Diseases were identified by symptom, and attacking the symptom as vigorously as possible was the high road to health. Bloodletting dominated the surgeon’s art, and dosing patients with powerful purgatives and cathartics became the order of the day in an attempt to match the power of the disease with the power of the drug. Bleed them till they faint. (It is difficult to sustain a raging fever or pounding pulse when there is too little blood in the body, so the symptoms, if not what we would call the disease, seemed to vanish.) Dose them with calomel till they drool and vomit. (Animals were thought to naturally expel toxins this way.) Cleanse both stomach and bowels violently to remove the poisons there. Certainly these methods were neither pleasant nor very effective at curing patients already weakened by disease. George Washington died in misery from bloodletting; Abraham Lincoln suffered chronic mercury poisoning and crippling constipation from his constant doses of “blue mass.” The “cure” was, all too often, worse than the disease. In the second half of the 19th century, things changed remarkably as the industrial revolution brought technological development to manufacturing and agriculture and inspired the development of medical technology. Spurred in part by a reaction against doctors and their toxic nostrums, patent medicines and in particular homeopathy (which used extreme dilutions of otherwise toxic compounds) became popular and provided an “antidote” to the heroic treatments of the past. Not helpful, but at least harmless for the most part, these new drugs became the foundation of a commodity-based medicine industry that galvanized pharmacist and consumer alike. Technology entered in the form of pill and powder and potion making. Almost by accident, a few authentic drugs based on the wisdom and herbal lore of the past were developed: quinine, digitalis, and cocaine. Ultimately, these successes launched the truly modern era. The century ended with the development of the first of two synthesized drugs that represent the triumph of chemistry over folklore and technology over cookery. The development of antipyrine in 1883 and aspirin in 1897 set the stage for the next 10 decades of what we can look back on in retrospect as the Pharmaceutical Century. With new knowledge of microbial pathogens and the burgeoning wisdom of vaccine technology, the first tentative steps were taken to transform medicines to a truly scientific foundation. From these scattered seeds, drug technology experienced remarkable if chaotic growth in the first two decades of the 20th century, a period that can be likened to a weedy flowering of quackery and patent medicines twining about a hardening strand of authentic science and institutions to protect and nourish it. 1 Staging the Pharmaceutical Century In the latter half of the 19th century, numerous beneficent botanicals took center stage in the world’s pharmacopoeias. Cocaine was first extracted from coca leaves in 1860; salicylic acid—the forerunner of aspirin— was extracted from willow bark in 1874 for use as a painkiller. Quinine and other alkaloids had long been extracted from China bark; but an antifebrile subcomponent, quinoline, was not synthesized in the lab until 1883 by Ludwig Knorr. The first truly synthetic pain reliever, antipyrine, was produced from quinoline derivatives. Digitalis from foxglove and strophantin from an African dogbane were both botanicals purified for use against heart disease. The opium poppy provided a wealth of pain relievers: opium, morphine, codeine, and heroin. But it was not until the birth of medical microbiology that the true breakthroughs occurred, and science—rather than empiricism—took center stage in the development of pharmaceuticals. Murderous microbes The hallmark of 19th-century medicine has to be the microbial theory of disease. The idea that infectious diseases were caused by microscopic living agents provided an understanding of the causes and the potential cures for ills from anthrax to whooping cough. Technology made the new framework possible. The brilliance of European lens makers and microscopists, coupled with the tinkering of laboratory scientists who developed the technologies of sterilization and the media and methods for growing and staining microbes, provided the foundation of the new medical science that would explode in the 20th century. These technologies offered proof and intelligence concerning the foe against which pharmaceuticals, seen thereafter as weapons of war, could be tested and ultimately designed. In 1861, the same year that the American Civil War began, Ignaz Semmel weis published his research on the transmissible nature of purperal (childbed) fever. His theories of antisepsis were at first vilified by doctors who could not believe their unwashed hands could transfer disease from corpses or dying patients to healthy women. But eventually, with the work of Robert Koch, Joseph Lister, and Louis Pasteur adding proof of the existence and disease-causing abilities of microorganisms, a worldwide search for the microbial villains of a host of historically deadly diseases began. In 1879, as part of the new “technology,” Bacterium coli was discovered (it was renamed Escherichia after its discoverer, Theodor Escherich, in 1919). It quickly became the quintessential example of an easily grown, “safe” bacteria for laboratory practice. New growth media, new sterile techniques, and new means of isolating and staining bacteria rapidly developed. The ability to grow “pathogens” in culture proved remarkably useful. Working with pure cultures of the diphtheria bacillus in Pasteur’s laboratory in 1888, Emile Roux and Alexandre Yersin first isolated the deadly toxin that causes most of diphtheria’s lethal effects. One by one over the next several decades, various diseases revealed their microbial culprits to the so-called microbe-hunters. Initially, most American physicians were loath to buy into germ theory, seeing it as a European phenomenon incompatible with the “truth” of spontaneous generation and as a threat to the general practitioner from the growing cadre of scientifically trained laboratory microbiologists and specialist physicians. “Anti-contagionists” such as the flamboyant Colonel George E. Waring Jr., pamphleteer, consulting engineer, and phenomenally effective warrior in the sanitation movement, ultimately held sway. Filth was considered the source of disease. A host of sewage projects, street-cleaning regimens, and clean water systems swept urban areas across the United States, with obvious benefits. Ultimately, the germ theory of infectious diseases had to be accepted, especially as the theoretical foundation behind the success of the sanitation movement. And with the production of vaccines and antitoxins, older medical frameworks fell by the wayside, though rural American physicians were still recommending bleeding and purgatives as cures well into the first few decades of the 20th century. 2 Victorious vaccines SOCIETY: Muckraking and The most significant outgrowth of the new germ theory, and the one medicine that created the greatest demand for new technologies for Media “muckrakers” exposed the implementation, was the identification and production of the new seedy underbelly of robber baron “immunologicals”—drugs that are, in essence, partially