# The Drug Hunters  ## Metadata - Author: [[Donald R. Kirsch, Ogi Ogas]] - Full Title: The Drug Hunters - Category: #books ## Highlights - Ötzi’s remarkable birch fungus embodies a simple truth about humankind’s quest for medicine. This Neolithic remedy did not arise from clever innovation or rational inquiry. No Stone Age Steve Jobs engineered this antihelminthic out of the visionary workings of his mind. No, Ötzi’s drug was the product of sheer unadulterated luck. All prescientific drug hunting advanced through simple trial and error. ([Location 72](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=72)) - Tags: [[aqua]] - Despite the best efforts of Big Pharma, the prime technique of the twenty-first-century quest for medicine remains the same as it was five millennia past: painstakingly sampling a mindboggling variety of compounds and hoping that one of them, just one, proves out. ([Location 77](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=77)) - Tags: [[aqua]] - But Sehgal, a seasoned drug hunter, was well aware of one of the most reliable facts about Big Pharma: rapid executive turnover. He bided his time. Whenever a new management team assumed control over the pharmaceutical research, he reintroduced his proposal to test rapamycin as an organ transplant therapy. ([Location 94](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=94)) - Tags: [[aqua]] - After spending my entire career searching for new medicines, I’ve learned that the only sure thing in the drug hunting business is that you almost never end up with the exact drug you started stalking. ([Location 108](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=108)) - Tags: [[aqua]] - Only about 5 percent of a scientist’s ideas for a drug discovery project get funded by management. Of these, only 2 percent end up producing an FDA-approved medicine. That means a drug hunting scientist can only expect to make a difference about one-tenth of 1 percent of the time. ([Location 115](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=115)) - Tags: [[aqua]] - Big Pharma companies are becoming increasingly frustrated with the massive research expenditures necessary to come up with new drugs—an average of about $1.5 billion and fourteen years for each FDA-approved drug—and the exasperating fact that the vast majority of their endeavors don’t produce a usable drug. Executives at Pfizer recently told me they are thinking about getting out of the drug-discovery industry entirely. Instead, they want to be in the drug acquisition industry: they would prefer just to buy drugs that other people have invented. Think about that. Finding new drugs is so formidable that one of the oldest, most talented, and wealthiest drug makers—the largest drug maker in the world, in fact—would rather let other people deal with the problem. ([Location 118](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=118)) - Tags: [[aqua]] - the core challenge of designing a new drug—the trial-and-error screening of immense numbers of candidate compounds—is a task not guided by any known equations or formulas. While an engineer knows if his bridge will bear weight before he ever lays a girder down, a drug hunter has no clear idea how a particular drug will work until a human subject actually ingests it. ([Location 129](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=129)) - Tags: [[aqua]] - Designing an effective drug requires two things: the right compound (the drug) and the right target (the druggable protein). The drug is like a key that turns the protein lock to start the ignition on a physiological engine. If a scientist wants to intentionally influence a person’s health in a specific way—to reduce depression, relieve itching, treat food poisoning, or produce any other health benefit—she must first identify a target protein that influences the relevant physiological processes in the human body or that, conversely, interferes with the physiological processes of a pathogen. ([Location 159](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=159)) - Tags: [[aqua]] - drug hunting—at least, thus far—is dismayingly difficult because every contemporary method of drug development relies, at some crucial juncture, on trial-and-error screening, just as it did when Neanderthals roamed the wilds. We still do not possess adequate knowledge of human biology to provide us with theories and principles that could rationally guide us to the salubrious molecules we so fiercely desire. ([Location 203](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=203)) - Tags: [[aqua]] - 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. ([Location 304](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=304)) - Tags: [[aqua]] - 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. ([Location 321](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=321)) - Tags: [[aqua]] - 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. ([Location 352](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=352)) - Tags: [[aqua]] - 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. ([Location 368](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=368)) - Tags: [[aqua]] - 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. ([Location 438](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=438)) - Tags: [[aqua]] - 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. ([Location 458](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=458)) - Tags: [[aqua]] - (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.) ([Location 484](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=484)) - Tags: [[aqua]] - 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. ([Location 502](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=502)) - Tags: [[aqua]] - 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. ([Location 536](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=536)) - Tags: [[aqua]] - Consider how different Squibb’s business model was from that of our own pharmaceutical industry. Squibb did not offer original or unique 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. ([Location 668](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=668)) - Tags: [[aqua]] - 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. ([Location 693](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=693)) - Tags: [[aqua]] - 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. ([Location 701](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=701)) - Tags: [[aqua]] - By the 1830s, a new subdiscipline of chemistry had emerged known as synthetic chemistry. Synthetic chemists were able to combine simple chemical elements together into more complex compounds, like fastening together increasingly elaborate Tinker Toys. And the first businesses to harness synthetic chemistry for big profits were the dye companies. ([Location 749](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=749)) - Tags: [[aqua]] - Most of the German dye factories sprang up along the Rhine because of its proximity to major European cities and because the river allowed for easy transport of both raw supplies and completed products across Germany, central Europe, northern Europe, and the rest of the world through the river’s egress into the North Sea. The Rhine dye companies not only became the world leaders of synthetic dye production, they also became the undisputed masters of synthetic chemistry, ([Location 766](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=766)) - Tags: [[aqua]] - For centuries, all drug hunters—including physician-botanists, physician-alchemists, and industrial formulators—took it as a given that drugs could only be discovered, like a vein of gold or a hot spring, rather than crafted through human ingenuity, like a steam engine or a typewriter. The notion that it might be possible to engineer a drug to fight a particular malady required an enormous shift in perspective, and the first step in this shift was propelled by the newfound power and precision of synthetic chemistry. ([Location 777](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=777)) - Tags: [[aqua]] - Up until this point, all the industrial pharmaceutical companies (such as Squibb) were focused on using chemistry to manufacture known drugs more efficiently and consistently. But Duisberg didn’t just want to improve the manufacture of existing drugs—he wanted to create drugs that had never existed before. The basic model of the synthetic dye business was to start with some molecules known to produce pretty colors and chemically tweak them to make even prettier colors. Duisberg asked, Why not do the same thing with medicines? Start with a good drug and chemically tweak it until it became an even better drug. One of Bayer’s first candidates for this speculative tweaking was a commonplace drug known as salicylic acid. ([Location 781](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=781)) - Tags: [[aqua]] - Even in this earliest of incarnations, the rudimentary Bayer drug development group was quite similar to the drug development teams found in Big Pharma today. There was a chemistry team composed of chemists who synthesized the compounds, and a pharmacology team composed of biologists who tested the compounds in animals and—if the animal tests were promising—in humans. ([Location 800](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=800)) - Tags: [[aqua]] - In general, organic compounds produced by plants are extremely complex and difficult to manipulate in a laboratory. It was Duisberg’s good fortune, however, that the salicylates were unusually good candidates for tweaking, for they are rather simple molecules that are easier to manipulate than most plant compounds. ([Location 805](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=805)) - Tags: [[aqua]] - My first boss in the pharma industry taught me that the most difficult and important decision in drug hunting is the decision to “fish or cut bait”—whether to continue investing resources in the pursuit of a potential drug or cut your losses and move on. These decisions are always based on inadequate information, so scientists often end up chasing after bad drugs instead of good, commercial ones. The frequency of the wrong decision to continue fishing helps explain why 50 to 75 percent of all clinical trials fail. On the other hand, the mistaken choice to “cut bait” occurs even more frequently. When I was at Squibb I was trying to develop an alternate version of an existing antibiotic that was effective but somewhat toxic. I believed our initial work showed significant promise, but research management overruled me and shut us down before we could start our clinical trials. They decided to cut bait. Our competitor, Lilly, was trying to develop a similar antibiotic, but unlike Squibb, they decided to keep fishing. Their antibiotic eventually received FDA approval and is currently generating over $1 billion in annual sales. ([Location 814](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=814)) - Tags: [[aqua]] - Even though it did not have an exclusive patent on the drug in Germany (Bayer did get one in the United States), it launched a very heavy marketing push, and Aspirin soon became the first blockbuster drug of the Age of Synthetic Chemistry. It was far superior to the old salicylate drugs derived from plant extracts. Aspirin performed just as well but exhibited markedly reduced side effects. Its global popularity grew still further when it became a standard treatment during the Spanish flu pandemic of 1918. After Bayer’s American patent on Aspirin expired in 1917, there was an explosion of aspirin generics and knock-offs, but as you know from any visit to your local CVS or Walgreens, Bayer’s formulation of Aspirin has remained a steady seller, one of a small handful of nineteenth-century drugs that have survived unchanged into the twenty-first century. ([Location 856](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=856)) - Tags: [[aqua]] - A solution arrived in the mid-nineteenth century with the invention of synthetic dyes. Dye manufacturers were like the aerospace industry of the nineteenth century, producing a variety of useful spinoff products as they developed the high-tech products for their core market. Microbiologists began to test off-the-shelf fabric dyes to see if they might also be useful for staining cells. ([Location 971](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=971)) - Tags: [[aqua]] - He was given an appointment at the Institute for Infectious Diseases in Berlin, where he set up one of the first successful models of a drug research lab. His lab included an organic chemist who developed new drug candidates (that is, new synthetic dyes), a microbiologist who tested the effects of drug candidates on pathogens (this was Ehrlich’s role), and an animal biologist who tested the effects of drug candidates on animals and—if the animal tests were successful—on humans. ([Location 995](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=995)) - Tags: [[aqua]] - After a seemingly interminable string of failures, Ehrlich realized he might need to modify his magic bullet theory. Perhaps it was simply too difficult to find a double-duty dye that both targeted a pathogen and slayed it. Instead, why not take a toxin that was already known to kill a pathogen, and use chemical synthesis to mount the toxin onto a dye known to target the pathogen, producing a kind of “toxic warhead”? Even if the toxin was harmful to humans, by attaching it to a dye that targeted a particular germ it could act like a guided missile, delivering its destructive payload directly to the germ. ([Location 1003](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1003)) - Tags: [[aqua]] - Never before had someone thought up a novel way to create a completely unprecedented kind of drug—and then gone out and actually made it. Salvarsan was not a better-engineered knockoff of an existing drug, like Squibb’s ether, or a minor tweak of an existing drug, like Aspirin. Instead, it was the product of a wholly original conception: find a dye that stains a pathogen, then find a pathogen-killing toxin that will attach to the dye. ([Location 1027](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1027)) - Tags: [[aqua]] - The enormous success of his drug made Ehrlich a public hero. Whenever he was congratulated for his achievement, however, he modestly replied: “For seven years of misfortune I had one moment of good luck.” ([Location 1042](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1042)) - Tags: [[aqua]] - The German-born Ehrlich concluded from his experience that a drug hunter needed what he called “the four G’s”: Geld (money), Geduld (patience), Geschick (ingenuity), and perhaps most importantly, Glück (luck). ([Location 1045](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1045)) - Tags: [[aqua]] - Ehrlich argued that a particular antibody binds to a particular toxin in a lock-and-key fashion and that this selective chemical binding triggered the immune system to eliminate the pathogen, a theory that we now know to be accurate. He extended the same lock-and-key thinking to drugs, believing that there was a specific molecular site on a pathogen or on a human cell (the “receptor”) that reacted with a specific part of a drug, thereby producing its effect. This is known today as “receptor theory.” Ehrlich’s novel conception of drug action was based on his discovery that chemical dyes only stained particular parts of cells, and his receptor theory now serves as the foundation for modern pharmacology. But in 1897, when Ehrlich first proposed receptor theory, he could not provide any direct evidence for the existence of receptors, which he claimed were too small to be visible under existing microscopes. Not surprisingly, other scientists regarded his idea of invisible antibody receptors as squatting somewhere between pseudoscientific and preposterous. ([Location 1063](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1063)) - Tags: [[aqua]] - We now know that most receptors within the human body are protein-based molecular switches that turn cellular processes on or off by reacting to hormones in the body. For example, there are a number of distinct adrenaline receptors in the human body, including the beta-2 receptor, a protein present in smooth muscle cells that reacts with adrenaline to produce muscle relaxation. Once scientists identified the beta-2 receptor as an adrenaline receptor, drug hunters began to search for medications that activated them. One of the best-known drugs to come out of this search was albuterol, used as an inhaler by asthmatic patients. Albuterol opens up a person’s air passages by relaxing the smooth muscle cells in the lungs, improving breathing and preventing or mitigating an asthma attack. ([Location 1092](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1092)) - Tags: [[aqua]] - Today, we enjoy the benefits of many “broad-spectrum antibiotics” such as penicillins and fluoroquinolones, drugs that fight a wide range of infectious pathogens. But Salvarsan was a “narrow-spectrum antibiotic”—a one-hit wonder. At the time of Ehrlich’s great discovery, there was not yet a clear notion that it might be possible to develop drugs that attacked multiple types of infections. Instead, the focus was on discovering any new cure, whether it turned out to be a silver bullet or a silver shotgun blast. ([Location 1119](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1119)) - Bayer’s great triumph—the creation of the first broad-spectrum antibiotic—was based on a false premise, the idea that a toxic dye was selectively targeting bacteria, the way Salvarsan did. Instead, it turned out to be pure biochemical chance that the mammalian physiology transformed the red Prontosil dye into an entirely new compound that cured infections. ([Location 1140](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1140)) - The massive outcry over the Elixir Sulfanilamide poisonings, including well-publicized letters to President Roosevelt from relatives of the victims, prompted Congress to pass the Food, Drug and Cosmetic Act in 1938 to regulate the sale and marketing of pharmaceuticals. This act established the modern FDA. These days, the Food and Drug Administration oversees the development of drugs from the very beginning, well in advance of any human testing. ([Location 1219](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1219)) - The fen-phen debacle points to the difficulty of getting the regulatory balance right. Unlike the development of Elixir Sulfanilamide, there was tight, cautious oversight at every stage of the development of each of the two weight-loss drugs. While AHP had never explicitly tested the fen-phen combination, it was neither unusual nor illegal for physicians to prescribe legitimate drugs in new combinations. Even though AHP management had decided to skip further experimentation on fenfluramine once the drug suddenly became popular, it is not obvious that this decision was ethically objectionable. After all, they had always hoped that the drug would become popular, and the rigorous system of FDA testing presumes that a drug’s use might be widespread. ([Location 1262](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1262)) - To my mind, where AHP appears to have crossed the line was in their marketing. While it was entirely legitimate for its salespeople to remind doctors about the University of Rochester study, it was both unethical and illegal for the salespeople to explicitly recommend that doctors prescribe the two drugs together unless the FDA had actually approved the use of the fen-phen drug combination. Despite this, AHP sales representatives frankly encouraged physicians to prescribe the cocktail. ([Location 1272](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1272)) - Why do drugs seem to produce so many unwanted side effects in the first place, even when you are only taking one particular drug for one particular reason? To my mind, there are two basic mechanistic explanations. First, many drugs affect multiple physiological targets in the body because different parts of the body often share similar biological targets. A good example are the classic chemotherapeutic agents that attack cancer. “Chemotherapy” destroys cancer cells by acting on the process of rapid cell division in the cancer cells. However, many other cells in the body also undergo rapid cell division (such as the bone marrow cells that create new blood), and they too are negatively impacted by chemotherapy. Another example is Viagra, which targets the PDE5 enzyme in the penis. PDE5 is also present in the cardiovascular system, which is why Viagra causes unintentional flushing and headaches. In addition, an extremely similar enzyme known as PDE6 is found in the retina of the eye, so high doses of Viagra can produce blindness. Because any given type of receptor in our body usually exists in multiple locations and is often similar to other types of receptors, it is very difficult to find a chemical that affects only one specific physiological target. ([Location 1285](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1285)) - There is another basic mechanical reason that drugs produce unwanted side effects. Drugs are chemicals. Whenever foreign chemicals are introduced into the body, they can interact with our body’s natural free-floating chemicals (known as metabolites, the by-products of healthy physiological processes) in undesirable ways. A drug can serve as an imperfect substitute for the metabolites, for instance, causing our body’s processes to operate in a flawed manner. A drug can even undergo a direct chemical reaction with our body’s metabolites, producing new and possibly toxic compounds. ([Location 1298](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1298)) - To find new cures and remedies, we must be willing to take some risk. Without risk, it is simply not possible to develop novel drugs. We can reduce this risk by establishing more regulations, but these regulations impose ever increasing costs on drug development, to the point where today the average cost of developing a new drug has been estimated to be in the range of 1.4 to 1.6 billion dollars. This exorbitant financial bar ensures that very few promising drugs will ever make it out of the planning stages. If we want to eliminate the prospect of another fen-phen disaster, the only solution is to expand the regulations for approving drugs to ensure that a wide variety of drug combinations is also evaluated, thereby increasing the cost of developing new drugs even further—which will reduce the number of new drugs even further. This remains the most daunting barrier to drug hunting in the modern era. It is almost inconceivably expensive to safely search for new drugs, but without those exorbitant safety expenses, vulnerable people might get injured or die. ([Location 1304](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1304)) - One of these gumptious capitalists was a man who came to be known as the Rattlesnake King. Clark Stanley, a cowboy, claimed that Hopi medicine men had revealed to him the wondrous power of prairie rattlesnake oil. He peddled his own snake oil concoction at the 1893 World’s Exposition in Chicago. His method of promotion demonstrated his understanding of the value of showmanship when hawking a new pharmaceutical product. In front of a rapt audience of potential customers, Stanley reached his hand into a wriggling sack and plucked out a long rattlesnake showing its fangs. He deftly slit it open with a knife and eviscerated it before plunging the serpent into boiling water. As the fat rose to the top of the cauldron, the Rattlesnake King skimmed it off and scooped it into a clear four-inch-tall bottle. Clark Stanley’s Snake Oil was snapped up by his enthralled spectators. ([Location 1348](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1348)) - As the 1940s dawned, even though consumers were demanding that the government do a better job of monitoring the development of new medicines, there was very little hard science that could be relied upon to guide the FDA’s oversight. Not only did the vast majority of medical schools in the 1940s lack a pharmacology department, most did not even offer a pharmacology course. One reason was that there were simply no fundamental philosophical tenets or organizing causal principles in drug science, in the same way that aeronautical science, for example, was organized around the four force vectors of flight, which enabled a practitioner to accurately predict the amount of lift that would be produced by any given wing design. Instead, pharmacology was a chaotic grab bag of ideas from microbiology, physiology, chemistry, and biochemistry, as well as an incoherent casserole of clinical observations about the effects of drugs in various circumstances. ([Location 1362](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1362)) - One of their boldest decisions was to structure their book around pharmacodynamics, a nascent field that studied the relationships between the dose of a drug and its physiological effects. Today, pharmacodynamics is a central concept of modern pharmacology, but in the 1930s many of Goodman and Gilman’s colleagues believed the field offered little of value. However, Goodman and Gilman wanted to gather together in a single place everything factual and proven that was known about medicines. ([Location 1384](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1384)) - Goodman and Gilman got their Scotch, and it took only six weeks. The first edition of the textbook went on to sell more than 86,000 copies. The Pharmacological Basis of Therapeutics was instantly embraced by the pharma community as its unifying bible. It contained detailed, evidence-grounded information about every known drug, and more than that, it was the first time that this information was organized around guiding scientific principles that attempted to draw a sense of deeper order from the cacophony of knowledge. For the first time, if you wanted to confidently learn about a particular drug—or if you wanted to teach yourself the entire science of drugs—all you needed to do was delve into Goodman and Gilman. In fact, if the book had any meaningful shortcoming, it was its extreme scholarliness, which often made it a difficult read for the medical students for whom it was originally intended. ([Location 1399](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1399)) - One day, the microbiologist came into the lab and found something strange. The scientist’s name was Alexander Fleming, and you probably know the story of what happened next. According to legend, Fleming left the window to the laboratory open, and when he examined his agar plate he discovered there was fungus growing in it, presumably fungus that had floated in through the window. (I have always doubted this account. I frequently work in laboratories with the windows closed—or without any windows at all—and I often end up with contaminated plates. Fungus spores are always lurking in the air.) Though we don’t know exactly where the fungus really came from, Fleming was sure about one thing—the staphylococcus colonies were not growing anywhere near the invading legion of fungus. Fleming guessed that the fungus was producing a substance that was toxic to the staph bacteria. He began to wonder: could this mysterious substance be the basis for another miracle drug? Fleming named the still-unidentified substance “penicillin” after the fungus that was growing in the dish, Penicillium chrysogenum. ([Location 1460](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1460)) - Fleming found that penicillin took a long time to stamp out bacteria. We now know that this mistaken conclusion was due to Fleming’s faulty method of administration. Instead of dosing his subjects with penicillin through an injection or a pill—methods that deliver the medicine into the patient’s bloodstream—Fleming administered penicillin as a topical agent. He chose to rub penicillin on his sick subjects’ skin because he was worried that the human body would break down the drug before it could start to work. Fleming’s penicillin was further weakened as a consequence of him using low doses, a necessity due to the difficulty of producing the antibiotic. Because of the difficulty of growing P. chrysogenum and the seemingly sluggish effects of the drug, Fleming could not persuade a chemist to help him create a more purified version. ([Location 1478](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1478)) - The manufacture of penicillin quickly turned into an exasperating problem of industrial production. England was at war with Nazi Germany and fighting for its very survival. It did not have the ability to divert its limited industrial resources from the desperate war effort to the manufacture of a drug, no matter how important. The Rockefeller Foundation, which had been funding Florey’s research, urged him to visit the United States and seek help from England’s ally. In July of 1941, Florey flew to New York, where he met with government agencies and private firms. Fortunately for Florey and Great Britain, the United States Department of Agriculture decided to get involved. The USDA had already been working on fermentation methods to increase the growth of fungal cultures in its Peoria, Illinois laboratory; now the Peoria team set to work looking for ways to increase the growth of P. chrysogenum. The USDA scientists eventually made two major contributions. First, they found a strain of P. chrysogenum growing on a moldy cantaloupe in a Peoria fruit market that produced far more penicillin than any prior strain of the fungus. Second, they discovered that they could produce much more penicillin much more quickly if they cultured the fungus in deep vats containing corn steep liquor (a cheap byproduct of corn milling) and then pumped air through the fungus-infused liquor (a process known as sparging). Best of all, this deep vat fermentation method was scalable. It finally lead to the industrial manufacture of the world’s first expanded-spectrum antibiotic. ([Location 1521](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1521)) - During the first five months of 1943, enough penicillin was produced in America to treat about four patients. Over the next seven months, enough penicillin was produced to treat 20 patients. Production methods continued to improve so that by the time the Allies invaded France on D-Day, there was enough penicillin to meet all the needs of the Allied forces. For the first time, wounded soldiers could recover rapidly from infections arising from battlefield wounds. ([Location 1537](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1537)) - The tuberculosis bacterium is a very slow-killing pathogen, which tells us that it is also a very highly evolved pathogen. Newly evolved germs like HIV, SARS, and the Nipah virus tend to kill their victims rapidly. This is a faulty strategy from the pathogen’s point of view, the equivalent of ripping up its own meal ticket. Fast-acting pathogens kill their host before they have a chance to spread to many other hosts. In contrast, highly evolved diseases milk their host for as long as possible, giving the pathogen a more prolonged opportunity to infect others. Tuberculosis is one of the most advanced of human diseases and seems to be as old as humanity itself. Even today, roughly one out of every three people on Earth is infected, with a new infection occurring once per second. Fortunately, most cases of consumption do not produce any symptoms, but even so, in 2016 there are fourteen million chronic cases worldwide producing about two million deaths each year. ([Location 1556](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1556)) - This was ultimately a screening problem. Waksman solved it by screening the Streptomycete compounds on a bacterium known as M. smegmatis, a species that is closely related to M. tuberculosis but is not harmful to humans. As a bonus, M. smegmatis grows much faster than M. tuberculosis, making it easier to carry out experiments. Waksman hoped that anything that killed the substitute bacteria would also kill tuberculosis. Fortunately for us all, his hypothesis turned out to be correct. ([Location 1589](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1589)) - Antibiotics kill bacteria by attacking them when the bacteria are growing; when bacteria are dormant, such as in a spore or cyst state, they cannot be killed by antibiotics. The faster a bacterium grows, the easier it is for an antibiotic to kill it, generally speaking. Unfortunately, the highly-evolved tuberculosis bacterium is extremely slow-growing, which meant that any antibiotic would require a particularly long period of treatment to rub out all the bacteria. ([Location 1599](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1599)) - Florey and Chain’s redevelopment of penicillin demonstrated to physicians, scientists, and the general public that antibiotic drugs existed that could completely extirpate pathogens within the body, eliminating all symptoms and ensuring the disease would not be spread to anyone else. It was the Holy Grail of early twentieth century drug hunting: a cure for infectious disease. It inaugurated an Age of Dirt, as every major pharmaceutical company had a team devoted to searching through the soil. ([Location 1622](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1622)) - The first reports of a pathogen developing resistance to penicillin appeared in 1947, just four years after the drug began to be mass-produced. But penicillin wasn’t the only miracle drug that stopped being so miraculous. Resistance to tetracycline, another early antibiotic, emerged within ten years of its introduction. Erythromycin resistance took fifteen years to emerge, while gentamicin resistance took twelve years and vancomycin sixteen years. At first, scientists were baffled. Every one of their new wonder drugs eventually lost their potency, like an aging stallion. But soon they realized that the pathogens were evolving. ([Location 1628](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1628)) - With the threat of lethal bacterial infections remaining quite real, you might be surprised to learn that in the 1980s Big Pharma started to give up on developing new antibiotics. Why would they abandon a product with such an obvious market? Because antibiotics do not offer a particularly profitable business model for drug companies. Big Pharma prefers drugs that need to be taken over and over again, such as pills for high blood pressure or elevated cholesterol. Medications for such chronic conditions must be taken every day of a patient’s life, which can drive tremendous sales. But antibiotics are only taken for a week or so, after which the patient is cured and does not need the drug again. This sharply limits profits. But the economics of antibiotics are even worse than their one-off method of treatment. As physicians began to realize that every new antibiotic would eventually cause pathogens to develop resistance, they started to stash away each new antibiotic drug to hold in reserve. They only brought these drugs out to use on patients with terrible infections caused by antibiotic-resistant bacteria. This was a sensible way to preserve the potency of new antibiotics, but it meant even more diminished sales for each new (highly expensive) antibiotic a pharma company managed to develop, since doctors would hoard the drug instead of prescribing it. ([Location 1642](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1642)) - Today, things have reached a dangerous state of affairs. Dr. Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA, recently stated that, “We are facing a huge crisis worldwide not having an antibiotics pipeline. It is bad now, and the infectious disease docs are frantic. But what is worse is the thought of where we will be five to ten years from now.” More than 23,000 people die in the United States each year from a bacterial infection that was once easily treated with antibiotics but that has now developed resistance. That’s more than the number of Americans who die from (virus-borne) AIDS each year. ([Location 1662](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1662)) - even though the library of plants produced a few ancient Vindications that survived into the twenty-first century—including morphine, ergot (a drug that is still in clinical use but that has been largely been replaced by new, superior medicines such as the triptan drugs to treat migraine headaches and oxytocin in labor and delivery), and digitalis (still used to treat heart conditions)—not a single pre-twentieth-century drug from the library of animals has made it into modern medicine. Why are there so many more useful medicinal compounds in plants than in animals? We do not know for certain, but one theory is that plants have been defending themselves against insects for hundreds of millions of years, and so plant immune systems produce a dazzling variety of compounds designed to repel, injure, or kill an extremely wide range of predatory bugs. These defensive compounds (which botanists call phytotoxins) are highly bioactive, since they are designed to influence or impair the physiology of insects. Even though human physiology is far more sophisticated than the physiology of beetles and moths, our bodies still share some of the same fundamental biochemistry. Thus, even if a particular phytotoxin does not have the exact same effect on our body that it does on an insect, the compound may still provoke some kind of effect within our own physiological processes—an effect that on occasion may be beneficial to us. Perhaps animals tend to produce far fewer substances with the potential to disrupt physiological processes because they have less of a need to fend off insects or other nibbling creatures, though a small number of animals do produce toxins designed to disrupt the physiology of predators or prey, such as poisonous snakes, scorpions, and toads. Similarly, soil microorganisms have been at war with one another for eons, and so they produce an impressive array of antifungal and antibiotic toxins that can be harvested for drugs. ([Location 1697](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1697)) - there was one widely accepted notion about the kind of drug that might be able to treat diabetes, an insight that emerged purely by happenstance. In 1889, two European physicians, Joseph von Mering and Oskar Minkowski, were conducting a series of experiments to determine the function of the mysterious oblong organ located between the stomach and small intestine, an organ known as the pancreas. Their methodology was simple. They removed the pancreas from a healthy dog and watched what happened. And what happened was that the housebroken dog began to urinate on the laboratory floor. All day long. The researchers knew that frequent urination was a symptom of diabetes, so they tested the dog’s urine. It was high in sugar. Von Mering and Minkowski speculated that they had just created the first artificially induced example of diabetes by removing the dog’s pancreas. Next, they tried to determine what a pancreas was actually doing that apparently prevented diabetes in healthy individuals. They proposed that the dog pancreases produced a hormone that controls how the body metabolizes glucose, a hormone we now call insulin. Glucose is used by cells as a prime source of energy. Insulin acts as a kind of key that unlocks a special door on the cell membrane, allowing glucose to enter hungry cells. In the absence of insulin, glucose builds up to high levels in the blood, but the sugar molecules cannot enter cells to feed them. After a while, the high level of glucose overwhelms the kidneys’ ability to reabsorb it and the excess sugar starts to spill out into the urine, producing the characteristic “honey urine.” ([Location 1740](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1740)) - Initially, drug hunters presumed that all they needed to do was remove a healthy pancreas, grind it up, extract the insulin, and inject it into a diabetic person. But harvesting useful insulin turned out to be a near-impossible task. The reason it was more difficult than anybody expected was because of an odd physiological complication unique to the pancreas. One of the two main functions of the pancreas is producing hormones, including insulin. But the other function is to produce enzymes that the small intestine uses to digest proteins. Unfortunately, insulin is a protein. Whenever researchers ground up a pancreas in the hope of extracting insulin, they inevitably mixed together the insulin protein with the protein-digesting enzymes, destroying the insulin. ([Location 1753](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1753)) - Macleod listened to Banting’s proposal with tremendous skepticism—unlike Banting, he was well aware of all the failed attempts at extracting insulin—but he was ultimately swayed by Banting’s passion and drive. ([Location 1778](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1778)) - there was no precedent at all for Banting’s novel extraction process. Until now, all commercial drugs were either extracted from plants or created through synthetic chemistry. Banting and Best had invented an unprecedented way to extract a useful drug directly from the bodies of animals. Yet if they wanted to harness this process to deliver enough medicine to treat even a handful of diabetes patients, they had to somehow ramp production up to an industrial scale, while their process barely worked on a micro scale. ([Location 1799](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1799)) - Banting had a very different reaction. He did not like the way Macleod had introduced him to the audience before his talk, speaking in a restrained manner that seemed to reserve all the credit for Macleod himself. He did not like the way all the scientists rushed to Macleod after Banting finished speaking, posing their questions to Macleod instead of Banting. He left the meeting feeling disappointed, angry, and aggrieved, convinced that once again other people were swiping credit for his hard work. ([Location 1821](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1821)) - Note: from pfeffer's work on power: not enough to be great. You also need to market yourself, brand yourself, and speak with authority - George Clowes was not going to take no for an answer. During the next four months, he made four trips to Toronto to press his case with Macleod. At each meeting, Macleod insisted that he wanted to keep the development of insulin within Canada, while Clowes talked up the advantages that Lilly could bring to the project. Macleod might have been able to maintain his resolve if not for the fact that his research team was falling apart. During the first few months of 1921, the relationships among the team members were deteriorating fast, and their interactions with the Connaught scientists were only adding to the friction. Much of the strife was driven by Banting’s jealous fear of losing credit for and control of a project he still considered his own. By early April, things had gotten so bad that Macleod finally succumbed to Clowes’s relentless advances. He wrote to Clowes informing him that they were on the verge of perfecting an insulin isolation method that could be used for commercial production at a new site—preferably a site far away from Toronto and the squabbling team. ([Location 1828](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1828)) - Note: Clowes's persistence and energy paid dividends. Do not accept the first no at face value - in the 1970s—a half-century after Banting extracted insulin from a dog pancreas—a new opportunity emerged. In 1972, Paul Berg, a Stanford University professor who studied viruses, performed one of the most important experiments of the twentieth century. He removed a piece of DNA from a cell of bacteria and inserted it into the DNA of a monkey cell. He accomplished this by attaching the bacteria DNA to a harmless virus that Berg used as a kind of Trojan Horse to penetrate the monkey cell’s defenses and deliver the bacteria’s genes directly into the monkey’s genome. This process is known as “recombinant DNA” since it combines the DNA of two different organisms—the bacteria and the virus. Why was this experiment so important? Because once the monkey cell took up the foreign DNA, the bacteria’s genes could begin to produce the same proteins that they would inside a bacteria cell. In other words, the bacteria’s genes could co-opt the machinery of the monkey cell and re-directed it to manufacture new molecular products. For drug hunters, it was the opposite kind of recombinant DNA that was so promising—taking the genes out of a mammal cell and inserting them into a bacterium. In 1975, a rabbit gene that creates hemoglobin became the very first mammalian gene to be transferred into another organism when it was inserted into an E. coli bacterium in a Petri dish. These bacteria cells could now be engineered to produce rabbit hemoglobin, marking a watershed moment in genetics—and the birth of genetic medicine. ([Location 1879](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1879)) - The insulin gene turned out to be a great choice for the early attempts at developing genetic medicine, and not just because of the huge demand for insulin. The gene for insulin is extremely short, and the smaller a gene the easier it is to manipulate. In 1976, Herb Boyer (a biochemistry professor at the University of California, San Francisco) and Robert A. Swanson (a venture capitalist) started a new company in San Francisco to develop drugs using the new recombinant DNA technology. Genentech’s very first project was to manufacture human insulin. This was an entirely new approach to drug hunting. Instead of searching for new molecules in plants during the Age of Plants, or searching for new synthetic tweaks to existing molecules during the Age of Synthetic Chemistry, or searching through the soil for new bacteria-fighting compounds during the Age of Dirt, Genentech was searching through the human genome for fragments of DNA that could produce useful protein-based drugs. ([Location 1894](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1894)) - Lilly appraised the situation in an entirely different way. They recognized that there was a small but meaningful chance that Genentech would be able to produce human insulin. If Genentech succeeded and Lilly was not involved, the economic consequences would be catastrophic for Lilly. Insulin was one of the most important market franchises for Lilly—they basically owned the only known treatment for diabetes—and they simply could not risk the possibility of losing the entire market, so matter how unlikely that potential loss. Thus, in 1978, Lilly agreed to collaborate with Genentech. ([Location 1926](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1926)) - At first, Big Pharma was thrilled by the realization that recombinant technology granted them virtually unlimited ability to cure any disease caused by a missing protein. But this initial flush of excitement soon dimmed. The fact of the matter is that there are simply not that many diseases caused by missing proteins. By the early 1990s, after producing about a dozen new recombinant drugs, the industry was running out of diseases to treat. Drug hunting followed the same trajectory it always did: a new library of potential molecules is discovered, there are a few major discoveries, the entire industry swarms through the library, and in short order the library is exhausted. Of course, there always seems to be a new library to search and the biotechnology industry soon found another one, known as recombinant monoclonal antibodies. Here’s how monoclonal antibodies work. In response to the presence of a pathogen, the human body’s white blood cells produce antibodies—chemicals that attack the invading bacterium, virus, fungus, parasite, or other foreign agent. But since every pathogen is different—sometimes extremely different (just consider the difference between, say, athlete’s foot fungus and tapeworms)—each pathogen is vulnerable to a different type of antibody. Thus, if we want to kill an intruder, our body needs to produce the right kind of antibody. Or, even better, produce multiple kinds of pathogen-specific antibodies, which each inflict different damaging effects on the target. Our white blood cells accomplish this using a very sophisticated process. When a germ is detected, the white blood cells (specifically, the B cells) start to rapidly reproduce, but each child cell is a different variant of the parent white blood cell. The body can produce literally millions of white blood cell variants in a very short period of time. Each of these variants produces a different kind of antibody. Thus, we might say the body uses a just-in-time “weapons on demand” system: if it detects an enemy jet fighter, it produces different types of anti-aircraft missiles; if it detects an enemy tank, it produces different kinds of anti-tank rockets; if it detects enemy soldiers, it produces different types of guns. If a drug hunter thinks that a particular type of antibody might make a useful drug, then he can put human white blood cells into a petri dish and manipulate them into producing the specialized white blood cells that manufacture the desired antibody (typically this is done by exposing the white blood cells to a substance that will trigger the formation of the requisite specialized cells). Next, the drug hunter can isolate the specialized cells that produce the target antibody and then, using recombinant DNA methods, extract the specific genes from these cells that are responsible for creating the antibody, and then use these genes to churn out as much of the antibody as he needs. Finally, he can take this antibody and convert it into a useful drug.… ([Location 1948](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=1948)) - Snow approached his investigation in a wholly original manner—so original, in fact, that it would lead to the founding of an entirely new field of medicine. He scrutinized a map of the Soho neighborhood and began to systematically document where each case of cholera had occurred. (Today, this area is the Carnaby Street shopping district in Westminster.) At each location where an afflicted Soho resident lived, he drew a short black bar, stacking multiple bars perpendicular to the adjacent street. He drew 578 bars in total. Next, he marked the location of each public water pump in the neighborhood. ([Location 2014](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2014)) - Tags: [[aqua]] - Snow noticed several interesting features on his marked-up map. Even though a large Soho workhouse just north of the Broad Street pump housed over five hundred paupers, very few of its residents came down with cholera. Similarly, not a single person who worked at a brewery one block east of the Broad Street pump contracted the disease. Nevertheless, despite these two anomalies, Snow’s map made one thing perfectly clear: most of the cholera deaths occurred in residents who lived near the Broad Street pump. ([Location 2022](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2022)) - Tags: [[aqua]] - Snow persisted. He showed that the workhouse near Broad Street, where almost no residents got sick, had its own independent well. He pointed out that the workers at the brewery near Broad Street, where nobody got sick, were allowed to drink all the beer they wanted, and he suspected something about the beverage prevented the disease (during brewing, the beer wort is boiled for an hour, killing most bacteria). Perhaps most tellingly, he observed that all the residents near the Carnaby Street pump who got sick were the very ones who traveled to fetch the supposedly clean water at the Broad Street pump. Eventually, the council relented and granted him permission to shut down the well. Snow immediately removed the handle from the Broad Street pump, making it impossible to get water … and that was the end of the cholera epidemic in Soho. ([Location 2029](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2029)) - Tags: [[aqua]] - We now know that the Broad Street well was contaminated with the pathogen Vibrio cholera, a bacterium that infected residents with every gulp. Yet, even without this knowledge, Snow’s original method of investigation—focusing on both geography and population—provided an effective means to control the disease. This was the first scientific example of epidemiology, the study of patterns of diseases in the population. Today, John Snow is regarded as the father of epidemiology. ([Location 2035](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2035)) - Tags: [[aqua]] - In some sense, Snow was quite lucky. Unlike an experiment (which can demonstrate cause and effect), an epidemiological study cannot prove causality. It can only demonstrate a relationship—in Snow’s case, a relationship between the location of victims and the location of water pumps. It could have been the case that something other than the water or the water pump was causing the disease; there was no way to know for sure solely using Snow’s map. Though Snow’s conclusion—that there was a contaminant in the… ([Location 2039](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2039)) - Tags: [[aqua]] - As one example, epidemiological studies in the 1930s found an extremely high correlation between the consumption of refined sugar and the incidence of polio. Does eating sugar cause polio? Not at all. Polio is caused by a virus that is transmitted through drinking water, similar to cholera. So what is the connection to refined sugar? Babies are born immune to polio because they inherit protective antibodies from their mothers. However, these antibodies wear off after a few months. If you are exposed to polio while you still possess your mother’s antibodies you will not get sick. Instead—and rather remarkably—the infection induces your immune system to produce its own antibodies, which will then protect you against polio for the rest of your life. If, on the other hand, you are exposed to polio after your mother’s antibodies wear off, you will develop the full-blown disease. These individuals still produce their own antibodies after the infection strikes, but in many cases this happens too late to protect them from the worst ravages of the disease—lifelong paralysis. Thus, if you contract polio as an infant, you will experience a barely noticeable infection. If you contract polio as a young child or adult, you will suffer devastating effects. In poor countries with inferior sanitation, almost everyone is exposed to polio during their infancy. No problem; they still have mom’s antibodies. But before the development of a polio vaccine, in developed countries with excellent sanitation, people usually did not encounter the polio… ([Location 2044](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2044)) - Tags: [[aqua]] - It was at this moment that serendipity struck. While Merck was working to find the most potent and efficacious carbonic anhydrase inhibitor, they stumbled upon a drug that did not inhibit carbonic anhydrase yet was an even more powerful diuretic than their existing drugs. They eventually named it Diuril. They had no idea how it worked, but when Merck tested Diuril on patients suffering from pulmonary edema they found it be safe and extremely effective. Thus, the hunt for a drug to treat blood acidity led to an entirely new kind of drug that treated pulmonary edema, a completely different condition. But that was not the end of the story. A Merck scientist named Karl Beyer thought that Diuril could be used for yet another purpose—to “treat” hypertension. Of course, at the time, the idea of treating hypertension was akin to how we might consider “treating” yawning—why would you want to mess with something so natural and normal? Even so, there was a minority of physicians who suspected that high blood pressure was dangerous rather than a marker of good health. Beyer quietly passed Diuril to his colleague Bill Wilkerson, a physician, and asked Wilkerson to slip the drug to a few hypertensive patients to see what happened. As expected, their blood pressure went down. Beyer knew then that Diuril could be the first clinically effective anti-hypertensive drug—but there was not yet a market for such a medication. When Diuril went on sale to the public in 1958, its primary use was as a treatment for edema. ([Location 2100](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2100)) - Tags: [[aqua]] - At first, these diuretic anti-hypertensive drugs were not used very often. But then the first round of the Framingham Heart Study came out, showing a link between hypertension and stroke. Even though many physicians reacted with skepticism to this finding, other doctors knew that safe and effective drugs—the thiazides—were available to lower blood pressure and decided that prescribing these drugs to their patients with high blood pressure presented a favorable risk to reward ratio. If the Framingham link between hypertension and stroke was actually due to cause and effect, well, the thiazides would probably reduce their hypertensive patients’ chances of a stroke. If the link was not causal, on the other hand, the physicians calculated they would be doing little harm by prescribing the thiazides. The FDA also supported the prescription of the various anti-hypertensive drugs to patients with high blood pressure, since the FDA realized that the only way scientists could establish a causal link between hypertension and stroke (instead of the correlational link in the Framingham Study) was by actually reducing hypertensive individuals’ blood pressure and observing what kind of effect it had—by conducting an ad hoc experiment, in other words. ([Location 2114](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2114)) - Tags: [[aqua]] - Dave Cushman and Miguel Ondetti. They were drug hunters at Squibb who happened to be very interested in the venom produced by pit vipers. The venom of these snakes knocks out their prey by drastically reducing their victims’ blood pressure, rendering their victim unconscious. Cushman and Ondetti reasoned that it should be possible to isolate the compound in pit viper venom that reduced blood pressure and convert it into an anti-hypertensive drug. ([Location 2159](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2159)) - Tags: [[aqua]] - Since neither prey nor patients enjoy injections, Cushman and Ondetti knew they needed an orally active compound if they were ever going to create a commercial version of the drug. They began synthesizing molecules that were similar to teprotide but which they hoped might withstand the rigors of the human stomach. At this stage, it is customary to evaluate thousands or even tens of thousands of molecules—this is the inevitable trial-and-error screening that all drug hunters must go through. But Cushman and Ondetti synthesized and tested only a few hundred molecules by taking a novel approach to the process of screening. The two scientists understood the biochemistry behind the action of the ACE enzyme and thus could predict the types of compounds that would likely inhibit the enzyme. As a result, the earliest compounds they synthesized worked fairly well, and then they proceeded to further tweak these compounds based on their insights into the likely activity of different molecular structures. After each tweak, they tested the new compound to gauge its effects and evaluate the accuracy of their guesses. If drug screening is usually like randomly spinning the reels on a slot machine, then Cushman and Ondetti’s approach was more like figuring out the internal mechanics of the slot machine and then pulling the lever when the machine was about to make a payout. Using this approach (now called “rational design”), Cushman and Ondetti rapidly synthesized a very effective ACE inhibiting compound, which they dubbed captopril. The rational design process was another landmark in the history of drug hunting. Paul Ehrlich was the first person to come up with a wholly original approach to designing a drug from scratch when he conceived of loading a toxin on a molecule of dye, though he still relied on blind trial-and-error to test a number of possible toxic warheads. In contrast, Cushman and Ondetti came up with another original approach to designing a drug from scratch, but instead of relying on blind trial-and-error, they used their knowledge of chemistry, biochemistry, and human physiology to make a series of increasingly effective educated guesses that allowed them to find what they wanted in record time and with minimal cost. ([Location 2175](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2175)) - Tags: [[aqua]] - Such overwhelming interest from academia in a shelved drug was unprecedented, and the executives at my company huddled together and finally decided to give captropril the green light. The ensuing clinical trials demonstrated that captropril was a fantastic and safe anti-hypertensive drug. The FDA approved it in 1981. During its first full year of unrestricted commercialization, captopril generated more than a billion dollars in sales. It was so profitable, in fact, that it made more money for Squibb than the rest of its drug portfolio combined. ([Location 2208](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2208)) - Tags: [[aqua]] - Marker knew that this was one of the great unsolved chemistry riddles of his era, and in 1936 he set about trying to devise a technique that would create the steroid hormone on an industrial scale. His approach was completely different from what anyone else was trying, and brilliant in its simplicity. Steroids are very large molecules, a fact that makes them difficult to assemble. Synthesizing a large molecule is a game of addition: chemists start out with a small molecule, then methodically attach molecule after molecule, like building with Tinkertoys, until they have assembled the full steroid. But it is fairly easy to accidentally attach an intermediate molecule in the wrong place, ruining the entire synthesis and forcing you to start all over. Generally speaking, the larger the molecule, the more difficult the synthesis. Synthesizing a small molecule (like aspirin) is usually as easy as making mac and cheese. Synthesizing a large molecule (like progesterone) is more like preparing stuffed squab chaud-froid. But Russell Marker turned the entire problem upside-down. Instead of viewing progesterone synthesis as a game of addition, he saw it as a game of subtraction. Rather than building the steroid out of smaller molecules, he decided to start out with an even larger molecule and whack off pieces until only progesterone was left. (In the jargon of chemistry, he intended to perform a degradation rather than a synthesis.) ([Location 2302](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2302)) - Marker approached pharmaceutical companies and touted his clever degradation method, hoping to partner with one of them to produce commercial progesterone. These meetings did not go well. Marker was far more skilled as a chemist than as a pitchman, often lapsing into dull and highly technical disquisitions. ([Location 2327](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2327)) - Despite her passion for a birth control pill, as 1951 rolled around, Sanger, now in her seventies, had all but given up. She had visited every major pharma company, some more than once, and had failed to persuade a single one of the potential value of such a drug; and she still had no idea about whether it was even scientifically possible to create the hypothetical pill. Sensing she was running out of time, she decided to switch tactics. Perhaps she could persuade a scientist to try to create a pill entirely on his own, outside of the pharma industry. If she had possessed any knowledge of the realities of drug development in the 1950s, she would have realized just how unlikely it was for an academic scientist to create a novel medication at a university; post-FDA, the development costs for new drugs were prohibitive even for the best-funded academic laboratories. Oblivious to the extreme impracticality of her idea, she began to contemplate which scientist to target. ([Location 2425](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2425)) - On June 8, 1953, Sanger took McCormick on a trip to Clark University in Massachusetts, where Pincus worked. He took the two septuagenarian ladies on a tour of his facilities—a short tour, since his lab was quite skimpy. Nevertheless, McCormick was persuaded by Sanger’s enthusiasm and Pincus’s confidence. “I believe you are the man to finally see our dream realized,” McCormick said, and right there in the lab wrote Pincus a check for $40,000. This sizable sum (about $350,000 in 2016 dollars) was more than 1 percent of the entire National Science Foundation budget. Pincus, whose lab at Clark University had been struggling just to stay afloat, now had more funding than many of the top biology laboratories in the country. ([Location 2470](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2470)) - Note: Sanger acted as a highly networked broker. She connected the talent (Pincus) with the capital (McCormick) and provided the vision herself - Pincus started searching for an oral version of progesterone by testing progesterone compounds on rabbits. There were more than two hundred different commercially available progesterone compounds—all produced using the Marker degradation method—and Pincus fed every one of them to the rabbits in his Clark University laboratory. Three of the compounds reliably prevented pregnancy without producing adverse effects. That was enough. Now he could test these three drug candidates on humans. ([Location 2497](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2497)) - In the 1940s, Rock began teaching his Harvard students about contraception, something unheard of in medical schools at the time. He believed that if people merely heard the logic and facts, they would come to embrace birth control as both rational and compassionate. He published a book about birth control, which he thought would lead to a sea change in people’s attitudes. It did not. However, it did draw the attention of a Jewish biologist at Clark University. ([Location 2513](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2513)) - Note: Example of writing and publishing increasing the surface area for luck - Pincus felt that Rock was the perfect choice to oversee the clinical trials. Still stinging from the negative publicity that had dogged his in vitro fertilization research, Pincus hoped Rock’s prestige, handsome looks, and staunch Catholic faith would help deflect the inevitable blowback once their contraception research became publicly known. ([Location 2530](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2530)) - Within two years of Enovid’s release, 1.2 million American women were on the Pill. By 1965, this number had risen to five million. The drug that no company wanted to touch turned out to be Searle’s best-selling product for more than a decade, far outstripping its sales of glucocorticoids. By the late 1960s, seven pharmaceutical companies were producing oral contraceptives and more than twelve million women were taking the Pill worldwide. Today, more than 150 million prescriptions for the Pill are written each year. ([Location 2596](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2596)) - The Pill did not originate in a Big Pharma science lab or a sales team meeting. First, Swiss dairy farmers who wanted to make their cows pregnant faster made a peculiar anatomical discovery. Then, a veterinary professor published this finding, leading to the identification of progesterone as an anti-ovulation drug. An eccentric and solitary chemist figured out how to make progesterone simply because it was an interesting puzzle. Two septuagenarian feminists selected a discredited biologist to realize their dream of creating an oral contraceptive. A devout and hopelessly idealistic Catholic gynecologist agreed to run the world’s first human trials of the oral contraceptive. Together, the biologist and gynecologist dodged federal and state laws—and medical ethics—by holding trials in Puerto Rico and ignoring clear signs of adverse side effects. They only succeeded in convincing a pharmaceutical company terrified of Catholic boycotts to manufacture the drug after the company fortuitously noticed that women were spontaneously using one of their other drugs for the off-label purpose of contraception. This, in a nutshell, is why it is so hard to develop new medicines. Imagine you want to replicate this process: “Can we develop a cure for baldness the same way we developed a birth control pill?” To become a successful drug hunter requires talent, moxie, persistence, luck—and even then, it might not be enough. And we should not overlook Big Pharma’s frustrating and unhelpful role in this process. Every single pharma company rejected Pincus and Sanger’s proposals when they solicited the companies for help developing the Pill. A previously hostile pharma company jumped in only after an independent team of drug hunters sweated and bled their way to an FDA-approvable clinical trial entirely on their own. The modern drug development process is drastically unfair and completely unreasonable, and yet it still managed to significantly improve the lives of hundreds of millions of women. And this is the true nature of drug hunting. ([Location 2620](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2620)) - One of the most basic truths of drug hunting is the uncomfortable fact that the vast majority of important drugs were discovered without the foggiest idea of how the drug actually worked. It often takes decades before researchers decipher how a new drug fully operates on the body. ([Location 2642](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2642)) - After six days Lind ran out of fruit, so he had to terminate his tests on group four. Yet, amazingly, one of the citrus-treated sailors was already fit for duty while the other had almost completely recovered. None of the other sailors had recovered at all except for the pair treated with cider, who showed a mild improvement. Today, of course, the interpretation of these results is obvious. We now know that scurvy is a disease caused by a dietary deficiency of vitamin C, a compound required for the synthesis of collagen. Collagen provides the strength, structure, and resiliency for our connective tissues, including our blood vessels, and without enough collagen our connective tissue breaks down and produces the symptoms of scurvy, including bleeding and the reopening of old wounds. Citrus fruits contain high levels of vitamin C, while apple cider contains small amounts of vitamin C; none of the other treatments that Lind employed contain any vitamin C. Since fruits and vegetables could not be stored on long sea voyages, eighteenth-century sailors subsisted on cured meats and dried grains—a diet that lacked vitamin C. ([Location 2679](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2679)) - All the way into the 1950s, not only was there no therapeutic drug for schizophrenia, depression, or bipolar disorder, most members of the psychiatric establishment believed there could never be a drug to treat these disorders, since it was widely believed that mental illness was primarily due to unresolved childhood experiences. This was the central conviction of Sigmund Freud, whose theory of mental illness—known as psychoanalysis—swept through the United States in the early twentieth century. (Ironically, Freudianism was almost completely wiped out in Europe for the same exact reason it became so popular in America. The vast majority of the early psychoanalysts were Jews, as was Freud himself, and as the Nazis rose to power in Hitler’s Germany, these Jewish psychoanalysts fled Europe for the safety of American shores, moving the world capital of psychoanalysis from Vienna, Austria, to New York City. It was as if the Holy See of the Catholic Church moved from the Vatican to Manhattan.) By 1940, psychoanalysts had taken over every position of power in American psychiatry, controlling university psychiatry departments and hospitals and completing a hostile takeover of the American Psychiatric Association. ([Location 2711](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2711)) - Smith, Kline, and French was stunned. They were offering for sale the first miracle drug proven to treat the symptoms of psychosis, yet psychiatrists refused to use it. The pharmaceutical company finally hit upon a solution. Instead of trying to coax psychiatrists into prescribing the drug, Smith, Kline, and French salesmen targeted state governments by arguing that if state-funded mental institutions used chlorpromazine, they would be able to discharge patients instead of warehousing them forever, drastically cutting costs and reducing the state’s bill. A few of these state institutions—more concerned with their bottom line than abstruse debates about the philosophy of mental illness—gave chlorpromazine a try. All but the most hopeless patients exhibited dramatic improvements, and just as Smith, Kline, and French had promised, many were discharged back into society. ([Location 2764](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2764)) - drug companies can never be sure that they will get a drug that works the way they hope it will. The reason is as simple as it is profound: there still are no clear scientific laws, engineering principles, or mathematical formulae that can guide an aspiring drug hunter all the way from idea to product. ([Location 2903](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2903)) - the unyielding difficulty of developing new drugs remains one of the biggest sources of the high costs of our medication. The R & D costs for the pharmaceutical industry are far higher than those of other technology-based industries such as automobiles, computers, and consumer electronics. One reason is that so many product development efforts by Big Pharma end up with bupkis, sometimes after a billion dollars was spent. Another reason is because of the high costs of complying with the strict and extensive FDA regulations designed to ensure the safety of our drugs. In addition, because of patent law and the lengthy drug development process, drugs have a relatively short window of market exclusivity (often ten years or less), so any potential profits must be accrued over a limited period of time. But despite the significant impact of FDA regulations and brief patent protections, if pharmaceutical companies could depend on the same clarity and reliability of engineering that auto makers and consumer electronics enjoy, then there’s little doubt that the price of drugs would come down dramatically. Instead, Big Pharma must price their few successful drugs to cover the immense costs from their myriad unsuccessful drugs. ([Location 2929](https://readwise.io/to_kindle?action=open&asin=B01HDVCRY0&location=2929))