Despite Waksman’s double disappointment, the indefatigable drug hunter remained confident that his team would prevail. They continued screening Streptomycete-produced compounds, and in 1943 tested a recently acquired strain of Steptomyces griseus that was found in a chicken’s windpipe. The team found that this unusual strain produced an antibiotic substance that obliterated a wide range of bacteria, including tuberculosis. They tested it on animals, and to their delight, discovered it was not toxic. They dubbed it streptomycin. Streptomycin was developed by Merck into a commercial product and by 1949 had begun to be administered around the world as the first cure for consumption. In short order, it had saved millions of lives.
In the United States, tuberculosis was particularly rampant among poor immigrants, more than half of whom died within five years of diagnosis. In the late nineteenth century, the best available treatment was considered to be sunshine and fresh mountain air. Sunny sanatoriums sprang up through the country, particularly in the Rocky Mountain states. One of the most popular tuberculosis sanatoriums was the Trudeau Institute, founded in the town of Saranac Lake in upstate New York by one Dr. Edward Livingston Trudeau. Ironically, the Trudeau Institute was in a location that was neither particularly sunny nor mountainous, though it didn’t really matter—the therapeutic effects of any sanatorium on tuberculosis are fairly negligible.
The introduction of anti-tuberculin drugs provoked a sea-change. Rather than waiting around in a sanatorium hoping that your disease might spontaneously remit, tuberculosis patients could now return home with the promise of an honest-to-goodness cure. Today, tuberculosis patients are treated with a cocktail of anti-tuberculin drugs, similar to the cocktails used to treat HIV/AIDS patients. Currently, the recommended cocktail consists of four antibiotics—isoniazid, rifampicin, pyrazinamide, and ethambutol—that almost always cure the disease when properly administered.
Waksman’s Nobel Prize–winning discovery threw open the doors to the library of dirt and set off a mad rush by the pharmaceutical industry. Hundreds of drug hunters began digging through the earth all around the world in the hope of finding new bacteria-murdering microorganisms, launching what is now regarded as the “golden era of antibiotic research.” Many antibiotics in our twenty-first-century medicine cabinets were discovered during this golden age, including bacitracin (1945), chloramphenicol (1947), polymyxin (1947), chlortetracycline (1950), erythromycin (1952), vancomycin (1954), and many others.
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. But penicillin also revealed something else—something extremely vexing. After getting exposed to an antibiotic drug, pathogenic bacteria could change their nature so that the drug would no longer harm them. It was as if the germs could pull on a new suit of armor specially designed to turn aside the pharmaceutical weapons slashing at them.
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.
This started one of the greatest battles in pharmacology—really one of the greatest battles in all of medicine—an endless arms race between diseases and cures. The pattern remained very consistent. Drug hunters would unearth some new antibiotic drug. It would kill pathogenic bacteria for a while. But eventually the fast-reproducing bacteria’s genome would mutate just enough so that the drug was no longer effective against it.
Often, pharma scientists could tweak an antibiotic into a slightly different compound (known as an analog) that would also kill the mutated pathogen, but eventually the pathogen would mutate again and the analog would no longer work, either. Antibiotic resistance remains an unsolved problem to this day. We still confront many antibiotic-resistant strains of bacteria that have become or are becoming just as lethal as they were before the discovery of penicillin, including Staphylococcus aureus (MRSA), Neisseria gonorrhoeae (gonorrhea), Pseudomonas aeruginosa (pneumonia and sepsis), Escherichia coli (E. coli), and Streptococcus pyogenes. There is even a new strain of Mycobacterium tuberculosis that can survive the standard anti-tuberculosis cocktails.
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.
In 1950, virtually every pharma company had an antibiotic research unit. By 1990, many of the largest American pharmaceutical companies had marginalized antibiotic research, or dropped it entirely. That same year witnessed a sudden resurgence of interest in antibiotics within the scientific community, triggered by the outbreak of MRSA and other antibiotic-resistant germs. The pharmaceutical industry did not embrace this renewed interest, however, continuing their steady withdrawal from the fight against infectious disease. In 1999, Roche pulled out of antibiotic discovery. By 2002, Bristol-Myers Squibb Company, Abbott Laboratories, Eli Lilly and Company, Aventis, and Wyeth had all terminated or severely downsized their antibiotic programs. Pfizer, one of the last holdouts, shut down its main antibiotic research center in 2011, perhaps signaling the twilight of the Age of Dirt. Today, fifteen of the eighteen largest pharmaceutical companies have abandoned the antibiotic market entirely.
I am one of the youngest people alive to have conducted research in a classic Big Pharma antibiotic discovery program—the source of my adventures wheeling around the Chesapeake in my lime-green Monobacvan. It was the dying days of searching for new soil in the hope of unearthing some previously undiscovered bacteria-butchering microorganism. I never did find a new antibiotic in the Delmarva dirt, and even if I had, it quite likely would have been shelved before it got developed into a commercial drug.
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 ant
ibiotics but that has now developed resistance. That’s more than the number of Americans who die from (virus-borne) AIDS each year.
Alexander Fleming made one of the greatest discoveries in human history: a single cure for many diseases. Sadly, this cure is not imperishable. It must be constantly refreshed and renewed, the remedy as dynamic and ever-changing as the blight itself.
9
The Pig Elixir
The Library of Genetic Medicine
Frederick Banting, Charles Best, and Dog 408
“Peace comes from within. Do not seek it without.”
—Buddha
For most of our species’ existence on our vast green planet, drug hunters searched through the variegated library of plants for new unguents and balms. Botanical medicines were found in abundance. In comparison, the stingy library of animals was a paltry source of drugs; one simple reason is that there is far less fauna than flora on our Earth. Nevertheless, from ancient times until the modern era, humans have extracted myriad drugs from animals. A handful actually worked. Most, however, provided no benefit at all—other than the placebo effect.
Take the rhinoceros horn. It is a common misconception that powdered rhinoceros horn was used as an aphrodisiac or a cure for cancer in traditional Chinese medicine. In truth, no Chinese medical text mentions such uses. Instead, traditional Chinese medicine promoted the rhinoceros horn as a treatment for fevers and convulsions, though it possesses the same power to cure these conditions as it does to cure cancer: none. In fact, a recent monograph entitled Chinese Herbal Medicine: Materia Medica compares the consumption of powdered rhinoceros horn to the consumption of fingernail clippings.
Even so, the misbegotten notion that the Chinese used the rhinoceros horn as an aphrodisiac has driven sales of the rare rhinoceros horn in Vietnam and other Southeast Asian countries. This demand has spurred rhinoceros poaching to the point where the International Union for Conservation of Nature now lists three of the five known rhinoceros species as critically endangered.
A similar situation exists for tiger parts. The bones, eyes, whiskers, and teeth of Panthera tigris have been used in traditional Chinese medicine for the treatment of a wide range of ailments, including malaria, meningitis, and bad skin. Traditional Chinese medicine claims that almost every part of the tiger can be used medically. Claws—a sedative for insomnia. Teeth—a treatment for fever. Fat—a cure for leprosy and rheumatism. Nose leather—a balm for superficial wounds and insect bites. Tiger eyeballs—a remedy for epilepsy and malaria. Whiskers—an analgesic for toothaches. Brain—an antidote for laziness. Penis—can be ground and stewed into a love potion. Tiger dung—a panacea for hemorrhoids. As you can probably guess, there is absolutely no evidence that any of these preparations have any medical value.
And just as happened with the hapless rhinoceros, the misguided faith in the therapeutic power of tiger pills, powders, and wines has resulted in a catastrophe for the graceful feline. Of the original nine subspecies of tigers, three have become extinct in the last eighty years. Four of the remaining subspecies are considered endangered, two critically so. The International Union for Conservation of Nature estimates that the total population of the six remaining subspecies is under four thousand individuals. (In comparison, there are more than forty million domestic cats in the United States alone.)
But 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.
By 1900, the consensus of the biomedical community was that medicinal preparations from animals were simply not useful, and pharma companies and drug hunters alike had abandoned all attempts at searching animal parts for beneficial compounds. Yet, twenty years after the turn of the century, one of the most important drugs in history was discovered within the organs of dogs.
The story behind this animal-borne Vindication commences in 1897, when Bayer first sold Aspirin to a grateful public and shoveled up undreamed-of profit. The global success of this synthetic remedy opened up a whole new world of pharmaceutical opportunity as drug companies realized that enormous revenues were waiting to be had for any truly original drug. As the twentieth century dawned, many large drug companies began to set up their own drug discovery units to search through the library of molecules for new therapeutic compounds, and one of the first American pharmaceutical companies to try to develop their own drugs was Eli Lilly.
The company was founded by Colonel Eli Lilly, a Civil War veteran and pharmacist, in 1876 in Indianapolis. Most of Lilly’s early products were hand-rolled pills coated with sugar, elixirs, and syrups, including the top-selling Succus Alterans, a useless formulation sold as a treatment for syphilis and “certain types of rheumatism and especially skin diseases like eczema, psoriasis, etc.” Josiah Lilly took over the family business in 1898 after the death of his father, and eventually Josiah’s grandson Eli (named after his great-grandfather) became company president and chairman of the board. Eli Lilly, a third-generation pharma executive, looked with envy upon Bayer’s success developing new drugs in Germany and decided that his own company should get into the drug hunting game.
In 1919, Lilly recruited a scientist named Alec Clowes to serve as a kind of roaming opportunist whose job was to sniff out new product opportunities, similar to the contemporary role of a licensing director. Clowes’s background was in cancer research. He had spent eighteen years at the prestigious Roswell Park Memorial Institute in Buffalo, where he made a name for himself as an exceptional scientist. He also possessed an entrepreneurial streak that made him attractive to Lilly as the right person to move the company out of drug repackaging and into drug discovery. In 1919, Clowes began reviewing various diseases and ailments to see which ones might be offer the best opportunities for drug development. He quickly settled on a malady without any known treatment: diabetes.
During the second millennium BC, Indian physicians observed that ants were attracted to the urine of certain patients; Egyptian manuscripts from roughly the same era, meanwhile, describe some patients as suffering from “too great emptying of the urine.” These are the oldest known records detailing the symptoms of diabetes. The Indians called it madhumeha, or “honey urine.” The Greeks called it diabetes, meaning “passing through,” referring to the excessive discharge of urine. In 1675, a British physician termed it diabetes mellitus, adding the Latin
word for “sweet tasting.” Today, this form of diabetes is most commonly known as type 1.
Type 1 diabetes almost always starts in childhood and—without treatment—is inevitably fatal. Its victims are usually unquenchably thirsty and insatiably hungry. Nevertheless, even though they consume prodigious amounts of water and food, they slowly lose weight and steadily waste away. Diabetes also impairs blood circulation and damages nerves. Poor circulation often causes blindness when there is not enough blood getting to the retina, and can even cause the loss of limbs. Simultaneously, as their nerves are slowly destroyed, victims feel escalating levels of pain.
When Clowes joined Lilly, most individuals with diabetes perished within a year of being diagnosed. Four thousand years after the “honey urine” disease was first documented, there was still no known remedy. Thousands of plant-based compounds were tried on diabetics during the Age of Plants, all without effect. The Age of Chemistry had also failed to produce any viable treatment. But Clowes hoped to change that.
Fortunately, 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.
The Drug Hunters Page 12