Unlike the Volt, Disney’s movie simply did not work. That’s because as much as Hollywood wishes there was some kind of cinematic blueprint for success, filmmaking is ultimately an artistic process, involving moments of inspired creativity and an abundance of trial and error. It is simply impossible to predict whether a particular script will become a successful movie.
This leads us to our concluding question: is the process of creating a new medicine more like designing the Volt or more like designing The Lone Ranger? Put another way, is drug discovery more like scientific engineering or artistic creativity? More than a century and a half after the establishment of a scientific pharmaceutical industry, the answer is clear. The development of new medicines—including antibiotics, beta blockers, psychoactives, statins, antifungals, and anti-inflammatories—is far more like trying to craft the next Avengers than developing a new car … or a new cell phone, vacuum cleaner, or satellite.
We instinctively presume that major medications—like insulin, Prozac, or the birth control pill—were developed through a rational process of scientific engineering similar to how the Volt was designed. Big Pharma executives identify the need for a particular drug, assemble a team of crack scientists, hand them a list of objectives, shower them with money, and wait for them to crank out the desired medicine. This is, in fact, a fair representation of the process that drug companies follow to develop copycat versions of existing drugs. For instance, just as General Motors hungrily eyed the impressive sales of the Prius, the drug company Lilly envied the sales of surprise blockbuster Viagra and assembled a drug development team to design its own erectile dysfunction drug. The result was Cialis, which carved out its own enviable share of the male arousal market. But Cialis was not some original creation, like the Volt. It was a knock-off; more like the way the Lincoln Navigator was a badge-engineered knock-off of the Ford Expedition. Cialis worked by acting upon the same physiological mechanisms as Viagra (namely, inhibiting the PDE5 enzyme). Lilly did not figure out how to treat erectile dysfunction in a way that avoided the existing side effects with Viagra (such as flushing, head-aches, indigestion, nasal congestion, and impaired vision). Its scientists merely duplicated Pfizer’s drug, but found a molecular tweak that prevented Lilly from violating Pfizer’s patent and added enough of a change in effect to allow Lilly some room for differential marketing (Cialis lasts longer than Viagra). Cialis was not an engineering breakthrough; it was Viagra 2.0—or, really, Viagra 1.1.
Game-changing drugs are almost never developed the way General Motors designed the Chevy Volt or Steve Jobs invented the iPhone or the way that most transformative consumer products are developed. Steve Jobs was able to tell his engineering team, “Go create a new kind of computer that is a flat tablet with a touch screen that runs Apple software” and expect that they would be able to build it. (Whether it would sell well is an entirely separate question; what is important is that he could be confident it could be built in a reasonable time frame and work exactly as he intended.) But Disney can never be confident when it tells its own team, “Go create a movie that makes people guffaw, cry, and cheer.” Similarly, 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. Even though there have been a number of advances that make different components of the drug hunting process more efficient—such as receptor theory, rational design, recombinant-DNA engineering, pharmacokinetic testing (evaluating how a drug is processed by the body from ingestion to elimination), transgenic animal disease modeling (genetically engineering an animal’s DNA to mimic some aspect of human disease in order to test the drug on the animal instead of a human), high-throughput screening (the ability to rapidly evaluate thousands of compounds), and combinatorial chemistry (the ability to generate thousands or even millions of different chemical compounds in a single process in order to use them for testing)—these are more akin to IMAX projectors, surround sound, and improved CGI rather than a blueprint for engineering a drug.
There’s another similarity between filmmaking and drug hunting. Hollywood professionals take big risks. If your movie turns into a hit, you will be rich, famous, and potentially shape culture. If your movie flops, on the other hand, you may be broke, notorious, and depressed, potentially hurting your chances of securing support for your next cinematic effort. If you want to try to make it in Hollywood, you need to be brave, vehemently optimistic, and endowed with a short memory so you can forget all the flops you were part of. Of course, some might say you need to be crazy or foolish to work in Hollywood. Most drug hunters I’ve met are brave and optimistic, though a few do qualify as crazy and foolish. Not too many fall in between these extremes.
Scientists who search for new medicines must expose themselves to hazards both conspicuous and unknown. Valerius Cordus died from a disease he contracted while searching the wilderness for new botanical drugs. James Young Simpson inhaled a variety of volatile organic liquids in his search for an ether replacement, including many toxic ones. I myself took an experimental drug that made me ill in the hope that my self-experimentation would bring a useful medicine to patients more rapidly. More severely, in 2016, a painkiller drug trial in France killed one man and critically injured five others; though the drug scientists appear to have done everything right and weren’t hurt themselves, they are facing litigation and will likely never work again—though they will be haunted by the man’s death for the rest of their lives.
What’s truly amazing, however, is how much success we have had in coming up with important drugs. We have cured dozens of major diseases and have effective treatments for everything from diaper rash to headaches to diarrhea to athlete’s foot. Even though the drug discovery process is highly random and relies more on individual artistry than rational design, we live in a world where we can expect to find medications for most of our ailments. If drug hunters are more like filmmakers than automobile engineers, then how can we account for this counterintuitive success?
The thing about trial and error is that if you keep on trying and keep on being willing to make errors, eventually you will find something that works. And the more drug hunters we have striving to make the next Star Wars, the greater the chance that one of them will prove to be a J. J. Abrams of pharmacology.
Nevertheless, 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.
The soaring cost of developing new drugs creates financial disincentives that prevent pharma companies from focusing on drugs that produce cures. Why? Because any medication that can resolve a medical condition all at once is a medication that does not need to be purchased over and over again, drastically limiting its profit potential. For example, as we saw, the economics of antibiotics are quite unfavorable to Big Pharma, since patients need only to t
ake a single course of the drug to get better, and doctors tend to hoard new antibiotics anyway. Vaccines are even worse, financially speaking, since (in principle) a person may need to take the drug only one time their entire lives. Moreover, there is a relatively low barrier to entry for competitors to make vaccines. Since vaccines tend to be public health drugs, they are often developed through government programs, which further reduces their commercial profitability. Antifungals—cures for fungus-based pathologies—suffer from the same profit limitations as antibiotics, with the added problem that there are far fewer people afflicted with fungus-based diseases than bacteria-based diseases. Antivirals, like Tamiflu, also tend to offer the same economic disincentives as other infectious disease cures, though HIV antiviral drugs have turned out to be a Big Pharma–enriching exception, since AIDS patients need to take a cocktail of anti-HIV medications every day for their entire lives.
This is not to say that incompetence, a prioritization of short-term gains over long-term goals, and naked greed (as opposed to economic disincentives) fail to play a role in keeping drug prices high or preventing valuable medicines from coming to the market. Human foibles are certainly present among pharma executives as they are everywhere else. But at its core, the pharma industry is predicated upon the same kind of profound and irremediable uncertainty as Hollywood. At the same time, there is a tiny handful of big movie studios who—against the odds—somehow seem to put out an unbroken stream of quality products that unceasingly delight audiences. At the moment, they may be the only ones. This handful has achieved rare consistency by granting their writers and directors unparalleled creative freedom with relatively little interference from producers and executives. Perhaps if Big Pharma were willing to grant their scientists the same kind of creative control over the drug hunting process, we might see a pharma company issue their own string of Toy Story, Wall-E, and The Incredibles.
Their own string of world-changing Vindications.
Appendix
Classes of Drugs
Neuropharmacological Drugs
Autonomic nervous system drugs
• Muscarinic
• Cholinesterase inhibitors
• Adrenergic drugs
Serotonin drugs
Dopamine drugs
Antipsychotics
Antidepressants
Anxiolytics
Hypnotics and sedatives
Opioids
General anesthetics
Anti-epileptics
Neurodegenerative disease drugs
Cardiovascular drugs
Renal drugs for hypertension
ACE-type drugs for hypertension
Beta blockers and other anti-hypertensives
Digitalis and anti-arrhythmia drugs
Anticoagulants
Anti-cholesterol drugs
Inflammation and the immune system
Antihistamines and related drugs
Aspirin-like drugs and related drugs
Immune system suppressants
Asthma drugs
Hormone drugs
Thyroid drugs
Estrogens and progestins
Androgens
Adrenal corticoid drugs
Insulin and other drugs for diabetes
Drugs acting on bone formation and degradation
GI drugs
Drugs for acid reflux and ulcer
Drugs acting on bowel motility
Anti-infective drugs
Malaria drugs
Protozoal infection drugs
Helminth infection drugs
Sulfa drugs
Penicillins
Streptomycin-like drugs
Quinolones and related drugs
Other antibacterial drugs
Drugs for tuberculosis and leprosy
Antivirals and drugs for AIDS
Cancer drugs
Cytotoxic drugs
“Oncogene” selective drugs
Reproductive System Drugs
Contraceptives
Gynecological and obstetric drugs
Erectile dysfunction drugs
Ocular drugs
Dermatology drugs
Notes
Introduction: Searching the Library of Babel
11: James Young Simpson: On October 16, 1846, at Massachusetts General Hospital, William T. G. Morton demonstrated that patients for the first time could be temporarily rendered unconscious prior to a surgical procedure. The drug he used was ether. Today when a pharmaceutical company gets FDA approval for a new kind of drug, competing companies promptly start their own research programs to find a similar drug. These are often called “me-too” drugs. Chloroform might be the first “me-too” drug of the industrial era.
As a more modern example, shortly after Squibb got a new kind of drug named captopril approved for the treatment of hypertension, Merck set to work developing its own me-too anti-hypertensive drug, which became enalopril. Similarly, when Lilly received FDA approval for Prozac in 1987, Pfizer quickly followed up with the me-too antidepressant Zoloft, while GlaxoSmithKline obtained approval for the me-too Paxil.
Chapter 1: So Easy a Caveman Can Do It: The Unlikely Origins of Drug Hunting
19: If we relegate alcohol to the status of a beverage: There are good reasons for classifying alcohol as a foodstuff and not a drug. The discovery of Stone Age beer jugs demonstrated that intentionally fermented beverages existed at least as early as 10,000 BC, and some historians even suggest that beer may have preceded bread as a food staple. Alcoholic potables were very important in ancient Egypt, and beer—commonly brewed at home—was considered a necessity of life. But alcohol was also used for medicine, as an offering to the gods, and was an important component of funerals; alcoholic drinks were frequently stored in the tombs of the deceased for their use in the afterlife. The Egyptian god Osiris was even believed to have invented beer, signifying the beverage’s divine nature.
Nevertheless, for most of human history alcohol has been regarded as a cure-all medication. Spirits, whose alcohol content was increased through distillation, were commonly used for medical purposes, and many of the names for these drinks reflect old beliefs regarding their curative properties. “Whiskey” comes from the Gaelic word usquebaugh meaning “water of life,” which is also the translation for eau de vie, what the French call non-barrel-aged distilled spirits. Legend has it that that when sick patients were dosed with these potent potables they would thrash about and become more animated, thus leading to the conclusion that the drink was putting life back into them. (This particular experiment can be repeated today in the privacy of your home.)
We now know that ethyl alcohol (the alcohol in fermented beverages) acts by stimulating GABA A (γ-aminobutyric acid) receptors. These receptors are the major neuro-inhibitory receptors in the brain, and stimulating these receptors causes a decrease in neurological activity, causing sedation. Benzodiazepines, commonly referred to as tranquilizers (which include Librium and Valium), target the same class of receptors. One common use of benzodiazepines is for the treatment of insomnia. I remember my grandmother on occasion treating her own insomnia by taking a little bit of schnapps before bedtime. Another common use for benzodiazepines is to treat the symptoms of anxiety.
This, in the end, points to the severe limitations of alcohol as a drug: the lack of separation between desirable therapeutic activity and undesirable side effects. Benzodiazepines are far more effective at treating anxiety because their effects are more targeted.
19: Opium is the active ingredient of the poppy: In this chapter we use opium as an example of a medicine that was found by ancient botanical drug hunts and still meets contemporary standards for a therapeutic drug. There are, however, several other examples. Ergot, for instance. Ergotamine and related compounds are produced by the ergot fungi in the genus Claviceps. These are pathogens that infect cereal plants, most commonly rye. When the fungus grows on the plant it produces ergotamine and a suite of other toxic compounds. In ancient times, th
ese ergot-related compounds were ingested by humans when they ate rye produced from plants infected by the fungus. Today, we would call these compounds “dirty drugs” because they act simultaneously on multiple targets in the body. As a result, eating ergot produces symptoms that are quite varied and complex.
One class of symptoms is convulsions, including seizures, nausea, and vomiting. The second class of symptoms from ergot poisoning is hallucinations. Chemically speaking, ergotamine is very closely related to LSD. Finally, ergot poisoning can also elicit gangrene. Ergotamine is a potent vasoconstrictor, meaning that it narrows blood vessels. This reduces the body’s blood supply, which poses particular difficulties for the peripheral regions of the body, such as hands, fingers, feet, and toes. The extremities initially feel a tingling sensation similar to the experience of “pins and needles” or a body part “falling asleep” when it is held in an awkward position for a period of time. Of course when that happens, you simply move your body and shake out the limb, restoring blood flow, making the numbness go away. That will not work if you are poisoned by ergot. Instead, the skin on the parts of your body feeling “pins and needles” will begin to peel off. Eventually, your appendages will swell, blacken, and die—“falling asleep” permanently.
Epidemics of ergot poisoning occurred periodically throughout history. The unexplained appearance and just-as-sudden disappearance of the pestilence together with the hallucinations and the blackening and dying of toes and fingers made it easy to imagine that the condition was caused by evil possession or the wrath of God. One early account of ergot poisoning appeared in the Annales Xantenses in 857: “a great plague of swollen blisters consumed the people by a loathsome rot, so that their limbs were loosened and fell off before death.” In the Middle Ages, ergot poisoning was called Saint Anthony’s Fire, after monks of the Order of Saint Anthony discovered a cure for the condition. How did these benighted medieval monks manage to produce a cure? Through prayer and penance—literally. When victims were afflicted with ergot poisoning, they would go to monasteries to perform prayers and penance and ask God for mercy. Medieval monasteries did not grow rye, however—they grew wheat and barley instead. So as long as a victim stayed at the monastery, they stopped eating the contaminated rye, causing the symptoms to recede. Of course, the recovered penitent would return home and resume eating bad rye and the symptoms would reappear. The monks explained the resurgence of Saint Anthony’s Fire by suggesting that the wayward Christian had returned to their lax and immoral ways, incurring the wrath of God once again. Naturally, a return to the piety of the monastery would set things right, morally and physically.
The Drug Hunters Page 21