cientific discoveries take mental muscle. From a well-formed hypothesis, you develop rigorous experiments, collect copious data, analyze that data, and finally hope to make some sensible conclusions. That’s the usual way things go. However, sometimes there are … accidents. Happy ones, the same sort of serendipity that leads complete strangers to go to the same coffee shop at the same time, order the same drink, start a conversation, and eventually fall in love. Like would-be lovers, scientists only reap the benefits of these accidents when they’re mentally ready for them.
French chemist and microbiologist Louis Pasteur said it best in 1854: “Chance favors only the prepared mind.” This was the Pasteur who famously discovered pasteurization (saving the beloved French wine industry from collapse by neutralizing its contamination woes) and developed anthrax and rabies vaccines. He knew from experience that it takes a mind primed for any possible outcome — not just the expected one — to take advantage of these beautiful bits of chance.
Nowhere is this truer than in the arena of drug discovery. We’ve been accidentally discovering useful pharmacologic treatments at a good clip since the late 19th-century. Not just obscure medications but well-known drugs that have saved or improved millions of lives, including some high profit blockbusters.
The classic serendipitous drug discovery, the one kids hear about in grade school science class, was penicillin. Alexander Fleming, working in England in the early 1900s, was hunting for an antibacterial substance. After the germ theory of disease was established, researchers were eager to make inroads against the germs. In the 1920s, Fleming identified a tear enzyme called lysozyme. Lysozyme has a mild antibacterial effect, but not strong enough to be effective as a drug. Fleming continued searching, growing bacteria in petri dishes and studying them. One day, while cleaning out old dishes, he saw mold growing in a particular dish. Having cultured bacteria myself, I know this happens all too often. It’s frustrating because mold contaminates experiments. Rather than yield to frustration, Fleming looked closer and saw that where the mold grew, bacteria didn’t. Fleming later showed that this mold, Penicillium notatum, caused the bacteria to lyse (break down) and die. Penicillium mold eventually led to creation of the antibiotic penicillin. It wasn’t until World War II that this miracle drug was mass-produced. Yet it all started with intimate observation of a common phenomenon, and the realization that something not so common was going on.
But penicillin is far from the only example of accidental drug discovery. Sometimes, as in the case of lithium, happy accidents are rooted in misconceptions about science and medicine. When it was determined in 1859 that a new potential medication called lithium could dissolve urate stones, doctors began using it to treat gout. Gout is a painful disease involving crystalline urate deposits in the joints. These crystals form when there’s too much uric acid in the blood, either because the body is producing too much such acid, or the kidneys aren’t getting rid of enough. Around this time, doctors believed that this acidic buildup in the body led to everything from gout (which it does) to cardiac disease and mental illness (which it does not). The latter was termed “cerebral gout.” Under that assumption, a doctor at Bellevue Hospital in New York City treated some mood disorder patients with lithium. It worked! But lithium quickly becomes toxic in the body, so the treatment fell into disuse. In the 1940s, lithium was rediscovered as a psychiatric treatment. Then, in the 1960s, it became possible to monitor lithium toxicity levels with blood tests. As a result, lithium continues to be a treatment for bipolar disorder today.
I appreciate the discovery of Topamax (generic: topiramate) on a personal level. In the late 1970s, a group of chemists were seeking ways to inhibit a gluconeogenesis enzyme called 1,6-FBPase. In plain English: they wanted to treat diabetes. After synthesizing compound after compound, they started testing one of them, called McN-4853, in mice. It was potent – not as an antidiabetic drug though, but as an anticonvulsant. Later branded as Topamax, the compound was eventually approved by the FDA to treat epilepsy. Scientists discovered that Topamax not only prevented seizures but also migraines. That’s why I take it — to manage what used to be debilitating headaches. While it’s now available as a generic, Topamax was a hot seller in its day, with annual sales in 2008 of $2.7 billion. All because a handful of scientists were open minded about a new development, rather than dismissive after their own ideas failed to bear fruit. As a lead researcher on the project later wrote, “There was no drug design, no lead generation, and no lead optimization!” In other words, they got really lucky.
Pfizer got really lucky with a drug called sildenafil citrate. Better known by its brand name of Viagra, this little blue pill began its research and development life as a treatment for angina (chest pain) and high blood pressure. It didn’t do much for either of these conditions during clinical trials. What sildenafil did do in clinical trials was cause penile erections. Viagra was approved in 1998 to treat erectile dysfunction. But scientists aren’t done with Viagra. Since its initial approval, researchers have been hunting for more potential uses. The neonatology lab where I worked studies whether sildenafil could treat a devastating lung disease that affects premature babies exposed to the high oxygen they initially need to survive. Stranger things have happened, like falling in love. They happen not when you’re looking, but when you’re ready.