• Big breakthroughs born of necessity, frustration and … chance

Big breakthroughs born of necessity, frustration and … chance

Research often doesn’t go in straight lines. Many times there are dead ends. On other occasions, almost by chance, scientists make breakthroughs that lead to new products, therapies or companies. Some of which are spectacularly successful and change lives for the better.

Take the case of two HIV-antiretroviral drugs that are now used by 95 percent of AIDS-infected patients in the United States. In the mid-1990s, Emory University researchers Raymond Schinazi, Dennis Liotta and Woo-Baeg Choi discovered the two drugs after giving up on conventional approaches to their pursuit of molecular synthesis.

Sold under brand names Emtriva (the Em stands for Emory and the tri for Triangle Pharmaceuticals, the company that originally developed the drug) and Epivir, both drugs are in the class known as nucleoside reverse transcriptase inhibitors (NRTIs), which work against the enzyme that copies HIV RNA into new viral DNA.

“When you do research, you try things that seem to make sense,” says Liotta, a chemistry professor. “And then you do them and they don’t work. But in this case, what we did worked beautifully and the rest is history.”

Novel approach out of failure
Liotta says he and his colleagues hadn’t been successful using conventional techniques to synthesize molecules. So they picked a highly unusual method that succeeded on the first try and was 300 times more selective than previous techniques they’d used.

“We never expected to be designing drugs,” he says. “But because we had this great chemical synthesis methodology, we were able to run circles around our competition and find compounds like Emtriva that really worked like a charm.”

Liotta says their breakthrough came from “serendipity with a little assist from necessity.”

“We would never have tried something that novel if we wouldn’t have had so much trouble with existing methods,” he says.

At the University of Wisconsin-Madison, another chemist’s work led to the creation of a highly effective rat poison and an anticoagulant widely used by heart patients. According to Kevin Walters, the Wisconsin Alumni Research Foundation (WARF) historian in residence, it all began in 1933 when an exasperated German farmer stormed into Karl Paul Link’s lab.

Link, whom Walters describes as a “colorful fellow,” said the farmer was carrying a bucket of cow’s blood, shouting “Mein Gott! (My God!) My cows are bleeding to death.”

When the farmer calmed down, he explained that after dehorning or castration, the animals’ blood continued to flow until they died. It turned out the cows were eating sweet clover hay that had spoiled, producing a deadly anticoagulant.

It took six years of research, but in 1940, Link and his lab mates synthesized the hemorrhagic agent, which they later named dicoumarol. It was patented by the university in 1942. In 1948, it was first promoted as a rodenticide and the product was named warfarin, after the university tech transfer office that had funded the research for it.

“No one knew that from the study of spoiled hay, you’d get a drug to prevent blood clotting in humans and kill rats,” Walters says. “That happened by chance.”

It wasn’t until 1954 that warfarin (under the brand name Coumadin) was approved for human use. The drug—and WARF—became famous in 1955, Walters says, after it was used to treat President Dwight Eisenhower, who had suffered a heart attack.

A saying at the time was “What’s good for a war hero and the president of the United States must be good for all, despite being a rat poison.”

Google, because the timing was bad
A third highly visible example of discovery by chance comes from Stanford University, where a pair of doctoral students—Larry Page and Sergey Brin—created the multi-billion-dollar search engine company known as Google. But that wasn’t their initial plan, says Luis Mejia, associate director of Stanford’s Office of Technology Licensing.

“The inventors did not want to do a startup company—they wanted to finish their Ph.D.s,” recalls Mejia, who worked with the pair in the mid-1990s. “They just wanted us to license the PageRank algorithm technology. So we spent half a year trying to market it and find licensees. But nobody really expressed much interest.”

Mejia says Page and Brin went to a few “road shows” with him and learned first-hand that no one understood what they were doing.

“So it was really out of frustration that they decided to start a company, because the timing for licensing a search engine wasn’t good,” he says. “In that respect, it was chance.”

Mejia says the pair—who never finished their doctorates—did not have a business model when they licensed the technology.

“But then a lot of things just sort of fell into place,” he says. “Maybe that’s where serendipity comes in. If we hadn’t licensed it to them, there is a chance we could have licensed it to another company for a very nominal sum of money. But it isn’t clear that they would have done anything with it. And there probably would be no Google today.”

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