Charles Esmon knows that, in some cases, it pays not to listen.
Not to listen, that is, when prevailing wisdom says that something can't be done. In the 1970s, Esmon was an assistant professor at the University of Oklahoma, where he has now been for more than 30 years. He was continuing his research on factor V, a protein necessary for blood clotting.
"I tried to work on factor V as a graduate student, but it had beaten me," Esmon says. He wasn't the only one. Researchers had been trying to isolate factor V and purify it since the 1930s. Dogma held that the protein was so unstable it could not be isolated; if by chance it were, the protein would simply fall apart.
In his Oklahoma lab, Esmon not only isolated and purified factor V but also purposefully dismantled it—and then put it back together.
"I remember thinking what an incredible amount of work this had been to make the protein and what a waste of time it would be [to try to recreate the protein]," he says. "But I put the [pieces] in a column with calcium ions, and it reassembled." He had done what he thought could not be done.
Esmon's work resonated throughout the field. Researchers later used his techniques to isolate factor VIII, a clotting protein missing in about 80 percent of people with hemophilia. Today, factor VIII replacement is the main treatment for this disease.
While working on factor V, Esmon had a second project going. "I thought that any researcher needs to have two projects, in case one of them doesn't work out," he says. So Esmon also was studying sepsis, a bacterial blood infection. About 700,000 Americans suffer from sepsis each year, and about 35 percent die.
Esmon and colleagues—working with Fletcher Taylor and Lerner Hinshaw—saw that when affected animals were hooked up to pumps that bypassed the heart, they survived septic shock. Further research showed that something generated in their blood was keeping them alive.
Prevailing wisdom said that septic shock killed by clotting the blood. But Esmon paid no mind. He showed that injections of thrombin (a major clotting protein) protected animals from septic shock.
"This was a paradox, that you could inject a clotting molecule and keep animals from dying," he says.
The behind-the-scenes answer: Esmon had been studying protein C, a protein that prevented blood clotting in the body, but not in test tubes. He wondered if something in the blood vessels might be "turning on" protein C. This idea was renegade: At the time, blood vessels were seen merely as conduits for blood, not as active participants in health or disease.
Esmon discovered that thrombin, bound to a specific protein on the blood vessel wall, was the "something" that activated protein C to prevent clotting. His work led to the 2001 approval by the Food and Drug Administration of Xigris (drotrecogin alfa), the first and only drug for treating severe sepsis.
More recently, Esmon's lab identified the endothelial protein C receptor (EPCR), the target for protein C. They found that high levels of EPCR reduce clotting and inflammation, similar to high levels of activated protein C. Low levels of the receptor, on the other hand, increase clotting and inflammation. They have found EPCR in both blood vessels and blood cells as well as on blood-forming (hematopoeitic) stem cells.
The lab remains deeply involved in researching activated protein C and its effects on inflammation. "The phenomenon of inflammation occurs in bowel diseases, diabetes, and atherosclerosis, to name a few, so understanding how we can turn this around has broad biomedical implications," Esmon says.
Esmon's work on the biochemistry of the blood seems a perfect match for him, though he nearly became a cancer researcher.
"As a new graduate student, I wanted to work on a cancer project, but the person I wanted to work with didn't take first-year students," he says. "One of the new professors was working on blood clotting, so I joined that lab instead."
With no regrets. "This work has a lot of interesting aspects," he says. "There's fun biochemistry and a lot of physiology that is not yet well understood. It's one of the few areas where almost anything you do has direct applicability to medicine. It's very rewarding."