A Crazy Idea

by Angela Spivey

arry Lentz, professor of biochemistry and biophysics, doesn’t sleep much at night. He’s got about eight papers to write and publish, and he wants to do it fast. Lentz has spent years studying just one element of blood clotting—phosphatidylserine (PS). And now he’s found something unusual, something that he believes will shake scientists up. But it won’t do that unless they read about it.

PS is a lipid—a long molecule with a water-loving "head" and a greasy, water-hating "tail." In water, lipids organize themselves into sheets so that the water-soluble heads face the outside of the sheet and the greasy, water-insoluble tails face the inside. This "lipid bilayer" is what forms cell membranes.

Most researchers have believed that the membranes of platelets help regulate the production of thrombin, which is an enzyme that helps your blood to clot at a wound. While these researchers have recognized that PS plays a role in this process, they have focused on the importance of the cell membrane surface. But work in Lentz’s lab shows that the water-soluble part of PS, without the cell membrane, enhances thrombin production.

Lentz had suspected that PS has a binding site all its own on Factor Xa, one of the proteins that helps make thrombin. But this was hard to prove with PS in a membrane—with the whole membrane involved, who could tell what exactly was binding to the Xa? Then Lentz asked a postdoc, Vishwanath Koppaka, now an assistant professor at the University of Pennsylvania, to work with a special soluble form of PS that has a very short, greasy tail. Koppaka found that the soluble PS would bind to Factor Xa, same as normal PS. And using fluorescence, the researchers were able to characterize the binding site. "People have thought that it was just the membrane that was important, that there wasn’t a specific interaction between the phosphatidylserine and Xa," Lentz says. "But we’ve shown that there is."

entz’s lab has since shown that another molecule, factor Va, also has binding sites for PS. Lentz now thinks that PS is a message molecule that signals clot formation at a wound, which may make it a target molecule for drug design.

Even once Lentz gets his papers published, this may not be a popular idea. "I am sure Barry is right," says Mac Monroe, assistant professor of medicine. "But for a while it may be hard for him." Since it’s been a "given" that all lipid actions occur as part of a membrane structure, the tendency may be to think that "anyone who thinks the water-soluble part of lipid has activity independent of its membrane association is ‘crazy,’" Monroe says. "But Barry is ‘crazy,’ and he is right."

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