Revealing the vascular system

In the late 1980s, William C. Sessa, Ph.D., then a doctoral candidate in pharmacology, read an editorial by Nobel Laureate George E. Palade, M.D., professor, chair, and founder of Yale’s then-named section of cell biology. Palade argued that long-held assumptions about the biology of the endothelium, or inner lining, of blood vessels, had become questionable, and he urged investigators to probe more deeply into the unknowns of the vascular system.

Sessa, now Alfred Gilman Professor of Pharmacology and professor of medicine, took Palade’s words to heart. He wanted to know how particles of LDL (low-density lipoprotein) cholesterol morphed from floating hitchhikers in the bloodstream to permanent lodgers in artery walls, where their effect on health can be profound.

Blood vessels had first caught Sessa’s attention when he was an undergraduate at Philadelphia College of Pharmacy and Sciences. As part of a research lab course, Sessa measured how the brain controls blood pressure, and he came away full of curiosity.

During that era, he says, science characterized the body’s vasculature as a network of passive garden hoses that merely shuttled blood and nutrients throughout the body. Three decades of inquiry have broadened that view.

“Vascular biology in the present world is really how blood vessels control different aspects of organs—particularly the brain, heart, and kidney,” says Sessa, director of the Vascular Biology and Therapeutics Program since 2007. The control, he explains, starts with biochemical changes within endothelial cells that protect blood vessels against potential antagonists, especially lipids.

While completing his doctorate in pharmacology at New York Medical College, Sessa crossed paths with Sir John R. Vane, D.Phil., who had won the 1982 Nobel Prize in physiology or medicine for discovering how aspirin works. “I wrote to him and said I would love to do a postdoc in your lab,” Sessa recalls. Soon the New Jersey native was working under Vane in London, studying the enzymatic pathway through which endothelial cells produce nitric oxide, which relaxes blood vessel walls.

“All endothelial cells make nitric oxide, and we know that with almost every cardiovascular disease, they stop making it to some degree,” Sessa says. During his second postdoctoral fellowship, at the University of Virginia, Sessa cloned the gene for the enzyme that makes nitric oxide. “It was very competitive,” he says. “Within three months, three papers came out from major institutions and I was the lone postdoc working on it.”

When he started his lab at Yale in 1993, Sessa wanted to learn which molecule regulates the gene and enzyme responsible for generating nitric oxide via the endothelial lining of vessels. More recently, based on his initial curiosity provoked by the Palade article, he has worked to identify undiscovered pathways through which LDL can damage blood vessels beyond those on which statins act. In June, Sessa received a $1 million Merit Award from the American Heart Association that will help him pursue that line of inquiry. On Nov. 21, Nature Communications published his first report of progress, in which he described the protein alk1 as a promising target for reducing atherosclerosis, which remains this country’s leading cause of death.

Sessa also took a recent sabbatical, the first in his more than 20 years at Yale. In the fall of 2015, he went to Cambridge, Mass., where Pfizer made him interim director of its global cardiovascular and metabolism unit. The role forced Sessa to think in a new way about pharmaceutical development, involving him in decisions to initiate, augment, or terminate research projects. “It is more complex than you think it is,” Sessa says. “There are so many moving parts and very tight timelines in drug development.”

He will apply lessons he took from industry to CavtheRx, a biotech company he founded in 2014 to develop a drug for the orphan disease uveitis, inflammation of the eye wall. “I’ve sharpened what we need to do to be successful therapeutically,” he says. He also says he has renewed appreciation for the freedom of inquiry he enjoys at his true professional home—his lab at Yale.