Cell Biology, Physiology
Dr. Bennett is also James B. Duke Professor of Cell Biology, Biochemistry, and Neurobiology and vice-chair of the Department of Cell Biology at Duke University Medical Center.
Vann Bennett is interested in how membrane-spanning proteins are localized to cellular sites that optimize their physiological efficiency, with a focus on vertebrate adaptations. He currently explores the cellular mechanisms underlying newly discovered ankyrin-dependent pathways responsible for localization of a variety of membrane transporters and cell adhesion molecules to specialized membrane domains. He also studies the physiological consequences, including human diseases such as cardiac arrhythmia, that result from failure of ankyrin-based membrane organization.
In 1970, Vann Bennett arrived in Baltimore to start medical school at Johns Hopkins. He remembers being shocked that there was no good surfing. He also needed footwear. Having spent most of his childhood in Hawaii (where it was a "point of honor" not to wear shoes) and his college years in California, Bennett didn't have a pair of shoes that would hold up to city sidewalks. "I think one of the first things I did was go to Sears and buy a pair."
He also didn't have a car. Nor did his roommate. "We were outliers. Bicycles were our means of transportation," Bennett remembers.
The son of a physician, Bennett was expected to go to medical school. But lab research called to him. In college, he tried his hand in the physical organic chemistry lab of John Brauman—motivated, perhaps, by a childhood interest in "mixing things together and making bombs … but not in the house." But it seemed to him that more exciting discoveries could be made in biology.
While at Hopkins, Bennett spent a summer in the lab of Pedro Cuatrecasas in the Department of Pharmacology. "Pedro learned protein chemistry from Christian Anfinsen and had been able to measure interactions between insulin and its cell surface receptor. I liked his approach of reducing complex biology to molecular interactions," says Bennett. In the lab, Bennett worked on a cell membrane protein called adenylate cyclase.
"The most exciting thing for me was figuring out how hormones activate receptors on cells. I wanted to know how cholera toxin"—the protein responsible for intractable diarrhea in people infected with cholera—"activated adenylate cyclase. My intuition was that if we could understand that, we could understand something important about how hormones work."
Bennett's enthusiasm for the research was catching. "I talked with my roommate, Peter Agre, about what I was doing, and he was excited about it," Bennett remembers. "He ended up in the lab, too. I think that's where the research bug bit him." Agre went on to discover aquaporins, the channels that move water in and out of cells. In 2003, Agre—then on the HHMI Scientific Advisory Board—shared the Nobel Prize in Chemistry with HHMI investigator Roderick MacKinnon.
Bennett and Agre remain close to this day. They like taking long wilderness trips together, and they still don't bother with a car. In 2005, they paddled the Seal River to the Hudson Bay, and in 2008 they spent three weeks canoeing in northern Alaska.
After earning his degrees at Hopkins, Bennett did a postdoctoral stint at Harvard in Daniel Branton's lab. The group studied red blood cell membranes. Bennett recalls, "As a med student I learned about hemolytic anemias—diseases in which the red cell membranes are fragile. They gave us some incomprehensible explanation for these anemias based on metabolism. It seemed to me there had to be something going on in the membrane."
Bennett also realized that red blood cells would be ideal for studying plasma membranes at a biochemical level, and they could be obtained from humans. He was interested in how a membrane protein called spectrin was attached to the rest of the membrane. At Burroughs Wellcome, he discovered a protein that anchored spectrin to cell membranes. He called it ankyrin. He also found that ankyrin interacted directly with the anion exchanger. This discovery established ankyrin as the first known molecular connection between a membrane transporter and the cytoskeleton.
Then Bennett looked for ankyrin in other cells. "The model at that point was that red cells were highly specialized, but I found early on that ankyrin was present in every cell I looked at," he says.
"Ankyrin organizes specialized membrane domains in many cells in our bodies, ranging from excitable membranes in the heart and nervous system to epithelial cells, photoreceptors in the eye, and striated muscle," he says.
"We have found that ankyrin has properties that do not fit established paradigms. It was like finding a computer in a farmer's field in 1940," he says. "The unusual thing is that ankyrin not only performs an expected 'scaffolding' role in stabilizing membrane proteins, but it also, with its partner spectrin, is actively involved in formation of the same membrane domains."
Bennett and his lab members have linked ankyrin dysfunction to cardiac arrhythmia. Work in progress suggests that ankyrin may also have a role in type 2 diabetes and aging as well as muscular dystrophy. Yet the more Bennett learns about the ankyrin family—and he has been studying it for nearly 30 years—the more, he says, there is to know.