Ethan Dmitrovsky: Leading by Example

September 1, 2008

Ethan Dmitrovsky is committed to proving himself wrong. That's one of the reasons he's an exceptional scientist.

"The way science is done is you try and disprove observations, until you can't," he says. "Maybe then you have something."

His scientific candor has led him to key discoveries about cancer, and a prestigious award from the American Cancer Society. He attributes his successes to a team effort among members of his research laboratory and medical and scientific experts across numerous disciplines at Dartmouth. Nevertheless, the high level of scientific insight to which he aspires requires strong, even inspirational, leadership.

"I've seen all different kinds of PIs," says Xi Liu, a fourth year doctoral student in Dmitrovsky's lab. Liu has worked with principal investigators whose leadership styles ranged from benign neglect to dictatorial. His description of Dmitrovsky sounds more like a conductor in front of an orchestra-inspiring each person's individual expression while leading everyone in the same symphony.

Mining the Gap

Ethan Dmitrovsky, MD, has never been content to simply accept the status quo. After graduating magna cum laude from Harvard in 1976, he earned his medical degree from Cornell, followed by a residency at New York Hospital-Memorial Sloan-Kettering Cancer Center and a fellowship at the National Cancer Institute. He returned to Sloan-Kettering and directed the Laboratory of Molecular Medicine, before coming to Dartmouth Medical School and Norris Cotton Cancer Center, in 1998, as the chair of the department of pharmacology and toxicology and then co-director with Margaret Karagas, PhD, of the cancer epidemiology and chemoprevention research program. Throughout, he has been both a practicing physician and a laboratory researcher-a demanding balancing act, but one that matches his view that the most important discoveries result from crossing traditional boundaries.

For over 20 years Dmitrovsky has investigated the role of retinoids, natural and synthetic derivatives of Vitamin A, in the treatment and prevention of cancer. Early on, his lab identified the biochemical pathway by which retinoids affect the cell cycle, and he subsequently helped run the first clinical trial in the country that proved retinoic acid could cause complete remission in a rare and deadly cancer, called acute promyelocytic leukemia, by causing leukemic cells to mature and die. It was one of the first examples of a treatment successfully targeting a specific genetic abnormality.

He considers himself fortunate to have been involved in a major scientific discovery at the beginning of his career. "The discovery process is not what you think. It's not the Eureka moment," he explains. It is incremental steps separated by what he calls "the gap," the place where barriers blur and new ideas emerge. "The gap is the place where most discoveries are made," says Dmitrovsky. But it often requires people from disparate disciplines to work cooperatively-and a special brand of leadership to bring them together.

Team Science

When Dmitrovsky came to the Cancer Center he already had his sights set on one of the deadliest malignancies-lung cancer. "There's a pressing societal need for improvements in lung cancer therapy and prevention," he says. "There have been marginal advances over the last thirty to forty years." It pains him that a preventable disease like lung cancer still afflicts about 175,000 people a year, of whom almost 90% will eventually die of it.

His background as an experienced researcher and a practicing oncologist has given him a passionate commitment to getting scientific discoveries out of the laboratory and into the clinic as quickly and safely as possible, a process called translational research. But turning research into clinical applications is not as easy as drawing a straight line from the test tube to the prescription pad. He reasoned that retinoids could be used successfully to treat and even prevent cancer, even though at that time there was little evidence supporting that approach. His insight paid off. A decade of noteworthy research into retinoids and the machinery of cell cycle regulation has resulted in promising treatments and possible prevention mechanisms for lung cancer, both developed at the Norris Cotton Cancer Center.

"We started out doing retinoids research, and now we use the retinoids as tools to uncover how cells function," explains Konstantin Dragnev, MD, a physician and clinical scientist who came with Dmitrovsky from Sloan-Kettering. They have worked together on innovative clinical trials that epitomize what can be accomplished when teams come together in the gap. "In theory these are very simple trials," explains Dragnev. "In reality, it's very complicated. You have to have a very good working relationship with many specialists for these trials to happen quickly, and still it's not easy."

But that's one of the reasons Dmitrovsky moved his research to Norris Cotton Cancer Center. Dartmouth's smaller size and cooperative culture make interdisciplinary "team science" possible. During recent clinical trials, surgeons, pathologists, oncologists, molecular pharmacologists, nurses and others worked together to gather and analyze biopsies from lung cancer patients undergoing new pre-operative chemotherapy regimes-an endeavor that might have been unworkable in a larger and less collaborative environment. Dmitrovsky has also collaborated with Dartmouth pharmacologist Michael Sporn, MD, a pioneer in cancer prevention. In laboratory experiments, they found that some of the same drugs used to treat lung cancer can successfully prevent lung cancer.

A Deep Commitment

For a brief period Dmitrovsky was acting dean of Dartmouth Medical School, until he became eager to return to research. "I had a deep feeling that we were at the middle of a life science revolution, and I wanted to take part in that revolution," he says.

For two decades, Mark Israel, MD, director of Norris Cotton Cancer Center, has been watching Dmitrovsky's research with intense interest - "He's done trail-blazing work in cancer therapy and chemoprevention." The American Cancer Society agrees. They recently presented their most prestigious research award, a Clinical Research Professorship, to Dmitrovsky. The ACS grants only two or three such multi-year funding awards each year. "It allows me to really test whether ideas that I've developed beginning ten years ago have merit," Dmitrovsky says. It's a challenge he relishes.

"He's always enthusiastic," says Sarah Freemantle, PhD. "Even when you're feeling down on a project, even when things don't go right, he's still up about it." She had been at Sloan-Kettering when he invited her to join his team at Dartmouth.

"One of the great rewards, beyond the conduct of successful translational research, is to help spawn the next generation of scientists interested in moving discoveries from the bench to the clinic," says Dmitrovsky, who spends a significant amount of time teaching aspiring researchers how to write papers, speak in pubic, and collaborate-the tools of a successful scientist. The life of a graduate student can be brutal. But Dmitrovsky has a reputation for taking an interest in his students and encouraging their ideas.

"You get your own style from your mentor," says Xi Liu. He hopes to return to China and lead his own lab one day. Dmitrovsky, he says, has taught him the value of collaboration and compassion.

It's not just graduate students who listen to Dmitrovsky's advice. He is on the scientific advisory board of the Lance Armstrong Foundation, the Board of Scientific Counselors of the National Cancer Institute, and Associate Director of the Samuel Waxman Cancer Research Foundation. In 2005 he testified to the President's Cancer Panel, which reports to the President of the United States, on the importance of cancer research. And he is scientific advisor to the president of Dartmouth College.

So far, however, his enthusiasm for the life sciences has not rubbed off on his children. He laughs when he says he still holds out hope for his eight year old. "My kids ask scientific questions all the time and I have no idea what the answers are," laughs Dmitrovsky. "But the most important aspect of doing science at a high level is not answering questions but formulating the right question. Most of us lose that refreshing inquisitiveness of a child, the ability to ask questions without preconceptions. But the best science is answering such questions."