Yale scientists offer glimpse of cutting edge research

“We are in the midst of one of the great revolutions in the history of medicine,” Richard P. Lifton, M.D., Ph.D., told medical school alumni during the reunion weekend, referring to progress in charting the human genome.

Dr. Lifton, professor of medicine, genetics and molecular biophysics and biochemistry, was one of three faculty researchers who highlighted their work to alumni. Joining him were Carolyn Mazure, Ph.D., professor of psychiatry and director of the Donaghue Women’s Health Investigator Program at Yale; and Eric J. Nestler, M.D., Ph.D., director of the molecular psychiatry program. Dr. Nestler studies genetic and biomedical links to addiction.

Dr. Lifton searches for genetic causes of diseases such as hypertension. Underlying the medical revolution he described are tools that include genetic maps of human chromosomes and the development of complete physical maps of the genome.

“With these tools we can begin to unravel the source of those diseases,” Dr. Lifton said. “Ultimately it gives us some insight to develop new strategies to treat those disorders.” He cited a family in which high blood pressure was identified in 23 members and was subsequently linked to a single gene, one of 10 genes he and members of his team have isolated that regulate blood pressure. After more than five years of exciting progress in this work, his lab is poised to apply the knowledge to more common forms of the disease affecting at least 50 million people in this country alone. “We can offer them specific treatment tailored to the genetic abnormality,” Dr. Lifton said. “This has really accelerated the pace of biomedical research. We can apply those tools coming out of the Human Genome Project to the investigation of disorders such as hypertension.”

Women, noted Dr. Mazure, live about six years longer than men on average but spend more time in the hospital. “We do need to know more about how to keep women healthy,” she said. “We need more data for understanding and treating the disorders which women present.”

Although federal regulations require the inclusion of women in federally-funded research projects, that was not always the case. “The assumption frequently was made that treatment and procedures which were developed for men also worked for women,” said Dr. Mazure. “We now have a growing body of significant data to cause us to revisit those assumptions.”

Dr. Nestler’s laboratory, in a study of gene expression using transgenic mice, has found that turning on certain genes recreates biochemical and behavioral changes characteristic of addiction. Dr. Nestler is trying to understand lasting effects of addiction on the brain. Scientists believe these changes are regulated by gene expression in neurons in areas of the brain known as the mesolimbic dopamine system.

“We can examine an animal,” said Dr. Nestler, “study molecular changes in specific brain regions, demonstrate that those changes are important for the behavior of addiction in our animal models, and then use that information to come up with ways to perturb that system in people.” This information is critical to the understanding of relapse and recurring addictive behavior, and may very likely provide the basis for new treatments for addiction in the next five to 10 years.