Dr. Israel and Ex-DMS Researcher Explore Body's Timing

November 24, 2009

Add the liver to the list of bodily systems whose biological rhythms current and former researchers from Dartmouth Medical School (DMS) and Norris Cotton Cancer Center are striving to understand.

Collaborating again with Cancer Center director Mark A. Israel, MD, and other former DMS and Cancer Center colleagues, University of Notre Dame biologist Giles Duffield, PhD, has published a paper in the Journal of Biological Chemistry, offering new insights into a gene that plays a key role in adjusting the body's circadian clock and at the same time may modulate its metabolism.

Israel, a professor of pediatrics and genetics, focused with two researchers from his lab on the livers of mice in their work with Duffield. Duffield is a former DMS and Cancer Center instructor who conducted postdoctoral research in the laboratories of DMS geneticists Jay Dunlap, PhD, and Jennifer Loros, PhD.

In a paper that the journal Current Biology published earlier in 2009, Duffield, Israel, and their teams described how they used DNA microarray techniques to identify a crucial gene called the "Inhibitor of DNA-binding 2" (ID2) as rhythmically expressed in various tissues. For that project, the researchers developed "knockout" mice that did not express the ID2 gene, then exposed them to a time-zone change in their cycle of dark and light. While examining the mice for the effect of artificial jet lag or shift-work adjustment, the researchers discovered that "knockout" mice needed one or two days to regain their circadian rhythms, versus four or five days for unaltered mice.

"We have been looking at the role of ID2 in metabolism for a long time," Israel says. "[Duffield] extended that work and he also added the circadian-rhythm timing aspect....Because the genes we study seemed important for their problem, [Dunlap] and Giles started working with us."

In the most recent project, Israel, Duffield, and DMS/Cancer Center research assistants Nathan Watson and Joana Murad used DNA microarray analysis to examine mouse livers at different times across a 24-hour day, comparing gene activity between normal and "knockout" mice. The leaner mutant mice stored smaller quantities of white fat in their abdomens and far less fat droplets in the liver itself.

While the implications of the research appear clear for cardiovascular disease, liver disease, obesity, and diabetes, "the implications of rhythms in cancer medicine are largely unknown," Israel said. "I would say this is of interest because tumors require large amounts of energy to support their rapid growth, and this provides important information about how those needs are likely to be met."