Gary Ruvkun is a professor of genetics at Harvard Medical School. His lab uses C. elegans molecular genetics and genomics to study problems in developmental biology and physiology. Dr. Ruvkun began to work with C. elegans as a postdoc with Bob Horvitz at MIT and Walter Gilbert at Harvard, where he explored the heterochronic genes that control the temporal dimension of development. This work led to the discovery of the first microRNA genes and their mRNA targets by the Ambros and Ruvkun labs, the discoveries by the Ruvkun lab that the mechanism of microRNA regulation of target mRNAs is post-transcriptional and that some microRNA genes are conserved across animal phylogeny, the computational discovery of hundreds of microRNAs by the Ruvkun and Church labs, and the discovery of a common core microRNA and RNAi mechanism by the Ruvkun and Mello labs. Dr. Ruvkun’s lab is now using functional genomic and genetic strategies to systematically discover the components of the RNAi and microRNA pathways in C. elegans.

Over the past decade, Dr. Ruvkun’s lab discovered that like mammals, C. elegans uses an insulin signaling pathway to control its metabolism and longevity. This analysis has revealed striking congruence of molecular mechanisms at many steps in the pathway, suggesting that insulin regulation of longevity and metabolism is ancient and universal. The discovery that an insulin pathway regulates lifespan and metabolism immediately suggested a concordance with studies of mammalian lifespan: it is reminiscent of the increase in mouse and rat lifespan that is induced by low calorie diets, which reduce insulin levels. The Ruvkun lab is now using RNAi screens and comparative genomics to reveal the downstream genes regulated by insulin signaling.

Functional genomic analyses using RNAi libraries of every C. elegans gene now allows a systematic study of metabolism and aging. Dr. Ruvkun's lab has surveyed 18,000 genes for their action in regulation of longevity, fat deposition, RNAi, and molting. This analysis gives a global view of the molecular machines that operate in these pathways. In the case of aging, it is now clear that insulin signaling is the most potent gene inactivation that can increase C. elegans lifespan, but about 100 other gene inactivations cause increases in lifespan. Current research in the Ruvkun lab attempts to weave these lists of aging regulatory genes into pathways that assess and regulate metabolic tempo and mode, repair and regeneration, and protective and degenerative pathways. Other gene inactivations perturb fat deposition without affecting lifespan and vice versa. These gene lists reveal the many steps in energy regulation, including metabolic enzymes that store and mobilize fat, as well as hormonal signals from fat stores to satiety centers in the brain. A neuroendocrinology of energy balance and longevity will emerge from these studies. Because 200 of the 400 C. elegans fat regulatory genes have human orthologs, new targets for the development of anti-obesity drugs may emerge from the C. elegans analysis.