Welcome to the Laboratory of Gary Ruvkun in the Center for Computational and Integrative Biology.

The Ruvkun lab uses C. elegans molecular genetics and genomics to study problems in gene regulation, developmental biology, and physiology. Research in the Ruvkun lab led to the discovery of the first microRNA genes and their mRNA targets by the Ambros and Ruvkun labs, the discoveries that the mechanism of microRNA regulation of target mRNAs is post-transcriptional, 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. Our lab is now using functional genomic and genetic strategies to systematically discover the components of the RNAi and microRNA pathways in C. elegans. We have recently identified many genes that positively or negatively regulate RNAi and microRNA pathways. These genes reveal the trajectory of siRNAs and miRNAs as they target mRNAs, as well as components that may be developed as drug targets to enhance RNAi in mammals.

Over the past decade, the Ruvkun lab has discovered that like mammals, C. elegans uses an insulin signaling pathway to control its metabolism and longevity. Our molecular genetic analysis revealed the many insulin superfamily members, the DAF-2 insulin-like receptor, an IRS like molecule, the AGE-1 PI 3-kinase, AKT-1, AKT-2, and PDK-1 kinases, PTEN/DAF-18 lipid phosphatase, and the DAF-16/Foxo transcription factor, and its many target genes we discovered by comparative genomics. Some of the steps in this pathway, for example, the kinases, were independently discovered by biochemical analysis of mammalian insulin signaling, but other steps, for example that the major output of the pathway is the DAF-16 transcription factor, emerged from our C. elegans genetic analysis of the insulin signaling pathway, and were subsequently shown to apply to mammals. 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.

Our finding 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. We showed that insulin signaling in the nervous system is key to lifespan. Production of free radicals in particular neurons with high insulin signaling may lead to their destruction, which may in turn cause a decline in a hormonal signal to muscles and skin that show the visible signs of aging in worms as well as humans. The regulation of when we die from hormones released by the brain is analogous to the regulation of other life stage events, such as puberty and menopause, by signaling centers from the brain such as the hypothalamus. We are now trying to identify by genetic analysis the longevity hormone produced by the brain, and to establish exactly which neurons produce it to control aging in muscles and skin. We are also using RNAi screens and comparative genomics to reveal the downstream genes regulated by the DAF-16 Foxo factor in the regulation of lifespan.

The molecular genetic dissection of the insulin pathway has also been important for understanding and treating diabetes, a disease of insulin signaling deficits. The insulin signaling field had mainly focused on acute responses of cells to insulin rather than the transcriptional responses. Our finding that the major effector of insulin signaling in C. elegans is a transcription factor conserved in mammals refocused the mammalian insulin signaling field on those transcriptional cascades from the previous focus on glucose transporter responses. The new genes of the insulin pathway that have emerged from these studies represent new targets for diabetes drug development.

Functional genomic analyses using RNAi libraries of every C. elegans gene now allows a systematic study of metabolism and aging. Our 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. Obesity is also a major health problem. 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.

The molting RNAi project seeks to identify components of the pathways that sense nutritional status and body size, and couple that to the neuroendocrine outputs that trigger an execute the molt. Nematodes and insects belong to the same molting clade of animals, the Ecdysozoans, and genes common to insects and nematodes but not conserved in vertebrates have emerged. These genes may reveal ancient and conserved components in the neuroendocrine pathway that assesses growth and metabolic status, as well as genes that trigger the molt; these targets may also allow the development a new generation of insecticides and nematicides with lower toxicity to humans.

We are developing protocols and instruments that use PCR primers corresponding to universal sequence elements of the 16S RNA gene to search for diverse microbes that may cause diseases unsuspected to be due to pathogens and microbes from extreme environments. One long term goal of this project is to send a robotic thermal cycler with these primers to Mars in search of microbial life that is ancestrally related to life on Earth.

Our research falls into four primary areas. Click on a link below for further information about each research area:

miRNA and RNAi Research
Regulation of Metabolism and Lifespan
Functional Genomic Analysis of C. elegans Molting
The Search for Extraterrestrial Genomes