Gary Ruvkun

Gary Bruce Ruvkun (born March 1952, Berkeley, California) is an American molecular biologist at Massachusetts General Hospital and professor of genetics at Harvard Medical School in Boston. Ruvkun discovered the mechanism by which "lin-4", the first microRNA (miRNA) discovered by Victor Ambros, regulates the translation of target messenger RNAs via imperfect base-pairing to those targets, and discovered the second miRNA, "let-7", and that it is conserved across animal phylogeny, including in humans. These miRNA discoveries revealed a new world of RNA regulation at an unprecedented small size scale, and the mechanism of that regulation. Ruvkun also discovered many features of insulin-like signaling in the regulation of aging and metabolism.
He was elected a Member of the American Philosophical Society in 2019.
Education.
Ruvkun obtained his undergraduate degree in 1973 at the University of California, Berkeley. His PhD work was done at Harvard University in the laboratory of Frederick M. Ausubel, where he investigated bacterial nitrogen fixation genes. Ruvkun completed post-doctoral studies with Robert Horvitz at the Massachusetts Institute of Technology (MIT) and Walter Gilbert of Harvard.
Research.
mRNA "lin-4".
Ruvkun's research revealed that the miRNA "lin-4", a 22 nucleotide regulatory RNA discovered in 1992 by Victor Ambros' lab, regulates its target mRNA "lin-14" by forming imperfect RNA duplexes to down-regulate translation. The first indication that the key regulatory element of the "lin-14" gene recognized by the "lin-4" gene product was in the "lin-14" 3’ untranslated region came from the analysis of "lin-14" gain-of-function mutations which showed that they are deletions of conserved elements in the "lin-14" 3’ untranslated region. Deletion of these elements relieves the normal late stage-specific repression of LIN-14 protein production, and "lin-4" is necessary for that repression by the normal "lin-14" 3' untranslated region. In a key breakthrough, the Ambros lab discovered that "lin-4" encodes a very small RNA product, defining the 22 nucleotide miRNAs. When Ambros and Ruvkun compared the sequence of the "lin-4" miRNA and the "lin-14" 3’ untranslated region, they discovered that the "lin-4" RNA base pairs with conserved bulges and loops to the 3’ untranslated region of the "lin-14" target mRNA, and that the "lin-14" gain of function mutations delete these "lin-4" complementary sites to relieve the normal repression of translation by "lin-4". In addition, they showed that the "lin-14" 3' untranslated region could confer this "lin-4"-dependent translational repression on unrelated mRNAs by creating chimeric mRNAs that were "lin-4"-responsive. In 1993, Ruvkun reported in the journal "Cell" on the regulation of "lin-14" by "lin-4". In the same issue of "Cell", Victor Ambros described the regulatory product of "lin-4" as a small RNA These papers revealed a new world of RNA regulation at an unprecedented small size scale, and the mechanism of that regulation. Together, this research is now recognized as the first description of microRNAs and the mechanism by which partially base-paired miRNA::mRNA duplexes inhibit translation.
microRNA, "let-7".
In 2000, the Ruvkun lab reported the identification of second C. elegans microRNA, "let-7", which like the first microRNA regulates translation of the target gene, in this case "lin-41", via imperfect base pairing to the 3’ untranslated region of that mRNA. This was an indication that miRNA regulation via 3’ UTR complementarity may be a common feature, and that there were likely to be more microRNAs. The generality of microRNA regulation to other animals was established by the Ruvkun lab later in 2000, when they reported that the sequence and regulation of the "let-7" microRNA is conserved across animal phylogeny, including in humans. Presently thousands of miRNAs have been discovered, pointing to a world of gene regulation at this size regime.
miRNAs and siRNAs.
When siRNAs of the same 21-22 nucleotide size as "lin-4" and "let-7" were discovered in 1999 by Hamilton and Baulcombe in plants, the fields of RNAi and miRNAs suddenly converged. It seemed likely that the similarly sized miRNAs and siRNAs would use similar mechanisms. In a collaborative effort, the Mello and Ruvkun labs showed that the first known components of RNA interference and their paralogs, Dicer and the PIWI proteins, are used by both miRNAs and siRNAs. Ruvkun's lab in 2003 identified many more miRNAs, identified miRNAs from mammalian neurons, and in 2007 discovered many new protein-cofactors for miRNA function.
C. elegans metabolism and longevity.
Ruvkun's laboratory has also discovered that an insulin-like signaling pathway controls C. elegans metabolism and longevity. Klass Johnson and Kenyon showed that the developmental arrest program mediated by mutations in "age-1" and "daf-2" increase C. elegans longevity. The Ruvkun lab established that these genes constitute an insulin like receptor and a downstream phosphatidylinositol kinase that couple to the "daf-16" gene product, a highly conserved Forkhead transcription factor. Homologues of these genes have now been implicated in regulation of human aging. These findings are also important for diabetes, since the mammalian orthologs of "daf-16" (referred to as FOXO transcription factors) are also regulated by insulin. The Ruvkun lab has used full genome RNAi libraries to discover a comprehensive set of genes that regulate aging and metabolism. Many of these genes are broadly conserved in animal phylogeny and are likely to reveal the neuroendocrine system that assesses and regulates energy stores and assigns metabolic pathways based on that status.
SETG: The Search for Extraterrestrial Genomes.
Since 2000, the Ruvkun lab in collaboration with Maria Zuber at MIT, Chris Carr (now at Georgia Tech), and Michael Finney (now a San Francisco biotech entrepreneur) has been developing protocols and instruments that can amplify and sequence DNA and RNA to search for life on another planet that is ancestrally related to the Tree of Life on Earth. The Search for Extraterrestrial Genomes, or SETG, project has been developing a small instrument that can determine DNA sequences on Mars (or any other planetary body), and send the information in those DNA sequence files to Earth for comparison to life on Earth.
Innate immune surveillance.
In 2012, Ruvkun made an original contribution to the field of immunology with the publication of a featured paper in the journal "Cell" describing an elegant mechanism for innate immune surveillance in animals that relies on the monitoring of core cellular functions in the host, which are often sabotaged by microbial toxins during the course of infection.
Microbial life beyond the Solar System.
In 2019, Ruvkun, together with Chris Carr, Mike Finney and Maria Zuber, presented the argument that the appearance of sophisticated microbial life on Earth soon after it cooled, and the recent discoveries of Hot Jupiters and disruptive planetary migrations in exoplanet systems favors the spread of DNA-based microbial life across the galaxy. The SETG project is working to have NASA send a DNA sequencer to Mars to search for life there in the hope that evidence will be uncovered that life did not arise originally on Earth, but elsewhere in the universe.
Published articles and recognition.
As of 2018, Ruvkun has published about 150 scientific articles. Ruvkun has received numerous awards for his contributions to medical science, for his contributions to the aging field and to the discovery of microRNAs. He is a recipient of the Lasker Award for Basic Medical Research, the Gairdner Foundation International Award, and the Benjamin Franklin Medal in Life Science. Ruvkun was elected as a member of the National Academy of Sciences in 2008.