Gary Ruvkun
Encyclopedia
Gary Ruvkun is an American
molecular biologist
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.
. His PhD work was done at Harvard University
in the laboratory of Fred 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.
' 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 (journal)
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.
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.
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.
Dr. 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. Recently, the Ruvkun lab discovered a deep connection between longevity and small RNA pathways, with the production of germline specific small RNA factors induced in somatic cells in long lived mutant animals.
The Ruvkun lab in collaboration with Maria Zuber at MIT and Michael Finney, George Church, Steve Quake, and Walter Gilbert is also developing protocols and instruments that use PCR primers corresponding to universal sequence elements of the 16S RNA gene to search for divergent microbes. 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. Closer to home, these protocols may reveal microbes that may cause diseases unsuspected to be due to pathogens and microbes from extreme environments.
As of 2010, Ruvkun has published about 130 scientific articles. Ruvkun has received numerous awards for his contributions to medical science, particularly his study 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.
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
molecular biologist
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
and professor of genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
at Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
in Boston
Boston
Boston is the capital of and largest city in Massachusetts, and is one of the oldest cities in the United States. The largest city in New England, Boston is regarded as the unofficial "Capital of New England" for its economic and cultural impact on the entire New England region. The city proper had...
. Ruvkun discovered the mechanism by which lin-4, the first microRNA (miRNA) discovered by Victor Ambros
Victor Ambros
Victor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
, 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.
Education
Ruvkun obtained his undergraduate degree in 1973 at the University of California, BerkeleyUniversity of California, Berkeley
The University of California, Berkeley , is a teaching and research university established in 1868 and located in Berkeley, California, USA...
. His PhD work was done at Harvard University
Harvard University
Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country...
in the laboratory of Fred Ausubel, where he investigated bacterial nitrogen fixation
Nitrogen fixation
Nitrogen fixation is the natural process, either biological or abiotic, by which nitrogen in the atmosphere is converted into ammonia . This process is essential for life because fixed nitrogen is required to biosynthesize the basic building blocks of life, e.g., nucleotides for DNA and RNA and...
genes. Ruvkun completed post-doctoral studies with Robert Horvitz at the Massachusetts Institute of Technology
Massachusetts Institute of Technology
The Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in...
(MIT) and Walter Gilbert
Walter Gilbert
Walter Gilbert is an American physicist, biochemist, molecular biology pioneer, and Nobel laureate.-Biography:Gilbert was born in Boston, Massachusetts, on March 21, 1932...
of Harvard.
Research
Ruvkun's research revealed that the miRNA lin-4, a 22 nucleotide regulatory RNA discovered in 1992 by Victor AmbrosVictor Ambros
Victor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
' 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 (journal)
Cell (journal)
Cell is a peer-reviewed scientific journal publishing research papers across a broad range of disciplines within the life sciences. Areas covered include molecular biology, cell biology, systems biology, stem cells, developmental biology, genetics and genomics, proteomics, cancer research,...
on the regulation of lin-14 by lin-4. In the same issue of Cell, Victor Ambros
Victor Ambros
Victor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
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.
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.
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.
Dr. 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. Recently, the Ruvkun lab discovered a deep connection between longevity and small RNA pathways, with the production of germline specific small RNA factors induced in somatic cells in long lived mutant animals.
The Ruvkun lab in collaboration with Maria Zuber at MIT and Michael Finney, George Church, Steve Quake, and Walter Gilbert is also developing protocols and instruments that use PCR primers corresponding to universal sequence elements of the 16S RNA gene to search for divergent microbes. 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. Closer to home, these protocols may reveal microbes that may cause diseases unsuspected to be due to pathogens and microbes from extreme environments.
As of 2010, Ruvkun has published about 130 scientific articles. Ruvkun has received numerous awards for his contributions to medical science, particularly his study of microRNAs. He is a recipient of the Lasker Award
Lasker Award
The Lasker Awards have been awarded annually since 1946 to living persons who have made major contributions to medical science or who have performed public service on behalf of medicine. They are administered by the Lasker Foundation, founded by advertising pioneer Albert Lasker and his wife Mary...
for Basic Medical Research, the Gairdner Foundation International Award
Gairdner Foundation International Award
The Gairdner Foundation International Award is given annually at a special dinner to three to six people for outstanding discoveries or contributions to medical science. Receipt of the Gairdner is traditionally considered a precursor to winning the Nobel Prize in Medicine; as of 2007, 69 Nobel...
, and the Benjamin Franklin Medal in Life Science. Ruvkun was elected as a member of the National Academy of Sciences
United States National Academy of Sciences
The National Academy of Sciences is a corporation in the United States whose members serve pro bono as "advisers to the nation on science, engineering, and medicine." As a national academy, new members of the organization are elected annually by current members, based on their distinguished and...
in 2008.
Awards
- 2005 Lewis S. Rosenstiel Award for Distinguished Work in Medical Research of Brandeis UniversityBrandeis UniversityBrandeis University is an American private research university with a liberal arts focus. It is located in the southwestern corner of Waltham, Massachusetts, nine miles west of Boston. The University has an enrollment of approximately 3,200 undergraduate and 2,100 graduate students. In 2011, it...
(co-recipient (with Craig MelloCraig MelloCraig Cameron Mello is a Portuguese-American biologist and Professor of Molecular Medicine at the University of Massachusetts Medical School in Worcester, Massachusetts. He was awarded the 2006 Nobel Prize for Physiology or Medicine, along with Andrew Z. Fire, for the discovery of RNA interference...
, Andrew FireAndrew FireAndrew Zachary Fire is an American biologist and professor of pathology and of genetics at the Stanford University School of Medicine. He was awarded the 2006 Nobel Prize for Physiology or Medicine, along with Craig C. Mello, for the discovery of RNA interference...
and Victor AmbrosVictor AmbrosVictor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
) - 2007 Warren Triennial Prize, Massachusetts General HospitalMassachusetts General HospitalMassachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...
(co-recipient with Victor AmbrosVictor AmbrosVictor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
) - 2008 Gairdner Foundation International AwardGairdner Foundation International AwardThe Gairdner Foundation International Award is given annually at a special dinner to three to six people for outstanding discoveries or contributions to medical science. Receipt of the Gairdner is traditionally considered a precursor to winning the Nobel Prize in Medicine; as of 2007, 69 Nobel...
(co-recipient (with Victor AmbrosVictor AmbrosVictor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
) - 2008 2008 Benjamin Franklin Medal in Life Science (co-recipient with Victor AmbrosVictor AmbrosVictor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
and David Baulcombe) - 2008 Lasker Foundation Award for Basic Medical Research (co-recipient with Victor AmbrosVictor AmbrosVictor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
and David Baulcombe) - 2008 National Academy of Sciences
- 2009 Louisa Gross Horwitz Prize, Columbia University (co-recipient with Victor AmbrosVictor AmbrosVictor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
) - 2009 American Academy of Arts and Sciences
- 2009 Shaul and Meira Massry Prize (co-recipient with Victor AmbrosVictor AmbrosVictor Ambros is an American developmental biologist who discovered the first known microRNA . He is a professor at the University of Massachusetts Medical School in Worcester, Massachusetts.-Background:...
) - 2009 Institute of Medicine
- 2011 Dan David PrizeDan David PrizeThe Dan David Prize annually awards 3 prizes of $1 million each awarded by the Dan David Foundation and Tel Aviv University to individuals who have made an outstanding contribution in the fields of science, technology, culture or social welfare. There are three prize categories - past, present and...