Gary Ruvkun

Gary Bruce Ruvkun (born 26 March 1952, Berkeley, California)[1] is an American molecular biologist at Massachusetts General Hospital and professor of genetics at Harvard Medical School in Boston.[2] 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.[3]

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.[4][5] 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.[6] In the same issue of Cell, Victor Ambros described the regulatory product of lin-4 as a small RNA[7] These papers revealed a new world of RNA regulation at an unprecedented small size scale, and the mechanism of that regulation.[8][9] 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.[10]

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.[11][12] 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.[13] 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,[14] 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.[15] Ruvkun's lab in 2003 identified many more miRNAs,[16][17] identified miRNAs from mammalian neurons,[18] and in 2007 discovered many new protein-cofactors for miRNA function.[19][20][21]

C. elegans metabolism and longevity

Ruvkun's laboratory has also discovered that an insulin-like signaling pathway controls C. elegans metabolism and longevity. Klass [22] Johnson [23] and Kenyon [24] 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.[25] 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.

Search for divergent microbes

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.

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.[26]

Search for extra-terrestrial life

In 2019, Ruvkun, together with Chris Carr, Mike Finney and Maria Zuber,[27] 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.[28]

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[29] and to the discovery of microRNAs.[30] He is a recipient of the Lasker Award for Basic Medical Research,[31] the Gairdner Foundation International Award, and the Benjamin Franklin Medal in Life Science.[32] Ruvkun was elected as a member of the National Academy of Sciences in 2008.

Awards

References
  1. Who's Who in America 66th edition. Vol 2: M–Z. Marquis Who's Who, Berkeley Heights 2011, p. 3862
  2. Nair, P. (2011). "Profile of Gary Ruvkun". Proceedings of the National Academy of Sciences. 108 (37): 15043–5. Bibcode:2011PNAS..10815043N. doi:10.1073/pnas.1111960108. PMC 3174634. PMID 21844349.
  3. Harvard Medical School faculty page
  4. Arasu, P.; Wightman, B.; Ruvkun, G. (1991). "Temporal regulation of lin-14 by the antagonistic action of two other heterochronic genes, lin-4 and lin-28". Genes & Development. 5 (10): 1825–1833. doi:10.1101/gad.5.10.1825. PMID 1916265.
  5. Wightman, B.; Bürglin, T. R.; Gatto, J.; Arasu, P.; Ruvkun, G. (1991). "Negative regulatory sequences in the lin-14 3'-untranslated region are necessary to generate a temporal switch during Caenorhabditis elegans development". Genes & Development. 5 (10): 1813–1824. doi:10.1101/gad.5.10.1813. PMID 1916264.
  6. Wightman, B.; Ha, I.; Ruvkun, G. (1993). "Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. Elegans". Cell. 75 (5): 855–862. doi:10.1016/0092-8674(93)90530-4. PMID 8252622.
  7. Lee, R. C.; Feinbaum, R. L.; Ambros, V. (1993). "The C. Elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14". Cell. 75 (5): 843–854. doi:10.1016/0092-8674(93)90529-Y. PMID 8252621.
  8. Ruvkun, G; Wightman, B; Bürglin, T; Arasu, P (1991). "Dominant gain-of-function mutations that lead to misregulation of the C. Elegans heterochronic gene lin-14, and the evolutionary implications of dominant mutations in pattern-formation genes". Development. Supplement. 1: 47–54. PMID 1742500.
  9. Ruvkun, G.; Ambros, V.; Coulson, A.; Waterston, R.; Sulston, J.; Horvitz, H. R. (1989). "Molecular Genetics of the Caenorhabditis Elegans Heterochronic Gene Lin-14". Genetics. 121 (3): 501–516. PMC 1203636. PMID 2565854.
  10. Ruvkun, G.; Wightman, B.; Ha, I. (2004). "The 20 years it took to recognize the importance of tiny RNAs". Cell. 116 (2 Suppl): S93–S96, 2 S96 following S96. doi:10.1016/S0092-8674(04)00034-0. PMID 15055593. S2CID 17490257.
  11. Reinhart, B. J.; Slack, F. J.; Basson, M.; Pasquinelli, A. E.; Bettinger, J. C.; Rougvie, A. E.; Horvitz, H. R.; Ruvkun, G. (2000). "The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans". Nature. 403 (6772): 901–906. Bibcode:2000Natur.403..901R. doi:10.1038/35002607. PMID 10706289. S2CID 4384503.
  12. Slack, F. J.; Basson, M.; Liu, Z.; Ambros, V.; Horvitz, H. R.; Ruvkun, G. (2000). "The lin-41 RBCC gene acts in the C. Elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor". Molecular Cell. 5 (4): 659–669. doi:10.1016/S1097-2765(00)80245-2. PMID 10882102.
  13. Pasquinelli, A. E.; Reinhart, B. J.; Slack, F.; Martindale, M. Q.; Kuroda, M. I.; Maller, B.; Hayward, D. C.; Ball, E. E.; Degnan, B.; Müller, B.; Spring, P.; Srinivasan, J. R.; Fishman, A.; Finnerty, M.; Corbo, J.; Levine, J.; Leahy, M.; Davidson, P.; Ruvkun, E. (2000). "Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA". Nature. 408 (6808): 86–89. Bibcode:2000Natur.408...86P. doi:10.1038/35040556. PMID 11081512. S2CID 4401732.
  14. Hamilton, A. J.; Baulcombe, D. C. (1999). "A species of small antisense RNA in posttranscriptional gene silencing in plants". Science. 286 (5441): 950–952. doi:10.1126/science.286.5441.950. PMID 10542148.
  15. Grishok, A.; Pasquinelli, A. E.; Conte, D.; Li, N.; Parrish, S.; Ha, I.; Baillie, D. L.; Fire, A.; Ruvkun, G.; Mello, C. C. (2001). "Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. Elegans developmental timing". Cell. 106 (1): 23–34. doi:10.1016/S0092-8674(01)00431-7. PMID 11461699. S2CID 6649604.
  16. Grad, Y.; Aach, J.; Hayes, G. D.; Reinhart, B. J.; Church, G. M.; Ruvkun, G.; Kim, J. (2003). "Computational and experimental identification of C. Elegans microRNAs". Molecular Cell. 11 (5): 1253–1263. doi:10.1016/S1097-2765(03)00153-9. PMID 12769849.
  17. Parry, D.; Xu, J.; Ruvkun, G. (2007). "A whole-genome RNAi Screen for C. Elegans miRNA pathway genes". Current Biology. 17 (23): 2013–2022. doi:10.1016/j.cub.2007.10.058. PMC 2211719. PMID 18023351.
  18. Kim, J.; Krichevsky, A.; Grad, Y.; Hayes, G.; Kosik, K.; Church, G.; Ruvkun, G. (2004). "Identification of many microRNAs that copurify with polyribosomes in mammalian neurons". Proceedings of the National Academy of Sciences of the United States of America. 101 (1): 360–365. Bibcode:2003PNAS..101..360K. doi:10.1073/pnas.2333854100. PMC 314190. PMID 14691248.
  19. Hayes, G.; Frand, A.; Ruvkun, G. (2006). "The mir-84 and let-7 paralogous microRNA genes of Caenorhabditis elegans direct the cessation of molting via the conserved nuclear hormone receptors NHR-23 and NHR-25". Development. 133 (23): 4631–4641. doi:10.1242/dev.02655. PMID 17065234.
  20. Hayes, G.; Ruvkun, G. (2006). "Misexpression of the Caenorhabditis elegans miRNA let-7 is sufficient to drive developmental programs". Cold Spring Harbor Symposia on Quantitative Biology. 71: 21–27. doi:10.1101/sqb.2006.71.018. PMID 17381276.
  21. Pierce, M.; Weston, M.; Fritzsch, B.; Gabel, H.; Ruvkun, G.; Soukup, G. (2008). "MicroRNA-183 family conservation and ciliated neurosensory organ expression". Evolution & Development. 10 (1): 106–113. doi:10.1111/j.1525-142X.2007.00217.x. PMC 2637451. PMID 18184361.
  22. Klass, M.; Hirsh, D. (1976). "Non-ageing developmental variant of Caenorhabditis elegans". Nature. 260 (5551): 523–525. Bibcode:1976Natur.260..523K. doi:10.1038/260523a0. PMID 1264206. S2CID 4212418.
  23. Friedman, D. B.; Johnson, T. E. (1988). "A Mutation in the Age-1 Gene in Caenorhabditis Elegans Lengthens Life and Reduces Hermaphrodite Fertility". Genetics. 118 (1): 75–86. doi:10.1093/genetics/118.1.75. PMC 1203268. PMID 8608934.
  24. Kenyon, C.; Chang, J.; Gensch, E.; Rudner, A.; Tabtiang, R. (1993). "A C. Elegans mutant that lives twice as long as wild type". Nature. 366 (6454): 461–464. Bibcode:1993Natur.366..461K. doi:10.1038/366461a0. PMID 8247153. S2CID 4332206.
  25. Kenyon, C. J. (2010). "The genetics of ageing". Nature. 464 (7288): 504–512. Bibcode:2010Natur.464..504K. doi:10.1038/nature08980. PMID 20336132. S2CID 2781311.
  26. Melo, Justine A.; Ruvkun, Gary (2012-04-13). "Inactivation of conserved C. elegans genes engages pathogen- and xenobiotic-associated defenses". Cell. 149 (2): 452–466. doi:10.1016/j.cell.2012.02.050. ISSN 1097-4172. PMC 3613046. PMID 22500807.
  27. Ruvkun, Gary (April 17, 2019). "YouTube Video (24:32) - Breakthrough Discuss 2019 - What is True for E. coli on Earth Will Be True for Life on Proxima Centauri b". University of Berkeley. Retrieved July 9, 2019.
  28. Chotiner, Isaac (July 8, 2019). "What If Life Did Not Originate on Earth?". The New Yorker. ISSN 0028-792X. Retrieved July 9, 2019.
  29. "Dan David Prize 10th Anniversary 2011 Laureates Announced: The Coen Brothers - for Cinema; Marcus Feldman - for Evolution; Cynthia Kenyon and Gary Ruvkun - for Ageing". www.newswire.ca. Retrieved 2018-04-25.
  30. "Gary Ruvkun" Archived 2008-05-12 at the Wayback Machine – The Gairdner Foundation (Retrieved on May 25, 2008)
  31. "Gary Ruvkun" Archived 2010-07-16 at the Wayback Machine– The Lasker Foundation (Retrieved on September 15, 2008)
  32. Franklin Award Archived 2008-05-15 at the Wayback Machine
  33. "Victor Ambros awarded 2016 March of Dimes prize for co-discovery of MicroRNAs". University of Massachusetts Medical School. 2016-05-03. Retrieved 9 September 2016.
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