Gary Ruvkun | Gruber Foundation

Gary Ruvkun was born in Berkeley, Calif., in 1952, but grew up in the nearby cities of Oakland and Piedmont. His father was a civil engineer, and his mother was a homemaker who slowly worked her way through college during Ruvkun’s childhood, receiving her undergraduate degree in psychology the same year that Ruvkun graduated from high school. Both parents encouraged their son’s enthusiasm for science—particularly space science—and bought him a telescope and a microscope at a very young age. Ruvkun attended the University of California, Berkeley, where he intended to major in electrical engineering, but quickly switched to physics. “I had a sense that those guys were the real thing, that this was real science,” he says. “It was only 20 years after World War II, and physics was the king of sciences at the moment, especially nuclear physics.” After graduating from UC-Berkeley in 1973 with a degree in biophysics, Ruvkun spent two years “drifting up Highway 1” in a blue-and-white ’69 Dodge van. He eventually landed a job working for a tree-planting cooperative in Oregon. “The idea of dropping out and doing something strange like that was not as weird then as it is today,” he says. Ruvkun then spent about six months travelling throughout South America, until one day, while at a Bolivian-American friendship club, he stumbled across a stack of Scientific American magazines. “Every so often, I would miss science, so I spent a day reading those magazines,” he recalls. “When I was done, I thought, ‘Wow, this is great. I think I’ll go back now.’” Ruvkun worked as a nuclear medicine technician at UC-San Francisco for a year before heading off in 1973 to Harvard University to study molecular biology. He wanted to use the new tools of recombinant DNA technology to better people’s lives, particularly those in developing countries. That goal led him to Harvard plant molecular biologist Fred Ausubel, who was investigating how to genetically engineer nitrogen fixation into plants to improve agricultural productivity. During the next six years, Ausubel and Ruvkun unlocked many of the genetic mysteries of nitrogen fixation — work for which Ruvkun was awarded a prestigious junior fellowship from Harvard’s Society of Fellows. After receiving his PhD in biophysics in 1982, Ruvkun decided to switch his research focus. “At that moment animal developmental biology seemed like the big mystery that people were just starting to solve, and genetics seemed like the way to do it,” he recalls. He did postdoctoral research with biophysicist and Nobel laureate Walter Gilbert at Harvard and biologist (and future Gruber and Nobel laureate) H. Robert Horvitz at the Massachusetts Institute of Technology (MIT). It was in Horvitz’s lab that Ruvkun began studying the genetic pathways that control the developmental timing of the nematode Caenorhabditis elegans. Using molecular cloning techniques, Ruvkun and his then postdoctoral collaborator Victor Ambros identified two key genes involved in that timing: lin-4 and lin-14. Further research revealed that lin-4 negatively regulates lin-14, but the molecular mechanisms behind that activity remained unknown.In 1985, Ruvkun accepted an assistant professorship at Harvard University/Massachusetts General Hospital, where he continued his work on the lin-14 gene. He discovered genetic anomalies in lin-14’s sequence—specifically in an area of the gene known as the 3' untranslated region (3' UTR)—that were associated with excess production of the lin-14 protein produced from the messenger RNA that lin-4 targets. Meanwhile, Ambros, who was now at Dartmouth College, had found that the gene product of lin-4 was not the typical regulatory protein, but a tiny (only about 22 nucleotides long) non-protein-coding strand of RNA. This was the first discovery of what would later be called a microRNA. One evening, Ruvkun and Ambros decided to compare the DNA sequences of the tiny lin-4 RNA and the lin-14 3' untranslated region (3' UTR). They discovered, to their amazement, that some of the sequences matched and that when the lin-4 microRNA binded to its complementary section on 3' UTR, the binding limited the amount of protein that the cell could produce, which, in turn, affected the developmental fate of the worm. In 1993, Ruvkun and Ambros published back-to-back papers in the journal Cell. Ambros described how the regulatory product of lin-4 was a 22-nucleotide-long RNA, and Ruvkun reported on how that RNA was able to suppress the translation of the protein from the lin-14 messenger RNA by binding directly to the mRNA itself. In 2000, Ruvkun reported the discovery of a second microRNA, let-7, that also regulated the larvae-to-adulthood development of C. elegans. He also demonstrated that let-7 was evolutionarily conserved across the animal kingdom, including fruit flies, zebrafish, sea urchins, and humans. This was a seminal discovery, for it meant that the regulatory role of microRNAs was not restricted to C. elegans. Ruvkun’s lab has made other important findings in the field, including the isolation and sequencing of the daf-2 gene, which is involved in the insulin-like signaling pathway that controls C. elegans metabolism and longevity. These pathways are similar to those implicated in human insulin resistance, or type 2 diabetes, and in human aging. Ruvkun’s groundbreaking studies have helped to revolutionize our understanding of gene regulation, and have played a central role in establishing the study of microRNAs as an exciting field of scientific research—one with many implications for human health and disease. “In 1993, the field had only two references, Victor’s and mine. Today, it has almost 22,000 references,” Ruvkun notes. Ruvkun lives in the Boston area with his wife, Natasha Staller, who is a professor of art history at Amherst College, and their daughter, Victoria, who is a junior in high school. He has received many honors and awards, including memberships in the National Academy of Sciences, the American Academy of Arts and Sciences, and the Institute of Medicine. Throughout his career, he also never lost his boyhood enthusiasm for space science. One of his lab’s long-term projects is to develop robotic tools that can search for life on Mars that is ancestrally related to life on Earth, using DNA or RNA, like life on Earth.