Gary Ruvkun, PhD: MicroRNA, Cancer and Heart Disease
As a child growing up in the Sputnik era, Gary Ruvkun, PhD explored the night skies through the lens of a telescope and, as he learned more astronomy, realized with fascination that the universe has secret layers.
“When you do visible astronomy, you see one set of stars. When you do X-ray as-tronomy, you see a completely distinct set of stars. Yet they’re all part of the galaxy’s clockwork,” says Ruvkun, now the Hans-Hermann Schoene Distinguished Investigator at Massachusetts General Hospital and professor of genetics at Harvard Medical School.
So it is with the galaxy of genetic regulation.
Ruvkun’s discovery of tiny nucleic acids called microRNAs earned him major prizes, including a Lasker Award and a $3 million Breakthrough Prize in Life Sciences last year. MicroRNAs regulate key developmental processes across the animal and plant kingdoms, working behind the scenes to turn genes on and off during the choreographed dance of cell differentiation.
But like the hidden layers of stars, these short genes remained invisible until Ruvkun and Victor Ambros, now a Professor at the University of Massachusetts Medical School, started to look.
“Before microRNAs, nobody ever looked for genes that small, and so molecular biology had missed an entire regulatory sphere. It’s akin to telescopes that look at different wavelengths of light. This unanticipated world of the tiniest genes was all around us, like dark matter.” he says.
Winners of the Breakthrough Prize – established in 2013 by a group of well-known entrepreneurs, including Google’s Sergey Brin and Facebook’s Mark Zuckerberg – are viewed as stars in their own right. The highly competitive prize trains the spot-light on biologists, physicists and mathematicians with the goal of inspiring others to pursue careers in science. Celebrities present the awards during a globally tele-vised ceremony with many elements of Hollywood, but actually from the latest in glamour center of California, Silicon Valley.
But decades before walking the receiving line, Ruvkun’s research on worm devel-opmental biology seemed an unlikely route to the red carpet. But, in 1993, a few years after starting his lab at MGH, Ruvkun and Ambros unveiled the smallest genes known to scientists and their mechanism of action in back to back papers published in the journal Cell.
Outside the more circumscribed fields of worm genetics and of RNA regulation, few scientists paid attention, he recalls. Those who noticed wondered why a worm re-searcher would set up shop at the MGH.
“It was always amusing to people that we studied these teeny tiny genes,” Ruvkun recalls. “This arcane world of developmental timing and worms, so divergent from human diseases. It could be viewed as just a weird quirk.”
Then something changed in 2000. In two papers in Nature, Ruvkun’s team de-scribed how a microRNA called let-7 coordinates biological development in the worm Caenorhabditis elegans and how its 22 nucleotide sequence was perfectly conserved all the way to humans. Since then, more than 45,000 studies have shown the involvement of microRNAs in health and disease, including cancer and heart disease.
Excitement began to simmer as RNA biologists took note of Ruvkun’s work. MicroRNAs, Ruvkun predicted, would be the next big thing. “Our prediction came true,” Ruvkun says. “We discovered a tiny RNA that we found to be conserved in all animals. Then the floodgates blew open and people started pulling out thousands of these tiny RNAs in different organisms.”
These discoveries are only the beginning, Ruvkun says. Researchers hope to reveal these short genes as interpreters of the instruction manual for human development.
“Gary Ruvkun’s discovery of miRNAs has had profound implications in our under-standing of how genes are regulated, thereby creating many new therapeutic opportunities for treating diseases ranging from cancer to heart disease,” says Fred Ausubel, PhD, a professor of genetics at MGH who initially helped recruit Ruvkun to Partners.
Daniel Haber MD, PhD, the Director of the MGH Cancer Center, explains the clinical impact of Ruvkun’s work. “MicroRNAs regulate profoundly important pathways in the cell and they impact a whole range of biological outcomes – most of which have been highly conserved throughout evolution, from roundworms where Gary first found them to humans. Already, there are multiple microRNAs known to affect the growth, survival and metabolic activity of cancer cells, with enormous therapeutic potential,” says Haber.
Reflecting on Ruvkun’s ability to discover a potential therapeutic tool of immense significance, Haber says, “Gary embodies the essence of the brilliant scientist. He is naturally curious about everything around him. He thinks about things in the most creative, out-of-the box way, and sees things that most of us miss. On top of that, he’s one of the most collegial, interactive and engaging faculty members in our en-tire institution.”
Ruvkun’s lab is currently exploring how various microRNAs interact with their mo-lecular targets in the cell to fine-tune gene expression.
“Once the glitter comes off, you still have the pleasure of your day job,” Ruvkun says. “Figuring it all out, step by step.”
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