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David Baulcombe shares Gruber Genetics prize

Baulcombe, Ambros, and Ruvkun Share $500,000 Gruber Genetics Prize for Pioneering Discoveries of microRNAs and small interfering RNAs, and their Key Role in Gene Expression

The 2014 Gruber Genetics Prize will be awarded to David Baulcombe, PhD, professor of botany at the University of Cambridge; Victor Ambros, PhD, professor of molecular medicine at the University of Massachusetts Medical School; and Gary Ruvkun, PhD., professor of genetics at Massachusetts General Hospital and Harvard Medical School. These three distinguished scientists are being recognized with this prestigious international prize for their pioneering discoveries of the existence and function of microRNAs and small interfering RNAs, molecules that are now known to play a critical role in gene expression.

The award will be presented to the recipients in San Diego, CA on Oct. 19 at the annual meeting of the American Society of Human Genetics.

“The discoveries of these three pioneering scientists have opened major new areas in chemistry, biology, agriculture and medicine and have revealed fundamental mechanisms that are shared among organisms as diverse as plants and animals, including humans,” said Robert Horvitz, Gruber and Nobel Prize laureate, and David H. Koch Professor at MIT.

The road to the discovery of microRNAs and their function began in the 1980s, when Ambros and Ruvkun were postdoctoral fellows in the lab of (future Gruber and Nobel laureate) H. Robert Horvitz, PhD, at the Massachusetts Institutes of Technology (MIT), studying the lin-4 and lin-14 genes that regulate developmental timing in the nematode Caenorhabditis elegans. Mutation of lin-4 kept the worm’s larvae from developing into fully formed animals, while mutations in another gene, lin-14, caused the larvae to mature prematurely. Ambros and Ruvkun collaborated on the isolation of the lin-14 gene.

In 1989, Ambros, in his own lab at Harvard, established that lin-4 acts as a repressor of lin-14 activity, although the molecular mechanism for that repression awaited further investigation. In 1991, Ruvkun and his colleagues in his Harvard lab established that genetic anomalies in lin-14’s sequence—specifically in an area of the gene called the 3' untranslated region (3' UTR)—were associated with excess production of the lin-14 protein produced from the messenger RNA that lin-4 targets. A year later, Ambros and his colleagues successfully isolated and cloned lin-4. To his surprise, Ambros also found that the gene’s product was not a standard regulatory protein, but a tiny non-protein-coding strand of RNA about 22 nucleotides long that is conserved in other nematode species, showing a selection on its RNA sequence. Around the same time, Ruvkun demonstrated that particular elements of the lin-14 3' UTR are conserved in other nematodes, suggesting evolutionary selection on their function. Working together, Ambros and Ruvkun compared the lin-4 and lin-14 sequences and discovered that the 22-nucleotide lin-4 RNA and the 3' UTR were partially complementary and that the short regions of complementarity were highly conserved in evolutionary comparisons to other nematode lin-4 and lin-14 genes. They hypothesized that lin-4 RNA regulated lin-14 by binding to its 3' UTR sequences. Ruvkun then showed that the repression mediated by lin-4 was via control of the translation of the lin-14 mRNA into protein.

The two scientists published back-to-back studies in Cell in 1993 that described these remarkable findings. But the broader importance of the findings—the idea that the small RNAs (later dubbed microRNAs) might play a role in gene expression beyond C. elegans—was not immediately clear. Then, in 1999, British plant biologist David Baulcombe reported on his own groundbreaking discovery that a similar class of RNAs is involved in a related silencing process affecting viruses, transposable elements and gene expression in plants. This was followed the next year by Ruvkun’s twin discoveries that he had found a second microRNA—let-7—in C. elegans and that let-7 was evolutionarily conserved across the animal kingdom, including in humans. The results showed that the activity of microRNAs was not just restricted to a single species of worm.

In the ensuing years, the study of these and other related classes of small RNAs has exploded into an exciting new field of research. Scientists have linked the gene-silencing abilities of these tiny molecules to a diverse range of important developmental and physiological process in both plants and animals.

“At one time, these small RNAs were considered just an unimportant scientific oddity,” says Huda Zoghbi, chair of the Selection Advisory Board to the Prize. “But thanks to the exciting work of Victor Ambros, Gary Ruvkun, and David Baulcombe, we now know that they are anything but unimportant, both to human health and to the health of the planet.”

In addition to the cash award, each recipient will receive a gold laureate pin and a citation that reads:
The Gruber Foundation proudly presents the 2014 Genetics Prize to Victor Ambros, David Baulcombe, and Gary Ruvkun for the discovery of small non-coding RNAs and for the demonstration of their central roles in the regulation of development and gene expression.

This research, which combined elegant genetics and molecular biology, demonstrated that a previously unknown class of RNAs (called microRNAs and small interfering RNAs) affected post transcriptional gene activity in nematodes and vertebrates (Ambros and Ruvkun) and in plants (Baulcombe). Their seminal findings led to an explosion in research that greatly increased our understanding of the control of such diverse processes as cell differentiation, developmental timing, cellular metabolism, cell death, and pathologies such as viral infection and cancer.