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Victor Ambros named co-recipient of 2014 Gruber Genetics Prize
Date:6/17/2014

WORCESTER, MA Victor R. Ambros, PhD, professor of molecular medicine at the University of Massachusetts Medical School, has been awarded the 2014 Gruber Genetics Prize, along with long time collaborator Gary Ruvkun, PhD, professor of genetics at Massachusetts General Hospital and Harvard Medical School, and David Baulcombe, PhD, professor of botany at the University of Cambridge. Dr. Ambros, the Silverman Chair in Natural Sciences and co-director of the RNA Therapeutics Institute, and his scientific colleagues, received the 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 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 H. Robert Horvitz, PhD, Gruber and Nobel Prize laureate, and David H. Koch Professor at the Massachusetts Institute of Technology (MIT).

Established in 2001, the Gruber Genetics Prize is awarded for fundamental insights in the field of genetics and may include original discoveries in genetic function, regulation, transmission and variation, as well as in genomic organization. The prize, which is awarded along with a gold medal and an unrestricted $500,000 cash award, will be presented to the recipients in San Diego on Oct. 19 at the annual meeting of the American Society of Human Genetics.

The unlikely discovery of microRNAs, also known as miRNA, and their function dates back to the 1980s when Ambros and Dr. Ruvkun were both postdoctoral fellows in the lab of Dr. Horvitz at MIT, studying how the lin-4 and lin-14 genes regulate developmental timing in the nematode C. elegans. Ambros and Ruvkun wanted to understand how mutations of the lin-4 kept the worm's larvae from developing into fully formed animals, while mutations in the lin-14 gene caused the larvae to mature prematurely.

In 1989 Ambros established that lin-4 acts as a repressor of lin-14 activity. How lin-4 achieved this repression, however, was not known. In 1991, it was Ruvkun who established that genetic anomalies in lin-14's sequencespecifically 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 successfully isolated and cloned lin-4. To his surprise, Ambros found that the gene's product was not a standard regulatory protein as he had expected, but a tiny non-protein-coding strand of RNA about 22 nucleotides long that is conserved in other nematode species.

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 complementary regions 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 lin-4 controlled the translation of the lin-14 mRNA into protein and it was through this channel that lin-4 achieved repression of lin-14.

Ambros and Ruvkun published back-to-back studies in Cell in 1993 that described these remarkable findings. The discovery, however, seemed more an oddity than a breakthrough at the time, in part because the lin-4 gene existed only in the worm.

The broader importance of the findingsthe idea that miRNAs might play a role in gene expression in other organismswas not immediately clear. Then, in 1999, Dr. Baulcombe, a British plant biologist, 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 microRNAlet-7in 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.

Since this discovery, researchers have identified almost 2,000 unique human miRNAs that are responsible for regulating more than half of all human genes. 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 processes in both plants and animals. miRNAs have now been implicated in a wide range of both normal and pathological activities including embryonic development, blood-cell specialization, muscle function, heart disease and viral infections.

"At one time, these small RNAs were considered just an unimportant scientific oddity," says Huda Y. Zoghbi, MD, professor of molecular and human genetics at Baylor University and chair of the selection advisory board to the Gruber 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."

Ambros completed his undergraduate and graduate degrees, as well as his postdoctoral research, at MIT. After completing his postdoctoral fellowship, Ambros joined the faculty at Harvard in 1984 and remained there until 1992, when he accepted a faculty position at Dartmouth. He arrived at UMass Medical School in 2007. Ambros has maintained a very close collaborative relationship with Ruvkun through the years, though the two have not worked in the same laboratory since the early 1980s.

At UMMS, Ambros continues his research on microRNA function and gene regulation during development, and is focused on understanding the genetic and molecular mechanisms that control cell division, differentiation and morphogenesis in animals.


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Contact: Jim Fessenden
james.fessenden@umassmed.edu
508-856-2000
University of Massachusetts Medical School
Source:Eurekalert

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