University of Massachusetts Medical School/ Stanford University School of Medicine

Winners.
Mello (left) and Fire.

Nobel Prize Awarded for RNAi

A pair of Americans won the coveted Nobel Prize in medicine or physiology for 2006 today for their groundbreaking discovery that strands of RNA can selectively silence genes. The finding has revolutionized genetics, offered new insights into cellular behavior, and energized medical research. Craig Mello of the University of Massachusetts (U Mass) Medical School in Worcester, and Andrew Fire of Stanford University in California learned early this morning that the $1.4 million prize was theirs, ending a years-long guessing game in the field of RNA interference (RNAi) about who would win, and when.

Although many had predicted that Fire and Mello would be winners, Fire says he still felt a "certain amount of disbelief" when the call from Sweden woke him at 2:00 in the morning California time. The award for RNAi came years earlier than many expected, and some, including Fire, believe others could have shared the prize. "We looked at this very, very complex jigsaw puzzle and put in a significant piece," he said, but didn't solve the whole puzzle.

That critical piece came in 1998, when the pair, with colleagues, reported in Nature that injecting double-stranded RNA into worms silenced genes with a complementary sequence. That nailed down the mechanism for seemingly disparate and baffling observations others had made in recent years. It also laid the groundwork for RNAi findings that came later, including the machinery's natural role in mammalian cells and ways to artificially manipulate it. Today, it's thought that one type of small RNA molecule, microRNAs, control upwards of a quarter of the human genome.

"It's one of the most well-deserved Nobel prizes ever given," says Phillip Zamore, who works with Mello at U Mass. Reading the Nature paper, Zamore notes, prompted him to leap into the RNAi field at the end of his postdoc 8 years ago. Adds Phillip Sharp of the Massachusetts Institute of Technology in Cambridge, who himself won a Nobel 13 years ago for RNA discoveries and now works with RNAi, "The avalanche was started down the hill by this paper."

Mello and Fire, who at the time was based at the Carnegie Institution of Washington in Baltimore, Maryland, together determined how to harness the power of RNA molecules to control gene expression in worms, proving that double-stranded RNA could explain the odd gene-silencing results that others had observed. Dozens of companies are now seeking to apply RNAi in medicine, for example by thwarting viral replication in hepatitis. Labs around the world routinely generate new cell-based systems and even animal models with RNAi-based gene silencing.

While RNAi researchers praised Mello and Fire's experiments and deemed them a key turning point for the field, some also voiced quiet disappointment that earlier research in plants and worms that first uncovered RNAi machinery went unrecognized. Even Fire admitted that "I feel slightly guilty to be here," given the strides taken by others in the field.

Still, those who did not win were gracious. David Baulcombe at the Sainsbury Laboratory in John Innes Centre in Norwich, U.K., one of those many cited as deserving recognition, called Fire and Mello's work "an immensely significant discovery." And, says Sharp, they needn't give up hope. He's betting another Nobel will be awarded for RNAi work in the future.

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