Nobel Causes

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The pair published these results along with other observations about RNAi in Nature in 1998. "The insight that double-stranded RNA was the key to the silencing is why they received the [Nobel] prize," Sharp says. Subsequent research by Fire, Mello, Sharp, and others established the molecular workings of RNAi, which is now known to occur in most organisms.

In humans, in other animals, and even in plants, RNA is normally present as single strands. Fire and others in the field believe RNAi probably developed as a defense against viruses. "When a cell sees double-stranded RNA, its first response is to chop it up into bits, which is understandable given that double-stranded [viral] RNA is [often present] when viruses replicate," Fire explains.

"But the cell goes one step beyond that. Not only does it want to chop the stuff up, it wants to go and find anything that looks like it, in case it's missed some RNA. So [a molecule in] the cell takes the bits of RNA that have been chopped up, and it goes searching for things that are similar. If it finds something, it chops that up."

That something could be the cell's own messenger RNA. When its messenger is destroyed, a gene is silenced.

"In theory," says Sharp, RNAi "can silence any gene"--from the genes of an invading virus to the gene that makes the protein thought to cause Parkinson's disease. That makes it therapeutically promising. Sharp and other researchers have founded companies to commercialize RNAi drugs. "If you could get RNA to the target [tissue], you could have some really cool therapeutics," says Fire.

Alnylam, the company Sharp cofounded in Cambridge, MA, is now conducting clinical trials of a drug for the respiratory virus RSV; Acuity Pharmaceuticals of Philadelphia and Sirna Therapeutics of San Francisco are both conducting clinical trials of drugs for macular degeneration.

Fire enjoys watching these ventures--but "only as a cheerleader," he says. He continues to study the molecular workings of gene silencing in his lab's favorite test subject, C. elegans.

RNAi has also proved to be a mechanism that cells normally use to control the activity of their genes. Victor Ambros '75, PhD '79, and Rosalind Lee '76 discovered that RNA plays a key role in controlling animal development; researchers have found many genes that code for double-stranded RNA, and it's now believed that interference by these RNAs is responsible for regulating 30 percent of the human genome.

These days, Fire is focused on establishing ties between gene silencing and human disease. "Lots of genes are silenced in cancer," he says. "That's been known for quite a while." He is currently working with pathologists at Stanford to understand how the disruption of RNA regulatory processes contributes to disease.