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The ability to selectively silence genes through a technique called RNA interference (RNAi) has revolutionized biology. When researchers give a cell in the lab a double-stranded RNA copy of a specific gene, the cell will prevent its native copy of that gene from being expressed. Researchers can now study the function of any gene by silencing it with RNAi, and then monitoring how a cell’s operations are impacted. Therapies relying on the technique to combat diseases such as macular degeneration are currently in clinical trials (see “RNAi Therapies in Development”).

RNAi was first observed in petunia plants in 1990 by researchers at the DNA Plant Technology Corporation, in Oakland, California, but at the time they did not know how or why it happened. In 1998, scientists led by Andrew Fire, now professor of pathology and genetics at Stanford Medical School, and Craig Mello, now professor of molecular medicine at the University of Massachusetts Medical School, characterized the mechanism of gene silencing. Their meticulous experiments on worms demonstrated that double-stranded RNA is the key player. “There were a lot of unexplained phenomena that we began to put together as a puzzle that looked like a purely RNA story,” says Fire. The pair won the 2006 Nobel Prize in Physiology or Medicine for their 1998 work on RNAi.

RNAi occurs naturally, says Fire, and is one of cells’ tools for regulating gene expression. The phenomenon appears to play a role in fighting viral infections and also may be involved in the molecular changes that cause cells to become cancerous. Technology Review spoke with Andrew Fire about the potential of RNAi for therapeutics and about his current work on how gene silencing is implicated in diseases such as cancer.

Technology Review: In general terms, how does RNA interference work?

Andrew Fire: The mechanism basically involves recognition and response. When a cell sees double-stranded RNA, its first response is to chop it up into bits, which is understandable given that double-stranded RNA is a characteristic structure when viruses replicate. If the cell sees it, it’s a good idea to chop it up. But the cell goes one step beyond that. Not only does it want to chop the stuff up, but it wants to go and find anything that looks like it, in case it’s missed some RNA that has found its way to being single-stranded (the cell doesn’t have as easy a time recognizing harmful single-stranded RNA). So 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. It’s not only that it chops up a threatening molecule, but it then uses that information to go after things that look like that, to make sure it’s not going to be victimized by a sequence that comes from double-stranded RNA–double-stranded RNA being an indicator to the cell that an RNA molecule is replicating, because that’s when it would go through double-stranded form.

RNAi Therapies in Development
DiseaseStage of developmentCompanyMacular degenerationEntering phase II clinical trials this yearSirna, AcuityRespiratory syncytial virus (Lung Infection)Entering phase II clinical trialsAlnylamViral hepatitisFiling application to begin clinical trialsSirnaParkinson’s diseasePre-clinical researchAlnylam

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Tagged: Biomedicine

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