Nobel Causes

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The Gene Silencer: Andrew Fire

Before 1998, identifying the function of a given gene was a laborious process whose success was determined in great part by luck. Researchers found cells or organisms with mutated copies of the gene and inferred from lost functions what the normal gene did. Or they tried to induce mutations in cells in the lab, a hit-or-miss technique that, in human cells, mostly missed. Now, thanks to the discovery of RNA interference (RNAi), biologists can essentially turn off individual genes in the lab. It's akin to flipping a switch to make a few light bulbs in an array of millions change color.

Understanding RNA interference has "radically changed how we do cell biology and understand, or probe, cells," says Phillip Sharp, an Institute Professor at MIT's Center for Cancer Research and a Nobel laureate himself. "We went from a position of not having a general approach to investigating the function of genes to being able to silence a gene to ask what it does. Every journal you look at, one or more or all the articles in it have utilized this technology. It really has been a fundamental advance."

Fire, now a professor of pathology and genetics at the Stanford University School of Medicine, shares the Nobel Prize with Craig Mello, now a professor of molecular medicine at the University of Massachusetts Medical School, for their discovery of the gene-silencing mechanism.

Fire came to MIT as a 19-year-old graduate student, having majored in math at the University of California, Berkeley. While partaking of what he calls Berkeley's "intellectual smorgasbord," he encountered molecular biology and got excited. A decade before Sharp won his Nobel Prize, Fire worked in his lab at MIT. As a student, Fire "did some important early research on the biochemistry of the control of gene expression in human cells," Sharp recalls. "It launched another 15 years of work in my lab and others'."

Before Fire and Mello published their breakthrough paper, RNA was known to have multiple roles, but it was primarily thought of as DNA's go-between, the messenger that translates genes into proteins. Researchers knew, however, that when injected into an organism, RNA could sometimes prevent the production of proteins and silence genes.

But the phenomenon could not be reliably reproduced, so it was unclear what form of RNA was responsible for it. Was it "sense" RNA, which follows the sequence of the messenger RNA that codes for a specific protein? Was it sense RNA's complement, "antisense" RNA? Or was it a double-stranded combination of the two?

Fire and Mello collaborated on a series of rigorous experiments using a nematode worm called C. elegans to determine whether sense, antisense, or double-stranded RNA caused gene silencing. In order to elicit strong visible signals from their test subjects, they worked with a gene that helps maintain normal muscle contractions in C. elegans: if the gene was silenced, the worms would twitch. When the researchers injected the worms with pure sense or pure antisense RNA, nothing happened. But when they injected double-stranded RNA, the worms twitched. Fire and Mello concluded that RNA had to be double stranded to silence the gene.