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Silenced. Special RNA molecules stop the synthesis of proteins from a target gene (top); other genes are unaffected (bottom).

The Silencing of the Genes

One of the best ways to find out what a gene does is to shut it off and see what goes wrong--often an arduous task. Now researchers have developed a new method for silencing specific genes in mammalian cells. Although still in its infancy, the approach, known as RNA interference (RNAi), could speed up genetic research.

Like much of molecular biology, the technique was inspired by nature. A variety of organisms, including plants, fruit flies, the roundworm Caenorhabditis elegans, and likely mammals, seem to enlist RNAi naturally to fight off viruses and restrain the movement of pieces of DNA that can hop around and disrupt a genome (Science, 26 May 2000, p. 1370). In RNAi, double-stranded RNA molecules target a messenger RNA with a corresponding sequence and cause it to be chewed up, thus preventing the messenger RNA from making its protein.

Recently scientists have harnessed this process as a research tool, injecting double-stranded RNA into worm and fly cells to turn off specific genes. But so far, silencing genes using RNAi has not worked well in mammalian cells; although the approach has been successful in mouse embryos, double-stranded RNA shuts down synthesis of all proteins, not just the target gene, in other types of mammalian cells.

Now scientists at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, report in the 24 May issue of Nature that they have finally overcome this barrier. They use specially constructed double-stranded RNA molecules called siRNAs that are much shorter than those used previously. In four cell lines derived from human and monkey, siRNAs substantially lowered the expression of three of four test genes--by as much as 90%. Though the technique won't replace gene knockout strategies, in which an animal is engineered to lack a certain gene entirely, RNAi is faster and easier. Furthermore, genes that are lethal when knocked out in embryos can be analyzed with RNAi in cell culture.

"It's going to totally revolutionize somatic cell genetics in mammals," predicts Phillip Zamore of the University of Massachusetts Medical Center in Worcester. "Instead of devoting 6 months to a year figuring out how to turn off expression [of a mammalian gene], people will be able to go in and in a week turn off the expression of 10 genes."

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