With such blunt instruments, researchers have been painstakingly disabling one gene at a time to gather information about what processes its product might be involved in. "There has been no concept of high-throughput gene knockouts in any mammalian system up to now," says David Beach, president of Cambridge, Mass.-based Genetica Inc. But Genetica is introducing that concept to the world of drug discovery with the help of a relatively new technology, RNA interference (RNAi).
First described in worms in 1998,1 RNAi operates in plants, fungi, flies, and mammals. An enzyme complex recognizes double-stranded RNA (dsRNA), and cuts it into roughly 22-nucleotide-long fragments. These fragments, termed siRNAs for "small interfering RNAs," then act as templates for the RNAi-inducing silencing complex to destroy the homologous message, thus specifically suppressing its expression. This form of RNAi is termed "post-transcriptional gene silencing," or PTGS; other forms are also thought to operate at the genomic ...