Leading Edge Essay RNA Interference: Big Applause for Silencing in Stockholm

If fields of study have birthdays, then RNA interference (RNAi) turned eight on February 19th this year. Even by the standards of 21st century science, RNAi has been precocious. A PubMed search for “RNA interference” retrieves more than 7900 articles, all published after the landmark 1998 Nature paper by Craig Mello at the University of Massachusetts Medical School and Andy Fire, then at the Carnegie Institution and now at Stanford University School of Medicine, that launched the whole field (Fire et al., 1998; see Figure 1). In this paper, Mello, Fire, and their colleagues working in the worm Caenorhabditis elegans provided the first demonstration that RNA interference (RNAi), as the new gene-silencing technique had just been named, is triggered by double-stranded RNA (dsRNA). For this discovery they are honored with this year’s Nobel Prize in Physiology or Medicine. The Fire and Mello discovery proved that RNAi is mechanistically distinct from antisense RNA-based strategies for inhibiting gene expression. More fundamentally, their 1998 paper, often referred to simply as the Fire and Mello paper, suggested that dsRNA—presumed by most biologists either to be inert or, to those studying mammals, to signal the presence of a viral infection—could repress the expression of a single gene. Such a role for RNA harked back to ideas from the 1960s that small pieces of RNA might bind to genes, turning them off, ideas abandoned after the discovery of transcription factors. Defining RNAi, Creating a New Field Rereading the 1998 paper, one is struck by how many of the salient features of RNAi were identified by Fire and Mello: the ability of a few molecules of dsRNA to direct destruction of a much larger amount of the corresponding mRNA, suggesting a catalytic mechanism; the transmission of RNAi across generations; the power of RNAi to bring genetics to any organism whose genome sequence is known; the near universality of RNAi among eukaryotes. Fire and Mello transformed into testable