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insight introduction

Revealing the world of RNA interference
Craig C. Mello1,2 & Darryl Conte Jr 2

Howard Hughes Medical Institute and 2Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA (e-mail: craig.mello@umassmed.edu)

The recent discoveries of RNA interference and related RNA silencing pathways have revolutionized ourunderstanding of gene regulation. RNA interference has been used as a research tool to control the expression of specific genes in numerous experimental organisms and has potential as a therapeutic strategy to reduce the expression of problem genes. At the heart of RNA interference lies a remarkable RNA processing mechanism that is now known to underlie many distinct biological phenomena.


heterm ‘RNA world’ was first coined to describe a hypothetical stage in the evolution of life some four billion years ago when RNA may have been the genetic material and catalyst for emerging life on Earth1,2. This original RNA world, if it ever existed on Earth, is long gone. But this Insight deals with a process that reflects an RNA world that is alive and thriving within our cells — RNAsilencing or RNA interference (RNAi). When exposed to foreign genetic material (RNA or DNA), many organisms mount highly specific counter attacks to silence the invading nucleic-acid sequences before these sequences can integrate into the host genome or subvert cellular processes. At the heart of these sequencedirected immunity mechanisms is double-stranded RNA (dsRNA). Interestingly, dsRNA does more thanhelp to defend cells against foreign nucleic acids — it also guides endogenous developmental gene regulation, and can even control the modification of cellular DNA and associated chromatin. In some organisms, RNAi signals are transmitted horizontally between cells and, in certain cases, vertically through the germ line from one generation to the next. The reviews in this Insight show our progressin understanding the mechanisms that underlie RNA-mediated gene regulation in plants and animals, and detail current efforts to harness this mechanism as a research tool and potential therapy. Here we introduce the world of RNAi, and provide a brief overview of this rapidly growing field.

Discovering the trigger
Crucial to understanding a gene-silencing mechanism such as RNAi is knowing howto trigger it. This is important from the theoretical perspective of understanding a remarkable biological response (see review in this issue by Meister and Tuschl, page 343); but it also has obvious practical ramifications for using the silencing mechanism as an experimental tool (see review in this issue by Hannon and Rossi, page 371). The observation by Fire et al.3 that dsRNA is a potenttrigger for RNAi in the nematode Caenorhabditis elegans (Fig. 1) was important because it immediately suggested a simple approach for efficient induction of gene silencing in C. elegans and other organisms, and accelerated the discovery of a unifying mechanism that underlies a host of cellular and developmental pathways. However, there were substantial barriers to the acceptance of the idea that dsRNAcould trigger sequence-specific gene silencing. First, at the time, dsRNA was thought to be a nonspecific silencing agent that triggers a general destruction of messenger RNAs and the complete suppression of protein

translation in mammalian cells4,5. Second, dsRNA is energetically stable and inherently incapable of further specific Watson–Crick base pairing. So a model in which dsRNAactivates sequence-specific silencing implies the existence of cellular mechanisms for unwinding the dsRNA and promoting the search for complementary base-pairing partners among the vast pool of cellular nucleic-acid sequences. Hypotheses that require a paradigm shift and depend on the existence of a whole set of hitherto unknown activities are rarely appealing. So why was dsRNA proposed as a trigger...