RNAi specificity: how big of an issue is it?

In 1998, Craig Mello, Andrew Fire and co-workers discovered that long double-stranded RNAs (dsRNAs) injected into the nematode Caenorhabditis elegans could stimulate the destruction of homologous mRNAs [1]. This phenomenon was termed RNA interference (RNAi), and was quickly utilized as a tool for gene functional analysis in C. elegans. It was tempting, though impossible at that time, to use RNAi in mammals. Indeed, in mammalian cells long dsRNA stimulates strong sequence-independent defense response (often referred to as ‘interferon’ or ‘stress’ response), which results in cell death through apoptosis. In 2001, Thomas Tuschl and co-workers demonstrated that if short RNA duplexes, resulting from natural intracellular cleavage of long dsRNA and called small interfering RNAs (siRNAs), are used, strong RNA interference can be achieved without stimulation of cell death [2]. This finding opened the doors for RNAi applications in mammals.