Prior to the discovery of RNA interference (RNAi) in the late 1990s, experiments to control gene expression were done using antisense messenger RNA (mRNA). Antisense mRNAs are single stranded sections of RNA that are complementary to the mRNA that codes for a particular protein. They can temporarily silence the expression of a targeted gene by binding to the coding, otherwise known as sense, RNA and inhibiting its translation. Unexpectedly, insertion of sense mRNA into the cell was also able to suppress protein expression. Despite initial interest, the results of key studies utilizing mRNAs to regulate gene expression were not very promising, and the biotechnology industrys interest in the technique waned.
In 1998, Andrew Fire and Craig Mello published a paper which found that a specific double-stranded RNA (dsRNA) injected into the nematode Caenorhabditis elegans interfered with the expression of a myofilament protein. This gene silencing method was more potent and specific than previous methods using sense or antisense mRNA. The mechanism for this was unclear, and researchers wondered whether it would function in other organisms.