The early 2000s were exciting times, thanks to the relatively recent discovery of RNA interference (RNAi): the ability of double-stranded RNA to trigger gene silencing. By 2010, many components of the RNAi machinery — including Dicer and the argonaute proteins — had been identified and shown to be highly conserved across species. Argonaute proteins, in particular, were found to contain a catalytic centre that could cleave target RNAs that have perfect complementarity to a bound small RNA. In mammals, argonaute-2 (AGO2) retained this conserved domain, and exploitation of the RNAi pathway soon became a popular and effective experimental approach to silence genes. So much so, that it is still in use and is bound to the clinic.

To address this question, the Hannon lab engineered mice with a catalytic inactive Ago2 allele. Homozygous mutants for this mutation died soon after birth with an obvious anaemia, providing the first evidence that catalysis by AGO2 was essential to vertebrates. It turned out that miR-451, a miRNA required for erythrocyte maturation, folds into an unusual hairpin structure that cannot be processed by Dicer. Instead, its biogenesis depends on AGO2-mediated cleavage, explaining the strong anaemia of the mutant mice.