MicroRNA research is enjoying an inflationary period of astonishingly rapid progress that began in 2001 after a relatively long gestation. The idea that small RNAs could regulate gene expression by base-pairing to messenger RNAs can be traced back more than 45 years. In a 1961 Journal of Molecular Biology paper, Jacob and Monod proposed an antisense RNA base-pairing model for the lac repressor/operator interaction that they had defined genetically. The lac repressor turned out to be a protein, but the field of antisense RNA mediated gene regulation grew steadily through studies of authentic antisense regulatory RNAs in bacteria. The identification in 1993 of the lin-4 microRNA and its antisense regulation of lin-14 did not trigger a surge of interest in antisense gene regulation in eukaryotes, primarily because lin-4 did not exhibit any evident conservation outside nematodes (although we now know that lin-4 is related to vertebrate mir-125, but is not close enough to be detected by the methods available in the era before the availability of genome sequences). Even the identification in 2000 of let-7, a second microRNA in C. elegans, did not immediately stimulate a sense among biologists that these exceptionally small RNAs could represent a general phenomenon. I must admit that I was among the skeptical majority.

The modern era of microRNA biology began with the finding from the Ruvkun laboratory, reported in a 2000 Nature paper, that the let-7 microRNA has been conserved almost precisely in all its 21 nt for more than 400 million years: since the common ancestor of all bilaterally symmetric animals.