Never one to be confined by the limits of existing technology, Gregory J. Hannon takes matters into his own hands, creating the tools he and his colleagues need to address important biological questions. Hannon is at the forefront of the field of RNA interference (RNAi), a powerful new tool for gene analysis and discovery. His initial interest in RNAi, he says, grew out of an intense frustration with the toolkit that was available for perturbing gene expression in mammalian cells and animals.
Hannon and his colleagues have harnessed RNAi, a naturally occurring process of gene regulation, to selectively turn off genes in living cells. Hannon uses the technique to study cancer development and to probe the mechanisms that make this method of gene control so effective. He also investigates the potential of small interfering RNAs (siRNAs) for cancer therapy.
Hannon discovered two enzymes at the heart of the RNAi mechanism: Dicer, which chews up large pieces of double-stranded RNA and converts them to the short bits known as siRNAs, and argonaute2 (Slicer), the central enzyme in the second step of RNA silencing—targeted cleavage of messenger RNA by siRNAs.
While RNAi has been a powerful tool in selectively turning off genes in many organisms, there have been challenges to using it in mammalian cells. Mammalian cells respond to double-stranded RNA as if they have been infected by a virus: shutting down all protein synthesis, not just that of the target gene, quickly resulting in death of the cell. Researchers had to modify the technique for use in mammalian cells, so Hannon's laboratory developed strategies for using short hairpin RNAs (shRNAs) to stably silence genes. The technique could greatly simplify gene manipulation and discovery for many biomedical applications.
Using Hannon's approach, researchers can switch off any combination of genes in mouse cells in a targeted or random fashion and then infer the function of a particular gene. By randomly switching off genes, researchers can select cells with interesting properties, such as improved response to cancer treatment, and identify potential targets for new therapies.
To Hannon, developing and disseminating technologies that will spur scientific discovery in diverse fields is as important as using those tools in his own laboratory. With Stephen J. Elledge, HHMI investigator at Harvard Medical School and Brigham and Women's Hospital, Hannon recently produced vast libraries of shRNAs that can be used to turn off individual human and mouse genes to study their function. They are distributing these libraries to academic investigators without restriction.