Hot on the heels of the 2006 Nobel for physiology or medicine for the technology behind RNAi--a procedure for at least partially blocking the translation of a gene into a functional protein--the Nobel Foundation handed out its 2007 prize for the discovery of a procedure for knocking out a specific gene altogether. The University of Utah's Mario Capecchi, Sir Martin Evans of Cardiff University in Wales and Oliver Smithies over at the University of North Carolina in Chapel Hill split the Nobel for their contributions to the designer mouse model-world we now live in. As a journalist (one who writes a lot about genetics, to boot), studies involving knockout mice are ubiquitous, the way box scores are in the sports pages. So the awarding of this prize strikes me as a no-brainer. Oddly enough, it didn't to a a Wired blogger (who, full disclosure, is a friend and former classmate of mine) who stepped into a small world of hurt when he adopted a "What have knockout mice done for me lately?"-sort of attitude. (He's since softened his position.) A press statement from the Nobel Assembly at the Karolinska Institute supports my initial impression:
To date, more than ten thousand mouse genes (approximately half of the genes in the mammalian genome) have been knocked out. Ongoing international efforts will make "knockout mice" for all genes available within the near future.
Thus far, genes have been quieted to study models for everything from cancer to mental retardation. Anyway, I'll try to describe what makes these men deserving of their medals: In the late-70s/early-80s, Capecchi and Smithies concurrently sought a technique to target and replace a specific gene in a cell's genome. They determined that if they inserted a similar (but inactivated) sequence of DNA into a cell, they could trick the cell into incorporating it during homologous recombination. (Homologous recombination occurs naturally when two complimentary strands of DNA cross and swap genetic material to form sex cells, like sperm and eggs.) However, Capecchi and Smithies' insights into gene targeting needed to be paired with a delivery system, which was developed primarily by Evans, who discovered embryonic stem cells. The pluripotent cells were repurposed as the ideal vehicle for these mutated genes: The inactive genes are placed in stem cells, and injected into a blastocyst (clump of cells that become the embryo), which then develops into a mouse with some cells that have the inactive gene and others that do not. When a "mosaic mouse" mates with a normal mouse, some of the offspring will not have the gene at all, while others will. Those lacking, are the "knockout mice." Then you watch the little knockout guys develop and see what's gone awry. The Reuters story on our site (available for limited time) regarding the Nobel announcement has a cherry quote from Capecchi: "If for example, you see a little finger disappear [in the knockout mice], then you know that gene is important for making little fingers." Brilliant. Nobel-worthy. Trust me. More Resources: SciAm senior writer Gary Stix wrote an excellent profile of Capecchi in 1999. It has been freed from behind a paywall for you to download. And Capecchi contributed a piece to the magazine in 1994 about targeted gene replacement. (This one, folks, will require you to shell out some pesos.)