[Science Vol 329, August 20, 2010]
Fans of the rat as a lab animal have watched in frustration as a parade of mice with specific genes deleted became available to researchers over the past 2 decades. While knockout mice have become models for many human diseases and developmental biology, scientists have longed for knockout rats because “the anatomy and physiology of the rat is closer to humans than is the mouse,” says Timothy Aitman, a molecular geneticist at Imperial College London and the Clinical Sciences Centre of the U.K.’s Medical Research Council. Time and again, however, knockout tricks that work in mice failed in rats. That maddening species barrier has now been breached. Last week, a group led by Qi-Long Ying, a stem cell biologist at the University of Southern California in Los Angeles, reported online in Nature about having successfully adapted to the rat the most widely used mouse knockout technique. This complements a different method for deleting rat genes described last year in Science. In addition to having two ways to knock out target genes, other groups have reported advances in techniques to produce transgenic rats as well as random knockouts that could be screened for interesting mutants. “It is an exciting time for rat genetics,” says Aitman. The breakthroughs were a long time coming. The first knockout mice were created in 1989, using homologous recombination of embryonic stem (ES) cells—a technique that netted a trio of researchers the 2007 Nobel Prize in physiology or medicine. It relies on creating a DNA string that can replace or disable a target gene. Inserted into ES cells, the substitute DNA is incorporated into some of the cells as they proliferate. Adding the cells to an early embryo implanted in a surrogate mother results in some pups carrying one copy of the original gene and one copy of the altered genetic material. Selective breeding can deliver mice lacking the target gene. Researchers have used homologous recombination to produce several thousand lines of knockout mice—but they could not apply it to rats because no one could fi nd a way to culture
rat ES cells.