After years of struggle, scientists have taken a system that helps them study how genes work in bacteria--and inserted it into mice. A test of the newly adapted system produces hair-raising results: The engineered mice change fur color depending on what's in their drinking water.
Researchers often figure out what a gene does by seeing what happens when it doesn't work. In mice, "knocking out" genes is a popular method, but many knockouts kill mouse embryos before they can develop. Alternative methods for turning genes on and off at will have their own limitations.
Taking a trick from bacterial genetics, neurogeneticist Heidi Scrable and colleagues at the University of Virginia in Charlottesville have now adapted a well studied regulatory system to the lab mouse. The system consists of a protein, called the lac repressor, that binds to DNA sequences called lac operators. Once bound to DNA, the lac repressor prevents other proteins from latching on and transcribing the DNA's message into RNA. But if the lac repressor binds to lactose--a common, edible sugar--it falls off and the DNA can be transcribed. The researchers fiddled with many variations of the lac repressor gene until they found one that would work in mice.
The team's proof of principle, described in the 15 June issue of Genes and Development, is dramatic. They constructed an artificial DNA molecule of lac operators joined to the gene for tyrosinase, an enzyme that helps create the pigment melanin. They put the DNA molecule into mice carrying the bacteria-derived lac repressor gene, but lacking their own gene for tyrosinase. The lac repressor prevented the artificially inserted tyrosinase from being expressed, resulting in albino mice. But when the mice drank water containing a chemical similar to lactose, the lac repressor fell off the DNA, the tyrosinase gene was turned on, and the mice turned brown. When mice drank normal water again, the gene shut off and the mice turned white.
"This is a blockbuster," says mouse geneticist Bruce Conklin of the University of California, San Francisco. But Conklin and others caution that it remains to be seen how readily the technique will transfer to other genes besides the test gene. If it does pan out, it is unlikely to completely supplant existing methods, but, says Tim O'Brien of the Jackson Laboratory in Bar Harbor, Maine, "it's good to have options."