An "ingenious" research technique published by a University of Utah researcher should aid research into genetic diseases by helping scientists produce mice with altered genes, scientists say.
The selection technique is described in the latest issue of the British journal Nature by Mario Capecchi, biology professor at the U. and member of the Howard Hughes Medical Institute, with colleagues Suzanne Mansour and Kirk Thomas.The procedure helps scientists select genetically altered cells to transplant into a growing mouse embryo, an initial step in creating the mice, researchers said.
While that can be done relatively simply now for a few genes, the new technique will work with many if not all mouse genes. It thus expands the usefulness of a recently developed strategy for targeting genes for replacement or alteration, the researchers said.
Such a strategy may be used one day to replace defective genes in people, said Capecchi.
The procedure is "ingenious," Brigid Hogan and Karen Lyons of the Vanderbilt University Medical School in Nashville, Tenn., wrote in an accompanying editorial.
In interviews, other scientists said alternative techniques also are under study, and the new procedure may turn out to be preferable for only some experiments.
Genes are the inherited chemical "blueprints" that govern the structure and functioning of cells. They lie along threadlike structures called chromosomes.
Scientists can alter genes or add new ones by inserting genetic material into cells. They have recently learned how to aim the insertions at particular locations on the chromosome.
But their aim is not perfect, leaving them with the problem of determining which cells have taken up the insertion in the right place, and which are carrying it somewhere else. Researchers want to select only the right cells to slip into a mouse embryo.
The key to the new procedure lies in the design of the stretch of genetic material to be inserted. Researchers add two genes to help in the later selection process.
One gene makes a cell resist a toxic drug called G418. The other gene, which makes a cell vulnerable to the drug gancyclovir, is added in such a way that it will be deleted if the inserted genetic material ends up in the correct place on the chromosome.
The selection process begins after researchers insert the genetic material into thousands of cells. The cells are exposed first to the drug G418, and then gancyclovir.
Only cells that have taken up the genetic material somewhere in their chromosomes will survive exposure to G418. And only cells that took it up in the right place will live after being exposed to gancyclovir, because only they will have removed the vulnerability gene.
In one experiment, only about one in every 2,000 cells that took up the inserted material had it in the right place. But 19 of 24 cells that survived the selection procedure had it in the right place, nearly a 2,000-fold improvement in the concentration of useful cells.
Alternatives to Capecchi's technique are under study, and the choice of which to use in research will probably depend on what a scientist seeks to accomplish, said Alexandra Joyner of the Mount Sinai Hospital Research Institute in Toronto and Raju Kucherlapati of the University of Illinois in Chicago.
Capecchi's method may be best for disabling genes, and a different method may be preferred for making tiny alterations, Joyner said.