A colony of transgenic mice may help scientists track cells from differentiated states to pluripotent ones. In 2006, researchers discovered that inserting a handful of genes is all it takes to shift a specialized cell back to the embryonic stem cell state of pluripotency. This has launched a race among researchers to dissect the mechanism of such reprogramming without the extra genes, largely because doing so might mean uncovering reprogramming techniques that have more clinical applications. Now Rudolf Jaenisch and colleagues at the Massachusetts Institute of Technology in Cambridge have created a tool that will help researchers move more quickly.

Finding out what happens as a cell reprograms is tough, because reprogramming happens rarely and is largely a matter of chance. The standard technique requires using viruses to insert multiple copies of four genes in random places across the genome. Thus, not only is reprogramming a rare event, but also every occurrence creates a genetically unique population of cells. The rarity and variability make it harder to figure out what exactly is happening.

Jaenisch and colleagues had previously made 'reprogramming-ready' mice. When reprogramming cells, they used versions of genes that could be induced with a small molecule. They mixed reprogrammed cells with normal mouse embryos, implanted them in surrogate mothers and used these to create mice that had all the necessary copies of the four genes. This system helped researchers evaluate what kinds of cells are easiest to reprogram as well as how long the genes needed to be active, but it did not allow them to probe single genes at a time.

Now the scientists have overcome this barrier by creating mice and cells that carry all possible combinations of two or three of the four necessary reprogramming genes. This created cells that were reprogrammed only when the missing gene or genes were added. Currently, the researchers are working to create mice that consistently produce offspring for every transgene combination, and these mice will be deposited with Jackson Laboratory in Bar Harbor, Maine. Besides helping researchers study reprogramming mechanisms, these cells will also allow researchers to use genetically homogenous cells to screen for small molecules or other factors that might replace the reprogramming genes.

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