Laboratories across the globe are in a reprogramming race. In last year's race, three labs tied last June to show that cultured mouse skin cells could be returned to a state so flexible that they could contribute to all cell types. In December, two labs tied to show that human cells could be reprogrammed. All of the laboratories, however, used retroviruses to insert a suite of pluripotency genes into the cultured cells. These randomly inserted genes result in cells that are both less predictable and more prone tumours, making them unacceptable for cell therapy. Therefore, a new race is on to reprogram cells without permanently modifying their chromosomes.

In the latest lap of the latest race, researchers led by Hans Schöler of the Max Planck Institute for Molecular Biomedicine in Münster, Germany show that a tissue-specific stem cell can be reprogrammed using just two of the standard four genes.

The four genes typically inserted for reprogramming are c-Myc, Sox2, Klf4, and Oct4. Instead of cultured skin cells, Schöler's team worked with cultured mouse adult neural stem cells, which naturally express genes for c-Myc and Sox2 at levels at least as high as mouse embryonic stem cells. Following previous techniques, they used genetically modified cells that would become green when cells' own copies of Oct4 became active, a key step in the reprogramming process. They treated these cells with combinations of retroviruses that inserted the genes and found that neural stem cells could be reprogrammed with only two genes: Oct4 combined with either Klf4 or c-Myc. When mixed with mouse embryos, the reprogrammed cells (called induced pluripotent stem cells) contributed to germ tissue, or the tissue that becomes sperm and eggs.

Interestingly, Schöler recently published another paper with Sheng Ding of the Scripps Research Institute showing that fetal neural stem cells could be reprogrammed without requiring the insertion of the Oct4 gene, though doing so required insertion of the other pluripotency genes plus a small molecule that inhibits an enzyme known as G9a histone methyltransferase that regulates how genes on spooled DNA are expressed.

Human neural stem cells can be cultured, and surely several labs are working to reprogram those cells. However, for these techniques to be used for cell therapy, the source material will need to be something that is more readily biopsied.

Nonetheless, this work demonstrates that researchers have more tools to work with than alternative methods of introducing genes into cells. “It's a very nice demonstration that when selecting the right target population, cell culture alone can get you half way to pluripotency,” says George Daley, who is working on reprogramming cells at Harvard University.

The next lap, reprogramming cells for possible clinical applications, has yet to begin.

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