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Settling In. Induced stem cells show up green in an eight-cell embryo (left) and the reproductive region of a chimera (center). The image on the right shows a chimeric mouse fetus.

H. Zhou et al., Cell Stem Cell 2009

Safer Stem Cells?

Working with cell cultures and live mice, scientists have devised what may be a safer recipe for transforming skin or other body cells into embryonic-like stem cells--so-called induced pluripotent stem (iPS) cells. The method eliminates a step used in earlier attempts to derive iPS cells that scientists fear might cause cancer-inducing mutations.

IPS cells have been touted as substitutes for human embryonic stem (ES) cells, which require the controversial destruction of embryos. IPS cells appear to be pluripotent, or able to develop into any type of bodily tissue. That means they may be able to replace ES cells for drug screening, for studying diseases, and perhaps even for cell therapies.

But scientists have yet to produce an efficient and reliable technique for generating these cells that would be safe for use in humans. The original method used viruses to smuggle into body cells the four genes whose transcription factors are needed to turn on pluripotency genes within the cells. But viruses and foreign genes carry risks; they could trigger cancer if the cells were implanted into patients. So scientists have been looking for other ways to turn on the pluripotency genes within the cells.

The field has been moving at breakneck speed. Last month alone, four groups reported advances in techniques for producing iPS cells from human skin cells using methods other than viruses to insert the genes. Some researchers have also devised ways to remove the inserted genes after they have done their job (ScienceNOW, 2 March). But introducing genes is still potentially problematic, as scientists can't be sure their effects won't remain even after their removal.

Now, chemist Sheng Ding of The Scripps Research Institute in San Diego, California, and colleagues have figured out a way to skip genes altogether and insert the necessary transcription factors--proteins that turn on the target genes--directly into fetal mouse cells.

The big challenge was how to get the four proteins needed to reprogram the cell to penetrate the cell membrane. Previous research has shown that attaching a molecular tag of 11 arginine amino acids to a protein allows it to cross cell membranes. So the team fused DNA encoding to tag each of the genes for the reprogramming factors. The genes then expressed tagged proteins that could slip into cells and activate the pluripotency genes.

With experiments in the dish and in live mice, Ding and colleagues showed that the resulting cells are fully pluripotent. For example, when introduced into early-stage mouse embryos, they produced chimeric animals that have body tissues containing two different genomes, the team reports today in the journal Cell Stem Cell. Ding says the method is not as efficient as methods using a viral carrier, but he says the success rate in generating iPS cells is still "much higher" than the approaches that put in genes and then remove them. The team hopes to show that their technique will also work with human cells.

Harvard University molecular biologist Konrad Hochedlinger, who last year reported using a harmless virus to reprogram mouse liver cells into iPS cells (ScienceNOW, 26 September 2008), says the paper is "an important proof of principle; ... using protein is generally better than using DNA, which can always integrate [into host DNA] and cause mutations." However, he cautions that the scientists have yet to show that the technique works on adult mouse as well as human cells.