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Scientists make stem cells from skin of mice instead of embryos

Three separate groups of scientists working in Japan and the US have used skin cells from adult mice to make cells that are indistinguishable from embryonic stem cells.

Scientists all over the world are now racing to replicate the remarkably simple method in humans, and if successful it could one day lessen or remove the need to use embryos. The three studies are published in the early online edition of the journal Nature. Embryonic stem cells are cells that can renew themselves indefinitely and can differentiate into any cell of the body.

They have the potential to replace damaged tissue such as that found in degenerative diseases like Parkinson's but their therapeutic use is controversial because of the ethical questions surrounding the destruction of embryos and making human clones. As well as posing ethical difficulties, harvesting stem cells from embryos for therapeutic use would be expensive and difficult.

The genetic material from unfertilized eggs has to be replaced with that from a cell of the patient. After that several stages of division are necessary before the stem cells are ready to be harvested. This latest method bypasses a lot of these difficulties. Last year, a team of scientists from Kyoto University in Japan, led by Shinya Yamanaka, pioneered a method that uses mouse skin fibroblasts instead of eggs. Fibroblasts are a little bit like stem cells in that they synthesize a range of materials that make the „scaffolding” or stroma that connect cells together.

They are the most common cell in connective tissue. Yamanaka and colleagues used retroviruses to insert four transcriptor genes into fibroblast cells harvested from the skin of adult mice. The genes code for a range of transcription factor proteins that control the expression of other genes. Giving the fibroblast cells this power essentially makes them into „master” cells, like embryonic stem cells; they acquire the potential to become any cell. „It's easy. There's no trick, no magic,” said Yamanaka. „Neither eggs nor embryos are necessary. I've never worked with either,” he added.

Other scientists are excited by the ease of the process and have plans to start using it straight away. For example, Alan Trounson of Monash University in Victoria, Australia said he could think of a dozen experiments he could start working on immediately. „It would change the way we see things quite dramatically,” he said. There were problems with the first generation of cells that Yamanaka produced. They were almost but not quite like embryonic stem cells.

They could do things like propagate indefinitely, make colonies and form the characteristic cancerous growths called teratomas, but they couldn't do other things that embryonic stem cells do, like make a chimeric mouse carrying DNA from the embryo and the new cells. Scientists were not happy then with the claim that these cells were truly „pluripotent” with all the potency of embryonic stem cells. The latest research by Yamanaka and colleagues uses a second generation of modified fibroblast cells which do perform like embryonic stem cells. And two other teams, one based at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and another collaboration between the Harvard Stem Cell Institute and the University of California, Los Angeles have also used the same four genes with similar results.

Yamanaka said he was relieved that others had managed to replicate their work, especially after the discovery that Woo Suk Hwang's cloning method was found out to be a fraud. Yamanaka and colleagues improved on their previous method by making it easier to isolate the cells in which the reprogramming had been successful. Before, they had used protein markers that couldn't identify the successful cells, but this time they and the other two groups of scientists, used protein markers Nanog and Oct4, with much better results.

All three teams were able to produce chimeric mice which also produced offspring with the new DNA. The work has been described by other scientists as „unbelievable”, and an accomplishment that is akin to Dolly the sheep. While the method in theory is relatively simple compared to human cloning from eggs, it has not yet been developed for use with human cells. Yamanaka thinks it will probably need more transcription factors than the four they used in the mice.

While the scramble to replicate and build on this method in the laboratory has seized the mind of scientists all over the world, even if proved in humans there remain numerous challenges before it could be used therapeutically. For instance, one of the side effects is that the method could trigger cancer, as it did in some of the chimeric mice. Also, the method uses retroviruses. Research using embryonic stem cells is likely to remain essential and continue for some time to come because of these safety considerations. (