

Shinya Yamanaka, leader of one of two research groups responsible for turning skin cells into embryonic stem cell equivalents, has duplicated his breakthrough without using a gene that made the new cells cancerous.

The results, published today in Nature Biotechnology, could answer some of the fine-print questions that dogged the original research, hailed last week as a potential peacemaker in the intractable ethical battle over embryonic stem cell research.

Embryonic stem cells, or ESCs, can grow into any other type of cell.

Someday they may be used to regrow organs and treat now-incurable diseases. However, producing individually-matched ESCs involves a process called somatic cell nuclear transfer, in which a cell's nucleus is placed inside an empty human egg. After the egg grows for a week, embryonic stem cells form. Harvesting these destroys the embryo – and that outrages people who consider embryos to be fully human. As a result, ESC research sits in the middle of a bitter, seemingly unresolvable culture war fight.

Less controversial than the embryo-destroying ethical problems, but perhaps just as significant, risky hormone treatments are used to acquire the eggs used in cloning. A limited egg supply also means that only a few people would have access to anticipated ESC therapies.

By inserting four growth-stimulating genes, researchers led by Kyoto

University's Yamanaka and a University of Wisconsin team led by Junying

Yu coaxed skin cells into an essentially embryonic stage. When injected into mice, the cells formed brain, muscle, bone and heart tissue.

Robert Lanza, chief science officer of biotech company Advanced Cell

Technologies, described this as the "Holy Grail" of stem cell research, a feat akin to "turning lead into gold" – useful, personalized, ethically trouble-free stem cells. But there was a catch: the procedure wasn't yet ready for medical applications. After turning into assorted human tissues, the new cells had a nasty tendency to go cancerous.

In today's Nature Biotechnology paper, Yamanaka reports that by scrapping one of the four genes – *c-Myc *– he was still able to produce de-differentiated stem cells, but without causing cancer. Of 36

mice injected with cells created through the four-gene process, six died from tumors after 100 days; of 36 mice injected with cells created through the minus-c-Myc process, not a single one died.

These findings come with multiple caveats. Whether the new cells will be similarly cancer-free in people isn't known, 100 days is a relatively short period of time, and making the cells safe will almost certainly require more than a single tweak. Junying Yu's team didn't use c-Myc to begin with, but did use the other three genes used by Yamanaka – and her cells still became cancerous. When I called Yu to ask about the C-myc findings, she reiterated what she said last week: she wants to find some way of inducing the cellular activity prompted by the genes, but without adding any genes at all.

Caveats aside, though, Yamanaka's findings are still exciting: they could very well prove to be an important step on the path to safe de-differentiated stem cells. They could guide other research, perhaps even Yu's. And for such a significant observation to emerge so soon after the original de-differentiation studies hints at how rapidly this potentially world-altering research is advancing.

Induced pluripotent stem cells without tumours [Nature Biotechnology]

Image: Yamanaka's mice, from Nature Biotechnology.

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