Hot on the heels of last week's announcement that two labs, one in Japan and one in Wisconsin, had transformed human skin cells into cells that act a lot like embryonic stem cells, comes an improvement in one of the methods.
In the afterglow of the breakthroughs came some important notes about both of the groups' techniques, which involved inserting four genes into the cells that coded for transcription factors that in turn activate other genes in the cell: The University of Wisconsin group used fetal and newborn fibroblasts (connective tissue cells that aid wound healing); the University of Kyoto researchers used fibroblasts from a 36-year-old woman and a 69-year-old man. Researchers reported success with the older cells, but, on the down side, noted that they had used a gene, c-Myc, that is known as a protooncogene, because it promotes tumor growth.
Now the Kyoto team, led by biologist Shinya Yamanaka, reports that it can reprogram adult skin cells in both mice and humans into induced pluripotent stem (iPS) cells without c-Myc. Further, in a mouse model, when the cells are incorporated into an embryo, the adult animal faces a dramatically lower risk of developing cancer. But there's a catch: "We found that the omission of [c-Myc] resulted in fewer numbers of iPS cell colonies," Yamanaka told ScientificAmerican.com via e-mail. "The process also takes longer. However, most of resulting iPS cells are very good."
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Robert Lanza, a stem cell biologist and the chief scientific officer at Advanced Cell Technology in Worcester, Mass., says this overcomes a key hurdle in process. This shows that "you can do this without the c-Myc and still succeed with the adult cells," he says.
The Kyoto team's method of transforming the skin cells for both mice and humans involved the same genes, which are randomly inserted into a cell's DNA via a retrovirus vector. Besides c-Myc, researchers also utilized Klf4 and two of the same genes used by the Wisconsin scientists—Oct3/4 and Sox2—which are well-known agents in stem cell research. Yamanaka had recently demonstrated that this cocktail was effective in reprogramming mouse skin cells into iPS cells. It turned out the same recipe could be used for human cells as well.
When the team removed the c-Myc gene, they were still able to create the iPS cells, but the process took weeks longer and yielded 100 times fewer cells. The new method, however, showed its effectiveness in a mouse model involving animals made up of normal and iPS cells. Six of 37 mice that carried iPS cells derived from the four-ingredient cocktail developed tumors within 100 days after they were born. In contrast, none of 26 chimeras made with the three-gene mixture showed any evidence of tumor growth.
Lanza says that problems still remain with both systems. "These cells have [still] been severely modified," he notes, referring to the method by which the genes are inserted into the skin cells. Because the genes can end up anywhere in the cell's DNA, the method itself increases the risk of cancer, even without c-Myc. There is also the matter of Food and Drug Administration (FDA) approval. "I don't think the FDA would allow us to use these virally modified cells," he says.
Members of both of teams say that a new delivery mechanism is necessary to get their transcription factors into skin cells. "It simply would make the reprogrammed cells much safer," says Junying Yu, an assistant scientist at Wisconsin who was instrumental in that institution's research effort.
Possibilities abound, but are extremely hard techniques to work out—small molecules, for instance, could bind to cell receptors and be taken into the membrane, but the right combinations have to be found so that delivery mechanisms do not get too bulky and so that they can properly (and as safely as possible) deliver their payload inside the cell. "We will examine the effect of retroviral integration in the future," Yamanaka adds. "We will also try to replace retroviruses with something else."
