Scientists this week reported major advances toward a central goal of stem cell research: directly reprogramming fetal mouse cells so that they are indistinguishable from embryonic stem (ES) cells. The technique, which they say should also work on adult cells, could one day enable researchers to generate cell lines tailored to individual patients without the use of eggs or embryos.
The advances, reported in two papers in tomorrow's issue of Nature and in another paper in the July issue of Cell Stem Cell, extend a finding made last year by Shinya Yamanaka of Kyoto University in Japan. By inserting various combinations of genes related to pluripotency active in mouse ES cells, the researchers discovered a combination of four genes that, when introduced into cells from mice's tails, conferred ES-like properties upon them (Science, 7 July 2006, p. 27).
The three teams, headed by Yamanaka, the Massachusetts Institute of Technology's Rudolf Jaenisch, and Harvard's Konrad Hochedlinger, all began by following Yamanaka's procedure, using a viral vector to introduce copies of genes for four transcription factors active in ES cells: Oct4, Sox2, c-Myc, and Klf4. Because the reprogramming works for only one in every 1000 cells, the researchers needed to weed out the nonstarters. Yamanaka did this by looking for the activity of a gene that, as it turned out, selected for cells that were incompletely reprogrammed. In the new studies, the scientists used the expression of Oct4 and Nanog--well-known pluripotency markers.
The cells selected using these markers appear to have all the same traits as ES cells. To test this hypothesis, the researchers tagged the reprogrammed cells, called induced pluripotent stem (iPS) cells, with a fluorescent dye and injected them into early-stage mouse embryos. Some of the resulting chimeric animals had descendents of the iPS cells throughout their bodies. The researchers confirmed this by successfully breeding the chimeras to normal mice. This showed that iPS cells had made it to the germ line in the chimeras.
Together, the three papers give a convincing picture of the reprogramming phenomenon, says Harvard stem cell researcher Chad Cowan. But Yamanaka's study showed a downside as well. The only author to study the offspring of the chimeras after birth, he observed that 20% of the 121 mice developed tumors. That finding, Yamanaka notes, shows the danger of using retroviral vectors, which can turn on cancer-causing genes.
The drawback highlights the long road to potential therapies with reprogrammed adult cells. But Cowan is optimistic: "The most amazing thing about these papers is you now take this whole idea of reprogramming out of the hands of cloning specialists and put it into the hands of anyone who can do molecular and cell biology."
In this environment, the reprogramming studies, preliminary as they are, are likely to be seized on by critics of ES cell research as further evidence that there is no need for the contentious practice of destroying early embryos to obtain stem cells. Hochedlinger and others hasten to point out that research needs to progress on all fronts because all systems "have their limitations."
For a more in-depth version of this story, see the Friday, 8 June, issue of Science.