1224NEWS>>THIS WEEKA king’s birthdaypresentDispute over fludata escalates12281229For a year and a half, stem cell researchersaround the world have been racing toward acommon goal: to reprogram human skin cellsdirectly into cells that look and act likeembryonic stem (ES) cells. Such a recipewould not need human embryos or oocytes togenerate patient-specific stem cells—andtherefore could bypass the ethical and politi-cal debates that have surrounded the field forthe past decade. The pace was set in June 2006, whenShinya Yamanaka of Kyoto University inJapan reported that his group had managedthe feat in mice by inserting four genes intocells taken from their tails (Science, 7 July2006, p. 27). Those genes are normallyswitched off after embryonic cells differenti-ate into the various cell types. The pacepicked up in June this year, when Yamanakaand another group showed that the cells weretruly pluripotent (Science, 8 June, p. 1404). Now the race has ended in a tie, with anextra twist: Two groups report this week thatthey have reprogrammed human skin cellsinto so-called induced pluripotent cells(iPCs), but each uses a slightly different com-bination of genes. In a paper published onlinein Cell on 20 November, Yamanaka and hiscolleagues report that their mouse techniqueworks with human cells as well. And in apaper published at the same time online inScience (www.sciencemag.org/cgi/content/abstract/1151526), James Thomson of theUniversity of Wisconsin, Madison, and hiscolleagues report success in reprogramminghuman cells, again by inserting just fourgenes, but two of the genes are different fromthose Yamanaka uses.Among stem cell scientists, the humancell reprogramming feats have somewhatovershadowed another major advancereported online in Nature last week: A teamat the Oregon National Primate ResearchCenter has officially become the first toobtain embryonic stem cells from clonedprimate embryos, an advance that bringstherapeutic cloning closer to reality forhumans. Taken together, these feats suggestthat scientists are getting very close touncovering the secret of just what occurs inan oocyte to turn back the clock in the DNAof a differentiated cell. The two human reprogramming paperscould help solve some of the long-standingpolitical and ethical fights about stem cellsand cloning. The technique produces pluripo-tent cells, cells with the potential to becomeany cell type in the body, without involvingeither embryos or oocytes—two stickingpoints that have made embryonic stem cellresearch so controversial. Ian Wilmut of theUniversity of Edinburgh, U.K., says that oncehe learned of Yamanaka’s mouse work, his labset aside its plans to work on human nucleartransfer experiments, otherwise known asresearch cloning. The new work now confirmsthat decision, he says. Direct reprogrammingto iPCs “is so much more practical” thannuclear transfer, he says.In the new work, Yamanaka and his col-leagues used a retrovirus to ferry into adultcells the same four genes they had previouslyemployed to reprogram mouse cells:OCT3/4, SOX2, KLF4, and c-MYC. Theyreprogrammed cells taken from the facialskin of a 36-year-old woman and from theconnective tissue of a 69-year-old man.Roughly one iPC cell line was produced forevery 5000 cells they treated with the tech-nique, an efficiency that enabled them to pro-duce several cell lines from each experiment. Thomson says he and his colleaguesalready had their own list of 14 candidatereprogramming genes when Yamanaka’smouse results were published. They, likeYamanaka’s group, gradually whittled downthe list through a systematic process of elimi-nation. Thomson’s experiments led to four fac-tors as well: OCT3 and SOX2, as Yamanakaused, and two different genes, NANOG andLIN28. NANOG is another gene associatedwith ES cells, and LIN28 is a factor that seemsto be involved in processing messenger RNA. Instead of cells from adults, Thomson andhis team reprogrammed cells from fetal skinand from the foreskin of a newborn boy. ButThomson says they are working on experi-ments with older cells, which so far lookpromising. Their experiments reprogrammedabout one in 10,000 cells. The efficiency isless than that of Yamanaka’s technique,Thomson says, but is still enough to createseveral cell lines from a single experiment. Comparing the two techniques might helpscientists learn how the inserted genes workto turn back the developmental clock,Yamanaka says. He says his team tried usingNANOG but saw no effect, and LIN28 wasnot in their initial screen. Thomson says histeam tried Yamanaka’s four genes withoutsuccess, but that they may have tried thewrong relative doses. The fact that Thomson’s suite doesn’tinclude a known cancer-causing gene is a23 NOVEMBER 2007 VOL 318 SCIENCE www.sciencemag.orgFull of potential. Human induced pluripotent cellsform teratomas, tumors with multiple cell types.CREDIT: J. YU ET AL., SCIENCEField Leaps Forward With New Stem Cell AdvancesDEVELOPMENTAL BIOLOGYPublished by AAAS on November 29, 2007 www.sciencemag.orgDownloaded from1225FOCUSA time for actionon climate1230Killing B cells relievesrheumatoid arthritis1232bonus, says Wilmut. (The c-MYC Yamanakaused is an oncogene.) But both techniques stillresult in induced cells that carry multiplecopies of the retroviruses used to insert thegenes. Those could easily lead to mutationsthat might cause tumors in tissues grown fromthe cells. The crucial next step, everyoneagrees, is to find a way to reprogram cells byswitching on the genes rather than insertingnew copies. “It’s almost inconceivable at thepace this science is moving that we won’t finda way to do this without oncogenes or retro-viruses,” says stem cell researcher DouglasMelton of Harvard University. “It is not hard toimagine a time when you could add small mol-ecules that would tickle the same networks asthese genes” and produce reprogrammed cellswithout genetic alterations, he says.Although the cells “act just like humanES cells,” Thomson says, there are some dif-ferences between the cell types. Yamanaka’sgroup reports that overall human iPC geneexpression is very similar, but not identical, tohuman ES cell gene expression. “It will beprobably a few years before we really under-stand these cells as well as we understandES cells,” Thomson says. But “for drugscreening, they’re already terribly useful. IVFembryos are very skewed ethnically,” he says.But with the new iPC technique, “you can iso-late