Safer iPS cells

Until now, reprogramming fully differentiated cells into a pluripotent state has had a major drawback: the use of genome-integrating linkurl:retroviruses;http://www.the-scientist.com/blog/display/54750/ to do the job. But a new study published tomorrow in Science reports on the creation of reprogrammed cells without such integrating viruses. "The number one priority for labs working on iPS translation is to alleviate this problem of integration of viruses into the human genome," linkurl:Ali Brivanlou;http://www.rockefeller.edu/research/abstract.php?id=127 of Rockefeller University, who was not involved in the study, told The Scientist. "This paper addressed this issue head-on," he said, noting that the ability not to compromise the genome brings the technique "one important step closer to clinical applications." The researchers, led by linkurl:Konrad Hochedlinger,;http://www.hms.harvard.edu/dms/bbs/fac/Hochedlinger.html from Harvard Medical School, used adenoviruses to introduce the four reprogramming transcription factors (Oct4, Sox2, klf4, and c-Myc) into adult mouse somatic cells. Unlike retroviruses, used in the linkurl:first reprogramming studies;http://www.the-scientist.com/blog/display/53873/ and experiments until now, adenoviruses do not integrate into the mouse genome and do not cause tumor growth, which has been the major challenge of using induced pluripotent (iPS) cells for therapies. Instead, adenoviruses temporarily express high levels of the transcription factors, in most cases without integrating permanently into the genome. In early studies researchers did not know how long the transcription factors had to be induced in the somatic cell genome. They knew that using retroviruses would maintain the transcription factor expression indefinitely, giving them the best shot for reprogramming pluripotency. Eliminating retroviruses is a "safer way of producing iPS cells," Hochedlinger told The Scientist. The study is a benchmark, linkurl:Brock Reeve,;http://www.boston.com/news/globe/health_science/articles/2007/06/11/he_hopes_to_change_culture_of_institute/ executive director of the Harvard Stem Cell Institute told The Scientist, "but not a final one. It's not where the field is going to stop. People are going to continue to look at what chemical compounds can replace all viruses." The fact that the researchers replaced retroviruses with adenoviruses is an important step, added Brivanlou, but adenoviruses still can integrate into the genome, albeit rarely. In order for iPS cells to be at all clinically relevant "we need [a method] so to not at all worry about genetic compromise of the genome," he said. One thing the study did put to rest was a linkurl:suggestion made last month;http://www.ncbi.nlm.nih.gov/pubmed/18660799?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum that the site of viral integration on the genome might be more important than the transcription factors -- or cargo -- the virus was carrying. "It wasn't a clear prerequisite of the whole reprogramming process that introducing the four transcription factors alone was sufficient to reprogramming somatic cell into pluripotent state," Hochedlinger said. "Our data show that the four transcription factors are sufficient to produce iPS cells, and it's not necessary to use integrating viruses." The site of viral integration on the genome, on the other hand, does not seem to be important. Last month, linkurl:Douglas Melton's;http://www.hhmi.org/research/investigators/melton_bio.html group at Harvard used adenoviruses to linkurl:reprogram pancreatic cells;http://www.the-scientist.com/blog/display/54976/ into beta cells, using a different set of transcription factors -- turning one differentiated cell type into another differentiated cell type without going through a pluripotent stage. But the real advance, said Brivanlou, will be new reprogramming technologies that eliminate the need for viruses entirely.

Safer iPS cells

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