The House of Representatives is slated to vote this week on legislation that could ease restrictions on embryonic stem cell research, but the issue may soon be moot. Three papers in this week's issues of Nature and Cell Stem Cell suggest that reprogrammed fibroblasts, or skin cells, could be a viable alternative to embryonic stem cells for use in therapeutic cloning. A fourth paper, also in this week's Nature, used fertilized eggs to generate cloned animals.

Research published by scientists from Kyoto University and the Japan Agency for Science and Technology in the journal Cell last year showed that inducing the expression of four genes in fibroblasts rendered them similar to embryonic stem cells in several respects (see BioWorld Today, Aug. 24, 2006.)

While those fibroblasts, which their discoverers called induced pluripotent or iPS cells, were still different from true embryonic stem cells in terms of both their gene expression and their epigenetic DNA methylation patterns.

Asked at the time to comment on the work, Robert Lanza, CEO of biotech company Advanced Cell Technology, said that while the cells had been modified extensively, "it does suggest that there will be ways one day to create stem cells from scratch."

Now, "one day" appears to have arrived. The Japanese team, as well as two groups of U.S. researchers, have managed to isolate cells that have the epigenetic features of embryonic stem cells as well, by combining the activation of the four previously reported genes with a marker that some of the reprogrammed fibroblasts express.

The new cells showed epigenetic features of embryonic stem cells, and the researchers were able to create embryonic stem cell lines and cloned animals using them for somatic cell nuclear transfer.

One paper concluded that "the biological potency and epigenetic state of in vitro-reprogrammed induced pluripotent stem cells are indistinguishable from those of ES cells." While all three research groups worked with mice, the obvious hope is that the same principle will apply to human fibroblasts.

Many adult stem cells, as well as a number of embryonic stem cell lines approved for federally funded research, show less flexibility than was once hoped for. But the Bush administration continues to show zero flexibility on federal funding for embryonic stem cells. So finding - or making - cells that have the regenerative potential of embryonic stem cells without being the real thing is one goal for those trying to bring the potential of stem cells to the clinic.

One of the most promising uses of stem cells would be for therapeutic cloning, that is, the creation of patient-specific stem cells, which would obviate the immunological problems of such transplants. In therapeutic cloning, or somatic nuclear cell transfer, researchers insert a patient's DNA into an unfertilized egg, and allow the egg to develop into a blastocyst, a very early stage embryo. Stem cells that match the patient genetically then could be used to treat a number of disorders.

The last claim of the creation of patient-specific stem cell lines, by a group of researchers from South Korea and the University of Pittsburgh, turned out to be a scientific fraud. (See BioWorld Today, May 20, 2005, and Dec. 19, 2005.)

But the method clearly is workable in principle, though not anywhere near ready for the clinic, making a source of noncontroversial cells that have the properties of embryonic stem cells a major breakthrough - though the Japanese authors of one of the Nature papers do note that oncogene activation, which was seen in last fall's initial report in Cell, was still a problem in their experiments.

A fourth paper, also published in this week's Nature, showed that fertilized eggs also could be used, in principle, for cloning. The researchers used fertilized eggs for somatic cell nuclear transfer, and were able to create embryonic stem cell lines from which they derived full-term cloned mice.

But the cloned offspring in that study showed serious health problems, with most of them not surviving, and in a sense, the fibroblast studies have leapfrogged that research.

While the use of fertilized eggs gets around the ethical concerns specific to egg donation, it's likely that those with ethical concerns about the status of blastocysts will find the use of fertilized eggs for therapeutic cloning even less palatable than the use of unfertilized ones. And reprogrammed skin cells, of course, come with no ethical baggage at all.

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