Oocyte-Assisted Reprogramming, Scientific Concerns

Dr. William Hurlburt, a member of the President’s Council on Bioethics, has proposed two possible techniques for the production of embryonic stem cells that, according to him, bypass the necessity of destroying human embryos to make embryonic stem cells. His two techniques are altered nuclear transfer (ANT) and oocyte nuclear reprogramming (OAR).

ANT proposes to inhibit a gene or group of genes that are necessary for the formation of the trophectoderm in an egg before a nucleus from an adult cell in inserted into it. Once the embryo develops, it will become a cluster of inner cell mass cell that can be directly cultured to make an embryonic stem cell line. Hurlburt recommends using techniques that temporarily inhibit the Cdx2 gene. The Cdx2 gene is required for embryos to form the outer layer of trophoblast cells (trophectoderm). Without functional Cdx2, the embryo defaults to a mass of inner cell mass cells.

Animal experiments have demonstrated the plausibility of this proposal. Experiments with mouse embryos in the laboratory of Rudolph Jaenisch at MIT used nuclei from tail-tip fibroblasts (a cell commonly found in connective tissue) as the sources for the nuclear replacement. Prior to nuclear replacement, the Cdx2 gene was conditionally inhibited by a procedure called RNA interference. Replacement of the egg nucleus with a pretreated nucleus from fibroblasts, followed by artificial stimulation of the egg produced abnormal embryos that failed to implant in the uterus, and when cultured in the laboratory, they formed embryonic stem cell cultures (Nature 439, (2006): 212–15).

OAR proposes the overexpression of the Nanos gene in the egg, and then after the transfer of a new nucleus, the embryo will form pluripotent stem cells that can be cultured to form embryonic stem cell cultures.  This website gives a clear presentation of OAR.

There are no animal experiments to support the feasibility of OAR. In fact, there are reasons to suspect that OAR would not work. The conversion of cells into pluripotent stem cells requires a network of genes of which Nanos is one (Critical Reviews in Eukaryotic Gene Expression, 16 (2006): 211-31; Stem Cell Reviews, 1 (2005): 111-8; Current Opinion in Genetics and Development, 16 (2006): 455-62; Stem Cells, 25 (2007): 2-9). Thus when it comes to the conversion of cells into pluripotent stem cells, Nanos does not work alone (Nature Genetics 38 (2006): 431-40; Cell 122 (2005): 947-56; Journal of Biological Chemistry 280 (2005): 24731-7; FASEB Journal 20 (2006): E1-E9). Thus there are good reasons to suspect that OAR, as proposed, will not work.  While these are not the only problems with OAR, it seems scientificallt dubious to endorse an alternative means of deriving embryonic stem cells that is rather unlikely to work.

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).