Advances in recent years have begun to elucidate the distinct mechanisms that maintain embryonic stem cells (ESCs) undifferentiated, self-renewing, and pluripotent. One of the "grails" of therapeutic stem cell biology is the ability to confer these special properties of the embryonic stem cell onto an easily accessible, differentiated cell from the adult (such as a skin or blood cell) without the creation of an embryo as a necessary intermediate step. Such a technology would not only provide an ethically acceptable alternative to research cloning, but it would also offer a method to interrogate the biological basis of "sternness," the constellation of gene expression and protein signaling that underlie self-renewal and pluripotency. A landmark study published in 2006 and many subsequent reports demonstrate that the reactivation of a handful of particular genes can "reprogram" a differentiated cell from a variety of rodent and human tissues into a cell with several properties of embryonic stem cells, including self renewal and pluripotency. These reports demonstrate that much of the "grail" has now been found, albeit with some important limitations. A number of studies have successfully demonstrated the viability of theoretical proposals previously offered by President Bush's Council on Bioethics to generate alternative sources of pluripotent cells, at least in the experimental setting. These promising advances stand in stark contrast to the earlier revelation that reports of highly efficient derivation of several new human ESC lines through research cloning by South Korean researchers were false. Nevertheless, it remains clear that clever and innovative efforts to generate pluripotent stem cells through research cloning as well as through alternative methods continue unabated. In this Article, I discuss the recent development of "alternative" methodsthat is, techniques that do not involve research cloning-to derive pluripotent stem cells, most prominently among them, induced pluripotent stem (iPS) cells. Here, easily obtainable differentiated cells may be genetically manipulated to revert the cell to a stem cell state, from which clinically desirable cell types can be derived. Similarly, a "parthenote" (derived entirely from one parent) that does not have the potential to develop into a person might be a source of cell lines with potential comparable to that of embryonic stem cell lines. Ironically, this is what was proven to be the origin of the so-called "cloned" human embryonic stem (ES) cell lines claimed by South Korean researchers in 2005.
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