The promise of using human embryonic stem cells to create customized tissue to replace that lost to disease has been heralded since these cells were first isolated and cultured in 1998. A steady drumbeat of reports of cell types derived from embryonic stem cells has maintained the excitement: neurons, liver cells, pancreatic islet cells, and heart muscle cells, to name a few. Nonetheless, patient-specific cell treatments for widespread use are still years away.
For one thing, embryonic stem cells are extraordinarily difficult to work with. For another, ethical concerns about destroying an embryo to obtain the cells have impeded research in many countries, including the United States. Such concerns, and politically imposed restrictions, are unlikely to vanish soon. Moreover, even were the path for research clear, the economics of developing practical treatments involving human embryonic stem cells would remain challenging, and the risks substantial.
Research involving such cells will surely continue, but now excitement is growing over alternative ways of producing human cells with embryonic stem cells' most valuable property—their ability to give rise to many different types of tissue, depending on the conditions in which they are grown. The article by Sa Cai, Xiaobing Fu, and Zhiyong Sheng, which begins on p. 655 of this issue of BioScience, provides a fascinating overview of progress toward one of these alternative ways. The authors discuss reversing the natural process of differentiation, whereby dividing cells become progressively less flexible in their developmental potential and more specialized to a particular task within a tissue. Until a few years ago, reversing differentiation was generally considered impossible to bring about in mammals. But biological dogmas have been toppling like the statues of Easter Island—pushed, in most cases. Dedifferentiation of some differentiated cells to form stem cells that can then be reprogrammed has been demonstrated in several systems. Although it is still early days, a few molecules that can bring about dedifferentiation have been characterized, and some signaling pathways implicated. The scientific rewards of understanding the mechanisms are unarguable, and the use of dedifferentiation in future therapies seems plausible.
That conclusion is reinforced by findings from work with mouse cells, reported since Cai and colleagues' article was accepted by BioScience. Research described in Nature by Shinya Yamanaka and by Rudolf Jaenisch's research group, as well as other studies published in Cell Stem Cell, by Konrad Hochedlinger and by Kathrin Plath, indicates that fibroblasts—readily available mature skin cells—can be turned into “induced pluripotent stem cells” (iPS cells) that apparently have all the coveted properties of embryonic stem cells. The dedifferentiation is brought about by using retroviruses to introduce into fibroblasts four genes encoding specific transcription factors (proteins that control the activity of genes). If the process works with human cells, and if it can be tweaked so that the iPS cells are less likely to develop tumors—as 20 percent of the mouse ones did—dedifferentiation will be bootstrapped into the limelight. The search will then truly be on for ways to reduce this elusive phenomenon to treatments that could greatly extend medicine's power.
