Will we ever see the long- promised medical benefits of stem-cell therapy? Last year that question loomed larger than ever, as some of the most promising lines of research hit daunting roadblocks.
When biologist James Thomson at the University of Wisconsin cultivated the first line of human embryonic stem cells in 1998, the work suggested an impending medical revolution. The cells, which could develop into any other type of cell in the body, promised tailor-made replacements for damaged or diseased organs and tissues. But isolating the cells required destroying human embryos, embroiling the research in religious controversy. Transplanted embryonic stem cells are ethically cleaner, but they have a genetic makeup different from the patient’s own, so they could be violently rejected by the immune system.
In 2006, Japanese biologist Shinya Yamanaka found a solution: He reprogrammed skin cells from a mouse, turning them back into embryo-like cells, with the potential to grow into any tissue, simply by adding four genes. The next year, both Yamanaka and Thomson made these cells—called induced pluripotent stem cells, or IPS cells—from human skin. The new technique seemed to avoid the political pitfalls, and also to evade the perils of rejection since the cells were the patient’s own.
Now it turns out that IPS cells—just like embryonic stem cells—are fraught with problems of their own. In one study, geneticist Joseph Ecker at the Salk Institute in California took various stem cell lines reprogrammed from skin, fat, and other tissues and examined each line’s genome for dna methylation, chemical marks that alter how genes are expressed. “Global levels of DNA methylation in IPS cells look amazingly similar to embryonic stem cells,” Ecker says, “but there are distinct regions that do not get reprogrammed properly.” In those regions, methylation of the reprogrammed cells’ genomes still resembled the tissues they came from, suggesting that the cells had not been fully set back to the embryonic stage. If so, they would not take on their desired therapeutic roles.
In an independent study, immunologist Yang Xu at the University of California, San Diego, set out to test the presumption that IPS cells would elude rejection. When he injected mice with embryonic stem cells genetically identical to the mice’s own tissues, the new cells thrived, growing into a large clump of adult tissues. But when he injected the mice with genetically identical reprogrammed stem cells, their immune systems attacked, destroying the cells. “The immune system is good at picking out even tiny things that aren’t normal,” Xu says.
The ongoing challenge is creating IPS cells that function as much like embryonic stem cells as possible. “Now that we’ve found these problems,” Ecker says optimistically, “we can try to correct them.” Until that happens, though, reprogrammed cells are far from ready for the clinic.