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Racing to Understand Differences in Induced Pluripotent Stem (iPS) Cells

Researchers in Boston and across the world are racing to understand the true nature and utility of these promising cells, called induced pluripotent stem cells, or iPS cells. “We are getting a variety of signals that suggest they are different [from embryonic stem cells] in key ways, and the road to using them as a therapy will require much more refinement of this big tool,’’ said Konrad Hochedlinger, a principal faculty member of the Harvard Stem Cell Institute.

The breakthrough discovery 4 years ago that scientists could transform adult cells into stem cells has sparked research in labs across the world, spawned start-up companies, and bolstered the long-term dream that a patient’s own cells could be used to regenerate damaged tissue. More recently, scientists have found that these cells, while similar in many ways to powerful embryonic stem cells, which can develop into any type of cell in the body, contain subtle differences that affect their biology and therapeutic potential.

Scientists are trying to discern whether the differences they have found can be circumvented and are searching for improved ways to make these cells.

A study by Hochedlinger published in the journal Nature in April found that in most mouse iPS cells, a cluster of genes known to be important in development was not activated. In the most stringent test, those iPS cells did not perform as well as embryonic stem cells. But he also found a small portion of iPS cells in which those genes were active, and the cells had the full development potential of embryonic stem cells.

He is now repeating the experiment using human cells, and says his work suggests that it may be possible to optimize the reprogramming process or to use the genetic differences to sort good iPS cells from bad.

In February, Stanford University School of Medicine researchers published a study in the journal PLoS ONE that found that when an adult cell, such as a fat cell or skin cell, is reprogrammed into the embryonic-like state, the slate is not wiped clean — cells still have residual gene activity of their original cell type. That suggests for a cell to be completely reset, more steps might be needed, or certain cell types might be better candidates for reprogramming. Also in February, a study in the journal Stem Cells by researchers at Advanced Cell Technology, a Worcester stem cell company, found that blood vessel and retinal cells made from iPS cells aged rapidly.

The discovery of iPS cells held the promise that they could be used as a plentiful and noncontroversial alternative to embryonic stem cells in research and, potentially, treatments;  if they were truly equivalent. Some people have objected to the use of embryonic stem cells because obtaining them requires researchers to destroy an embryo, which the critics consider equivalent to taking a life. No embryo is destroyed in reprogramming. Instead, scientists add a cocktail of genes or chemicals to an ordinary skin cell to create iPS cells. These cells can in turn be coaxed to become more specialized cells, such as heart or nerve tissue.

But even slight differences could limit their use, both as potential therapies and as tools to study the origins of disease or test drugs. For example, scientists have made iPS cells from patients with illnesses such as Parkinson’s disease and Lou Gehrig’s disease, and then created in a laboratory dish the brain cells genetically identical to those in the patient that go awry.

But if the iPS cells are not truly equivalent to embryonic stem cells, it is possible that researchers studying the disease in a dish might see differences in the cells that are caused not by the disease, but by the process of making iPS cells, said Hochedlinger, who also works at the Massachusetts General Hospital Center for Regenerative Medicine.

Dr. George Q. Daley, a stem cell scientist at Harvard and Children’s Hospital Boston, is working with a large group of collaborators in other laboratories to further elucidate the differences between iPS and embryonic stem cells with a $3.4 M federal stimulus grant. In May, he published a paper in the journal Cell Stem Cell, describing fundamental differences between iPS cells created from a patient with Fragile X syndrome and stem cells generated from embryos with this form of inherited mental retardation. “I think what it’s really highlighting are the technical limitations inherent in the reprogramming process,’’ Daley said. “We’re still working on improving the fidelity of the protocols, and hoping to get closer and closer to embryonic stem cells. . . . They may be good enough for certain types of research, and they may — we hope — be good enough for therapy.’’ (HWM and Carolyn Johnson, Boston Globe)