It is not known exactly how boosting the expression of just four genes manages to induce such a powerful state. Two of the genes are known oncogenes, or tumor promoters, that help cells proliferate; the other two are involved in maintaining the pluripotency of stem cells. Although the study provides a proof of concept, much has to be done before the reprogrammed stem cells could be used in the clinic. At present, they are considered unsafe for use in humans because the way they are engineered has the potential to cause cancer. Wernig says that the next major effort is “to try to reprogram human cells without the use of a retrovirus and without oncogenes,” perhaps by targeting the genes with drugs.
For many years, a small group of patients with Parkinson’s disease have received experimental cell transplants using dopamine neurons derived from fetuses. But the use of fetal tissue poses ethical and logistical hurdles for widespread use. Scientists have performed similar experiments in animals using stem cells derived from embryos or created with nuclear transfer, also known as therapeutic cloning. But iPS cells offer a way to avoid the use of embryos as well as the technical challenges of nuclear transfer. And if the cells came from a patient’s own skin, there would be no potential complications from immune rejection of foreign tissue.
When the team first performed the experiment, many rats developed tumors, which seemed to arise from the fact that not all of the iPS cells had fully transformed into neurons when they were transplanted. Tumors such as these have also been observed in experiments with embryonic stem cells. In this study, however, the researchers performed another set of transplants, first using a cell-sorting method that can identify and remove any cells that have failed to differentiate. “When we eliminated the undifferentiated cells from mixture, we got very clean transplants,” says Ole Isacson, a neurologist at Harvard Medical School who collaborated on the transplant experiments. The rats given these purified cells did not go on to develop tumors. He believes that the varying purity of transplants may prove to be a key factor in why some of the fetal cell transplants have not succeeded as well as others.