Safer Stem Cells on Horizon, Harvard Researchers Say

Researchers at the Harvard Stem Cell Institute have inched closer to fulfilling the promise of stem cell research for treating human disease by partially overcoming a key obstacle to their use.

HSCI co-director Douglas A. Melton and his colleagues have successfully created induced pluripotent stem (iPS) cells using a chemical that can replace two of the four potentially cancer-causing genes previously needed to reprogram adult cells into a mutable state.

The findings, published Sunday on the Web site of the journal Nature Biotechnology, open another avenue for researchers hoping to create iPS cells that are safe for treating human disease.

Scientists have been exploring alternatives to the traditional—but harmful—retrovirus approach since researchers first reprogrammed human skin cells with the method late last year. Integrating these viruses into the cells' DNA causes permanent genetic manipulation, which can trigger malignant tumor growth, making them unsafe for human use. Scientists ultimately hope to clear this hurdle and treat a wide variety of human diseases by transplanting body tissues created from stem cells.

Only three weeks ago, Harvard Medical School professor Konrad A. Hochedlinger and his colleagues at HSCI reported that they created mouse iPS cells using harmless adenoviruses that don’t alter the genetic makeup of the cells.

But Melton’s research is the first to demonstrate that scientists may be able to use chemicals instead of viruses and genes to reprogram adult cells into a more mutable state, a development long hoped for by stem cell researchers.

The next step, according to lead author Danwei Huangfu, will be to find a combination of chemicals that can replace the remaining two genes needed to create iPS cells.

Huangfu said that she and her colleagues initially used mouse cells to screen chemicals that she had previously shown to improve the efficiency of the gene-induced reprogramming process.

“One was particularly powerful,” Huangfu said. “So we tried it in human cells.”

Matthias Stadtfeld, the lead author for Hochedlinger’s paper on the use of harmless adenoviruses, cautioned that the efficiency of producing iPS cells using this method is “already very, very low.”

Only one out of every 100,000 cells currently yields the desired result, Huangfu estimated.

Stadtfeld added that though chemicals do not permanently alter the genetic makeup of the cells, they are not necessarily safer than viruses.

Huangfu acknowledged that more rigorous testing needs to be done, but said that the chemical used in this research does not cause any known changes in the cells’ DNA.

Still in the early stages of her work, Huangfu said that it is too difficult to tell which method scientists would ultimately prefer.

“We need to be really open-minded,” Huangfu said of finding safe alternatives to the cancer-causing retroviruses. “I think that this brings us one step forward, but we are still not there.”

—Staff writer June Q. Wu can be reached at junewu@fas.harvard.edu.