Stem cell research progresses by turning back the clock

The field of stem cell research passed a critical landmark last November with the discovery that one could “turn back the clock” on human skin cells, reverting them to a state resembling an embryonic stem cell. The discovery, made by researchers at the University of Wisconsin and Kyoto University and independently confirmed by scientists at HSCI, was widely hailed as the long-awaited advance needed to put an end to the ethical debate surrounding the field, since it does not require the destruction of human embryos.

Scientists cautioned, however, that such proclamations were premature, since there may be subtle differences between these reprogrammed cells and true embryonic stem cells, and risks would make it unsafe at this time to use them to treat disease in humans. Perhaps foremost among those risks is that the method introduces four new genes into the skin cell, one of which (an oncogene) is known to be associated with cancer. These genes act as master switches, turning other genes on and off and inducing the cell to become pluripotent – or capable of turning into any of the 220 cell types of the human body. The second potential risk is that the method delivers the genes into the cell using a retrovirus, which can insert them randomly into the chromosome – a biological dart game that could possibly lead to cancer-causing mutations.

Following quickly on the heels of the discovery, researchers at MIT’s Whitehead Institute and the University of Alabama showed that the induced pluripotent stem cells (iPS) can cure a mouse suffering from sickle cell anemia. Similar procedures could be envisioned to mend a broken spine, repair a diabetic pancreas, or reverse the effects of a heart attack with cells genetically matched to the patient. It is a hopeful scenario, but still some distance from safely treating humans.

While iPS cells cannot be used yet in humans, they will have a more immediate use in the laboratory. Scientists welcome the possibility of a limitless supply of stem cells containing the genetic code of any individual, especially those with specific diseases. Reprogramming could be used to create cellular models of complex diseases such as Alzheimer’s disease or diabetes. That could give a tremendous boost to scientists studying disease mechanisms or screening for new drugs because most experiments today rely on cell lines derived from relatively healthy cells. HSCI has several teams and labs working on reprogramming and other approaches to creating disease specific cell lines, such as cell fusion and somatic cell nuclear transfer, and a Therapeutic Screening Center dedicated to testing new chemical compounds for their effects on the new cell lines.

George Daley, MD, PhD, Executive Committee member of HSCI, and Associate Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School, said his team is interested in creating cell lines from patients with sickle-cell anemia and Fanconi anemia, a hereditary disease in which the bone marrow does not produce enough blood cells. Growing these cells in the laboratory would enable Daley to more readily test therapeutic options.

Daley’s concern, and that of many other scientists, is that iPS research is relatively new and many issues remain to be worked out, such as the risk of mutations and tumors, and the question of whether the iPS cells are truly equivalent to their embryonic stem cell counterparts. “Despite success in generating iPS cells, we are not abandoning our efforts to derive new human stem cell lines by nuclear transfer,” he said.

Concerned that the reprogramming discovery might lead to a loss of support for areas of stem cell research that depend on human embryonic stem cells, several leaders in the field, including Shinya Yamanaka, MD, PhD, of Kyoto University, Konrad Hochedlinger, PhD, of HSCI and Rudolf Jaenisch, MD, of the Whitehead Institute, emphasized in a letter to the journal Cell Stem Cell: “that research into all avenues of human stem cell research must proceed together.”

For now, work continues at HSCI on multiple fronts – embryonic stem cells, adult stem cells, SCNT, and reprogramming – any one of which, or all of which, may eventually lead to treatments and cures for a host of diseases. Human embryonic stem cells will provide a necessary standard by which the new methods can be compared and an improved set of inducing genes for reprogramming can be identified.