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Daley's paper, published online in Nature in December 2007, described his ability to reprogram human adult skin cells using even fewer genes. Scientists refer to the new cells as induced pluripotent stem (iPS) cells, meaning they have been coaxed to regress to a state in which they could become any of the various cell types that make up the body. In human cell lines, such pluripotency is shared only by embryonic stem cells, although the iPS technique bypasses one of the steps that has hampered the development of patient-specific human lines; the new process created stem cells without the costly and difficult step of harvesting eggs. And no embryos are required.
Researchers around the world are elated by this apparent breakthrough. “Clearly, this work is a very big step,” says Alan Trounson, president of the California Institute for Regenerative Medicine, which was founded to support embryonic stem cell research but now expects to fund efforts using the new technique as well.
Some researchers are even transcending their usual penchant for understatement. In The New England Journal of Medicine, Douglas R. Higgs, of Oxford's Weatherall Institute of Molecular Medicine, pointed out iPS cells' clinical implications, particularly their potential for overcoming the immune system incompatibility issues of existing transplant technology. Reprogramming a patient's own somatic cells, he wrote, is “the biologic equivalent of an alchemist's dream of turning lead into gold.”
But iPS cells are a new discovery with plenty of questions that need exploring. Daley notes that while iPS work holds promise as an easier route to his goal of making patient-specific stem cells, none of his physician colleagues would consider using iPS cells as a treatment, at least for now. To insert new genes into cells to form iPS cells, researchers attached the genes to fragments of a virus that can cause cancer.
Scientists are working on methods to revert cells to a pluripotent state without using such viruses—by employing drugs, for example, or by injecting proteins directly into the cell.
“I think we'll see this happen soon,” says Konrad Hochedlinger, a colleague of Daley's at the Harvard Stem Cell Institute who also works on iPS cells. “Then the big question will be how similar these induced cells are to embryonic stem cells.”
“People take it for granted that they are identical,” he says, but iPS cells are not yet as well understood as their ES counterparts. Thus, Hochedlinger wants to grow human iPS cells alongside human ES cells and then direct both to become adult tissues such as muscle or nerve cells. He points out that with mouse cells, molecular analysis of the two cell types found no major differences, but when he attempted to grow adult heart cells from the mouse iPS cells using a protocol developed with ES cells, the iPS cells didn't seem to form tissue as easily.
“Superficially, things look okay, but as you look more closely, the iPS cells don't develop quite normally,” says HHMI investigator Stuart H. Orkin, at Children's Hospital Boston. “They're pretty close but they ain't perfect.”
Orkin studies ES cells, trying to understand exactly what processes keep them from differentiating into adult tissue. The initial iPS experiments reported last fall created something of a “black box,” he explains. Scientists know that four specific genes cause the cells to regress to a pluripotent state, but they don't know how they do it, or why the process takes weeks longer than transferring a nucleus from an adult cell into an egg.
In a series of experiments described in the March 21, 2008, issue of Cell, Orkin examined nine genes that are known to help ES cells maintain themselves, including the four used in the recent iPS experiments and five others. Each of those nine genes produces a transcription factor, a protein that causes other genes to turn on or off. Orkin identified hundreds of genes that are targeted by one or several of the transcription factors, work that he hopes will help scientists tease out the cellular-level processes that help ES cells maintain and reproduce themselves. Similar work on iPS cells could help explain the differences between the two types of stem cells.
“We're gathering a complete parts list of the things that are involved and required,” Orkin says. “Maybe adding something that hasn't been considered yet might make it better.”