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Stem Cell Advance May Avoid Cancer Risk Non-Virus Method Called Safer, Simpler

October 10, 2008

By MARK JOHNSON

Japanese scientists have demonstrated a new way to reprogram cells without viruses, an important advance toward the goal of one day turning our own cells into a powerful tool to fight a wide range of diseases.

The new technique, reported Thursday in the journal Science, appears to be both safer and simpler than previous methods, bypassing the cancer risk associated with using viruses and genes that remain inside a cell.

The Japanese team, led by Shinya Yamanaka of Kyoto University and the Gladstone Institute of Cardiovascular Disease, delivered the reprogramming genes into mouse cells with plasmids. Plasmids are essentially small, very stable circles of DNA.

Just two weeks ago, a team at Harvard showed another way to improve safety by using a different kind of virus that delivers reprogramming genes, then dilutes out of the cells along with the outside genes. Still, some scientists had suggested that it would be preferable to avoid using a virus at all, which is precisely what the Japanese team has now done.

“I think it’s very significant,” Alexander Meissner, an assistant professor at the Harvard Stem Cell Institute, said of the new paper. “It shows you really can make these cells without any use of viruses. . . . All of these things are the most basic biology that can be done.”

“This is a major step forward,” said Timothy Kamp, co-director of the Stem Cell and Regenerative Medicine Center at the University of Wisconsin-Madison.

But Kamp also sounded a note of caution, saying: “The field is advancing very quickly. We need some time to study these cells in detail. I have to think we’re still many years from this getting into clinical trials.”

It was only two years ago that Yamanaka launched the reprogramming revolution when he and another scientist sent mouse cells back to the embryonic state by infecting them with a virus carrying four genes. Last November, groups led by Yamanaka and UW- Madison’s James Thomson reprogrammed human cells, and in the last year others have sought to apply and refine the methods.

After years of ethical controversy surrounding the destruction of human embryos, reprogramming has re-energized this scientific field, demonstrating an avenue for obtaining cells similar to human embryonic stem cells. The reprogrammed cells appear able to multiply and become any cell in the body, and they avoid the use of human embryos entirely.

Already scientists have begun collecting skin cells from patients with ALS, Alzheimer’s and other diseases in order to reprogram them and develop them into the cells that are damaged in these illnesses. By doing so they hope to learn more about the disease process and to test thousands of drugs to see if any will help the affected cells.

Still, many researchers have urged that work be allowed to continue with embryonic stem cells, since the new cells have raised safety concerns. Also, scientists have not firmly established that the new cells match the embryonic originals in all respects.

In the Science paper, Yamanaka and his colleagues say that the new cells do not appear to have any traces of the plasmids or the reprogramming genes. The plasmids dilute out with each cell division.

Up to now, scientists have worried that the insertion of viruses and outside genes could change the way a cell’s native genes behave, turning on a harmful process or turning off a beneficial one. For example, there could be disastrous consequences if reprogramming stopped a gene that causes programmed cell death. Despite its ominous name, programmed cell death plays an important role in preventing the early formation of tumors.

Both the Japanese and Harvard studies were done using mouse cells, and other researchers have stressed the importance of now showing that these methods will also work with human cells. Some experts disagree about how challenging that transition should be.

“There’s no major reason why this shouldn’t work in humans,” Meissner said.

Mouse cells easier

Beverly Torok-Storb, a researcher at the Fred Hutchinson Cancer Research Center in Seattle, said that the mouse isn’t a good model for translating therapies into the clinic. Mouse cells are easier to reprogram. And because humans are so much larger and live longer, transplanted tissue must produce many more cells. That means there is more opportunity for something bad to happen, for example, a rare instance in which the plasmid DNA somehow fails to dilute out and integrates into the cell.

Torok-Storb said the advances by the Harvard group and the Japanese team, “going to an adenovirus, going to plasmids, these are steps in the right direction.”

However, she added, “I don’t think the best method has been found.”

She and her colleagues have been searching for small molecules that can trigger the reprogramming mechanism without inserted genes or viruses. So far they have screened “small numbers and had some promising hits,” but they are preparing to screen hundreds of thousands.

Despite the rapid pace of discovery this year, she and other scientists believe that much work remains before reprogrammed cells can be used on humans in clinical trials. She said the cells will need to be tested first in larger animals, such as primates, dogs or pigs.

Meissner said scientists must also develop ways of ensuring quality control in reprogramming.

They will need to be sure that the new cells are fully reprogrammed. He said the fast pace of improvements in reprogramming should continue.

“We’re not searching for something unknown,” he said. “We’re trying to optimize something that’s known.”

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