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Scientists solve some safety issues in reprogrammed cells: New method uses a virus that doesn't stay in cells, cutting cancer risk
(Milwaukee Journal Sentinel, The Via Acquire Media NewsEdge) Sep. 26--Researchers in Boston have taken a major step toward resolving the safety issues surrounding a novel technique in which mature cells are reprogrammed back to the embryonic state.
The latest advance by scientists at Harvard continues a yearlong surge of discovery and draws the stem cell field closer to one of its great goals: a cell that is safe for human use and offers the power of an embryonic stem cell without destruction of the embryo. Such a technology could someday allow doctors to heal patients using their own reprogrammed cells.
A team led by Konrad Hochedlinger of the Harvard Stem Cell Institute reprogrammed mouse cells using a virus that accomplished its mission without integrating into the cells. The adenovirus infected cells for a brief period, long enough to deliver genes that switch on reprogramming.
Then, after a few cell divisions, the virus and outside genes were diluted out of the cells.
The new finding, published Thursday in the online edition of the journal Science, builds on the reprogramming work of teams led by Japanese scientist Shinya Yamanaka and James Thomson of the University of Wisconsin-Madison. In November, both teams created cells that appear similar to human embryonic stem cells but do not require the destruction of an embryo. The cells are known as induced pluripotent stem cells, or iPS cells.
But the methods the teams used -- infecting the cells with viruses carrying genes -- can trigger cancer, making the reprogrammed cells unsafe for use in humans. Adenoviruses, which cause respiratory illness and gastroenteritis, among other ailments, are able to infect without integrating into a cell's DNA.
"That's the beauty of adenoviruses," Hochedlinger said.
Now that the virus has been used to reprogram mouse cells, scientists are trying the technique on human cells.
"I don't think there's any reason it should not reproduce in human cells," Hochedlinger said. "We're trying, but we haven't succeeded so far. Human reprogramming seems to be more difficult. It takes three times as long."
Since the announcements by the Yamanaka and Thomson groups in November, scientists have been seeking ways to remove the viruses and inserted genes from the process.
In June, researchers at Scripps Research Institute in La Jolla, Calif., showed they could reprogram cells with methods that relied less on the use of viruses and genetic modification. They were able to replace two of the genes inserted by Yamanaka's group with small molecules. A number of scientists have been trying to find molecules to replace all of the inserted genes.
Robert Blelloch, a stem cell researcher at the University of California-San Francisco's Institute for Regeneration Medicine, called the paper on the adenovirus important work, though he cautioned that the best method of safe reprogramming has yet to be decided.
"I think we will see a lot of different approaches coming out in the next few months," Blelloch said. "The safety issue is certainly not resolved. We have a lot of very bright people working on it."
Deepak Srivastava, director of UC-San Francisco's Gladstone Institute of Cardiovascular Disease, where Yamanaka has a lab, said the new work provides important evidence that integration of the virus is not necessary to reprogram a cell. However, he said the use of the adenovirus does not completely resolve the safety concern.
Srivastava said truly safe reprogrammed cells may not be far off.
"I think we're very close. I think you'll see something very soon about that," he said. "It's on the horizon."
Clive Svendsen, co-director of UW's Stem Cell & Regenerative Medicine Center, said the research by Hochedlinger's team is "definitely the big next step, proof of concept that you can reprogram without the virus integrating (into the cell)." He stressed that it will be important to demonstrate that the technique works with human cells.
"It seems like it should work," Svendsen said. "Sometimes, the human cells are tricky to get to work."
Once scientists do replicate the method in human cells, they will still have to tackle another more fundamental question: Just how similar are the reprogrammed cells to the embryonic stem cells they may someday replace?
"There are data suggesting subtle differences," Hochedlinger said.
Scientists now are trying to document these differences. Embryonic stem cells can develop into any other cell in the body, such as heart, liver, muscle and blood. Researchers want to know whether the reprogrammed cells can do the same.
And if scientists can make heart cells from both, they will need to test whether those heart cells are the same and can do all of the same things. Because there are more than 200 types of cells in the human body, this is no trivial task.
"The differences may be very subtle, but when you actually get to clinical practice, it could be meaningful," Blelloch said.
This is one reason scientists have urged that research on embryonic stem cells continue.
Hochedlinger said the next step is to extend the comparison by looking for differences between cells reprogrammed with the adenovirus, those reprogrammed using Yamanaka's method and the originals, embryonic stem cells.
To see more of the Milwaukee Journal Sentinel, or to subscribe to the newspaper, go to http://www.jsonline.com.
Copyright (c) 2008, Milwaukee Journal Sentinel
Distributed by McClatchy-Tribune Information Services.
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