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Scientists overcome hurdles to stem cell alternatives

By Rob Stein
Washington Post Staff Writer
Thursday, September 30, 2010; 10:51 PM

Scientists have invented an efficient way to produce apparently safe alternatives to human embryonic stem cells without destroying embryos, a long-sought step toward bypassing the moral morass surrounding one of the most promising fields in medicine.

A team of researchers at the Harvard Stem Cell Institute in Boston published a series of experiments Thursday showing that synthetic biological signals can quickly reprogram ordinary skin cells into entities that appear virtually identical to embryonic stem cells. Moreover, the same strategy can then turn those cells into ones that could be used for transplants.

"This is going to be very exciting to the research community," said Derrick J. Rossi of the Children's Hospital Boston, who led the research published in the journal Cell Stem Cell. "We now have an experimental paradigm for generating patient-specific cells highly efficiently and safely and also taking those cells to clinically useful cell types."

Scientists hope stem cells will lead to cures for diabetes, Alzheimer's disease, spinal cord injuries, heart attacks and many other ailments because they can turn into almost any tissue in the body, potentially providing an invaluable source of cells to replace those damaged by disease or injury. But the cells can be obtained only by destroying days-old embryos.

The cells produced by the Harvard team, known as induced pluripotent stem cells, or iPS cells, would avoid that ethical objection and could in some ways be superior to embryonic stem cells. For example, iPS cells could enable scientists to take an easily obtainable skin cell from any patient and use it to create perfectly matched cells, tissue and potentially even entire organs for transplants that would be immune to rejection.

'Game changer'

While cautioning that the work needs to be repeated elsewhere and explored further, other researchers said the technique appears to represent a major development in the promising field of "regenerative medicine," which aims to create treatments tailored to individual patients.

"All I can say is 'wow' - this is a game changer," said Robert Lanza, a stem cell researcher at Advanced Cell Technology in Worcester, Mass. "It would solve some of the most important problems in the field."

The results were so striking that the Harvard Stem Cell Institute where Rossi works had already ordered every scientist working on iPS cells to switch to the new process.

"This paper is a major paper, in my view, in the field of regenerative medicine," said Douglas A. Melton, a leading stem cell researcher who co-directs the institute.

The announcement comes as the future of federal funding for embryonic stem cell research hangs in doubt. A federal judge stunned the field Aug. 23 by ruling that the Obama administration's more permissive policy for funding the research violated a federal law barring taxpayer money from being used for studies that involve destroying human embryos. An appeals court Tuesday let the funding continue until the case is resolved.

Opponents of human embryonic stem cell research seized on the development as the most convincing evidence yet that the morally questionable cells are unnecessary.

"With each new study it becomes more and more implausible to claim that scientists must rely on destruction of human embryos to achieve rapid progress in regenerative medicine," said Richard M. Doerflinger of the U.S. Conference of Catholic Bishops.

Rossi and other researchers, however, said that embryonic stem cells are still crucial because, among other things, they remain irreplaceable for evaluating alternatives.

"The new report provides a substantial advance," said National Institutes of Health Director Francis S. Collins. "But this research in no way reduces the importance of comparing the resulting iPS cells to human embryonic stem cells. Previous research has shown that iPS cells retain some memory of their tissue of origin, which may have important implications for their use in therapeutics. To explore these important potential differences, iPS research must continue to be conducted side by side with human embryonic cell research."

In 2006, researchers discovered that they could coax adult cells into a state that appeared identical to embryonic stem cells and then, just like embryonic stem cells, morph these iPS cells into various tissues. But the process involved inserting genes into cells using retroviruses, which raised the risk that the cells could cause cancer. Since then, scientists have been trying to develop safer methods. Several approaches using chemicals or other types of viruses have shown promise. But none has eliminated the safety concerns, and most have been slow and balky.

Cell conversion

The new approach involves molecules known as "messenger RNA" (mRNA), which cells use to create proteins they need to carry out vital functions. Working in the laboratory, the researchers created mRNA molecules carrying the instructions for the cell's machinery to produce the four key proteins needed to reprogram into iPS cells.

After tinkering with the mRNA molecules to make signals that the cells would not destroy as dangerous invaders, the researchers found that a daily cocktail of their creations was remarkably fast and efficient at reprogramming the cells. The technique converted the cells in about half the time that previous methods did, about 17 days, and with surprising economy - up to 100 times more efficient.

"We ended up with so many colonies of cells all over the place that we had to stop the experiment," Rossi said.

Moreover, the cells had not experienced any disturbing changes in their DNA caused by previous methods and appeared much more indistinguishable from embryonic stem cells than iPS cells created using other methods. In addition, the researchers went one step further and showed that they could use the strategy to quickly and easily convert the iPS cells they created into a specific cell types - in this case muscle cells.

"If you put all these things together, several of the major hurdles toward clinical translation of iPS cells are addressed by this technology," Rossi said. "That's what we've very excited about."

Others agreed. Lanza, for example, called the approach "almost too good to be true," saying it evoked the magical alchemy of "turning lead into gold."

"The ability to safely and efficiently generate patient-specific cells has the potential to transform transplantation medicine," Lanza said.

In an e-mail, stem cell pioneer Shinya Yamanaka of Kyoto University in Japan, who helped discover iPS cells, said he plans to try the technique in his lab.

"The standard method to generate [iPS cells] for clinical applications has yet to be established," Yamanaka wrote. "I think this method has the potential for it."

Rossi said the approach should also be useful far beyond stem cells by offering a way to treat any genetic condition in which a protein is missing, deficient or defective.

"It has amazing potential in the therapeutic realm," Rossi said.

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