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Clones May Be Trouble-Prone

Copycat mice look OK, but may have serious gene errors

THURSDAY, July 5, 2001 (HealthDayNews) -- Cloned mice that seem outwardly normal may bear serious gene-related errors that could affect their development, a new study by U.S. researchers says.

Mice derived from embryonic stem cells look fine on the outside, but on closer inspection the rodents have abnormalities in certain instructions linked to proper growth, says the study, reported this week in Science magazine.

"This is all the more reason to be wary for anyone who is attempting do human cloning," says David Humpherys, a graduate student at MIT's Whitehead Institute and a co-author of the paper.

The flaws aren't in the cloned animals' structural genes but in "epigenetic" information that helps determine if those genes are switched "on" or "off." While the mice are outwardly normal, Humpherys says, it's extremely difficult if not impossible to know whether the errors have caused cognitive or behavioral changes.

The study may be further evidence of the potential hazards riddling cloning, but the researchers stress that it doesn't suggest stem cells would face the same problems when used in the much narrower context of disease therapy. Stem cells can be coaxed into becoming virtually any cell in the body, and may one day be used to treat Parkinson's disease, spinal cord injury, and a vast array of other conditions that require re-growing tissue.

The Bush administration is now considering whether to fund research on human embryonic stem cells. Many conservatives oppose such research, arguing that destroying an embryo, even in the name of a search for cures, is effectively the murder of a potential life.

To sidestep the issue, scientists have begun exploring the prospects of using stem cells derived not from embryos but from adult tissue -- raising the possibility that a patient could be his or her own cell donor.

Since the first cloned mammal, Dolly the sheep in 1997, researchers have replicated a veritable ark of creatures, from mice to monkeys. But cloning procedures are far from perfect: Many cloned embryos die early in pregnancy, and offspring that do result are often plagued with a variety of health problems, from respiratory failure to extreme growth.

In the latest work, Rudolf Jaenisch and his colleagues at the Whitehead Institute and the University of Hawaii found that mouse embryos cloned from embryo-derived stem cells were extremely unstable. However, this instability resulted from flaws in the donor cells, not the cloning process.

Following a half-dozen developmental genes "imprinted" by epigenetic instructions, they saw that the dividing stem cells shed these important cues apparently at random. The mice that ultimately survived into adulthood also had imprinting errors, but they somehow managed to overcome them.

"It seems that these mice are rather tolerant to these errors," Humpherys says. "If one gene's not expressed correctly, others can compensate."

Tony Perry, an embryologist at Advanced Cell Technology, a Worcester, Mass.-based cloning and stem cell company, says the latest findings aren't bad news for his firm or others like it. "On the contrary," says Perry, "this is very exciting for us. This paper shows that you actually have an imbalance of imprinting and still have full development" of a cloned animal.

Perry, who is familiar with the findings, says it will be important to learn whether the same imprinting errors that occur with embryonic stem cells also crop up with clones derived from adult stem cells. The MIT study did not address that question.

What To Do

For more on cloning, check out the U.S. Department of Energy or this article in Scientific American.

To learn more about stem cells, try the National Institutes of Health or the U.S. Department of Health and Human Services.

SOURCES: Interviews with David Humpherys, graduate student, MIT's Whitehead Institute, Cambridge, Mass., and Tony Perry, Ph.D., Advanced Cell Technology, Worcester, Mass.; July 6, 2001 Science
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