Cloning Clue Uncovered

It may be safer to clone humans than sheep, new research contends, because people don't have a genetic defect implicated in producing oversized offspring.

However, cloning experts cautioned that the finding, published in Wednesday's issue of the journal Human Molecular Genetics, does not mean cloning would necessarily be easier in humans.

Just last week, scientists debated bitterly over cloning at a National Academy of Sciences seminar in Washington. A central issue was whether cloning would produce humans with severe defects.

At the conference, at least three scientists indicated they were pressing ahead with plans to attempt to clone humans, perhaps by the end of this year. One hinted that experiments to that end are already under way.

Concern over human cloning prompted the House of Representatives to ban all forms of it last month. Some members wanted cloning for research allowed, but the ban covers both research and reproduction.

Normal reproduction involves the pooling of genes carried in chromosomes provided by the male and females parents. Cloning takes genes from just one person.

Scientists don't know all the factors that determine whether cloning succeeds or fails, or how important each factor is.

The gene in the research, insulin-like growth factor II receptor (IGF2R), is a suspect in some of the problems in cloned animals, but it is not the only one, said Ian Wilmut, a professor at the Roslin Institute, the home of Dolly the sheep, the first mammal to be cloned from an adult.

"I hope this will not be used to give encouragement to those who wish to clone humans," Wilmut said from his lab in Edinburgh, Scotland.

The research, by scientists at Duke University Medical Center in Durham, N.C., involved the working of the IGF2R gene, which suppresses tumors and regulates fetal growth.

"There are going to be other things that potentially go awry. You're not home free, assuming that you wanted to do this (cloning), but you're getting closer," said Randy Jirtle, one of the Duke researchers.

Jirtle, a radiation oncologist, and Keith Killian, a molecular evolutionist, found that humans, other primates and their closest relatives have two activated copies of the gene. People get one functional copy from each parent.

However, sheep, pigs, mice and nearly all non-primate mammals receive only one working copy of the gene. The other copy, from the father, is intact, but permanently switched off. That is caused by a phenomenon known as gene imprinting, where the gene carries chemical markings that turn off its function.

With one copy of the gene knocked out, the animals are more prone to developing cancer and, if cloned, to suffer from complications like overly large offspring, underdeveloped lungs and enlarged hearts, the scientists said.

"You hear over and over that we've cloned sheep, mice, cows, pigs and they've all hd this problem of large offspring syndrome and therefore you will have these problems in humans. This shows that you don't necessarily have these problems," Jirtle said.

Failure of placental development is very frequent in cloned livestock, and this probably reflects errors in the working of other genes specifically involved in making the blood vessel network of the placenta, Wilmut said.

Also, oversized cow fetuses are apparently the result of overactivity in the IGF2 gene itself, not underactivity of the receptor, he said.

"It seems that a little knowledge is a dangerous thing and the authors have allowed themselves to over-interpret their interesting findings," Wilmut said.

Lee Silver, a molecular biologist at Princeton University, added that the IGF2R gene is just one of many genes that get silenced in animals and could potentially cause problems in cloning. Until scientists discover whether those other genes are switched on or off in humans and how important a role they play in the overall success of cloning, it will remain unclear whether cloning will be safer in humans than in other animals.

Killian said the findings also could revive several potential drugs that were discarded after being tested in mice and other animals.

"Clinical development of hundreds of potential disease-treating drugs have been abandoned after rodent studies have shown them to be potential carcinogens — studies that might have had a different outcome if rodents possessed two functional copies of the tumor suppressing gene, Killian said.

The study was paid for by the U.S. National Institutes of Health, the U.S. Department of Defense and Sumitomo Chemical Co. Ltd.

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