Mar. 20, 2003 CAMBRIDGE, MA – Only 1 percent to 3 percent of animals cloned from adult cells survive to birth; many die mysteriously very early in development, around the time of implantation. A new study suggests that a set of genes important in early development fails to reactivate in adult, or somatic, cell-derived clones, a finding that could help scientists skirt a major roadblock in cloning.
"Most animals cloned from somatic cells fail in all seven species, while animals cloned from embryonic stem cells survive much better," said Rudolf Jaenisch, a researcher at Whitehead Institute for Biomedical Research and co-author of the new study, published in the current online issue of the journal Development. "We wanted to know why embryonic stem-cell derived clones survive so well while those derived from somatic cells do so poorly."
Scientists already knew that among those genes essential to normal embryonic development is the Oct4 gene, which prompts embryos to create pluripotent cells – cells that can form any tissue in the body. Researchers working with Whitehead Institute member David Page identified more than 60 genes that are expressed in normal mouse embryos. With an eye toward the Oct4 gene, they whittled the larger set of genes down to 10 that behave similarly to Oct4.
A team of scientists at Whitehead Institute and the University of Hawaii cloned two types of mouse embryos: one derived from embryonic stem cells and another from somatic cells. Scrutiny of the clones' genetic activity revealed that those made from embryonic stem cells expressed all 10 genes normally, while only 62 percent of somatic cell-derived clones correctly expressed the genes, said Alex Bortvin, a postdoctoral associate at Whitehead Institute and lead author of this new paper.
"This finding suggests that other genes that function together with Oct4 in control of early development also might be inefficiently expressed in somatic clones," Bortvin said.
Because the genes are involved in early development, they are turned off in adult cells. But as the debate over embryonic stem cell research continues, scientists must look to adult stem cells for cloning studies that could yield vital information about disease and cell development. So, figuring out how to help somatic cell-derived embryos survive to birth is high on the minds of researchers such as Jaenisch and his colleagues.
The scientists also are curious about the role Oct4-related genes play in pluripotency development, not an aim of this latest study.
"The functional importance of these genes has yet to be fully investigated," said Bortvin, whose future research will involve a deeper analysis of the function of Oct4-related genes.
At first glance, it may appear that the clones' failure to turn on this set of genes is the key to understanding early clone development failure. But the researchers are careful to note that while it may be possible to figure out a way to reactivate Oct4-related genes in clones created from somatic cells, that likely won't solve the problem of clone survival.
"There are hundreds of genes that are not correctly expressed in cloned animals," said Jaenisch, whose interest lies in therapeutic cloning designed to study disease. "The issue now is to make cloning more efficient."
This study, which is available now online, will be published in the mid-April print edition of the journal Development. Study co-authors include Kevin Eggan with Whitehead Institute; Helen Skaletsky and Deborah Berry, both with the Howard Hughes Medical Institute and Whitehead Institute; and Hidenori Akutsu and Ryuzo Yanagimachi, both with the University of Hawaii. The research was supported by the Howard Hughes Medical Institute and the National Institutes of Health.
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