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Mice Cloned From Mature Cells

Two-step method moves beyond embryonic stem cells, says study

SUNDAY, Feb. 10, 2002 (HealthDayNews) -- In what could be another breakthrough in genetics, researchers have cloned animals from fully mature adult cells, not embryonic stem cells.

However, there appears to be a caveat. The two-step method requires coaxing the mature cells back to the embryonic phase before they are implanted in an embryo.

The cloned mice produced by the study – the first ever cloned from lymphocytic cells, the white blood cells active in immune defense – raise hopes of producing cells for medical applications in humans, say the researchers.

The research, performed at the Whitehead Institute for Biomedical Research in Cambridge, Mass., will be published online tomorrow by the journal Nature.

Gail R. Martin, a professor of anatomy at the University of California, San Francisco, is familiar with the study. "They were able to prove unequivocally that you can use a differentiated cell nucleus to produce an intact animal," Martin says.

Although Dolly the sheep was supposedly cloned from a differentiated cell, the cloning efficiency was very low, Martin notes.

"You could always argue that in the population from which they took the nucleus, that there were stem cells in the population," she says. "The one that worked … could have potentially been an undifferentiated stem cell."

Konrad Hochedlinger and his co-author, biology professor Dr. Rudolf Jaenisch, wanted to find out whether cells that had already matured into fully specialized, differentiated cells could be used to make a cloned animal.

The researchers used a DNA marker found only in mature lymphocytic cells. These cells, which include B and T cells involved in the immune system, undergo "genetic shuffling" that reorganizes the immunoglobulin genes in their DNA in a way that can't be reprogrammed.

If an animal could be cloned from those cells, in theory, every cell in the cloned animal's body should carry this DNA marker.

According to Martin, "if you make a mouse that has that rearrangement, it can only have come from a cell that was differentiated."

In conventional cloning, an embryo carrying the genetic material from a donor cell is transferred into the uterus of a surrogate female, which carries the animal to term.

The two-step process used in this latest experiment was different.

The researchers directed the lymphocytes to become embryonic stem cells, and then injected those into carrier embryos, which developed into healthy, fertile mice. All of the animals carried the signature DNA marker from the original lymphocytes.

Hochedlinger says that because lymphocytes are rather inefficient for making cloned embryos, compared to other cell types such as skin cells, manipulating them to become ES cells changes is critical. "Embryonic stem cells … are much more efficient in generating those cloned embryos," says Hochedlinger.

"Biologically, it tells you that the DNA of the fully specialized cell still has all the components which are necessary for developing an entire animal," says Hochedlinger. "All the previous experiments on cloned animals have not really answered that [question]."

"This is important to know if you want to repeat it for clinical purposes to induce [embryonic stem] cells to become neurons or heart cells or skin cells for medical purposes," he says.

Recent studies have identified methods for creating embryonic stem cells from unfertilized monkey embryos, as well as a way to stimulate those cells to produce dopamine, raising hopes for Parkinson's disease therapies.

However, a recent report by a U.S. government advisory panel warned the federal government to ban human cloning, in light of the controversy and technical hurdles that continue to surround this area of science.

What To Do

Check out this cloning primer from Oak Ridge National Laboratory, or take a look at this illustration of the cloning process used to create Dolly the sheep in Scientific American.

Ethical concerns about cloning a human being are a controversial issue. Here's an article on the technical limitations from the Roslin Institute, home of Dolly.

SOURCES: Interviews with Konrad Hochedlinger, M.Sc., visiting scientist, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Mass.; Gail R. Martin, Ph.D., professor, Department of Anatomy, University of California, San Francisco, San Francisco, Calif.; Feb. 10, 2002, Nature online
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