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Stem Cells from Skin Cells

Success may help erase practical hurdles—if not ethical ones—to cloning human embryonic stem cells to study and treat degenerative disorders
reprogrammed cells



MARIUS WERNIG AND ALEXANDER MEISSNER
Two methods for creating embryonic stem cells just got a big boost. In one development, three teams of scientists report they have turned back the clock on mouse skin cells, changing them into embryolike cells by introducing a cocktail of four genes. "You can now basically reverse development in a culture dish," says Marius Wernig of the Massachusetts Institute of Technology's Whitehead Institute for Biomedical Research, a member of one of the teams.

If extended to humans, the technique would allow researchers to create potentially all-purpose stem cells without using embryos. However, experts say they will still have to study cells from human embryos to figure out how to make the jump to humans and, beyond that, how the two kinds of cell would stack up as ways of regenerating diseased tissue.

In a second approach, a group of researchers successfully cloned mice from fertilized embryos instead of unfertilized eggs. Because fertilized human embryos are far more accessible than unfertilized eggs, which cannot be frozen and stored, extending the result to humans could lower the practical barriers against creating human embryonic stem cells to study and potentially treat disease.

Neither technique works outside of mice yet, but researchers are optimistic they can apply at least some of the findings to human cells. "There's good reason to believe the rules will be the same" for human and mouse cells, says stem cell biologist Kevin Eggan of the Harvard Stem Cell Institute (HSCI).

Both studies hinge on the concept of nuclear reprogramming, or removing the molecular changes that keep adult DNA from returning to the embryonic state. The traditional way to reprogram a cell is to remove its nucleus, which contains the DNA, and inject it into an unfertilized egg that has had its own nucleus removed—in other words, cloning. Cloning researchers had thought that only unfertilized eggs were capable of reprogramming adult DNA.

Stem Cells Sans Embryos

Imagine researchers' excitement, then, when Kyoto University's Shinya Yamanaka reported last year that his group had created embryolike cells directly, without transferring chromosomes, simply by injecting mouse fibroblast cells with four genes that are active in embryonic cells but not in adult ones. The reprogrammed cells did not contribute to adult tissues when injected into embryos, however, which is the hallmark of embryonic cells.

Three groups—those of Yamanaka, Whitehead's Rudolf Jaenisch and Konrad Hochedlinger of the HSCI—report they have independently surmounted that obstacle by selecting reprogrammed cells that produced molecules more characteristic of embryonic cells. When harvested after several weeks and injected into blastocysts, the cells contributed to all three of the embryo's layers and in some cases turned up in the offspring of blastocysts that reached adulthood.

The reprogrammed cells are "almost indistinguishable" from embryonic cells, says stem cell researcher Alex Meissner, part of the Whitehead team, which has published its results online today in Nature alongside those of Yamanaka's group.

The next step is to see if the process works and is safe in human cells. "If we're lucky and it's just the [same] four factors, it will be very quick [to happen] in humans," Meissner says. But researchers will have to figure out how to eliminate the viral DNA used to introduce the genes, which in Yamanaka's experiments led to cancers in 20 percent of mice grown from blastocysts.

Ethicist Nigel Cameron of the Illinois Institute of Technology, an opponent of embryonic stem cell research, praises the reprogramming findings. But Hochedlinger, whose group's paper appears in a new journal called Cell Stem Cell, stresses that researchers still need to study human cells to learn how to reprogram them and have no idea yet which approach would work better in the long run.

"It would be a big mistake," Meissner notes, "to say, 'now we can generate these [reprogrammed] cells, [so] we have to stop all human embryonic stem cell research.'"

Stem Cells from Fertilized Eggs

New results by Eggan and his HSCI co-workers may have made that research easier by showing how to extract stem cells from single-celled fertilized embryos, or zygotes, which researchers have long considered impossible.

Collecting unfertilized eggs has proved challenging, Eggan says, because donors are not compensated beyond the cost of the extraction procedure. A year after receiving approval to study cloning in human cells, "we have yet to find a woman who's willing to participate as an egg donor," he says.

Eggan's group hit on a way around this barrier by injecting the chromosomes from embryonic and adult mouse cells into zygotes that were chemically frozen midway in the process of dividing into two cells. Twenty percent of the cells cloned in this way grew into early embryos, called blastocysts, and 5 percent of them yielded embryonic stem cells, which is comparable with results obtained from unfertilized eggs.

When implanted into female mice, nine of 174 cloned blastocysts survived until birth, although they died soon after, possibly because the reprogramming was incomplete, the team notes in a third Nature report.

The researchers believe the experiment worked because the zygotes were paused at a stage in which the nucleus has dissolved and the molecules responsible for reprogramming are mixed throughout the cytoplasm where they can affect the injected DNA. They believe prior experiments failed because researchers removed the reprogramming factors from the zygotes along with their nuclei.

It may sound potentially more ethically troublesome to clone stem cells from a fertilized egg than an unfertilized one. "This certainly does not lessen the ethical issues at stake," Cameron says, because extracting stem cells from the reprogrammed embryo would destroy it.

It benefits researchers, however, because Eggan's group found that the technique works on zygotes carrying an extra set of chromosomes, which can occur if two sperm fertilize an egg. Up to 5 percent of all zygotes have extra chromosomes and they may exist in the tens of thousands in the banks of in vitro fertilization (IVF) clinics, whic routinely discard such zygotes because they develop abnormally, Eggan says. His team, he says, has already begun studies on donated fertilized eggs.

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