GET WITH THE PROGRAM: In one of two new techniques that may lower the barriers to growing embryonic stem cells, three teams reprogrammed mouse skin cells to enter an embryonic state [above]. Image: 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.'"