Stem Cells without Embryos

Can four little genes (or maybe six) really make the whole bitter debate about human embryonic stem cells go away?

Two separate teams of scientists are announcing this morning that they can create the precious cells, which have the potential to turn into any of the 200-plus kinds of cells in the human body, without producing, let alone destroying, human embryos, which until now have been the only source of embryonic stem cells. If they're right, and if the recipe works reliably, then stem cells could be created from cells no more ethically problematic than human skin.

Every cell of the human body contains the exact same DNA (sperm, eggs and red blood cells being the only exceptions)—that is, the complete human genome. But neither skin cells nor muscle cells nor liver cells nor any other specialized cell follows the whole program. Only fertilized eggs—the union of egg and sperm—do that, using all the genes to produce a complete individual. Because the vast majority of genes in adult cells are silent, no one has been able to take, say, skin cells and make them turn into any chosen kind of cell, such as neurons to treat patients with Parkinson’s disease. Only the cells in very early embryos—stem cells—can transform into whatever cell you want, and you all know the ethical problems that research on stem cells raises in some quarters.

If only it were possible to take one of those specialized, or differentiated, cells and roll back the clock, back to when that skin or kidney or liver or other cell was a stem cell and had that unlimited potential. According to this morning announcement, it is possible, and scientists in the U.S. and Japan have done it.

Researchers at the University of Wisconsin took human fibroblast cells, which form connective tissue (the scientists actually got the cells from foreskins; who said circumcision has no medical rationale?) and inserted four human genes into them. Previous studies by scientists at Kyoto University had identified proteins that can turn back the hands of time in mouse fibroblast cells. In 2006 the Japanese scientists identified genes for four of those proteins. This past summer, three teams of scientists announced that they had used that recipe to insert the four genes into mouse fibroblast cells, turning them into stem-like cells able to bloom into most or possibly all kinds of mouse cells.

In people, the Wisconsin scientists are now reporting, the four genes—called OCT4, NANOG, SOX2 and LIN28—re-programmed the fibroblast cells in exactly the same way, returning them to their embryonic state of virtually unlimited potential. The Kyoto group, not to be beaten to the finish line, is announcing essentially the same feat in online edition of the journal Cell, also today, though two of the genes the Wisconsin group inserted are different from those the Kyoto group used: OCT3/4, SOX2, KLF4, and c-MYC. The Kyoto group used skin from the face of a 36-year-old woman and another sample from a 69-year-old man.

If either of these recipes for producing “pluripotent” cells really works, notes the journal Science (where the paper describing the Wisconsin experiment is being published), we “would not need human embryos or [eggs] to generate patient-specific stem cells—and therefore could bypass the ethical and political debates that have surrounded the field for the past decade.” And that would mean that last week’s stem-cell news—that scientists at the Oregon National Primate Research Center had become the first to clone a primate (monkey) embryo and obtain embryonic stem cells from it—would be less important.

Ian Wilmut, the University of Edinburgh scientist who led the team that cloned Dolly the sheep, has told reporters that the Kyoto work so impressed him he has decided not to try the human version of the Oregon experiment—taking the nucleus of an adult human cell and inserting it into a human egg, in hopes that it will develop into an early embryo and yield custom-made stem cells. Instead, he is focusing on the Kyoto approach, reprogramming adult cells by inserting the turn-back-the-calendar genes.

Scientists will have to resolve which batch of genes is best at turning adult cells into pluripotent stem-like cells. (The Kyoto team had no luck using one of the genes, NANOG, that worked for the Wisconsin scientists, and the Wisconsin team had no success with the Kyoto group’s four genes, but say they may have gotten the proportions wrong.) Also, it would be far better to switch on these roll-back-the-calendar genes, which all cells contain but in inactive form, rather than inserting new, active copies with a virus, which can cause problems.

The impact on the stem cell debate remains to be seen, but already researchers are worried that significant progress on human embryonic stem cells (from early embryos) will soon find itself in the crosshairs even more than it has been. As scientists put it in a paper last month in Cell Stem Cell, “ some policymakers and citizens might be tempted to jump to the conclusion that research on human embryonic stem cells (hES cells) is unnecessary in light of” these advances in reprogramming adult cells to behave like embryonic stem cells, but that “would be a serious mistake.” Most important, they say, “progress toward socially beneficial applications of stem cell science would be indefensibly delayed if [reprogrammed]-cell research is pursued at the expense of further hES cell research. Research on [reprogrammed] cells has barely begun.”

It may turn out that the recipe for turning adult cells into stem-like cells is not reliable, or that using viruses to ferry in the turn-back-the-clock genes produces dangerous mutations or infections. But you can hear the debate turning even now.