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Biomedicine

Stem Cells without the Embryos

An easy method for reprogramming adult cells may resolve ethical objections.

Two groups of scientists appear to have independently achieved one of regenerative medicine’s holy grails: reprogramming human adult cells to behave like embryonic stem cells, without the use of an embryo or a human egg. The method could provide a way to make patient-specific stem cells, a feat not yet achieved in humans. Such cells could eventually be used for studying complex genetic diseases, or for cell or tissue transplants without fear of immune rejection.

Breakthrough cells: Researchers at the University of Wisconsin-Madison successfully reprogrammed skin cells (shown here) to act like embryonic stem cells. The method could provide a more efficient way to generate stem cells–one that doesn’t provoke ethical concerns.

The new technique also removes the major ethical objections to embryonic stem-cell research: the creation and destruction of human embryos. “It’s been 10 years since we derived the first embryonic stem-cell lines, which unleashed a storm of controversy that has lasted until today,” says James Thomson, a biologist at the University of Wisconsin-Madison who isolated the first human embryonic stem cells in 1998 and led the new work. “I believe these results are the beginning of the end of this controversy.”

Two groups–one led by Shinya Yamanaka at Kyoto University, in Japan, and one led by Thompson and Junying Yu at the University of Wisconsin–separately engineered human skin cells to express four different genes. For reasons not yet clear to scientists, exposing cells to these genes appears to turn back the developmental clock. Both groups found that the resulting cells exhibit two major properties that define embryonic stem cells. They are pluripotent, meaning that they can develop into any type of cell in the body, and they can divide apparently indefinitely in their undifferentiated state.

“I’d welcome this other method because it’s easier to obtain the material and doesn’t raise ethical questions that some find troubling,” says Doug Melton, director of the Harvard Stem Cell Institute. “Equally importantly, using this other approach should enormously increase the amount of funding available for the research.”

Embryonic stem cells have been the target of both hype and hope due to their potential ability to replace cells damaged in diseases such as Parkinson’s and diabetes. They are also the source of ethical controversy: the cells are derived from excess human embryos discarded after in vitro fertilization, and obtaining them requires destruction of the embryos. President Bush severely restricted federal funding of embryonic stem-cell research in 2001.

Beyond reprogramming’s potential impact on the ethical debate surrounding embryonic stem cells, one of its biggest advantages is that it provides an alternative way to produce stem cells that are genetically matched to an individual. Reprogrammed, pluripotent cells derived from an individual’s skin cells could eventually be used for tissue transplants without risk of immune rejection. Cells derived from someone with Parkinson’s or diabetes could provide scientists with new models for studying these complex genetic diseases. (See “Stem Cells Reborn” and “The Real Stem Cell Hope.”)

The only other way to produce such cells–human therapeutic cloning–carries its own technical and ethical issues, and has not yet been achieved. It also requires human eggs, which have proved to be extremely difficult to obtain. (See “Human Therapeutic Cloning at a Standstill.”) Ian Wilmut, the scientist who led the effort to clone Dolly the sheep, announced on Friday that he plans to focus his group’s efforts on reprogramming rather than on cloning.

But scientists urge the continued funding of embryo-based methods until more is known about these new types of cells. “Until the alternative is shown to produce the same kind of extremely versatile, normal cells that we derive from previously frozen human blastocysts, it would be unfair to patients to renounce that approach,” says the Harvard Stem Cell Institute’s Melton.

While the new cells look and act like embryonic stem cells, it’s not yet clear just how similar they are. “Most of the markers we know of in embryonic stem cells are expressed by these stem cells,” says the University of Wisconsin’s Yu. “But we really have no idea if there is a significant difference.” Initial experiments from Yamanaka’s Kyoto lab suggest that at least some differences exist: a screen of the expression of 30,000 genes showed that the pluripotent cells are similar but not identical to embryonic stem cells.

Both teams used viral DNA to introduce genes for four transcription factors–proteins that turn on other genes in the cell–into fibroblasts, a type of skin cell. (Two of these transcription factors were the same in both groups; two were different. All had previously been identified in embryonic stem cells.) Scientists theorize that when expressed in the adult cells, the transcription factors activate a genetic cascade that returns the cell and its DNA to an embryonic-like state.

When implanted into mice, the cells generated a ball of tissue containing multiple differentiated cell types, a standard test for cell pluripotency. Yamanaka’s team also showed that the cells could differentiate into muscle and nerve cells, employing the same protocols used with embryonic stem cells. The findings were published online today in the journals Cell and Science.

Before these cells can be considered for human therapeutics, the researchers will need to develop an alternative way to express the transcription factors. The viruses currently used can integrate into the genome and pose potential safety concerns. It’s not yet clear how difficult this will be to achieve, but Thomson says that his group and others are already working on this problem.

While much work remains to be done, Thomson says that the findings are likely to speed the pace of research by encouraging more scientists to study stem cells and by increasing funding for the field. “My personal barometer of optimism has gone up a lot,” he says. “I think young investigators avoided getting into this field because of the ethical issues … Now I believe more and more labs will move to this method.”

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