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Reprogramming complicates stem cell debate

This may sound like a widely exaggerated vision of the future, based on the politically controversial use of stem cells extracted from made-to-order human embryos. But that assessment would be wrong on two counts: First, somatic cell reprogramming avoids the political controversy. And second, it's sounding less and less like a wild exaggeration with each passing month.

In fact, experts on both sides of the stem cell debate say the scientific hopes for somatic cell reprogramming, also known as dedifferentiation, are rising sharply — although they caution that much more work remains to be done.

"Just a few years ago, it was beyond the reach of the existing science at the time ... almost like alchemy, where you're trying to turn lead into gold," said Dr. Robert Lanza, vice president of medical and scientific development at Massachusetts-based Advanced Cell Technology.

But today, new tools have changed the landscape: "Our group, and I know at least two or three others, are playing with different techniques, and it's very clear that something is going on here. We're definitely getting reprogramming," Lanza said.

Dr. Leon Kass, chairman of the President's Council on Bioethics, sees cell reprogramming as the "most exciting new development" in stem cell research.

"I think that's where the gold is buried," he told

The research is already having an effect on the political debate, even as Congress considers the Castle-DeGette bill, H.R. 810, to widen federal support for human embryonic stem cell research. On the political landscape, the science of cell reprogramming plays into the central controversy over stem cell research.

Science and politics

Stem cells are the master cells that replenish all the body's tissues, from skin and blood to the brain and heart. In children and adults, particular types of stem cells are distributed throughout the body, and are specialized to create particular types of tissues. But in the early embryo, all-purpose stem cells can make virtually any kind of tissue, a quality known as pluripotency.

Currently, the only sure way to get pluripotent stem cells is to extract them from surplus frozen embryos or from embryos created through nuclear transfer — a procedure also known as therapeutic cloning.

Either way, the process of extraction destroys the embryo — and critics of the procedure see that as tantamount to abortion. Thus, they emphasize alternate ways to take advantage of "stemness" — by using less versatile adult stem cells, or umbilical-cord blood, or cells from a newborn's placenta, or exploring different avenues of research.

One of the bills proposed as an alternative to the Castle-DeGette bill, H.R. 3144, would fund four different approaches cited by the President's Council on Bioethics:

  • Harvesting stem cells from frozen embryos that are considered "dead" and thus unsuitable for implantation in the womb.
  • Taking one cell from an embryo at the eight-cell or 16-cell stage, known as the blastomere stage, when the rest of the cells could still develop into a viable fetus. This procedure is already done for a type of test called preimplantation genetic diagnosis or PGD.
  • Genetically or biochemically altering cells to create an embryo-like tissue that has no chance of developing into a fetus, but yet produces embryonic stem cells.
  • Reprogramming garden-variety cells — somatic cells — so that they have the pluripotent characteristics of embryonic stem cells.

The first three approaches have raised questions from one side or the other in the stem cell debate. For example: How do you determine if an embryo is dead, and can useful cells really be harvested from such an embryo? What medical risks and moral issues are involved in taking one cell from an early embryo? Would genetically altering cells create a kind of "Franken-embryo," sparking a new set of ethical concerns, and would the stem cells taken from such an altered cell mass even be safe for medical use?

Reprogramming, however, would win support from all sides — if only it could be done.

New signs that it can be done

In the three months since the President's Council on Bioethics issued its report on alternative approaches to stem cell research, at least three research studies have revealed that the field is "moving much more rapidly than we had any reason to suspect," said Kass, the council's chairman.

What's more, researchers are hinting that yet more dramatic studies will be coming out in the weeks and months ahead.

"You'll start seeing publications in the next year," Advanced Cell Technology's Lanza said.

Among the researchers cited by Kass are:

  • Dr. Yuri Verlinsky of Chicago's Reproductive Genetics Institute, who says he has produced a dozen new human stem cell lines by taking a stem cell from an existing line, removing its nucleus, then fusing it with a somatic cell — a skin cell, for example. "The result is a cell which is genetically like the skin cell of the donor, but retains the stem cell properties of the original," Kass said. Such research would be eligible for federal funding today if it is carried out with the federally approved stem cell lines, he said.
  • Alan Trounson of Australia's Monash Institute of Reproduction and Development, who put mouse stem cells in a centrifuge, separated out bits of their nuclear material, then fused those bits with adult mouse cells. The process "produced cells that carry the properties of the adult cell but ... have reverted to having the functional properties of stem cells," Kass said.
  • Dr. Kevin Eggan of Harvard University, who has conducted cell fusion experiments with human cells to produce a hybrid that has the genetic characteristics of the adult donor cell but the regenerative characteristics of stem cells. "He's got cells that have the nuclei of both, and he's not yet figured out how to get the stem cell nucleus out of there," Kass said.

There are also more speculative strategies: Some researchers are looking into a cloning technique with eggs, or oocytes, that are modified so that they wouldn't produce viable embryos. The idea, known as oocyte-assisted reprogramming, has attracted interest from Kass and other bioethicists who are opposed to "traditional" nuclear transfer techniques. However, other researchers think the concept raises more ethical problems than it resolves.

Lanza favors another technique, called parthenogenesis, in which an egg is coaxed to start dividing without being fertilized by sperm. "It does have the ability to create stem cells," he said — and theoretically, the resulting cells would pose less risk of tissue rejection.

"With parthenogenesis, we could create a small, manageable cell bank that would match 70 to 80 percent of the population," he said. However, the technique has not yet been successfully applied to produce human stem cells.

One way or another, most top researchers are devoting at least some effort to the puzzles of reprogramming, which Lanza called the "holy grail" of the stem cell quest.

The path to the grail

Although virtually no one disagrees with the view that the quest for reprogramming is well worth pursuing, there is wide difference of opinion about how to get to the grail.

The way Kass sees it, focusing on the alternate roads to reprogramming could provide a short-cut around the ethical problems posed by the use of frozen embryos or cloned embryos.

"Wouldn't it be wonderful if scientific ingenuity ... comes to the table and says, 'Look, we're going to find a way to get exactly what we want scientifically, in a morally uncontroversial and unproblematic way that all of our fellow citizens can enthusiastically support, and that will not leave a bitterly divided polity,'" Kass said.

But some scientists fear that lawmakers would use support of the alternate approaches as a political lever — to divert attention from embryonic research, to keep the current limits on federal funding in place, and perhaps even to tighten restrictions on research into embryonic stem cells and therapeutic cloning.

"What a lot of people would like to see done is a law banning the use of nuclear transfer in medicine, and not allowing new federal money for new stem cell lines," said Michael West, Advanced Cell Technology's chairman, president and chief scientific officer.

Most researchers would say all the avenues to stem cell therapies — ranging from embryonic research to adult stem cells and reprogramming — should be pursued. If resources are diverted from studies using human embryos, West said, it would hold back scientists just when the first fruits of their labors were about to come into view.

"Nuclear transfer is sort of a miracle. It's magic. We really don't know how it works," he told "It's a cellular time machine, a way of taking the cell all the way back to the beginning of life. It's this gift to mankind, and it's like someone is saying, 'Yeah, but you can't use it. Go figure out how this time machine works, and make it work some other way.'"