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Research questions remain following stem-cell breakthrough

Superlatives reigned last week as scientists and political activists celebrated a breakthrough that could end America’s pitched battle over stem cells taken from human embryos.

Not so fast, experts in the field are cautioning this week as they launch science’s laborious ritual of scrutinizing and testing new discoveries.

“This is important new technology and it will affect a whole range of projects with stem cell biology around the world,” said Jonathan Slack, who directs the Stem Cell Institute at the University of Minnesota.

But it is “premature to say that never again will any biological research be done” with cells from human embryos, he said.

For some time to come, the human version of the stem cells will be the “gold standard to which we can compare these new cells,” said Dr. Dan Kaufman, who works in one of two University of Minnesota labs where human embryonic stem cells are used for medical research.

“There still are a lot of questions about these cells,” Kaufman said.

The news trumpeted last week was that scientists at the University of Wisconsin-Madison and Kyoto University in Japan had created the equivalent of embryonic stem cells from ordinary adult skin.

Slack predicted it will take up to a year to resolve two problems that were embedded in the scientific reports.

Jonathan Slack
Courtesy of the University of Minnesota
Jonathan Slack

Key problems
One problem is the abysmal success rate in the initial experiments. The breakthrough technique involved inserting four genes into skin cells to reprogram them. It worked in about 1 in every 10,000 of the cells that got the genes.

“We need to know the variables that explain those odds,” Slack said.

A second problem is that the research teams used a retrovirus to ferry the genes into the cells’ chromosomes. Such viruses sometimes cause mutations that lead to cancers. Scientists who published the landmark studies acknowledged this problem and said the search for a different gene insertion technique already is underway.

“Everybody wants to resolve that problem,” Slack said.

But those obstacles probably are temporary road blocks rather than permanent barriers to research, he said.

A longer-term question that will determine the full reach of the discovery is whether the reprogrammed cells differ in subtle ways from true embryonic cells.

The question is especially important for studies of human development.

Only recently have scientists been able to explore the amazing process by which the complex human body, with its myriad of fine-tuned functions, grows from a few microscopic cells — how some cells specialize for the work of keeping a heart beating while others take on the tasks of sheathing the body with skin capable of constantly renewing itself.

Dr. Dan Kaufman
Courtesy of the University of Minnesota
Dr. Dan Kaufman

‘Perfect model’
More than curiosity is at play. The studies are expected to eventually propel medicine into an era that would make many of today’s approaches seem primitive guess work.

And embryonic stem cells are seen as the key to that future.

“Human embryonic stem cells are the perfect model,” Kaufman said.

It is unclear at this point whether a reprogrammed cell would correctly follow every minute step in the development process, turning on specific genes precisely when their work is needed to make all of the body’s active cell types.

Still, the reprogrammed cells may be quickly useful for many avenues of research, especially when it comes to creating models for better understanding of diseases.

Kaufman described two of his projects to illustrate where reprogrammed cells might be useful and where scientists may opt to continue work on true embryonic cells.

One project where the reprogrammed versions could be a boon involves creating research models of genetic diseases such as cystic fibrosis and sickle cell anemia. The ideal models would be embryonic cell lines created from patients affected by the disease.

“But getting the embryos is hard,” Kaufman said. “If we could do the same thing from a skin biopsy of these patients, that would be tremendous.”

For a different project, though, Kaufman was lukewarm about shifting to the reprogrammed cells with all of their unknown baggage. His lab already is getting promising results from efforts to develop a blood cell Kaufman calls a “natural killer.” It attacks tumor cells in animal models, and if the same holds true in humans it could provide new therapies against cancer. Embryonic stem cell lines are the raw material for the research, and shifting to unproven cells could risk setting the project back.

“It’s still quite early to know what these cells are all about,” Kaufman said.

He is keeping an open mind, though.

“If it does pan out and there are advantages, then we would go with whatever works the best,” he said.

The one certainty at this point, Slack said, is that none of the cells — true embryonic or reprogrammed — is going to deliver instant results for patients.

“If we are talking about new treatments in the clinic, we still are looking at 10 years,” he said.

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