Another Stem-Cell Setback

By Amy Tsao More than three years ago, the Bush Administration imposed restraints on public funding for embryonic stem-cell research. The logic behind this was fairly straightforward. To create repositories of versatile stem cells for use in biomedical research, scientists must destroy human embryos donated by fertility clinics and other sources. Harvesting the cells is thus a controversial procedure -- one the President had no wish to endorse. So he determined that scientists receiving federal grants should simply make use of "cell lines" that existed at a number of U.S. research laboratories prior to August, 2001.

At that time, many scientists worried that there would not be adequate supplies of embryonic stem cells, which have the ability to mature into any of the body's many types of tissues, and therefore may possess almost magical potential to repair diseased organs, including hearts and brains. Scientists also feared that the cell lines already under development might prove unsuitable for use in human subjects.

"SERIOUS TECHNICAL PROBLEM." Now their fears seem to be at least partially justified. Reporting in the February issue of Nature Medicine, researchers from the University of California at San Diego and the Salk Institute say they have found a contaminant -- a nonhuman molecule called Neu5Gc -- in one of the federally approved human embryonic stem-cell lines.

The problem may have occurred during the process of growing the stem cells. For most of the federally approved cell lines, this process makes use of cell cultures that include proteins and other nutrients derived from mouse cells. The Neu5Gc molecules may well have originated in those materials.

"What we have identified is a serious technical problem," says Ajit Varki, professor of cellular and molecular medicine at UCSD and one of the researchers involved in the study.

CALIFORNIA'S PRECEDENT. This study provides the first concrete evidence that at least one important stem-cell line, and potentially all of the government-approved ones, is unusable in human tests. That is because the contaminated cells are likely to cause an immune reaction in patients, says Evan Snyder, head of the stem-cell program at the Burnham Institute, a biotech research organization in La Jolla, Calif.

In addition to potential harm to humans, the presence of these molecules could taint the conclusions scientists reach on the basis of their observations. "We had nebulous complaints before [of immunologic problems], but they were hypothetical," says Snyder. "This study is a concrete point of data."

The finding is already fueling frustration among academic researchers in the U.S. And it is likely to accelerate efforts by states to fund their own stem-cell initiatives on the model of California's Proposition 71, as well as programs at privately backed companies. "We need to look at approaches that are not within the boundaries of federal funding," says David Scadden, co-director of the Stem Cell Institute at Harvard.

TROJAN HORSES? There's nothing wrong with state-funded or private programs, of course. In fact, they may go a long way to offset the federal government's underwhelming commitment to this important field. Still, many of these efforts are likely to be focused on near-term commercial development, not on basic science. And no matter how you slice it, it's unfortunate that U.S. laboratories backed by the most prestigious federal grants will be placed at a disadvantage, vis-a-vis other researchers.

Though the promise that stem cells could help cure debilitating diseases is real, scientists have long worried that embryonic stem cells might trigger harmful immune reactions, says Scadden. Until now, the biggest concern was that they might release substances that the adult immune system would be unable to process. The findings by the UCSD and Salk researchers point to "something even more foreign," says Scadden.

Molecules from the Gc family appear on the surface of all cells. But animal variations of the sort described in Nature Medicine could conceivably function as Trojan Horses, says Varki, sneaking viruses or other pathogens into a patient's cells. says Burnham's Snyder: "We need new cell lines produced under better conditions."

"ELEGANT, CLEAN, AND PURE." Researchers with federal grants are barred from creating new cell lines. But plenty of other scientists are free to do so. In Singapore, for example, scientists from various countries are using all-human materials to grow embryonic stem cells. (See BW, 1/10/05, "Asia Is Stem Cell Central").

In California, Burnham researchers are devising ways to grow cells in environments completely free of animal or human-based cultures. Meanwhile Geron (GERN) in Menlo Park, Calif., grows embryonic stem cells using a recombinant protein and a growth factor. "It's elegant, clean, and pure -- and it works," says Geron CEO and President Tom Okarma. "All of our lines have been propagated in that way for years." The contamination problem highlights how one important segment of the U.S research community continues to be hamstrung. But it also highlights the fact that there is no shortage of ingenuity in this nascent field. Tsao is a reporter for BusinessWeek Online in New York.

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