Most or all of the human embryonic stem cell colonies approved for research funding under a new Bush administration policy have been mixed in the laboratory with mouse cells, which may create substantial hurdles for scientists trying to turn the colonies into treatments for Parkinson's disease, spinal-cord injuries and other ailments.
The cell colonies, or "lines," were created for early-stage research with no thought that they would become the only embryonic cells eligible for federal money. But that is the status President Bush conferred on them in his first prime-time address to the nation on Aug. 9.
The standard technique for creating human embryonic stem cell lines has been to extract cells from inside a microscopic embryo, then grow them atop embryonic mouse cells, known as "feeder" cells. The latter excrete some unknown nutritional or growth factor that helps the human cells stay healthy. Because they have been in close contact with mouse cells, the human cells pose a small but real risk of transferring potentially deadly animal viruses to people.
Because of that, under guidelines the Food and Drug Administration has been developing for several years, it would be difficult, though not impossible, to use the cells in human clinical tests.
Under the FDA rules, which are designed to prevent the accidental creation of a new plague, transplants of these embryonic cells into people would be treated as though they were "xenotransplants," or transplants of animal tissue. The guidelines impose stringent requirements on researchers and patients alike. They would likely rule out some groups of patients who might otherwise be eligible to participate in human stem cell tests -- notably, for instance, young diabetes patients whose disease can be treated in other ways.
The human embryonic stem cell lines reported in scientific literature were all grown in direct contact with mouse cells and might have picked up mouse viruses, which government officials acknowledged would bring them under the FDA policy.
Scientists are working on ways to grow human embryonic cell lines without using mouse cells, but any created after Bush's speech Aug. 9 would be ineligible for federal research money.
Patient groups and people who work with them expressed concern when told about the xenotransplant restrictions.
"This would be the exclamation point" on an already lengthy list of questions about the quantity and quality of the cell lines eligible for research funding under the Bush policy, said Kevin Ryder, a consultant to the American Cell Therapy Research Foundation, a New York foundation that supports research into many types of treatments using cells. "We would have a very difficult time getting those advanced into the clinical setting unless we get the FDA to make some exceptions down the road."
Most people on Capitol Hill are unaware of the issue, but as word of it began spreading late yesterday, some legislators expressed concern. "The president's going to have to make available lines of stem cells that will be available for the full measure of research anticipated," said Sen. John F. Kerry (D-Mass.) "If he doesn't, Congress will need to act to make that happen."
Jay Lefkowitz, a White House adviser who helped craft the Bush policy, said the administration was aware that the stem cell lines Bush approved for funding had been mixed with mouse cells and would come under the FDA's xenotransplant rules.
The White House concluded that the issue would not be a serious barrier at this stage, when scientists still need to do several years of fundamental laboratory work before human tests can begin, he said. By the time researchers are ready to begin those tests, he said, officials are confident that scientists will have found a way to grow stem cells without mouse cells, or will be able to work within the FDA's guidelines.
"President Bush has unlocked the door so that critical, basic research can be conducted in an area that is currently uncharted," Lefkowitz said. "To fulfill that mission, we believe the existing stem cell lines are more than adequate."
Opinion among scientists is mixed about how much of a problem the xenotransplant issue will be, but at the least, they say, it presents yet more practical difficulties in the execution of a policy already rife with them.
In the 15 days since Bush announced his policy, other lingering questions -- about how many cell lines exist, who owns them and how accessible they will be to academic scientists -- have gone largely unanswered by the National Institutes of Health and the Department of Health and Human Services. NIH administrators are negotiating with companies and labs to try to work out many of the details. Congressional hearings are scheduled in two weeks.
In an interview, a senior NIH administrator and an FDA regulator acknowledged that the xenotransplant issue could pose hurdles but said it was premature to speculate about how serious those might be.
"There is so little experience with these cells," said Lana Skirboll, director of science policy at the NIH. "There's a lot that needs to be done. I just think the scientific community is in a position that we have a lot more to learn."
FDA administrators who developed the xenotransplant policy declined to comment. But they pointed to written reports and meeting transcripts going back five years that make their position clear. The documents, posted on the Internet, leave little doubt that stem cells grown by current techniques would be covered. Although the guidelines are not final, officials said the agency has been following them.
Some laboratories that work with stem cells appear to be unaware of the policy; others are operating under the assumption that it will be a large hurdle in creating treatments from any of the existing cell lines. "It could be a real killer," said George Daley, a stem cell researcher at the Whitehead Institute for Biomedical Research in Cambridge, Mass.
Executives of BresaGen Inc., the U.S. unit of an Australian stem cell company, met with the FDA last spring and learned then that their four lines of human embryonic stem cells, all grown atop a layer of mouse cells, would be treated as xenotransplant products. "We were a little bit shell-shocked," said Allan Robins, senior vice president and chief scientific officer. "I think a lot of companies will see it as a large burden."
This view is not universal, however, even among scientists who oppose the Bush plan.
Hugh Auchincloss Jr., a surgeon at Harvard Medical School and chairman of an FDA committee that reviewed the xenotransplant issue, noted that the FDA policy, while stringent, is not an absolute bar to research. Indeed, several hundred patients have already participated in various types of xenotransplant tests, including the transfer of fetal pig cells into patients' brains in an attempt to treat Parkinson's disease.
Moreover, Auchincloss said, with enough time and lab work, scientists might be able to alleviate FDA concerns. He noted that human tests of stem cell therapies are probably years away, largely because scientists know so little about the cells.
In his speech Aug. 9, Bush said 60 genetically distinct embryonic stem cell lines had been derived by laboratories around the world and approved federal funding for work only on those cell lines. To reduce incentives for further destruction of embryos, he ruled out funding for any cell lines created after his speech.
Because they can be used to grow almost any kind of human tissue, which could then be used to repair ailing body parts, the cells offer considerable, but unproven, hope for cures. The cell lines were created from early-stage human embryos slated for destruction at fertility clinics. Many anti-abortion activists, one of Bush's most important constituencies, oppose the research.
Several scientists have said publicly that they are working on ways to grow embryonic stem cells without mixing them with mouse cells. But no scientist has publicly claimed to have created an entirely new cell line by such a method before Aug. 9.
That has led most scientists familiar with the issue to conclude that all 60 lines were probably created using mouse feeder cells and will have to be treated as xenotransplant products.
"I don't think there's any one of the 60 lines that has not been derived using mouse embryonic feeders," said Daley, of the Whitehead Institute.
However, the possibility cannot be entirely ruled out until the location and details of all 60 cell lines have been disclosed.
The implications of treating most or all of the lines as xenotransplant products would be substantial.
The draft FDA guidelines make clear that labs researching stem cells will have to meet special burdens to win approval for any human test involving xenotransplantation. They will have to perform extensive research and documentation on their cells that go beyond normal FDA requirements, including elaborate study of potential animal viruses. At a minimum, this will introduce delay and extra expense.
Given the complexity of the FDA restrictions, Robins, the BresaGen scientist, predicted that few companies would plunge into human tests of stem cells grown together with mouse cells. He said those will be used for research for the next few years, but eventually companies will create new cell lines grown only on human feeder cells. They will do so either with private money or by overturning the Bush limitations on federal funding, Robins and other researchers predicted.
In fact, it appears the FDA restrictions have already set off a behind-the-scenes race among labs to create -- and patent -- alternative means of growing stem cells that don't depend on mouse feeders.
The only company that has publicly claimed success with a mouse-free technique is Geron Corp. of Menlo Park, Calif. "We have accomplished it," said David Greenwood, the company's chief financial officer. But he declined to say whether Geron had managed to create any new stem cell lines using the technique before Aug. 9.
Several researchers predicted that if stem cells began to show promise, the politics would change, and they would win permission to work on new cell lines with federal money.
"If the research looks great and we're ready to go to human trials, we will need more stem cells," said Jeffrey Rothstein, a neurologist at Johns Hopkins University in Baltimore who works in the field. "We'll turn to the president or Congress and get them to do the right thing."
Staff writer Rick Weiss contributed to this report.