8-20-2001: Mounting uncertainties about the quantity and quality of embryonic stem cells available for research under a new Bush administration policy have persuaded many biologists that the president's approach poses serious constraints for the development of new medical treatments for diseases such as Parkinson's, diabetes and stroke.

Skepticism among those scientists focuses on the existing stocks of stem cells available for research. Under Bush's guidelines, federal dollars may be used to study the versatile and medically promising cells only if they came from donated fertility clinic embryos that were already destroyed by Aug. 9.

Bush said at least 60 self-replenishing colonies, or "lines," of such cells existed by that date, a number four times greater than many scientists were aware of. But the National Institutes of Health has yet to produce information about the lines or their producers, feeding speculation that many of those 60 do not exist, are of poor quality or are under such tight commercial control as to make them unattractive to researchers hoping to study and perhaps profit from them.

NIH officials have asked scientists to be patient, reassuring them that plenty of cells are available and promising that details will soon be forthcoming. But contrary to predictions made by top government officials, only a few companies or laboratories have emerged after Bush's announcement to say publicly that they, too, have eligible cell lines.

And new questions have begun to arise about the adequacy of the consent processes used to obtain the cells and the racial diversity of the available cells -- a factor that could ultimately affect the availability of stem cell-based therapies for some minorities.

The number and variety of cell lines available is important because stem cells are highly finicky and quite volatile. Cell lines can "crash" -- or die -- at any moment, or they can spontaneously turn into specialized cells, rendering them useless for later work. In addition, there are subtle genetic differences between each cell line, differences that can affect their behavior and utility in research.

To limit researchers to 60 cell lines, critics say, is like telling mathematicians they can pursue their studies but they can never use numbers bigger than 10. "I think it's a ridiculous policy," said George Daley, a leading stem cell researcher at the Whitehead Institute for Biomedical Research in Cambridge, Mass. Evan Snyder, another stem cell expert at the Harvard Medical School, called Bush's approach "scientifically naive."

The NIH has not yet produced any information on the condition of the 60 cell lines, a critical issue for scientists aiming to work with them. And the agency appears to have only sketchy information on whether the cell lines were created after receiving proper consent from the embryos' donors, a fundamental criterion laid down by the president.

NIH administrators say the Bush policy is workable, and they are scrambling to answer growing doubts. They have summoned top executives and scientists from about nine stem cell laboratories around the world to attend meetings at the NIH's Bethesda campus this week to gather information and seek pledges of cooperation.

Bush administration lawyers are negotiating an initial agreement to give government scientists access to some of the most important cell lines. They hope that agreement will become a model for universities around the world.

Lana Skirboll, director of science policy at the agency, said NIH aims to release more detailed information on the cell lines in coming weeks. "Our goal, our single goal, is to get these cells to the investigator community," she said.

Still, it is clear the Bush administration will have to work hard to reassure the scientific community of its approach. On Friday, the world's largest scientific body, the American Association for the Advancement of Science, called on the White House to give immediate access to the list of 60 cell lines as well as details of how the White House policy will work.

Research on human embryonic stem cells is one of the most promising, but controversial, fields of modern biology. The cells are usually derived from microscopic, days-old embryos that are due to be discarded at fertility clinics. The value of the cells is their flexibility -- they have the ability to become any of the more than 200 specialized cell types in the human body, offering a potentially unlimited source of new tissues for ailing patients.

Since 1996, federal law has prohibited the use of tax dollars to destroy human embryos. The Clinton administration, however, adopted rules saying federally funded scientists could conduct experiments on stem cell lines as long as they did not themselves participate in embryo destruction. Cells were to be derived from embryos destroyed with private money in private labs, then shipped to federally funded scientists for study.

The government was on the verge of issuing its first stem cell grants when Bill Clinton left office. Bush's new policy seemed to be an artful compromise between the Clinton plan and conservatives' calls to ban the research altogether. Bush's plan will permit federal funding on stem cell lines created before his speech Aug. 9, but prohibit funding for any that might be created later.

The policy was predicated on the existence of 60 genetically distinct lines of stem cells, which the administration said would supply enough diversity to allow scientists to undertake serious work on new treatments.

But the number 60, based on a relatively hasty NIH telephone survey, came as a shock to virtually every scientist working in the field. Fewer than a dozen cell lines have been identified in scientific literature.

Andy Cohn, spokesman for a University of Wisconsin foundation, watched the Bush speech with James Thomson, the scientist who in 1998 first isolated human embryonic stem cells. When Bush made the claim about 60 cell lines, "we both almost fell off our chairs," Cohn said.

Since then, counting by news organizations, including The Washington Post, has turned up new cell lines, mostly in laboratories already known to be working in the field. But none of those counts has produced more than 23 lines.

Requests from lawmakers and news organizations that the White House document its claim of 60 cell lines have gone unanswered. "The burden of proof is on anyone who doubts" the claim, White House spokesman Ari Fleischer said.

The debate over the number is more central than it might seem at first, for several reasons. For one, a larger number of cell lines would be insurance against the risk that some of the existing cell lines prove unusable.

Secondly, there is the issue of genetic diversity. Scientists envision using stem cells to create more specialized cells, such as those of the heart, liver or brain. Those would be implanted into ailing patients to restore organ function. Much as with a liver or heart transplant, it may prove critical to find a good immunological match between the implanted cells and the recipient to try to stave off rejection.

Such matching is easier within racial and ethnic groups that are more closely related. The NIH has not obtained information about the ethnic origin of the 60 cell lines. Many of the ones that have come to light in recent days were created in Asia, which might limit their usefulness in treating people of European or African ancestry. "Ours would come from people of Chinese-Asian background," said Robert Klupacs, chief executive of a Singapore company, ES Cell International Pte Ltd., that controls six stem cell lines -- 10 percent of the total cited by Bush.

"Too often we have learned that procedures used in other parts of the world in research with human subjects do not measure up to the ethical standards we embrace in this country," according to AAAS, the scientists' federation.

If some of the consent forms are inadequate, American researchers would be left with an even smaller pool of cell lines.

Another unresolved issue is the degree to which American academic researchers will have access to the 60 cell lines covered by the Bush policy. They are controlled by a few companies and laboratories around the world. Those labs have been filing patent applications on aspects of stem cell technology, and the pending applications are believed to number in the dozens.

Researchers may get ready access to the cells, but on the terms of the labs that created them -- namely, that those labs retain potentially lucrative commercial rights to future discoveries. This is likely to be unacceptable to many universities, which hope to profit from fresh discoveries their scientists make.

NIH lawyers are negotiating a master agreement with the Wisconsin Alumni Research Foundation to give government scientists access to five cell lines it controls. The agency hopes that agreement will serve as a "gold standard," a model that universities could use to cut deals of their own with the cells' owners.

But each university will be responsible for making its own deals with the labs and companies that control cell lines, and the Bush policy could make that more complicated. Because no new cell lines will be eligible for federal funds, the owners of old lines are likely to have more leverage in their dealings with scientists who want to undertake such work. Most people in the field express optimism that the patent difficulties can be worked out, but they acknowledge it will be tricky.