Many scientific organizations and researchers were relieved that the president, who had opposed human ESC research on ethical grounds, decided to allow any federal funding at all. "If the president is correct and there are 60 lines, and they are available in an unrestricted way, that would be a great start," stated Lawrence A. Soler, chairman of the Coalition for the Advancement of Medical Research.

"The proposed compromise will slow the research, but the compromise is better than halting the research entirely," added James Thomson, a pioneering University of Wisconsin biologist who first isolated and cultured human ESCs with a team in 1998. "The president's policy has some limitations, but it is a good place to start to expand the base," said John D. Gearhart, another pioneering researcher whose Johns Hopkins University lab first isolated human pluripotent stem cells from fetal germ cells, also in 1998.

What About the Cell Lines?

Much of the attention following Bush's announcement focused on the number, quality, and accessibility of the approved cell lines. Scientists in the field had presumed that fewer than a dozen human ESC lines existed worldwide. But Skirboll's staff had uncovered other sources while doing research for a recent stem cell report,1 Thompson explained: "All of us were surprised by the number of 60. But you need to understand, no one had ever done a formal aggressive count." The science policy staff confirmed and reconfirmed their findings. Much of the research had been proceeding "behind closed doors" and was "closely protected for proprietary reasons," Thompson said.

To be eligible for federal research funding, the cell lines must have been derived from excess embryos originally produced solely for fertility purposes, and the donors must have given written informed consent for research without any monetary inducement. Officials said the research organizations already have provided them with copies of the consent forms.

The cell lines are in varying stages of development, said Jay Lefkowitz, general counsel for the Office of Management and Budget (OMB), who had participated in many of the planning meetings. Because of this, NIH will require evidence that the cell lines are established by showing "a certain number of passages, certain cell surface markers," Skirboll said. Though only cell lines generated as of Aug. 9 will be eligible for funding, Thompson said it was "probable" that additional lines will be uncovered. As of mid-August, nearly 70 lines had been confirmed.

About half of identified cell lines were derived by institutions in the United States, Lefkowitz said. The other half are in Israel, Sweden, Australia, Singapore, and India, according to Skirboll. Citing requests for commercial confidentiality by the suppliers, she identified only three sources: the WiCell Research Institute at the University of Wisconsin/Madison; BresaGen Ltd. in Adelaide, Australia; and ES Cell International, based in Singapore and with offices in Australia. These three account for 17 of the 60-70 cell lines. "We're going to be working with [the other suppliers] aggressively in the next few days and weeks to get them all to be able to roll out," Skirboll said.

First, Basic Research

The public registry will include contact and basic scientific information about each stem cell line. Information subsequently derived from investigators, especially about how each line propagates and differentiates, could be added. "In the long run, whether one of these lines or a line derived in the private sector is the line that will literally lead to a product for new treatment remains to be seen," Skirboll said. "But first and foremost, basic research." Once procedures and the registry are in place, NIH will accept grant applications, acting NIH Director Ruth Kirschstein said. Applicants will indicate from which approved source they are getting the cell lines, "and we will immediately go to our dual peer-review system," she said.
This approach eliminates the need for the ethical oversight process involving the Human Pluripotent Stem Cell Review Group (HPSCRG), a committee that would have evaluated submitted research protocols for compliance with NIH ethical guidelines for ESC research established by the Clinton administration. Those guidelines were never implemented by Bush and his recent funding decision makes them obsolete.2

Acknowledging there are some "very strong proprietary and patent issues to work through," Thompson stressed that discussions with stem cell owners thus far had been heartening. "We will certainly try our best to work with companies to ensure access" through conventional material transfer agreements, Skirboll said, but she emphasized it will be up to the parties involved to work out the details. "We're in a [facilitative] role. It will be between the company and the university that they are giving the cell lines to."

Legal, Commercial Questions

But some scientists fear that suppliers will demand excessive royalties or restrict the research that can be done using their cell lines. Indeed, less than one week after Bush's announcement, an intellectual property dispute erupted between the largest U.S. human ESC patent owner--the Wisconsin Alumni Research Foundation (WARF), a nonprofit technology transfer organization affiliated with the University of Wisconsin--and the largest U.S. human ESC biotech company, Geron Corp. of Menlo Park, Calif. WARF is seeking through a lawsuit to block Geron's attempt to license additional stem cell types.
WARF holds broad patents on embryonic stem cells and associated technologies based on James Thomson's research, which was funded in part by Geron. In exchange, Geron had been granted exclusive commercialization rights to six cell lineages (hepatocytes, myocytes, neural cells, pancreatic islet cells, hematopoietic cells, and osteoblasts).

In a statement, Geron said it exercised an option to exclusively license additional cell types; WARF disagrees with Geron's contract claim and instead wants to license the cells to a larger number of academic and private researchers. By mid-August, both sides were predicting the matter would quickly be settled through negotiation. "This action will ensure that future research is conducted in the public interest by preserving the broadest access to these original stem cell lines," said John Wiley, chancellor of the University of Wisconsin/Madison. WARF licenses its stem cells through the WiCell Research Institute Inc. For academic researchers, WiCell charges $5,000 for a material transfer agreement per human stem cell line. For-profit companies and their funded researchers pay extra for an industry research license, negotiated separately.

Unless clarified, the patent and licensing issues may well put a roadblock to future stem cell research efforts. Thomas B. Okarma, Geron's president and CEO said the company looks forward to "collaborating" with others for stem cell R&D. In addition to its licenses from WARF, Geron holds patents that "are to the process of deriving the cells and to the cells themselves," Okarma said. "So we have essential control over all the cells that are developed or derived by anyone who uses the technology that we developed."

Ted Agres (tagres@usa.net) is a freelance writer based in Washington, D.C.

References

1. Stem Cells: Scientific Progress and Future Research Directions, Washington, D.C.: National Institutes of Health, July 2001.
2. T. Agres, "On the brink," The Scientist, 15[11]:1, May. 28, 2001.

... and the Wrangling Begins

While the National Institutes of Health puts finishing touches on federal grant-making procedures to fund human embryonic stem cell (ESC) research, the controversy now shifts to Congress and the courts. At least one lawsuit has been filed that, if successful, would effectively overturn the president's decision. Competing bills are pending in the House and Senate to either limit or expand federal funding for human ESC research.
For the near term, however, it appears neither side in Congress will be able to effect great change. While anti-abortion lawmakers in the House are not totally comfortable with Bush's decision, they are generally pleased that further destruction of human embryos is prohibited. They are not likely to seek further changes other than to reauthorize an annual rider to the Health and Human Services (HHS) appropriations bill that bans federal funds for which human embryos are harmed or destroyed. (The Bush decision circumvents this prohibition because the embryos had been destroyed using private funds.)

The Senate is a different matter. A majority of senators want greater federal funding for human ESC research, including support for deriving the cells from surplus embryos from infertility clinics. But it appears the Senate lacks sufficient votes to override the veto that the president has promised for any such legislation.

Despite this, action is expected early this month as Congress reconvenes from recess. Sen. Arlen Specter (R-Pa.) will push for a vote on the Stem Cell Research Act of 2001 (S 723) that he and Sen. Tom Harkin (D-Iowa) have introduced. That bill would allow federal funding for both ESC research and derivation. The companion legislation (HR 2059) has been introduced in the House by Rep. Jim McDermott (D-Wash.), but Republican leadership will probably not permit it to come to a vote. Sen. Edward M. Kennedy (D-Mass.) has scheduled a Sept. 5 hearing on stem cell research in an attempt to push for broader legislation.

Opposing legislation, the Responsible Stem Cell Research Act of 2001 was introduced in the House (HR 2096) by Rep. Chris Smith (R-N.J.) and in the Senate (S 1349) by Sen. Sam Brownback (R-Kans.). That bill would only allow federal support for "qualifying" non-embryonic human stem cells, such as from human placentas, umbilical cord blood, or adult tissues and organs, or tissues of unborn human offspring who died of natural causes, such as spontaneous abortion. House lawmakers appear satisfied with the president's actions and probably will not push this version, at least for now.

At least one federal lawsuit is seeking to block taxpayer support for human ESC research altogether. A group of faith-based organizations led by the Christian Medical Association earlier this year filed suit against HHS and NIH seeking to uphold the ban against research that harms human embryos. In response, seven ESC researchers, including James Thomson from the University of Wisconsin and John Gearhart from Johns Hopkins University, filed motions to intervene as defendants and cross-claimants. The judge put the case on hold pending the president's decision. But now the plaintiffs said they would press the litigation forward.

Separately pending, in the area of ethics, is the creation of a new President's Council on Bioethics to be chaired by Leon Kass, a professor of social thought at the University of Chicago. The panel will replace the National Bioethics Advisory Commission that President Clinton had established and whose charter will expire in October. The new council will "study the human and moral ramifications of developments in biomedical and behavioral science technology," the White House announced, including such issues as embryo and stem cell research, assisted reproduction, cloning, genetic screening, gene therapy, euthanasia, psychoactive drugs, and brain implants.
 

© Copyright 2001, The Scientist, Inc