Panel: Clinical use of embryonic stem cells jeopardized by Bush's policy on federal funding

November 10, 2003

The human embryonic stem cell lines currently eligible for research with federal funds are not suitable for use in future clinical trials, nor would they ensure fair access to new stem cell-based therapies, according to the scientists, philosophers and lawyers on a panel convened at Johns Hopkins.

The federally approved human embryonic stem (ES) cell lines were initially grown on mouse cells and therefore might harbor mouse-specific viruses. Ethically and scientifically, potentially exposing study participants to a mouse virus -- which people's immune systems might be unable to combat -- is not a risk worth taking in the face of safer alternatives, the panel unanimously agreed.

"Conducting a federally funded clinical trial of human ES cells, under current federal policy, would require using cell lines that none of us feel should be used in people, since it is now feasible to create safer lines," says Ruth Faden, Ph.D., M.P.H., a leader of the panel and executive director of the Phoebe R. Berman Bioethics Institute at Johns Hopkins. "So, all clinical trials -- and by extension the experiments leading to them -- should be conducted with newer cell lines not eligible for federal funding. The likelihood of getting to a clinical trial using only private funds, however, is very slim.

"Moreover," she adds, "the absence of federal funding would mean a reduced role for federal oversight of the ethics of human embryonic stem cell research."

By contrast, the Food and Drug Administration has said that growth of human ES cells on mouse cells need not be a sticking point for clinical research. Instead, they say the ES cells would then merely fall under guidelines for so-called xenotransplantation, or cross-species transplantation.

"But techniques now exist to create and maintain human embryonic stem cell lines without using mouse cells, and such cell lines already exist, so the risk of creating cross-species infection is unnecessary," says John D. Gearhart, Ph.D., a leader of the panel and the C. Michael Armstrong Professor of Medicine in gynecology and obstetrics at Hopkins. (Researchers in Gearhart's lab were the first to isolate and grow primitive stem cells from human fetal tissue.)

Human ES cells are obtained from embryos created for in vitro fertilization. Because the cells can become any type of cell in the body, they may one day offer a chance to treat or cure diseases such as Parkinson's disease or type I diabetes. As research with ES cells advances and the cells' use in humans grows nearer, the panel wanted to anticipate and consider issues of patient safety and fair access that are likely to arise for Americans.

The federal government is by far the largest funder of biomedical research in the United States. However, according to President George W. Bush's policy, only human ES cell lines created before 9 p.m. ET, Aug. 9, 2001, can be used in federally funded research. But many ramifications of this policy conflict with the panel's carefully determined conclusions, which are reported in two papers: one in the November issue of Fertility and Sterility, and one in the November/December issue of The Hastings Center Report.

For example, even if scientists were willing to use mouse-exposed human ES cells in a clinical trial, the dozen or so cell lines approved for federal funding are likely to be appropriate for relatively few human subjects and patients, thanks to humans' genetic diversity, the panel concluded.

At issue is the likely event that transplanted ES cells and the recipient's cells probably will have to "match," just as required for blood, organ and bone marrow transplants. By matching key proteins called human leukocyte antigens (HLA) on cells' surfaces, the immune system distinguishes between the body's own cells and foreign invaders. Essentially, transplanted ES cells would need to blend in.

Complicating matters is that common combinations of versions of HLA proteins vary considerably within ethnic or racial groups, and quite dramatically between racial groups. No information is available on the federally approved cell lines' particular combinations of HLA proteins, but the lines' small number and their derivation from embryos created for reproductive use indicate their HLA diversity is likely to be woefully inadequate.

Instead, researchers will need access to a group of human ES cell lines that match as many people as possible. Because there would be limited resources for establishing such a "bank" of ES cell lines and because of concerns for early human life, the panel carefully considered how to optimize Americans' "biological access" to future therapies with these cells.

"The question for the panel was one of justice, justice with respect to which groups are likely to benefit and which groups are likely to lose if research proceeds in certain ways," says Faden. "We asked: If not everyone can benefit because of biological factors, what is the fairest way to design future trials and therapies?"

For fast clinical research, the panel concluded unanimously that researchers should establish a "bank" with the fewest number of cell lines that reflect the most Americans. Because of the country's demographics, the lines would match mostly white Americans, but several HLA types common in other ancestral groups should be included so research can address diseases that occur more frequently or have different characteristics in non-white groups. This would be the fastest way to see whether the cells' clinical potential is worth pursuing, the panel concluded.

"The faster the cell-based therapies can be proven safe and effective, the faster everyone can benefit," says Faden. "At the same time, even during the research stage, care must be taken to make sure that groups are not systematically disadvantaged by their biology."

Once the use of human ES cells and their progeny is validated in clinical trials, most panel members agreed that all ancestral groups in the U.S. should have an equal chance of finding a match in an ES cell line bank aimed at providing clinical treatments.

African-Americans have a greater variety of HLA profiles, so more cell lines would be needed in the bank to potentially match the same percentage of that population as, say, white Americans. According to the panel's calculations, 40 cell lines representing the most common HLA varieties of white Americans would be expected to match about 71 percent of that population. By contrast, 40 cell lines matching the 40 most common HLA types of African-Americans would cover just over 45 percent of that group. Regardless of what percentage of the population is covered, however, new cell lines would have to be established, the panel said.

"No matter how we look at it, the federally approved cell lines are inadequate," says Gearhart. "We can do a lot of work with them, but we can't move into clinical trials or offer therapies with them."

"At every step of our deliberations, there was keen attention to conflicts between respect for early human life, safety for human subjects and justice for those who are ill," adds Faden. "Society may well have to choose what it values more -- ensuring that all benefit safely and fairly from advances in stem cell science, or protecting embryonic human life."

Faden also notes that the panel did not decide whether a national advisory committee should be established to oversee future clinical trials with ES cells. "That remains an open question," she says.

The panel acknowledges in both papers that future advances in science may be able to relieve some safety and accessibility concerns presented by use of human ES cells in people. However, techniques being developed for organ transplantation, such as immunosuppression, genetic engineering, and inducing immune tolerance, are likely to supplement, not supplant, matched ES cells when used clinically, the panel decided.

The panel, known as the Working Group on Criteria for Cell-based Therapies, was called together by Johns Hopkins' Program in Cell Engineering, Ethics and Public Policy (PCEEPP), with a grant from the Greenwall Foundation. PCEEPP is a joint program of the Berman Bioethics Institute and Johns Hopkins' Institute for Cell Engineering and is co-directed by Faden and Gearhart.

The Working Group was composed of eight internationally known experts from outside Johns Hopkins, the scientists and ethicists of the PCEEPP and one additional Hopkins faculty member. For the project, working group members were interviewed individually, the whole group met twice over the course of 22 months, and deliberations via e-mail, telephone, and meetings between individuals and small groups rounded out the process. Additional experts were consulted as needed to provide missing information as the panel developed their conclusions.

Members of the panel were Liza Dawson, Alison Bateman-House, Dawn Mueller Agnew, Hilary Bok, Dan Brock, Aravinda Chakravarti, Mark Greene, Patricia King, Stephen O'Brien, David Sachs, Kathryn Schill, Andrew Siegel, Davor Solter, Sonia Suter, Catherine Verfaillie, LeRoy Walters, Faden and Gearhart. A complete list of all authors' affiliations is available at .

All members of the panel were authors of the Fertility and Sterility paper on safety issues related to initial clinical trials with human ES cells. All panel members were also authors on The Hastings Center Report paper on issues surrounding biological access and the structure of ES cell banks for research and therapy. In addition, HLA experts Xiao-jiang Gao, of the National Cancer Institute, and John Hansen, of the Fred Hutchinson Cancer Research Center, were authors of that report but not members of the Working Group.

Brock is Professor Emeritus of Philosophy at Brown University. King is with the Georgetown University Law Center. O'Brien is with the Laboratory of Genetic Diversity at the National Cancer Institute. Sachs is with the Transplantation Biology Research Center at the Massachusetts General Hospital and Harvard Medical School. Solter is with the Max Plank Institute of Immunobiology, Freiburg, Germany. Suter is with the George Washington University Law School. Verfaillie is with the Stem Cell Institute at the University of Minnesota. Walters is with the Kennedy Institute of Ethics at Georgetown University. All other authors are affiliated with The Johns Hopkins University, The Johns Hopkins University School of Medicine or the Johns Hopkins Bloomberg School of Public Health.
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