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 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, 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.
John D. Gearhart, a leader of the panel and the C.
Michael Armstrong Professor of Medicine in
gynecology and
obstetrics at Hopkins, says, "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." (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 on 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, or 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.
According to Faden, "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. 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 nonwhite 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," Faden
says. "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 United States 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," Gearhart says. "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," Faden adds,
"there was keen attention to conflicts between respect for
early human life, safety for human subjects and justice for
those who are ill. 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, 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 and 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 its
conclusions.
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.
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.
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 Planck 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.
The other authors are affiliated with The Johns
Hopkins University. Chakravarti is director of the
McKusick-Nathans Institute of Genetic
Medicine; the others are affiliated with the Johns
Hopkins Program in Cell Engineering, Ethics and Public
Policy, a project of the Phoebe R. Berman Bioethics
Institute in conjunction with the Institute for Cell
Engineering.
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