A Seismic Shift for Stem Cell Research
- From: "浪人 ronin" <Kotyto@xxxxxxxxx>
- Date: Tue, 5 Feb 2008 15:22:23 -0800 (PST)
A Seismic Shift for Stem Cell Research (Science Magazine)
Constance Holden and Gretchen Vogel
The development of pluripotent cells from individual skin cells has
opened up a new world of research, but scientists say they still need
to work with embryonic stem cells
Advocates and opponents of embryonic stem (ES) cell research don't
agree on very much, but both have long said that avoiding the use of
human embryos--through direct reprogramming of cells--would solve a
lot of problems, both ethical and scientific. Now that goal has been
achieved, but the picture is not quite as simple as some had hoped.
At the end of last year, two teams--one in Japan, the other in the
United States--announced that they had generated human ES-like cells
simply by introducing a handful of genes into skin cells. Soon after,
a third group at Harvard University joined the fold, also reporting
the creation of these cells, called induced pluripotent stem (iPS)
cells, from a variety of tissues.
But after the initial excitement, both sides are finding that although
iPS cells have answered some questions, they have also raised new
ones. Opponents of ES cell research were quick to argue that embryos
are no longer needed to realize the promise of stem cells and that
tight restrictions on ES cell research should be maintained, even
strengthened. But researchers were equally quick to respond that it is
too early to close the book on human ES cells, especially because it
is not clear that iPS cells will ever be safe for use in patients.
New promise
Shinya Yamanaka of Kyoto University in Japan sent a wave of excitement
through the stem cell field when he announced in June 2006 that he had
reprogrammed mouse skin cells into something that closely resembles ES
cells by inserting just four functioning genes into the cells (see
sidebar, p. 562). The cloning experiments that produced Dolly the
sheep--which involved removing the nucleus of an egg cell and
replacing it with one from an adult cell--had demonstrated that the
DNA in adult cells is still capable of directing development, when
given the right cues. But no one knew whether those cues came from
hundreds of genes or just a few. Yamanaka's work showed that a handful
could do the trick, suddenly turning the idea of embryo-free
pluripotent cells into reality.
When Yamanaka's group, and a group led by James Thomson of the
University of Wisconsin, Madison, announced in November 2007 that they
had performed the same feat with human cells, the excitement turned
into a frenzy. Research teams around the world are now adding iPS
cells to their repertoire. "It is an incredibly rapidly moving field,"
says Harvard stem cell researcher George Daley, author of the most
recent iPS paper. "There's a huge energy to the science, a sense of
infinite possibility." Cultivating iPS cells is "so easy to do now,
papers are coming out every week," adds Konrad Hochedlinger of the
Harvard Stem Cell Institute in Cambridge, who predicts "a huge gusher
of new data."
Because iPS techniques offer a way to generate cell lines from a
patient's own tissues, they supply "an incredibly powerful new tool"
for research, says stem cell researcher Renee Reijo Pera of Stanford
University School of Medicine in Palo Alto, California. Previously,
scientists had thought the only way to create a cell line from a
patient with, say, Parkinson's disease was through the technique that
produced Dolly, known as somatic cell nuclear transfer (SCNT) (see
diagram below). That requires hard-to-obtain human oocytes and
involves the destruction of an embryo. But now, scientists can
reprogram cells with tools available in any molecular biology
laboratory. "It's like transfection. It's really very
straightforward," says Hans Schöler of the Max Planck Institute of
Molecular Biomedicine in Münster, Germany.
Kevin Eggan's group at Harvard is already collecting skin cells from
patients with amyotrophic lateral sclerosis to generate iPS cell
lines. Similarly, Lawrence Goldstein, director of the stem cell
program at the University of California, San Diego, says his group is
about to collect skin biopsies from Alzheimer's patients. In the
meantime, he says, he has put plans for SCNT research on hold. The iPS
lines will be useful not only for studying disease mechanisms, he
says, but also for testing the efficacy of new drugs against those
diseases.
IPS cells may also help speed the search for better ways to coax
pluripotent cells to differentiate into desired cell types. Currently,
scientists can reliably steer human ES cells to make heart cells and
several kinds of neurons, but reproducible chemical recipes for most
cell types are still elusive.
Embryo-free, eventually?
The promise of iPS cells has prompted some opponents to assert that
human ES cell research is no longer necessary. "The embryonic stem
cell debate is over," wrote columnist and physician Charles
Krauthammer, a former member of the President's Council on Bioethics,
in a widely cited 30 November 2007 column. "Scientific reasons alone
will now incline even the most willful researchers to leave the human
embryo alone."
But that's far from the case, scientists say. "We'd be glad to
eventually give [embryo research] up," says Douglas Melton, a Harvard
stem cell biologist. But "it would be premature" to do so now.
At every step in iPS research, comparisons with ES cells will be
required, Daley points out. "Right now, we're not certain iPS cells
are the absolute equivalent" of ES cells, capable of forming all the
desired tissue types. Adds Fred Gage of the Salk Institute for
Biological Studies in San Diego, California: "Many of the existing ES
cell lines are different from each other, so it depends what you
compare them to. It's likely that iPS lines are different from each
other" as well. To validate and improve iPS cells, says Eggan,
scientists will "need to make huge [numbers] of these cells from many
different people and compare them in a battery of tests with human ES
cells." This will take a while because scientists can't do definitive
experiments with human cells that they can do in mice, such as
creating chimeric animals.
But even then, some scientists are dubious that iPS cells will ever
substitute for ES cells in therapies for heart, neurological, and
other diseases. The reason: So far, scientists have used retroviruses
to ferry the reprogramming genes into the cells, and those viruses may
interfere with important genes and lead to cancer. Right now, says
Eggan, there's "no clear road to getting rid" of those retroviral
vectors.
Harvard's Hochedlinger says one alternative might be a "transient
delivery system" such as adenoviruses that don't permanently insert
into a chromosome. But the best option would be to forgo introducing
genes and instead use small molecules to slip through a cell's
membranes and into the nucleus to turn on the genes that make the cell
revert to a pluripotent state. Biologist Ding Sheng of The Scripps
Research Institute in San Diego says he is partway there. In as-yet-
unpublished work, Ding says his group has found small molecules that
will substitute for some of the genes needed to turn mouse cells from
a variety of sources--including neurons and skin cells--into iPS
cells. "We start by throwing in all four genes and seeing which
molecule can improve the process, then we start subtracting genes," he
says. Advanced Cell Technology (ACT) in Worcester, Massachusetts--a
U.S. company with a large commitment to ES cells--is also at work on
finding ways to turn on the relevant genes in adult cells without
inserting either viruses or genes, says Robert Lanza, chief scientific
officer at ACT.
But at least one company that hopes to commercialize stem cell
treatments says it is sticking with human ES cells. Geron Corp. in
Menlo Park, California, which funded the initial research on deriving
human ES cells and which owns key licenses and patents involving their
therapeutic use, has "no plans to deviate from naturally derived ES
cells," says company president Thomas Okarma. He says that's based not
on intellectual property claims--he asserts that Geron's licenses
apply to all pluripotent cells, including iPS cells--but on science.
Even if iPS cells can be grown without the aid of a potentially cancer-
causing virus, he says that they "can't possibly be used for
therapies." Starting with a skin cell that might have been altered by
aging or toxins instead of a "pure crystal-clear" human embryo would
add unpredictable risks, he explains.
Even if iPS cells eventually prove safe for use in humans, scientists
say the notion of generating individually tailored cell populations
for every patient will still be a pipe dream. "Patient-specific
therapy is totally impractical, even with iPS," says Lanza. "You would
need millions of lines." Furthermore, there's no time to generate the
cells if they are needed rapidly, as after a heart attack or spinal
injury. "The idea that you would use iPS cells for individual
treatments is lunacy," agrees Stephen Minger of King's College London.
"It takes 6 months of really hard slog to make a cell line."
Instead, Lanza and others say, the most likely approach will be to
create banks of 100 or so cell lines with different immune properties
that would provide acceptable matches with most of the population.
They could be generated from donated embryos, iPS cells, or cell lines
gained through SCNT. Because no human cell lines have yet been
generated via SCNT, it's far too early to know which would work
better, he says (see sidebar, p. 563).
Political question marks
For that reason, iPS cells have sharpened rather than solved the
ongoing political battles over embryo research. "For once," says
Eggan, "the cell du jour for the opponents is actually based on good
science"--and that has only reinforced the opposition. In the United
Kingdom, the Human Fertilisation and Embryology Authority postponed a
decision on whether scientists should be allowed to insert DNA from
human cells into cow eggs, in part to consider the implications of iPS
cells. (It gave Minger and another group the green light in January.)
Opponents also cited iPS cells in their efforts to add new
restrictions to a long-planned law updating regulations on embryo
research.
In the United States as well, the cells are influencing several
ongoing debates. In Missouri, voters in late 2006 amended their
constitution to allow any type of embryo research not banned by
federal laws--including SCNT. But iPS cells are bolstering opposition
to the measure. Opponents have regrouped and are pushing to put the
question back on the ballot in November. Now, says William Neaves,
president of the Stowers Institute for Medical Research in Kansas
City, "efforts of opponents are so overreaching and broad, they could
affect even [research using] existing [ES cell] lines."
On the national level, an aide to Representative Michael Castle (R-DE)
says that Castle intends to introduce legislation again in the next
Congress to overturn the Bush Administration's ban on federal funding
for work on ES cell lines derived since August 2001. Similar bills
sponsored by Castle and Representative Diana DeGette (D-CO) were twice
vetoed by President George W. Bush. The cloning wars may also be
starting up again on Capitol Hill: Representative Dave Weldon (R-FL)
has announced plans to reintroduce a cloning ban that would include
SCNT, and Senator Dianne Feinstein (D-CA) says she will reintroduce a
bill that bans reproductive cloning but allows SCNT. "The iPS
developments will require additional educational efforts" on Capitol
Hill, predicts lobbyist Tony Mazzaschi of the Association of American
Medical Colleges in Washington, D.C.
Where the political debate will go next is anyone's guess, says stem
cell researcher Sean Morrison of the University of Michigan, Ann
Arbor. "Nobody could have predicted the twists and turns this field
has taken over the past 3 or 4 years. ... If this experience shows us
anything, it is that we can't predict where the field is going to be
even 1 year down the road."
.
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