Stem Cells: The Hope
And The Hype
The debate is so
politically loaded that it's tough
to tell who's being
straight about the real areas
of progress and how
breakthroughs can be achieved.
TIME sorts it out
By NANCY GIBBS,
TIME.com: TIME Magazine on the Web, July 30, 2006
When there's nothing else to
prescribe, hope works like a drug. A quadriplegic patient tells herself
it's not a matter of if they find a cure but when. Who's to say whether
salvation is still 10 or 15 years away? After all, researchers have been
injecting stem cells into paralyzed rats and watching their spinal cords mend.
"Stem cells have already cured paralysis in animals," declared Christopher Reeve
in a commercial he filmed a week before he died.
But what is the correct dose of hope when the diseases are dreadful and the
prospects of cure distant? Last month, when President George W. Bush
vetoed the bill that would have expanded funding for human embryonic-stem-cell
(ESC) research, doctors got calls from patients with Parkinson's disease saying
they weren't sure they could hang on for another year or two. The doctors
could only reply that in the best-case scenario, cures are at least a decade
away, that hope is no substitute for evidence, that stem-cell science is still
in its infancy.
It is the nature of science to mix hope with hedging. It is the nature of
politics to overpromise and mop up later. But the politics of stem-cell
science is different. Opponents of ESC research--starting with Bush--argue
that you can't destroy life in order to save it; supporters argue that an
eight-cell embryo doesn't count as a human life in the first place--not when
compared with the life it could help save. Opponents say the promise of
embryo research has been oversold, and they point to the cures that have been
derived from adult stem cells from bone marrow and umbilical cords; supporters
retort that adult stem cells are still of limited use, and to fully realize
their potential we would need to know more about how they operate--which we can
learn only from studying leftover fertility-clinic embryos that would otherwise
be thrown away.
Back and forth it goes, the politics driving the science, the science pushing
back. Stem-cell research has joined global warming and evolution science
as fields in which the very facts are put to a vote, a public spectacle in which
data wrestle dogma. Scientists who are having surprising success with
adult stem cells find their progress being used by activists to argue that
embryo research is not just immoral but also unnecessary. But to those in
the field, the only answer is to press ahead on all fronts. "There are camps for
adult stem cells and embryonic stem cells," says Douglas Melton, a co-director
of the Harvard Stem Cell Institute. "But these camps only exist in the
political arena. There is no disagreement among scientists over the need
to aggressively pursue both in order to solve important medical problems."
Trapped in all this are patients and voters who struggle to weigh the arguments
because the science is dense and the values tangled. Somewhere between the flat-earthers
who would gladly stop progress and the swashbucklers who disdain limits are
people who approve of stem-cell research in general but get uneasy as we
approach the ethical frontiers. Adult-stem-cell research is morally fine
but clinically limiting, since only embryonic cells possess the power to
replicate indefinitely and grow into any of more than 200 types of tissue.
Extracting knowledge from embryos that would otherwise be wasted is one thing,
but scientists admit that moving forward would require a much larger supply of
fresh, healthy embryos than fertility clinics could ever provide. And once
you start asking people about creating embryos for the purpose of experimenting
on them, the support starts to slow down.
So where do things stand, five years after Bush provided the first federal
funding but radically limited how it could be used?
HOW RED TAPE SLOWED THE SCIENCE
In a prime-time speech from his Texas ranch in August 2001, Bush announced that
federal money could go to researchers working on ESC lines that scientists had
already developed but no new lines could be created using federal funds.
"There is at least one bright line," he declared. The speech was a
political and scientific landmark. It gave Democrats that rare gift:
a wedge issue that split Republicans and united Democrats, who declared
themselves the party of progress. Five years later, with midterms looming,
they hope to leverage the issue as evidence that they represent the
reality-based community, running against the theocrats. States from
Connecticut to California have tried to step in with enough funding to keep the
labs going and slow the exodus of U.S. talent to countries like Singapore,
Britain and Taiwan. Meanwhile, private biotech firms and research
universities with other sources of funding are free to create and destroy as
many embryos as they like, because they operate outside the regulations that
follow public funds.
For scientists who choose to work with the approved "presidential" lines, the
funding comes wrapped in frustration. Today there are only 21 viable
lines, which limits genetic diversity. They are old, so they don't grow
very well, and were cultured using methods that are outdated. What's more,
the chromosomes undergo subtle changes over time, compromising the cells'
ability to remain "normal." Back in the late '90s, when the lines were
created, "we didn't know much about growing stem cells," says Kevin Eggan,
principal faculty member at the Harvard Stem Cell Institute. "They can't
do what the newer cell lines can do." Curt Civin, a cancer researcher at
Johns Hopkins, has spent the past several years trying to differentiate the
presidential lines into blood cells that could be used to treat leukemias and
other blood-based cancers. But the age and quality of the cells have been
a constant hindrance. "We want to study normal cells," he says. "We're
working with Version 1.0. I'd like Version 3.3."
The presidential lines, scientists say, are wasting money as well as time.
Larry Goldstein's lab at the University of California at San Diego is a
life-size game of connect the dots. Each machine, cell dish, chemical and pretty
much every major tool bears a colored dot, signaling to lab workers whether they
can use the item for experiments that the government won't pay for.
Goldstein's team is working on a cancer experiment that relies on a $200,000
piece of equipment. They can use either an approved cell line that will
yield a less reliable result or a freshly created line that would require the
purchase of another machine with private funds. "It's a ball and chain,"
Goldstein says. "It's goofy. Imagine if your kitchen was a mixture
like that, where you can't use those pots with that soup."
Congress tried to address the problem with its bill to allow funding for
research on any leftover embryos donated by infertility patients. But even
if Bush hadn't vetoed the bill, it wouldn't have solved the supply problems.
One study estimated that at best, a couple hundred cell lines might be derived
from leftover IVF embryos, which tend to be weaker than those implanted in
patients. The very fact that they come from infertile couples may mean
they are not typical, and the process of freezing and thawing is hard on
delicate cells.
SOLVING A PROBLEM CREATED NEW ONES
In the wake of Bush's original order, Harvard decided to use private funding to
develop about 100 new cell lines from fertility-clinic embryos, which it shares
with researchers around the world. Scientists, desperate for variety, snap
them up. "Not all embryonic-stem-cell lines are created equal," says Dr.
Arnold Kriegstein, who runs the Institute for Regeneration Medicine at the
University of California, San Francisco. "Some are more readily driven
down a certain lineage, such as heart cells, while others more easily become
nerve. We don't understand how it happens, but it does mean we need
diversity."
At the same time, Harvard has opened another battleground in the search for
cells. After exhaustive ethical review, its researchers announced this
summer that they would develop new cell lines through somatic cell nuclear
transfer, or therapeutic cloning. In this process, a cell from a patient
with diabetes, for instance, is inserted into an unfertilized egg whose nucleus
has been removed; then it is prodded into growing in a petri dish for a few days
until its stem cells can be harvested. Unlike fertility-clinic embryos,
these cells would match the patient's DNA, so the body would be less likely to
reject a transplant derived from them. Even more exciting for researchers,
however, is that this technique can yield embryos that serve as the perfect
disease in a dish, revealing how a disease unfolds from the very first hours.
The long-term promise is boundless, but the immediate barriers are high.
The only people who claim to have succeeded in creating human-stem-cell lines
through nuclear transfer were the South Korean researchers who turned out to be
frauds. It will take much trial and error to master the process, but where
do you get the human eggs needed for each attempt, particularly since
researchers find it ethically inappropriate to reimburse donors for anything but
expenses? And even if the technique for cloning embryos could be
perfected, would Congress allow it to go on?
THE HUNT FOR NEW SOLUTIONS
To get around political roadblocks, scientists are searching for another source
of cells that is less ethically troublesome, ideally one that involves no embryo
destruction at all. One approach is "altered nuclear transfer," in which a
gene, known as CDX2, would be removed before the cell is fused with the egg.
That would ensure that the embryo lives only long enough to produce stem cells
and then dies. That strategy, promoted by Dr. William Hurlbut, a member of
the President's Council on Bioethics, has its critics. Dr. Robert Lanza of
biotech firm Advanced Cell Technology considers it unethical to deliberately
create a crippled human embryo "not for a scientific or medical reason, but
purely to address a religious issue." The most exciting new possibility
doesn't go near embryos at all. Dr. Shinya Yamanaka of Kyoto University
reported tantalizing success in taking an adult skin cell, exposing it to four
growth factors in a petri dish and transforming it into an embryo-like entity
that could produce stem cells--potentially sidestepping the entire debate over
means and ends.
Even if scientists discover an ideal source of healthy cell lines, there is
still much to learn about how to coax them into turning into the desired kind of
tissue. Parkinson's patients suffering from tremors caused by damaged
nerves could benefit from replacement neurons, while diabetics who can't produce
insulin could control their blood sugar with new pancreatic islet cells.
But so far, no human ESCs have been differentiated reliably enough that they
could be safely transplanted into people, although animal studies with human
cells are under way. Not surprisingly, the groups closest to human trials
are in the biotech industry, which operates without government funds.
Geron claims it is close to filing for permission to conduct the first human
trials relying on ESC-based therapy. It is using stem cells to create
oligodendroglial progenitor cells, which produce neurons and provide myelin
insulation for the long fingers that extend out from the body of a nerve cell.
Lanza's group is also close to filing for FDA permission to begin clinical
trials on three cell-based therapies: one for macular degeneration, one
for repairing heart muscle and another for regenerating damaged skin. Not
to to be outdone, the academic groups are just a few steps behind. Lorenz
Studer at Memorial Sloan-Kettering Cancer Center in New York City has been able
to differentiate ESCs into just about every cell type affected by Parkinson's
disease and has transplanted them into rats and improved their mobility.
Next, he plans to inject the cells into monkeys.
THE RISKS ON THE NEW FRONTIER
But the closer scientists come to human trials, the more concerned the FDA will
be with ensuring patient safety. The government will look at how the cells were
grown and whether there would be risk of contamination from animal products used
in the process. Regulators want data on how the cells will behave in the human
body. Stem cells have shown a dismaying talent for turning into tumors. Will
they migrate into unwanted areas? No one knows. You can't find out for sure
until you test in humans, but it's hard to test in humans until you can be
reasonably sure you won't harm them in the process.
When human trials finally begin, there's no method for precisely determining
whether the transplanted stem cells are functioning correctly. "If we
transplanted cells to regenerate a pancreas," says Owen Witte, director of
UCLA's Institute for Stem Cell Biology and Medicine, "we can measure in your
blood if you're producing insulin, but we can't see whether the cells have grown
or evaluate whether they might grow into a tumor." So scientists are
seeking to develop marking systems that let them trace a transplant's
performance.
THE PROMISE AND PITFALLS OF ADULT CELLS
Even as scientists press ahead with embryo research, exciting news has come from
the least controversial sources: the stem cells in umbilical-cord blood
and placentas, and even in fully formed adult organs. While not as
flexible as embryonic cells, cord and placental cells have proved more valuable
than scientists initially hoped. Although about 90% of cord-blood stem
cells are precursors for blood and immune cells, the remaining 10% give rise to
liver, heart-muscle and brain cells and more. Over the past five years,
cord-blood transplants have become an increasingly popular alternative to
bone-marrow transplants for blood disorders, particularly when a bone-marrow
match can't be found.
If you want to lean out over the edges of science and marvel at what is now
possible, visit Dr. Joanne Kurtzberg's program at Duke University Medical
Center. Children with blood diseases that were almost certainly fatal a
decade ago have got cord-blood transplants that essentially cure them. Now
she and her team are taking a more targeted approach by attempting to
differentiate cord-blood cells to address heart, brain and liver defects.
"I think cord-blood cells have a lot of promise for tissue repair and
regeneration," says Kurtzberg. "But I think it will take 10 to 20 years."
Less plastic than cord-blood cells are adult stem cells, which until recently
researchers thought couldn't do much more than regenerate cell types that
reflected the stem cells' origin--blood and immune cells from bone marrow, for
example. Even so, some scientists believe adult stem cells may prove to be
a powerful source of therapies. "In some cases, you may not want to go all
the way back to embryonic stem cells," says Kurtzberg. "You may want
something more specific or less likely to stray. You wouldn't want to put
a cell in the brain and find out later that it turned into bone."
Researchers in Thailand have taken stem cells from the blood of cardiac
patients, grown the cells in a lab and reinjected them into patients' hearts,
where they set about repairing damage. Two UCLA researchers last week
published a study demonstrating that they could transform adult stem cells from
fat tissue into smooth-muscle cells, which assist in the function of numerous
organs. Welcome as the advances are, the subject of adult stem cells is
highly political and invites a conflation of real hopes and false ones.
"There are papers that have claimed broad uses for certain adult stem cells, and
some people say that is sufficient cause to not work on embryonic stem cells,"
Witte says. "Many of those claims were overblown."
Even the true believers among scientists, however, dispute eager politicians who
have called for a Manhattan Project approach to research. "I hate to say
it, but biology is more complicated than splitting the atom," Witte says.
"The physicists on the Manhattan Project knew what they needed to accomplish and
how to measure it. In biology, we're codeveloping our measurement tools
and our outcome tools at the same time." Indeed, a massive centralized
effort controlled by the Federal Government could do more harm than good.
The key is to have the broadest cross section of scientists possible working
across the field. When it comes to such an impossibly complicated matter
as stem cells, the best role for legislators and Presidents may be neither to
steer the science nor to stall it but to stand aside and let it breathe.
[This article contains a diagram. Please see hardcopy or pdf.] Making
Sense of STEM CELLS WHAT THEY ARE Stem cells are nature's master cells, capable
of generating every one of the many different cells that make up the body.
They have the ability to self-renew, which means that they are theoretically
immortal and can continue to divide forever if provided with enough nutrients.
Because they are so plastic, they hold enormous promise as the basis for new
treatments and even cures for disorders ranging from Parkinson's and heart
disease to diabetes and even spinal-cord injury
WHERE THEY COME FROM
LEFTOVER OR DEAD-END IVF EMBRYOS
Why they are useful More than
400,000 embryos created during in vitro fertilization lie frozen in clinic tanks
in the U.S. Many of them will be discarded, so the embryonic stem cells
that exist inside them could be salvaged.
Drawbacks The freezing process may make it harder to extract stem cells.
Some of the embryos were the weakest ones created by infertile couples and may
not yield high-quality stem cells
ADULT STEM CELLS
Why they are useful They exist
in many major tissues, including the blood, skin and brain. They can be
coaxed to produce more cells of a specific lineage and do not have to be
extracted from embryos
Drawbacks They can generate
only a limited number of cell types, and they are difficult to grow in culture
NUCLEAR-TRANSFER EMBRYOS
Why they are useful These
embryos are created using the technique that created Dolly, the cloned sheep.
Stem cells can be custom-made by inserting a patient's skin cell into a hollowed
human egg. Any resulting therapies would not run the risk of immune
rejection
Drawbacks The process has not yet been successfully completed with human
cells, and it requires an enormous amount of fresh human eggs, which are
difficult to obtain
UMBILICAL-CORD CELLS
Why they are useful Although they are primarily made up of blood stem
cells, they also contain stem cells that can turn into bone, cartilage, heart
muscle and brain and liver tissue. Like adult stem cells, they are
harvested without the need for embryos
Drawbacks An umbilical cord is not very long and doesn't hold enough
cells to treat an adult
The Process
1) EMBRYO
An egg is fertilized or cloned to form an embryo. The embryo begins to
divide.
2) 1 TO 5 DAYS
The embryo divides into more and more cells and forms a hollow ball of cells
called a blastocyst
3) 5 TO 7 DAYS
Embryonic stem cells begin to form along the inside of the blastocyst, creating
the inner cell mass
4) STEM LINE
The cells are scraped away and grown on a layer of feeder cells and culture
medium
5) TISSUE PRODUCTION
Groups of stem cells are nurtured under specialized conditions, with different
recipes of nutrients and growth factors that direct the cells to become any of
the body's more than 200 various tissues.
Pancreatic islet cells Could
provide a cure for diabetes
Muscle cells Could repair or replace a damaged heart
Nerve cells Could be used to treat Parkinson's, spinal-cord injuries and
strokes
With reporting by Reported by Alice Park/New York, Dan
Cray/Los Angeles
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