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Sunday, Jul. 30, 2006
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

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 TIME Graphic
With reporting by Reported by Alice Park/New York, Dan Cray/Los Angeles

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