All Federally Funded Stem Cells Contaminated, Report Says
By Karen Kaplan
[LA]Times Staff Writer
8:18 PM PST, January 23, 2005
All human embryonic stem cell lines approved for use in federally funded research are contaminated with a foreign molecule from mice that may make them risky for use in medical therapies, according to a study released Sunday.
Researchers at the University of California, San Diego, and the Salk Institute for Biological Studies in San Diego report that if the stem cells are transplanted into people, the cells could provoke an immune system attack that would wipe out their ability to deliver cures for diseases such as Parkinson's, Alzheimer's and diabetes.
The finding is a setback to the Bush administration's controversial policy that only provides federal funding for research using embryonic stem cell lines that were created before August 2001. Evidence that all such stem cell lines are contaminated fuels long-standing concern among leading researchers that the lines eligible for federal money are insufficient to propel research forward.
The scientists who wrote the study say it could take at least a year or two -- if it is possible at all -- to find a way to salvage the stem cells by wiping them clean of the mouse molecules.
"We don't know, but I'm trying to be optimistic," said Fred H. Gage, a professor of genetics at the Salk Institute who coauthored the paper in the current issue of Nature Medicine.
The researchers said the safest course was to create fresh batches of stem cells that were free of contamination from animal molecules -- a process that could also take years.
The need to develop new, uncontaminated embryonic stem cell lines would bolster the influence of the California Institute for Regenerative Medicine, a $3 billion funding agency established by state voters in November to circumvent the Bush restrictions.
"This is why Prop. 71 is so important," Susan Fisher, a UC San Francisco professor of cell and tissue biology, said of California's stem cell research measure. "We will be able to do this basic research to be able to really produce a strong foundation on which this work can continue."
The new state agency specifically allows the creation of new stem cell lines and will fund about $300 million a year in embryonic stem cell research for the next decade -- more than 10 times the yearly spending at the federal level. The initiative was intended as a rebuke to Bush's federal policy and marks the largest state investment ever in basic scientific research, an area traditionally funded by the National Institutes of Health.
Federal policy strictly limits federal funding to lines that existed at the time of President Bush's August 2001 decision to allow taxpayer dollars to support some embryonic stem cell research. Those lines were derived from embryos donated by couples who no longer needed them for in vitro fertilization.
Bush, in a nationally televised address, said at the time: "This allows us to explore the promise and potential of stem cell research without crossing a fundamental moral line ... "
From the start, however, researchers raised questions about the Bush approved lines. The president said 60 such lines existed worldwide, a number that startled many working in the field. Only 22 lines proved usable, although concerns persisted about the techniques that had been used to create them and keep them alive.
When the stem cells were first isolated, they were grown in petri dishes lined with cells from mice and bathed in blood serum from calves and other animals. The animal material was used to encourage the stem cells to multiply while preserving their unusual ability to mature into any kind of human cell.
This "pluripotency" is why embryonic stem cells have been so promising for both researchers and patients. Doctors could treat patients with juvenile diabetes by growing replacements for islet cells that fail to make insulin. Stem cells could also be directed to become oligodendrocyte cells to insulate nerve fibers in patients with spinal cord injuries so that electrical signals could once again travel to their limbs.
Researchers have suspected that exposing the stem cells to animal products could have contaminated them with viruses, proteins or other molecules that could be dangerous to people.
Now they have evidence that it did.
According to the study published Sunday, human stem cells have incorporated a type of sialic acid that is common in many mammals but isn't produced by people.
The possibility that federally sanctioned lines were contaminated was discussed by Gage in October when he spoke to a National Academy of Sciences panel that is drawing up ethical guidelines for such research. Details of the findings were embargoed until publication.
When the acid, named Neu5Gc, enters the human body -- typically by eating meat or drinking milk -- antibodies rush to attack it.
Dr. Ajit Varki, a professor in UC San Diego's department of cellular and molecular medicine, questioned whether stem cells containing the acid would also be vulnerable to attack if transplanted into humans. He and his colleagues exposed the stem cells to human blood serum that contained Neu5Gc antibodies.
"It kills the cells," said Varki, one of the authors of the study. "It's reasonable to assume the same thing would happen inside peopleThe problem needs to be solved before the cells can be put into humans."
The most straightforward solution would be to start again with uncontaminated stem cell lines.
"If none of these funding issues and legal issues and ethical and moral issues existed, then it would make sense to start over," Varki said.
But to develop new lines, scientists must destroy 8-day-old embryos -- typically left over from in-vitro fertilization procedures. Some religious leaders, social conservatives and others oppose the practice, saying it is tantamount to murder.
However, Bush's research restrictions came under sharp attack from high-profile figures including former first lady Nancy Reagan and actors Christopher Reeve and Michael J. Fox. The issue took center stage in last year's presidential campaign, and although Bush won reelection, advocates scored a victory with the passage of California's Proposition 71.
Since then, several other states, including Wisconsin, New York and New Jersey have announced major funding initiatives as part of an effort to keep top researchers and scientists from going to California. Even before the influx of money from states, many leading embryonic stem cell researchers chose to forgo federal funding for their work, instead getting private grants that allowed them to create new embryonic stem cell lines.
Fisher said the other strategy of cleansing existing stem cells of the mouse acid might solve the immediate problem. But there is still the possibility that there are other animal molecules that could alter the cells and make them unsuitable for human use.
"Many people have been very uncomfortable with the derivation of human cell lines using mouse [cells] and animal proteins," said Fisher, who was not involved with the research published Sunday. "This is like being able to put your finger on why you're paranoid."
Time staff writer Megan Garvey contributed to this report.
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and from Forbes,
U.S. Embryonic Stem Cell Lines Contaminated
By E.J. Mundell
HealthDay Reporter
SUNDAY, Jan. 23 (HealthDayNews) -- In what could prove to be a setback for an already controversial area of research, scientists say all federally approved lines of embryonic stem cells are contaminated with a non-human molecule.
Because the human immune system typically seeks out and destroys cells bearing this molecule, therapies using the contaminated stem cells may fail, explained researcher Dr. Ajit Varki, a specialist in cell biology at the University of California, San Diego.
"Even worse, in the process of killing the contaminated cells, the patient might have a bad reaction," Varki explained. "It could be like receiving a bad blood transfusion."
The full details of the study are published in the Jan. 23 issue of Nature Medicine after being outlined to a panel of stem cell experts at the National Academies of Science in October.
The findings could put the brakes on a type of research already under fire from conservative policymakers in the United States, experts said.
"This is going to slow things down in embryonic stem cell research," said stem cell researcher Paul R. Sanberg, director of the Center for Excellence for Aging and Brain Repair at the University of South Florida College of Medicine, in Tampa.
"People will need to now take this into account, not just for the lines previously used but for cell lines around the world, as well as those in the U.S.," he added.
The building blocks of life, stem cells have the ability to grow into a diverse range of tissue cells including bone, muscle, organs or even brain and nerve tissue. Cells sourced from human embryos have proven especially useful in this regard. For medical researchers, the ultimate goal is to use stem cells to replace tissues lost to such diseases as Alzheimer's, cancer or heart disease.
However, many in the United States oppose the harvesting of embryonic stem cells on moral grounds, pointing to the embryo as the first stage of human life. Current Bush Administration policy limits embryonic stem cell research to just the cell lines derived before Aug. 9, 2001.
Varki's research now suggests those lines may not prove useful as therapeutic agents.
To increase the number of stem cells available for use, scientific labs typically immerse the cells in a nutrient-rich biological bath. "They use cells from mouse embryos, called 'feeder cells,'" Varki explained. "They also put -- as in most culture mediums -- serum [blood] from animals to help grow the cells."
According to Varki, those animal cells can be a source of unwanted contamination. All living cells carry a dense outer coating of sugar molecules, including compounds called sialic acids.
"There's one sialic acid, called Neu5Gc, you find it on the surface of cells from pigs, dogs, mice, chimpanzees," Varki said.
At some point in human evolution, people lost the ability to add Neu5Gc to the outsides of their cells, however. In fact, Varki added, human immune systems now recognize the molecule as "alien" and automatically attack Neu5Gc-bearing cells.
In his research on these surface compounds, Varki discovered human cells appear to pick up Neu5Gc whenever they are in proximity to animal cells.
"We knew that was happening in normal cultured human cells, so we thought 'Gee, maybe this could be happening in the embryonic stem cells,'" he said.
Close inspection in the laboratory proved that all U.S. embryonic stem cell lines currently used in research have picked up Neu5Gc during the culturing process, Varki said.
"In their current form, therefore, if this problem isn't solved, putting embryonic stem cells into humans in some form of treatment will probably result in some kind of immune reaction against the cells, in most humans," Varki said.
He stressed that the federally approved lines remain useful for in vitro or animal studies in the lab. Furthermore, the discovery of Neu5Gc contamination shouldn't invalidate the results of any stem cell research done to date, Varki said.
However, the finding should spur research into new, uncontaminated sources of embryonic stem cells for use in humans.
"This is yet another reason to look at non-embryonic [adult] stem cell sources, such as umbilical cord blood, bone marrow, fat cells, other types," Sanberg said.
While adult stem cells may not always be as easily manipulated as embryonic cells, they can often be harvested and transplanted whole, without the need for culturing, he added.
And Sanberg said scientists are still not sure whether embryonic stem cells need to survive over the long term in the human body to work their magic.
"A lot of us think stem cells work by providing chemicals like growth factors, cytokines, other compounds, to enhance the body's own repair mechanisms," he said. "If that's the case, putting in cells that don't last might be ok -- the new donor cells will be gone, but the host cells will have responded."
Researchers are also hard at work developing new methods of culturing stem cells without animal-cell contamination. For example, Varki's lab has developed a strain of mice with human-like cells that do not pick up Neu5Gc. Using feeder cells from these mice in the culture medium may be "another long-term solution," Varki said.
"Someday, of course, you'd like to see embryonic stem cells grown in serum from the person who's going to receive them," he said. "But that's still a long ways away."
"Theoretically, it's possible to get around this problem, but it raises more general questions," Varki added. "This is just one example of a problem using animal cells -- who knows what else is going on? It's telling us to be cautious. Don't think that just because we can solve this problem we've solved all the problems."
More information
To learn more about stem cells and stem cell research, head to the International Society for Stem Cell Research. |
