Scientists in stem-cell cover-up
Deliberately exaggerate embryonic advances, ignore adult
Insight/News World Communications Inc.
Researchers are engaged in a "stem-cell war," a deliberate effort to downplay
the proven value of adult stem cells to attract more attention to the potential
of embryonic stem cells.
It's a war being fought partly over ethics, but mostly over money.
Stem-cell research constitutes one of the most exciting areas in medical
science. It promises to prevent, ameliorate and cure diseases for which there
are now few if any treatments. Far easier is listing what stem cells don't have
the potential to do, but here are a few of the wonders in progress:
More than 30 anticancer uses for stem cells have been tested on humans, with
many already in routine therapeutical use.
By some accounts, the area in which stem-cell applications are moving fastest
is autoimmune disease, in which the body's own protective system turns on
itself. Diseases for which stem cells currently are being tested on humans
include diabetes, lupus, multiple sclerosis, Evans syndrome, rheumatic disease
and amyotrophic lateral sclerosis [Lou Gehrig's disease], among many others.
Just last February, two different human-autopsy studies demonstrated that stem
cells transfused into the marrow work their way into the brain, where they can
repair neurons and other vital cells. Other studies have shown that when
injected into animals with severed spinal cords, stem cells rush to the injury
site effecting repairs.
"I think the stem cells may act as a repair squad," says the leader of one of
the two studies, Helen Blau of the Stanford University Brain Research
Institute. "They travel through the bloodstream, respond to stress, and
contribute to brain cells. They clearly repair damage in muscle and other
tissues."
At a conference in late 2002, French researchers reported that during the last
14 years they had performed 69 stem-cell transplants with an 85 percent
disease-free survival rate. Since improving their procedure in 1992, all 30 of
the last transplants have been successful.
Stem cells have been injected into damaged hearts and become functional muscle.
This destroyed the dogma that heart muscle cannot be repaired, just as
stem-cell research also wrecked the firmly held belief that brain tissue cannot
regenerate.
Unless you've spent the last several years stranded on a deserted island,
you've probably heard of at least some of these medical miracles. But here's
what you may have missed. While the overwhelming majority of favorable media
coverage of stem cells concerns those pulled from human embryos, called
embryonic stem cells, or ESCs, not a single treatment listed above has used
that kind of cell.
In fact, while activists such as spinally injured actor Christopher Reeve rage
that but for Bush administration and congressional restrictions on ESC funding
he might be walking in a few years, there are no approved treatments -- and
have been no human trials -- involving embryonic stem cells. Each of the above
therapies and experiments has involved cells that require no use of embryos.
These are called "adult stem cells," or ASCs, though they also refer to cells
found in nonadult tissue such as umbilical cords, placentas and amniotic fluid.
Like ESCs, they are precursors that eventually will become a mature,
specialized cell. ASCs actually have been used therapeutically to treat
leukemia and other diseases since the 1980s. A bone-marrow transplant is a
transplant of stem cells from marrow.
Yet when an ESC so much as hiccups, it makes international news, while
tremendous breakthroughs with ASCs are as a rule ignored.
Welcome to what's been called "stem-cell wars," a deliberate effort to downplay
the proven value of ASCs to attract more attention to the potential of ESCs. It
is a war that is being fought partly over ethics, but mostly over money.
Okay, so if ASCs have such a huge advantage over ESCs then why did anybody
begin researching ESCs anyway, to a point where labs and researchers all over
the world now are working with them?
Blame it on the dogma -- scientific dogma that is. It's long been acknowledged
that ESCs carry a boatload of physiological and ethical problems. For example,
ESCs implanted into animals have a nasty tendency to cause malignant tumors.
That's a major hurdle to overcome, as is the fact that the body rejects them
just as it rejects donated organs.
Yet it was always believed that ESCs had one huge advantage over their ASC
counterparts -- that while an ASC could become or "differentiate" into only a
few types of mature tissue with those tissues dictated by the source of that
ASC, the ESCs could become any type of tissue in the entire body. In medical
terminology this is known as "plasticity."
But this has never been more than theory, and lately that theory has begun
crumbling under the weight of empirical findings. Or, in other words, it's had
a run-in with reality.
"We do not yet know enough about adult stem cells or ESCs to make dogmatic
statements of either," declared Dr. Darwin Prockop, director of the Gene
Therapy Center at Tulane University, in a letter that appeared in Science.
"There's no law of physics or such that I know of that says that [ASCs] are
inherently more limited than embryonic stem cells," Prockop told Citizen.
We do know that ESCs give rise to all three germ layers [as in "germination"]
that become all the forms of human tissue. But this doesn't necessarily mean
that they can be converted into each and every one of those tissues.
Moreover, Catherine Verfaillie and her colleagues at the University of
Minnesota's Stem Cell Institute recently have found stem cells in human marrow
that appear to transform into all three germ layers.
"I think Verfaillie's work is most exciting and translatable into the clinical
arena," says Dr. David Hess, a neurologist at the Medical College of Georgia in
Augusta. "They seem to give rise to every cell in the body. She seems to have a
subpopulation with basically all the benefits of ESCs and none of the
drawbacks."
Verfaillie calls the cells "multipotent adult progenitor cells," and has
isolated them from mice, rats and people. They already have been transformed
into cells of blood, the gut, liver, lung, brain and other organs. Just a few
months ago, researchers at the Robert Wood Johnson Medical School in New Jersey
published a paper explaining that in a mere five hours they had been able to
convert bone-marrow cells into neurons both in petri dishes and in rats. Under
the old dogma, that was simply impossible.
More importantly, "We found that they express genes typical of all three
embryonic germ layers," the researchers told Citizen. "In aggregate, our study
and various others do support the idea that one [ASC] can give rise to all
types of tissue."
And the good news keeps pouring in. One problem with Verfaillie's cells is
that, in part because they come from marrow, they are difficult to extract.
That problem won't matter down the road when culturing practices are perfected,
say researchers, but currently it hinders efforts to keep labs supplied.
Enter Elizer Huberman and his colleagues at the Argonne National Laboratory
outside Chicago. They wanted to find highly plastic ASCs in blood, as they
would be far easier to extract and to store. Just how plastic they might be
remained to be seen and wasn't even a prime concern. But when the Argonne
scientists reported their results in the March 2003 issue of the Proceedings of
the National Academy of Sciences, it showed that their stem cells had in fact
differentiated into mature cells of all three lineages that ESCs can produce.
Even if it somehow turned out that none of the ASCs really can produce all the
cells of the body, perhaps we don't need the ability of cells that are "one
size fits all." That's because in recent years researchers have found that they
can tease ASCs into many more types of mature tissue than was previously
thought possible.
Moreover, researchers now seem to be finding ASCs essentially wherever they
look -- including blood, bone marrow, skin, brains, spinal cords, dental pulp,
muscles, blood vessels, corneas, retinas, livers, pancreases, fat, hair
follicles, placentas, umbilical cords and amniotic fluid. You don't need "one
size fits all" if you can provide all sizes.
At the same time, ESCs have become even more suspect ethically in the eyes of
many people. The original ethical concern was that many see the destruction of
human offspring, no matter how young, as an abortion. Some prominent abortion
opponents believe human life only begins upon implantation in the uterine wall;
therefore destruction of embryos would not count as such. Nonetheless, even to
some of these people the thought of ripping apart the byproduct of human
conception for the sake of science invokes images of Nazi eugenicist Josef
Mengele or of Mary Shelley's Dr. Frankenstein.
This more recent worry has nothing to do with destroying life but rather with
the creation of it -- cloned human life. While growing embryos into blastocysts
[see note at end of article] often is referred to as "therapeutic cloning" or
"research cloning" to distinguish it from the process of creating a human
being, the two processes follow parallel tracks. If that blastocyst is
implanted into the womb and it survives, voila! -- nine months later you have a
clone just like something out of Star Wars Episode II. No doubt most ESC
researchers haven't the least desire to take the next step, but that's not the
issue. What counts is that they are developing a technology that others can
build upon to refine the process of creating human clones.
Thus, ESCs have in their favor nothing more than a decaying theory that they
may have greater plasticity. Going against them are the ethical concerns and
that they are years behind ASCs in commercial applications.
But there's a huge ESC industry out there, with countless labs packed with
innumerable scientists desperately seeking research funds. Private investors
avoid them because they don't want to wait perhaps 10 years for commercial
products that very well may not materialize and because they're spooked by the
ethical concerns.
That leaves essentially only Uncle Sam's piggy bank, primarily grants from the
National Institutes of Health, to keep these labs open. This, in brief,
explains the "stem-cells wars," the perceived overwhelming need grossly to
exaggerate petri-dish advances with ESCs, while life-saving new applications of
ASCs are downplayed or ignored.
Thus the announcement in 2001 that ESCs could be made into blood cells received
almost 500 "hits" on the Nexis media database even though published
medical-journal reports of ASCs differentiating into blood cells go back at
least to 1971. It's possible to read lengthy articles on the promise of stem
cells that mention nothing but ESCs. The influential pro-life figure and former
U.S. senator Connie Mack, R-Fla., even questioned whether ASCs exist, which is
on par with questioning the existence of Starbucks.
It's probably not a coincidence that Mack has been a paid lobbyist for ESCs,
but most reporters have no financial stake in the issue and it is a complex
one. They take their cues from the professional medical journals. And,
unfortunately, these are among the leaders in the war against ASCs. The world's
most prestigious science journal, Nature, published two in-vitro studies in
March 2002 widely interpreted to mean either that ASCs are grossly inferior to
what had earlier been believed or even that they're outright worthless.
The Nature writers indicated their studies showed that ASCs probably were not
differentiating and multiplying at all; rather that it appeared the cell nuclei
were merely fusing and the resulting fusion gave the impression of a new,
differentiated cell forming. The media gobbled it up.
Agence-Presse France headlined: "'Breakthrough' in Adult Stem Cells Is Hype,
Studies Warn." The Australian Associated Press declared, "New Research Tips
Debate on Stem Cells." The Washington Post's subhead flatly declared: "Adult
Cells Found Less Useful than Embryonic Ones." It was damning ... and false.
Stanford's Helen Blau countered with a big "So what?" In a Nature commentary,
she noted that "Cell fusion has long been known to achieve effective
reprogramming of cells" -- so long in fact that her own laboratory was doing it
20 years earlier. Thus, far from showing that ASC research is "hype" or
whatever term the particular newspaper or newswire chose to apply, it turns out
that cell fusion both complements and encourages the differentiation of adult
stem cells -- something that's already proved valuable and is clearly very
promising.
The idea that differentiation wasn't happening at all was simply bizarre in
light of myriad studies and therapeutic applications showing otherwise,
including one that appeared in the journal Blood shortly thereafter. Showing
that bone-marrow stem cells can be converted into kidney cells, it pointedly
concluded: "The process does not involve cell fusion."
"We found no evidence of nuclear material from two cells fusing into one cell,"
one of the coauthors emphasized to me.
In an interview last spring, Prockop told me, "It may well be that fusion is
part of the healing process. But clearly we can take mesenchymal cells and
differentiate them into various tissues because it's into bone or fat and it's
been done over 20 years."
Indeed, he specifically explored the fusion issue in a study released in the
Sept. 30, 2003, issue of the Proceedings of the National Academy of Science,
concluding "Most of the [mesenchymal cells] differentiated without evidence of
cell fusion, but up to one-quarter underwent cell fusion with the epithelial
cells. A few also underwent nuclear fusion."
Yet another Blood study released last September concluded, "Analysis of DNA
content indicates that donor-derived endothelial [stem] cells are not the
products of cell fusion." A Lancet study in early 2003 looked at cheek cells
from five living women who had received bone-marrow transplants from their
brothers several years earlier. They found cells containing the male Y
chromosome, a sign that donor marrow stem cells had differentiated into cheek
cells. Moreover, the group found almost no evidence of fusion among the cells
in the cheek. Of the 9,700 cells that were examined in the study, only two
showed signs of possible fusion. And yet in late October 2003, Nature rushed
into publication yet another letter claiming that there was no evidence that
stem cells from marrow do anything but fuse. Of all these studies, guess which
was the only one to get media attention -- and lots of it.
Shortly after Nature's first effort to establish that the wheel doesn't exist,
its chief competitor, Science, attempted to show that the Earth is flat after
all. First it ran a letter in which authors from the Baylor College of Medicine
claimed that they earnestly had tried but failed to find bone-marrow cells that
had differentiated into neurons in the brain.
Shortly thereafter it ran a paper from Stanford University scientists, led by
Irving Weissman, claiming to show that a type of stem cell from marrow could
replenish that type of marrow, but that it appeared worthless for creating
other tissues. The typical media reaction was UPI's "Promise of Adult Stem
Cells Put in Doubt." Weissman eschewed the usual cautionary scientific
terminology such as "it appears" or "evidence indicates," or "our particular
study has found." Instead he smugly told UPI: "They [the cells] don't make
brain; they don't make heart muscle or any of these things."
According to Blau, it was surprising to see this published so rapidly and in
such a prestigious and influential publication as Science. The Baylor study,
she notes, failed to detect not only neurons but also something far more
readily detectable called microglial cells. And forget that "At least 20
reports over the past 15 years have shown that bone-marrow transplantation
results in readily detectable replacement of a large proportion of microglial
cells in the brain." Some of these reports have even appeared in Science.
Says Blau, "If they couldn't see those, how could they possibly see neurons?"
It would be like announcing that you had failed to detect a tiny virus under
your microscope when you also hadn't been able to see a gnat that accidentally
got trapped between the slides. Either your microscope is faulty or you don't
know how to use it.
"As to Weissman's paper, where you look and how you look determines what you
see, and he doesn't define where he's looking," she says. "Our own experiments
have shown there can be a thousand-fold frequency of stem-cell incorporation
depending on where you look."
Because he didn't say where he looked, "It would be quite difficult to
replicate his experiments," she notes. "You could replicate ours, but he did
not. The other false assumption he made was to look at a fraction of marrow,
the hematopoietic part, and he looked in absence of any damage to the body; yet
these are damage-repair cells." In other words, one shouldn't think it
remarkable that no ambulance shows up when there's no need for an ambulance.
Weissman is also a notorious opponent of adult stem-cell research insofar as he
has made millions of dollars with numerous companies that work with ESCs,
according to an exposé in the Washington Monthly. "Was the publication of these
two papers a political act designed to harm the image of ASCs in the image of
the public?" Insight asked Blau.
"That's been a question in many people's minds," she says. "Why these negative
findings should have been published in such a prominent way does suggest a
political agenda."
In a commentary in the Journal of Cell Science in February 2003, British
researchers asked in the very title: "Plastic Adult Stem Cells: Will They
Graduate From the School of Hard Knocks?" In a good-humored, indeed sometimes
humorous, piece the angst nonetheless came through.
"Despite such irrefutable evidence of what is possible, a veritable chorus of
detractors of adult stem-cell plasticity has emerged, some doubting its very
existence, motivated perhaps by more than a little self-interest." While
certain issues still need resolving, the researchers said, "slamming" the
"whole field because not everything is crystal clear is not good science."
Even scientists who strongly favor ESC funding readily admit that the issue is
highly politicized, with ASCs getting the short end of the stick from research
publications, the popular media and the scientific community. Blau, Prockop,
Black and Verfaillie are among them.
"Most scientists never want a door closed, they want all doors open," says
Hess. "And anybody who disagrees with that stance is seen as trying to hold up
medical progress."
Another ASC researcher who strongly supports funding for ESCs is Patricia Zuk,
whose lab has shown that America's most plentiful natural resource -- body fat
-- can provide a limitless source for stem cells capable of differentiating
into bone, muscle, cartilage and fat that can be used to fill in scars and
wrinkles.
"Certainly it's politicized," she says. But, she adds, "I think a lot of
embryonic stem-cell people are right in trying to protect their jobs."
Understandable, yes. But is it right? Forget for the moment the questionable
morality of a mass campaign to fool the American public. Zuk admits that the
stem-cell wars are "very worrisome" in that they could harm her own efforts to
get grant money.
Says Hess, "Certainly one of my motivations is I don't want money from adult
stem-cell research being pushed into embryonic, though it's already starting to
happen."
Activists such as Christopher Reeve have it backward when they say that
restrictions on ESC research funding will prevent him from walking again.
ASC studies already have enabled quadriplegic animals to walk again, and human
trials should be right around the corner. But the chance of ESCs helping people
such as Reeve in the next 10 years is practically nil. Reeve should know about
this: Many of the amazing ASC studies, including Ira Black's, have been funded
by something called the Christopher Reeve Paralysis Foundation.
Moreover, to the extent that breakthroughs with ASCs are confused with ESC
technology, it harms public support for ASC research. ESC propagandists are
hoping for a seesaw effect; that by exaggerating ESC research and denigrating
ASC research they'll push up their side of the board. But, to the extent they
succeed, they're only delaying the stream of miracles coming from adult stem
cells.
Michael Fumento is author of "BioEvolution: How Biotechnology Is Changing Our
World," which has just been published by Encounter Books of San Francisco.
Note: When fertilization initially takes place, whether within a fallopian tube
[in vivo] or in a petri dish [in vitro] it forms a single-cell embryo called a
zygote. The zygote divides progressively into a multicell embryo. After about
five days, the embryo contains many cells with a cystic cavity within its
center and is called a "blastocyst." If this blastocyst implants into the
uterus and continues to develop, it becomes a fetus. But this is also the stage
at which the individual cells become viable for use in ESC experimentation.
"Blastocyst" is not to be confused with "blastocyte," which is simply another
term for an ESC.
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