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Insight
on the News
May 24, 2004
The Stem Cell
Cover-Up
By Michael Fumento
[Michael Fumento is author of BioEvolution: How Biotechnology Is Changing
Our World, which has just been published by Encounter Books of San
Francisco.]
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 (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" (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 (AAP) 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.
*****
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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