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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.
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 exposè 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. * Read Michael Fumento’s additional work on biotechnology.