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Stem cells: Miracle postponed

by Peter AldhousNew Scientist
March 11th, 2006

HYEONI KIM believed. He had been paralysed at just 8 years old when he was hit by a car on his way home from school. So when South Korea's science superstar, Woo Suk Hwang, asked if his team could take skin cells from Kim and use them to obtain stem cells that might one day provide a cure, Kim and his family were delighted. When Hwang visited him in hospital in April 2003, the boy, then 9, asked him if he would walk again. "I promise," Hwang replied.
That promise became immortalised in a Korean postage stamp showing a man rising from his wheelchair. But it was always highly questionable. Even if Hwang had managed to derive cloned embryonic stem cells (ESCs) from the skin cells of Kim and 10 others - as he claimed in May 2005 - he would still have been a long way from mending Kim's spinal cord. Cloning merely provides ESCs that will not be rejected by a patient's immune system. Whether cells derived from them could ever fix a spinal injury, especially an old one like Kim's, is far from clear.

Not only was Hwang's promise rash, we know now that he did not even clear the first hurdle when it came to fulfilling it. The evidence of cloned ESCs was fabricated, and his scientific papers have been retracted. This was fraud piled on hype. Yet Kim's family still cling to hope. "We told him, yes, one day you will walk again," Kim's father told the Los Angeles Times in January. "But you might have to wait a little longer."

Looked at in the grim light of the Hwang affair, an uncomfortable truth becomes apparent: stem cell science is no stranger to claims that don't stack up, results that can't be replicated and doctors willing to rush into the clinic.

"It is common knowledge that the bar for publication in this field often has appeared remarkably low," wrote David Shaywitz, an endocrinologist at the Harvard Stem Cell Institute, in an article in The Washington Post in January. "The result of this frenzy has been an entire body of literature that is viewed with extreme skepticism."

Many leading stem cell scientists agree with Shaywitz's damning assessment. "Things are not reproduced. You really wonder what's going on," says Gordon Keller of the Mount Sinai School of Medicine in New York city, president of the International Society for Stem Cell Research.

Despite the Hwang scandal, most stem cell scientists believe outright fraud is not a major issue. Some argue that teething problems are common in any new area of science, particularly if researchers let their enthusiasm get the better of them. Part of the problem may be that interpreting the results of stem cell experiments requires mastery of a variety of complex techniques, so researchers occasionally convince themselves they are seeing things that aren't really there. "What you're looking at is a hot field that attracts people who are not trained to jump in," says Irving Weissman, a veteran stem cell biologist at Stanford University in California.

The unprecedented political and media spotlight on stem cell research has also contributed. As self-styled "pro-life" groups have lobbied against work on human ESCs, which are usually derived by destroying embryos just a few days old, scientists have been forced to champion this research or risk losing the right to carry it out. Meanwhile, hints that the "adult" stem cells found in many of our tissues might be more versatile than was thought have been seized upon by opponents of research on ESCs. This feverish debate has seen those on both sides make statements that they have later come to regret (see "Careless words").

The upshot is that scientists, politicians and activists of various persuasions have been making a great deal of some very shaky findings. Take some of the claims about the "plasticity" of adult stem cells. Unlike ESCs, which can develop into any of the body's tissues, adult stem cells were traditionally thought to replenish only one type of tissue. In the late 1990s, however, reports started appearing claiming that some adult stem cells could turn into all kinds of tissues. If true, there might be no need for ESCs.

Yet many of these findings, including some published in the most prominent scientific journals, have proved extremely difficult to repeat. And if other groups do not get the same results despite many attempts, something is clearly wrong.

In a 1999 paper in Science (vol 283, p 534), for example, researchers led by Angelo Vescovi, now at the San Raffaele Hospital in Milan, Italy, described how they irradiated mice to kill their bone marrow, which contains the stem cells that replenish blood cells. They then injected the mice with neural stem cells taken from the brains of other mice. These neural stem cells apparently replaced the bone marrow stem cells that had been destroyed by the radiation, giving rise to a variety of blood cell types.

Other researchers have failed to replicate the experiment. According to Weissman, the results were always perplexing. The blood cells apparently derived from the neural stem cells did not turn up in the animals' circulation for over 20 weeks. "Then suddenly, the whole system came from nowhere," says Weissman.

A 2002 paper in Nature (vol 418, p 41), from Catherine Verfaillie's team at the University of Minnesota in Minneapolis, also attracted much attention. As reported a few months earlier by New Scientist (26 January 2002, p 4), Verfaillie claimed a rare type of bone marrow stem cell could differentiate into almost any kind of tissue. Unsurprisingly, campaigners against embryo research championed the cells as a morally acceptable alternative to ESCs.

Since then, a company called Athersys in Cleveland, Ohio, has refined methods for extracting similar cells and hopes to begin trials to treat patients with heart disease in 2007. Academic groups, however, have had mixed success in trying to repeat Verfaillie's results. Even her own team was unable to isolate new cultures of the cells over a period of more than six months in late 2003 and early 2004.

Perhaps the biggest controversy surrounds a 2001 paper in Nature (vol 410, p 701). Piero Anversa's team at New York Medical College in Valhalla described experiments in mice in which bone marrow cells repaired the damage caused by a heart attack by forming new heart muscle. Two teams, one led by Weissman, the other by Chuck Murry of the University of Washington in Seattle, have since tried without success to replicate the findings. "We failed miserably," says Murry.

That has not deterred doctors from trying the therapy in people. Several clinical trials are under way on both sides of the Atlantic. So far, the results have been mixed. While heart function has improved in some patients, there is no firm evidence that this is due to transplanted cells forming new muscle tissue (New Scientist, 25 September 2004, p 38). Instead, the bone marrow cells might have temporarily boosted the natural healing process by releasing chemical signals, or by causing local inflammation. "Perhaps we don't need cells at all," says Murry.

Given that nobody really knows what is going on, Murry is not alone in thinking that it was unwise to start clinical trials so soon. No serious safety problems have so far arisen in the cardiac trials, but stem cell biologists worry that rushing into the clinic on the basis of unreplicated findings could end in disaster. Their nightmare scenario is a repeat of the 1999 Jesse Gelsinger tragedy, in which an 18-year-old volunteer with a liver disease died from an inflammatory reaction to the virus used to deliver genes. The case cast a pall over the field of gene therapy that remains to this day.

So why have some adult stem cell studies proved so hard to repeat? One major problem is that the property of "stemness" - the ability of a cell both to renew itself and to give rise to other, more specialised cells - is somewhat elusive. You cannot tell if a cell is a stem cell simply by looking down a microscope. Biologists usually identify stem cells by using antibodies that bind to proteins found on their surfaces, but this can yield ambiguous results. In some cases, teams that cannot repeat one another's results might not even be working with the same cells.

Tracking the fate of stem cells after they are injected into a lab animal is even more difficult. If, say, they turn into heart muscle cells, they will look exactly like any other heart muscle cells. One solution is to add genes to the stem cells that make them fluoresce, but unlabelled cells can fluoresce of their own accord, particularly when damaged. All it takes is a little tweaking with a microscope's controls, or playing with a digital image on a computer, and a dim fluorescent signal can seem as clear as day.

Another method is to replace one of the bases in the stem cells' DNA with a molecule called BrdU. Fluorescent antibodies that bind to BrdU should then reveal the cells' location. Verfaillie, however, has found a serious shortcoming with this technique: if cells die, they can release their BrdU, which may then be taken up by other cells in the vicinity.

So perhaps it is not surprising that stem cell biologists often disagree about what they are seeing in their microscopes. Yet as excitement mounted about the versatility of adult stem cells, the healthy scepticism that would normally prevail seemed to fall by the wayside. "The scientific standards for publication appeared to get lower and lower as the magnitude of the claims made by those papers got higher and higher," says Sean Morrison, a stem cell researcher at the University of Michigan in Ann Arbor.

Numbers matter
What's more, the issue is not just whether some adult stem cells can turn into this or that tissue type. It is how many of them do so, something that few papers on adult stem cell plasticity attempt to quantify. Too much has been made of results that are unlikely to be of any medical significance, Keller says.

In some cases, it has turned out that transplanted adult stem cells do not actually give rise to new tissues at all, but instead fuse with cells that are already there. Cell fusion might itself be useful for treating some diseases (New Scientist, 16 December 2005, p 14). But had the phenomenon been recognised earlier on, those in the field might not have got so carried away with the potential of adult stem cells to cure all manner of ills.

Many researchers are just as sceptical about much of the work on human ESCs, which is fraught with many of the same difficulties. For now, however, the biggest questions about ESCs relate to what is going on in culture dishes, rather than in experimental animals.

If ESCs are injected directly into animals, they can form tumours called teratomas. So unlike adult stem cells, ESCs would have to be turned into the specific cell type required before transplantation into people.

For instance, Hans Keirstead of the University of California, Irvine, has got human ESCs to start turning into the precursors of nerve support cells called oligodendrocytes, which in animal experiments seem to repair damaged nerve cells, boosting recovery if injected a week after a spinal injury (but not 10 months after). On the basis of his work, stem cell company Geron of Menlo Park, California, is planning a clinical trial.

Geron would not be considering trials unless it was convinced that Keirstead's team can reliably transform ESCs into oligodendrocyte precursors. The same cannot be said of many other groups. The scientific literature is filled with recipes for turning human ESCs into this or that kind of cell by adding various signalling molecules. Most are little more than "black magic", Keller says.

For starters, many researchers grow their ESCs in a fluid called fetal calf serum, which contains a cocktail of signalling molecules and varies in composition from batch to batch. There is also little quantification of how many cells in a culture adopt a particular fate.

Su-Chun Zhang of the University of Wisconsin-Madison, who has spent several years developing reliable techniques to turn ESCs into neurons, thinks there is an even more fundamental problem. He claims that many cultures that are supposed to contain ESCs have begun to develop into other cell types even before experiments begin. "The vast majority of them are not stem cells," he says. If he is right, much of this research is meaningless.

In part, stem cell researchers only have themselves to blame for the state their field is in. They reviewed the papers that are now being questioned, and in most cases recommended publication. "What we didn't do is review the papers critically enough," Keller admits. Others argue that the journals, which jostled to publish the hottest papers, must share the blame.

Whoever is at fault, there is now a consensus that tougher standards are needed. Leading stem cell scientists hope that we have seen the end of extravagant claims based on a single line of evidence. "If the phenomenon is real, almost any way you look at it, the same answer will come out," Weissman points out.

Even if stem cell biologists do manage to inject new rigour into their field, outside the laboratory the war of words looks set to continue. Anti-ESC campaigners are already taking advantage of the Korean scandal. "To win public support and government funding, ESC advocates have long made hyped claims and exaggerated promises," wrote a campaigner for the US Conference of Catholic Bishops, Richard Doerflinger, in the Catholic publication Tidings Online. "In short, they acted like political hucksters instead of scientists, and now are beginning to pay the price."

Such attacks are being met with a vigorous response. "Many of the same critics decrying the overhyping of embryonic stem cell research are the same ones touting equally extravagant claims involving adult stem cells," Shaywitz says. Indeed, Doerflinger has repeatedly promoted contentious claims about the clinical value of adult stem cells.

With the US Senate due to debate various bills on stem cells and cloning, we can expect further claims that stretch the evidence. An end to the hype? Don't believe it.

From issue 2542 of New Scientist magazine, 11 March 2006, page 42

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