Can Adult Stem Cells Do It All?

Scientists may have turned mouse skin cells into embryolike stem cells, but prior claims for the power of adult cells have yet to stand the test of time
cell culture

Stem cells have been hailed by scientists as the great hope to one day prevent, halt and even reverse damage from diabetes, spinal cord injuries and degenerative diseases like Parkinson's and Alzheimer's.

Stem cells obtained from human embryos seem to offer the best chance of new therapies, because unlike other stem cells they have the ability to morph into almost any type of tissue. But researchers complain that political roadblocks are keeping them from determining the full potential of these cells.

Six years ago, President Bush limited federally funded research to about 20 viable lines of cells that had been extracted from embryos prior to August 9, 2001. The stem cell community has repeatedly called for the restrictions to be lifted, charging that the designated cell colonies have been compromised or corrupted and that failure to ease the ban is hobbling U.S. efforts to discover new life-saving treatments. But opponents say such research is immoral, because embryos must be destroyed to obtain their cells.

Last week, Congress sent legislation to Bush that would allow federally funded scientists to study cells from frozen embryos that fertility clinic patients no longer need and have chosen to donate instead of discard. The Stem Cell Research Enhancement Act of 2007 also spells out ethical guidelines governing such research.

Bush immediately renewed his pledge to veto the bill (as he did similar legislation that reached his desk last year)—and it is questionable whether the Senate can muster the votes to override it. The Senate passed the measure in April by a 63-to-34 margin—just four votes shy of the two thirds majority needed to nix a veto—on a day when two supporters of the bill were absent.

In vetoing the measure, Bush said it would be "a grave mistake" for "American taxpayers [to] be compelled to support the deliberate destruction of human embryos."

Critics argue further that embryonic stem cell research is unnecessary because stem cells from adults are purportedly just as promising. In fact, just a day before the House vote last week, researchers announced that they had coaxed plain old skin cells taken from adult mice to mimic embryonic cells, which—if they learn to do the same for humans—could offer a simple and seemingly less controversial way to create scores of stem cells.

Although researchers said the finding did not negate the need for studies on true embryonic stem cells, critics seized on it as further proof that such research is superfluous: If adult cells could be transformed into embryolike cells, they argued, then why not use them instead of destroying embryos?

The claim echoes those made many times in the emotional debate over federal funding of new human embryonic work. In particular, opponents of embryonic stem cell research have repeatedly pointed to the supposed power of stem cells extracted from the adult body, which in the hands of at least one laboratory seemed to nearly match that of embryonic stem cells.

In contrast to last week's study other laboratories have never reproduced the dramatic findings on which such arguments are based. And in the past six months investigations have exposed strange flaws in the data from one lab that claimed to have successfully manipulated adult stem cells to act like embryonic tissue.

At first blush, a flurry of unreproducible results might suggest problems within the field itself.

In recent interviews top stem cell experts said that the failures reflect the field's high public profile and its politicization, which obscure real progress. "I hate it when [big claims go unreplicated], because it makes our field look like a field full of shams and frauds," says stem cell biologist Irving Weissman of Stanford University.

Conventional wisdom has long held that adult stem cells are only capable of forming their tissue of origin. Researchers have isolated stem cells from only some of the body's organs and tissues, including the blood, brain, skeletal muscle, heart muscle and most recently from skin. They hope to discover whether stem cells also exist for other key organs such as the pancreas, liver and spinal cord. Much adult stem cell research focuses on identifying the genes and molecules that define such cells and allow them to replenish themselves indefinitely as they produce the various cell types of their organs—the defining characteristics of a stem cell. Learning to grow and manipulate adult stem cells in the lab might also allow researchers to create tissue regenerating treatments from them.

A series of headline-grabbing results in the late 1990s and early this decade suggested that specific adult stem cells such as those from the blood seemed able to exceed expectations and transform themselves into other organs and tissues. When engineered to glow green and injected into mice, these studies revealed glowing cells in unexpected organs such as the brain, heart and liver. The discoverers dubbed the process transdifferentiation.

Within a few years, however, laboratories that tried to replicate the findings either failed or came up with simple explanations for them such as fusion between the injected cells and those in the identified organs. A September 2002 follow-up study found no evidence for widespread transdifferentiation of blood-forming stem cells in brain, liver, kidney, gut and other tissues. Transdifferentiation may occur, but if so it must be a rare event, says stem cell and cardiovascular researcher Kenneth Chien of the Harvard Stem Cell Institute.

Scientists were even more stunned in July 2002 when researchers led by stem cell biologist Catherine Verfaillie at the University of Minnesota reported that bone marrow–derived cells they had injected into young embryos contributed to all three embryonic layers, just as embryonic stem cells would do.

Verfaillie and colleagues were trying to grow stem cells extracted from rodent mesenchyme, a component of bone marrow that contributes to fat, skeleton and muscle. Bone marrow cells do not normally grow in the lab, but the team reported that by carefully controlling the amount of oxygen the cells received along with other growth conditions, they could keep the cells alive for at least a year. In the process, the cells seemed to turn into something else, the experiments indicated. Rather than showing up only in the mesoderm, or middle layer of the embryo where future mesenchymal cells reside, the cells had spread to the two adjacent layers, which form other tissues such as skin, brain and gut, according to the group's report in Nature.

The researchers speculated that their cells, which they called multipotent adult precursor cells (MAPCs), might have regressed to a more primitive state in culture or were left over from embryonic development. "That started a lot of excitement that there might be these adult stem cells that had the potential of embryonic stem cells,'' says stem cell researcher Amy Wagers of the Joslin Diabetes Center in Boston.

Hoping to confirm the result by replicating it, other laboratories tried unsuccessfully to grow the cells. Wagers, then a postdoctoral fellow in the Stanford University lab of stem cell biologist Irving Weissman, spent a week in Verfaillie's lab in 2002 trying to learn to culture MAPCs. "They're very fussy," she says. Even Verfaillie, who announced she would teach a course on growing the cells in lab dishes, had problems culturing them at times, according to Weissman.

Difficulties growing stem cells are not unheard of. "The culture conditions needed to grow various kinds of stem cells can be very tricky," down to the source of the water, says neural stem cell biologist David Anderson of the California Institute of Technology in Pasadena. But the longer a study goes unreplicated, despite researchers' best efforts, the less sound a result seems.

Against that backdrop, the London-based magazine New Scientist reported in February that data presented in Verfaillie's July Nature paper appeared under a different label but was otherwise identical in a second paper published in Experimental Hematology in August of 2002. The data referred to cell surface proteins that supposedly defined the cells. That month, an expert panel convened by the University of Minnesota deemed the data "significantly flawed" and "potentially incorrect" for further inconsistencies in the data, but did not accuse Verfaillie or anyone in her lab of deliberately manipulating it.

The flawed data did not contradict the paper's main claim that the injected cells have a potential similar to that of embryonic stem cells, researchers say, because they could simply have had other cell surface proteins not included in the data. [see endnote]

Additional problems cropped up in March, however, when New Scientist reported that a single image had appeared three different times in data from Verfaillie's lab—once referring to bone and once to cartilage in a 2001 Blood paper about human MAPCs, and once again to describe bone cells in a 2006 patent application.

In January, shortly before the first data problems came to light, Verfaillie's work had received a boost when her lab together with Weissman's reported they had replicated a second finding from the 2002 Nature paper—that MAPCs could partially replace the destroyed bone marrow (where red blood cells are manufactured) of mice, which by itself is unusual because they did not come from blood-forming stem cells, Weissman says. He adds, however, that if they work as reported, MAPCs are still not very efficient: one adult blood-forming stem cell replaced as much bone marrow as a million MAPCs.

"There's still a lot of skepticism about the paper, even though Irv is on it," says Chien. Weissman says his lab has still not created MAPCs. For the experiment with Verfaillie, who now heads stem cell research at the Catholic University of Leuven in Belgium, one of his current postdoctoral fellows, Scott Dylla, implanted the cells in mice in Leuven and brought them to Stanford to be examined.

Experts hesitate to pass judgment on Verfaillie, whom they describe as a careful researcher. Still, the fishy figures and lack of replication have raised eyebrows. "It all smells really bad," says stem cell biologist Sean Morrison of the University of Michigan at Ann Arbor Center for Stem Cell Biology. The important question, he says, is still whether the findings can be reproduced. "There's a tendency now for people to really tee off on Catherine" prematurely, he says. Verfaillie did not return phone calls or e-mails asking for comment.

Although opponents of embryonic stem cell research latched onto transdifferentiation and MAPCs, few scientists have ever proposed adult stem cells as an alternative to embryonic ones, Morrison says. Eva Mezey, a stem cell biologist at the National Institutes of Health who published one of the transdifferentiation studies and stands by the effect, notes that embryonic cells are naturally more versatile than adult stem cells. "That's their job," she says.

Morrison says the transdifferentiation studies have left a black mark on the field but represents only a subset of research. "There are always people with a get-rich-quick mentality," Morrison says. "It's an occupational hazard in any field where there's a possibility of having your paper end up on the front page of the New York Times. … The fact that this is a high profile field means that when people make mistakes it gets more attention."

"Where all of this gets really risky," Caltech's Anderson adds, "is when clinicians start to move forward with trials that are based on experimental results that may not be solid."

Transdifferentiation studies spawned a number of clinical trials, including several in which heart attack patients received an injection of blood-forming stem cells in their hearts in hopes of replacing dead cardiac muscle. The results came in last year and were not encouraging: In two shorter trials, heart function improved by a few percentage points or not at all, and one longer study found a slight but temporary benefit.

Weissman says that most clinical studies of stem cells fail to meet what he sees as key criteria: They should be based on clear, peer-reviewed demonstrations of tissue regeneration, replicated by a large number of independent groups that provide rapid, long-lasting benefits.

Chien agrees that basic stem cell biology has not kept pace with clinical studies, but he says there is a compelling need for new treatments. "I can understand why people are motivated to try to do something" by conducting trials, he says. "They're going to go on and we will learn something from them," he notes, although he adds that treatments currently in the clinic are unlikely to enter the mainstream.

Stem cell researchers maintain that whatever the potential of adult stem cells, embryonic research could help them achieve it. Last December, for instance, Chien's group reported finding markers for heart muscle stem cells by tracing their development from embryonic tissue.

Similarly, the three research teams that last week reported turning mouse skin cells into embryolike cells say they will have to study embryonic cells to learn how to reprogram human cells in the same way and to understand their potential.

Update: On June 13, Nature published a corrected version of the figure. The journal said it checked the data with independent experts, "who concur that the data in Figure 1 are flawed, but agree that [the retraction] does not negate the central findings of the paper."

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