Controversy doesn't derail stem cell progress

Almost unnoticed amid the revival of stem cell politics this year, progress and peril in the science behind the controversy continues to hum along.

Human embryonic stem cells, with their ability to turn into every kind of organ tissue in the body, have tantalized biomedical researchers ever since their 1998 isolation by University of Wisconsin scientists. Organ replacement tissues free from immune system rejection, grown from embryonic stem cells or from more recently discovered "induced" stem cells grown from skin cells, have been envisioned for a decade.

"At this moment, the full promise of stem cell research remains unknown, and it should not be overstated," President Obama said in March while announcing a lifting of the previous administration's restrictions of federal funding on human embryonic stem cell research. He added, "Scientists believe these tiny cells may have the potential to help us understand, and possibly cure, some of our most devastating diseases and conditions."

In a study in the current Nature journal, a team led by George Daley of Children's Hospital Boston offered fresh insight into reaching that goal, demonstrating a novel, purely physical way to make stem cells turn into, or "differentiate" into, blood cells. Without using chemicals to trigger differentiation, the usual approach, the team placed mouse embryonic stem cells into a rotating "flow device," essentially between the inner ring and outer ring of a record-player. The viscous flow, or shear stress, on the cells caused by rotating the rings at different speeds for two days triggered the transformation from unspecialized stem cell to blood cell.

"By itself, the shear stress did it," said study team member William Lensch, in an interview conducted while we were both changing planes last week at Boston's Logan Airport (a small world, science reporting). "We tried all sorts of ways to push a flow along on the cells and they all gummed up, until the rotation method."

Shear flow alone on the cells triggered a jump in the expression of a blood cell gene and blood cell chemicals and limited the stem cells' production of nitric acid, which blocks their differentiation. "Collectively, these data reveal a critical role for biomechanical forces in haematopoietic (blood cell) development," says the study.

Whether similar physical forces play a role in the differentiation of other organ tissues is an open question, Lensch says.

However, other papers out last week say some even more fundamental questions remain.

"The link between stem and tumor cells in science is a very old one," says Paul Knoepfler of the University of California Davis School of Medicine in the current Stem Cell journal. But no one talks about it much, he adds, even though understanding the link remains "an essential bridge to cross along the way" in someday turning embryonic cells into organ transplants.

After all, the most basic test of whether stem cells are truly "pluripotent" or able to turn into any type of tissue in signature embryonic cell fashion, Knoepfler says, is to inject them into a mouse and see if they grow into tumors. "Why would (embryonic stem cells), supposedly normal counterparts to (cancer cells), also have the ability to cause tumors?" he asks. "The simplest but most troublesome answer is that (embryonic stem cells and cancer cells) are in fact, as was originally assumed, quite similar types of cells."

That raises the nightmare possibility of stem cell transplants that trigger tumors in patients. A February report in the PloS Medicine journal, for example, described the case if an Israeli child who received injections of "fetal neural stem cells" in a Russian clinic, triggering tumors.

At least four methods can make embryonic stem cell transplants safe for "regenerative medicine" if they are intrinsically cancer-tainted, Knoepfler suggests. The simplest way "may seem paradoxical: to not transplant stem cells at all into patients." Instead, in an approach that gained Food and Drug Administration approval for the first stem cell safety study in people in January, physicians differentiate the stem cells to the point that nearly every cell is a specialized organ tissue and then "sort" them to make sure no stem cells remain. "How few remaining stem cells are enough to cause concern about tumors? If the answer is 'zero,' then it may be difficult to achieve this goal because the reality is that the only pure cell population is that consisting of a single cell," he writes.

Alternately, stem cells transplant doctors could:

•Insert a "suicide" gene into stem cells that turns on after transplant and isn't passed on to their differentiated progeny.

•Use chemotherapy aimed at proteins found solely on the surface of stem cells, or genes that stems solely rely upon, an approach using the drug Rapamycin in a report in the April 28 Proceedings of the National Academy of Sciences journal.

•Treat the stem cells to remove their tumor-propensities before differentiating them into organ tissues. "Of course, at this time no such methodology exists and the notion of using stem cells directly for transplants would appear to be strongly out of favor with regulators," Knoepfler says.

All of these alternatives have problems, he adds, saying, "a much more open discussion and investigation of the tumorigenic nature of stem cells than has yet to occur, particularly that of (induced cells and human embryonic stem cells), will undoubtedly prove essential for the development of safe and effective regenerative medicine therapies."

Even cancer isn't the biggest question in stem cell science, says gene therapy researcher James Wilson of the University of Pennsylvania in the May 8 Science journal. In Obama's March announcement, "he took pains to temper Americans' hopes for quick fixes," Wilson writes. "Unfortunately, some stakeholders in (human embryonic stem cell) research have failed to exhibit the same restraint, effectively promising cures for Parkinson's disease, Alzheimer's disease, spinal cord injuries, diabetes, cancer, heart disease, multiple sclerosis, muscular dystrophy, macular degeneration, and hearing loss, to name a few."

Wilson has an interesting history, best known for the gene therapy experiment that killed 18-year-old Jesse Gelsinger in 1999, "in a trial that I led," he writes. Alongside success in treating inherited blindness and immune disorders, he notes that gene therapy has triggered cancer in patients, which has "derailed" the field. "It would be unfortunate if the field of (human embryonic stem cell) research missed this lesson from history and took a similar trajectory."

Unfortunately, he suggests that many of the things that drove gene therapy to try clinical trials before the biology behind the science was understood are in play for stem cells today: Patient groups suffering from deadly diseases are "clamoring for stem cell—based therapies." Political support from universities has expanded. And "unrealistic expectations have been fueled by relentless media coverage, driven in part by a factor not present in the gene therapy roll-out: a debate over the ethics of research on human embryos and embryo cells."

Last year, the International Society for Stem Cell Research unveiled guidelines for human experiments of stem cell therapies, calling for increased regulation of clinical trials and care for research participants. Wilson suggests these guidelines should be written into law as part of a drive to put the brakes on stem cell clinical trials before history repeats itself, he writes. "It is difficult to avoid getting caught up in the unabashed enthusiasm that attends the emergence of a novel, but untested, therapeutic technology platform for which I can attest."

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