NEW YORK CITY--When it comes to new developments in biology, hardly anything has had such a profound effect on the public consciousness as stem cells. And that's "even before anything has been demonstrated with them," notes stem cell researcher John Gearhart of Johns Hopkins University in Baltimore, Maryland.
In a bid to counteract some of the hype, scientists came to Rockefeller University here last week for a 1-day conference that offered a clear-eyed look at obstacles that will have to be surmounted before human embryonic stem (ES) cells can be used in therapy. The meeting was the first of what is intended as an annual conference on translational stem cell research sponsored by the New York Stem Cell Foundation, a group started last year by two mothers of kids with diabetes. The foundation is quickly putting its stamp on the New York stem cell scene. Last March, the foundation opened a privately-funded "safe haven" lab in Manhattan where researchers from Columbia and Harvard are working to create disease-specific cell lines free of federal funding constraints.
The Rockefeller meeting may have been a downer for patient advocacy groups that have been holding up rosy promises of cures for intractable diseases including Parkinson's, Alzheimer's, and diabetes. "We aren't much wiser than we were a few decades ago"--when mouse embryonic stem cells were first isolated--said Harvard diabetes researcher Douglas Melton.
Perhaps the chief challenge researchers currently face is learning how to reprogram a cell's nucleus. This is essential to create and study disease-specific cell lines in a dish. But the favored reprogramming technique, somatic cell nuclear transfer (SCNT), otherwise known as research cloning, is fraught with ethical pitfalls as well as technical difficulties because it entails creating a human embryo by inserting an adult cell nucleus into an ooctye.
No one has yet shown success with SCNT using human tissue: The closest effort so far has been the cloned blastocyst reported last year by workers at the Newcastle Fertility Centre in the U.K., but that did not yield ES cells. And getting good eggs for such research is trickier than it may seem. Alison Murdoch of the Newcastle center noted that crucial knowledge is still lacking on what constitutes a "good" egg, on "what is the appropriate activation signal" for the oocyte, and on how long nuclear reprogramming takes.
In discussing the potential therapeutic roles for ES cells, the scientists had a consistent message: years of work lie between the dream and the reality. Allen Spiegel, dean of Albert Einstein College of Medicine in New York, said he has a ready answer for people who ask him the old question: if we can put a man on the moon, why can't we cure disease X with stem cells? His response: "This isn't rocket science"--cell biology is much more complicated. For example, we still don't even have a precise definition of "stemness," noted Ali Brivanlou of Rockefeller University, who is doing studies to see exactly which genes get up- or down-regulated at what stages in ES cell development.
Although diabetes is one of the most oft-mentioned applications for ES cell research, it may be one of the most difficult to treat, speakers said. There do not appear to be any stem cells for beta cells, the pancreas's insulin-producing cells. The pancreas, unlike the liver, for example, is "pathetic" at cell regeneration, said Melton. So there are only two ways to get more beta cells--from human cadavers, which nowhere near fill the need, or from ES cells that have been coaxed to become beta cells.
So far, animal studies have shown that it's possible to push ES cells through the stages necessary to become beta cells, but the process is extremely inefficient: sometimes only 1 in 1 million in a cell population will develop in the right direction. Melton and colleagues are now doing large scale screening with microarrays to track gene activity as cells develop and discover gene products that move cells along the proper paths. But since diabetes is an autoimmune disease, the immune system also has to be brought to heel. And that, said Melton, suggests the need to enter as-yet little-explored terrain: developing ES cells into immune system cells. For such reasons, said Melton "I don't think this could lead to a therapy for quite a long time." The good news? "We haven't learned anything that leads us to believe that this is not a solvable problem."
Lots of obstacles also remain to using stem cells for rebuilding damaged heart tissue. "We've had so many reports of heart cells from ES cells you'd think the problem was solved," said Kenneth Chien of the Massachusetts General Hospital Cardiovascular Research Center. But it's all been in the lab dish. The fact is, there have not yet been any clinical trials using those cells.
More than 40 clinical trials are underway using other kinds of stem cells, mainly bone marrow cells from the patients themselves. But only a small subset—5%--of heart patients are suitable candidates for stem cell injections, said Amit Patel of the University of Pittsburgh, Pennsylvania. And the utility of bone marrow cells is becoming increasingly "unclear," said Chien, especially in light of the ambiguous results of three studies reported last month in the New England Journal of Medicine. The bone marrow cells are almost certainly not turning into heart muscle cells, Chien said. And if there are stem cells in the heart itself, they have not so far been identified. So, he said, "the search is [still] on" for the right kind of cell.
Stem cell treatments for neurological diseases also seem far away, and it all comes back to the crucial matter of reprogramming the nucleus. Harvard's Kevin Eggan, for example, wants to use to SCNT to develop ES cell populations from patients of amyotropic lateral sclerosis, which affects motor neurons. By differentiating cells over and over under various conditions, his group intends to use them to screen for small molecules that might interfere with the disease process.
With so much work needed in studying the nature of stem cells and using them to study disease processes, therapies based on ES cells seem very far down the line, noted Lorenz Studer of Memorial Sloan-Kettering Cancer Center in New York, who pointed out that so far there have only been two published papers on therapeutic cloning, both of them in mice. Developing therapeutic cell populations from human ES cells will be far more demanding: cells will have to be stable, predictable, pure, have proven functionality, be nontumor-forming, and be "scalable"--capable of growing in very large numbers. And, said Gearhart, getting approval for any stem cell treatment is going to be tortuous. He related that the Food and Drug Administration has already told people at Hopkins that "if you're putting 3000 cells into a given site, we want to know what each cell is doing." It sounds like the New York Stem Cell Foundation may be holding similar meetings for many years to come.
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