Another side to stem cell research
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| Fri, 04-17-2009 - 12:07am |
By Peter Jamison
published: April 15, 2009
The first few months of 2009 have been among the most auspicious for stem-cell research since the field's inception. In January, the Palo Alto–based biotech firm Geron Corporation announced it had received U.S. Food and Drug Administration approval to begin clinical trials of a stem-cell–based spinal cord therapy in humans. Just last month, President Barack Obama announced that he was reversing Bush administration restrictions on government funding for embryonic stem-cell research.
In light of such developments, you might expect that these would be exciting days for Arnold Kriegstein, who oversees the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UC San Francisco. Kriegstein's research facility is one of the biggest of its kind in the world. It is also the second-largest recipient of grants from the California Institute for Regenerative Medicine (CIRM), the state agency created to fund stem-cell research through Proposition 71, the 2004 state ballot initiative designed to sidestep Bush-era research restrictions.
But Kriegstein isn't rejoicing. Right now, he's worried.
On a recent afternoon, he sat in his 12th-floor corner office at UCSF's Parnassus campus. On his desk was a month-old Israeli study describing the story of a teenage boy who had traveled from Israel to Russia — a country known for its loose regulations on cell therapies — for an implant of neural stem cells to treat a rare degenerative disease. Four years after the procedure, according to the study, the therapy hadn't worked, and the transplanted stem cells had morphed into a brain tumor. As Kriegstein shuffled through his papers, looking for the report, he explained his fear that current efforts in California to create stem-cell–based cures, which he views as premature, could have similar results.
"The likelihood of something going wrong is pretty high," he said. "Something like tumors are probably going to happen. This is an area where the risks are great. The public has to be prepared."
Almost five years after Californians approved Prop. 71, the field of stem-cell research is at a turning point. Many scientists like Kriegstein say their understanding of stem cells has not advanced sufficiently to benefit the severe degenerative diseases for which the field once held such promise, or to administer safe tests of therapies for those ailments in humans. You wouldn't know it from listening to Obama or the promises of the Prop. 71 campaign, but human embryonic stem cells are, when not tightly controlled, a substance akin to poison. Their potential for developing into any tissue type is also a source of great danger. Implanted in mice, embryonic stem cells have been frequently observed to create teratomas, potentially cancerous tumors that can sprout hair and teeth as the cells mutate and multiply into the various organs they can create.
But with the clock ticking, CIRM — allowed a 10-year lifespan by California voters — is seeking to deliver on its campaign promises and push stem-cell science from the lab benches to patients' medicine cabinets. In its next round of grants, the agency plans to devote up to 10 times as much money to research projects that offer to produce cell-based medical therapies in the next several years as it will to basic scientific inquiries into how stem cells work. (The latter have so far consumed a majority of CIRM funds.)
The rub is that many of the stem-cell therapies ready for safe clinical applications — the ones medical researchers are more comfortable with — don't exactly live up to the public's expectations of what their tax dollars are funding. The success of the ballot initiative, a remarkable authorization of $3 billion in research money by 59 percent of the electorate in a state wracked by chronic budget deficits (with repayment of the bonds' interest, the total cost of the initiative is expected to reach $6 billion) was driven by the promise of cures and therapies that appeared, to the layperson, little short of miracles. Neural tissue derived from embryonic stem cells capable of becoming any part of the body — scientists call them pluripotent — would rebuild the spinal cords of paraplegics, allowing them to walk again. Lab-made pancreatic cells could regulate the blood sugar of diabetics, freeing them from daily injections of insulin.
By contrast, the conditions first in line for stem-cell therapies in 2009 seem pedestrian. Two diseases expected to see near-term trials of a cell therapy are arthritis and age-related macular degeneration (failing eyesight). The reason is that these conditions can be treated using adult stem cells, a safer and better-researched form of cells with a narrower range of possibilities than their embryonic precursors. Indeed, many in the medical community, while paying lip service to the optimism of 2004, acknowledge the very real possibility that people suffering from the incurable conditions typically associated with stem cells — not just Parkinson's or diabetes but Huntington's disease, multiple sclerosis, and HIV/AIDS, among others — will not see a therapy or cure from the state's $3 billion investment.
The J. David Gladstone Institutes — a triad of laboratories devoted to researching heart disease, brain disease, and AIDS — reside in a state-of-the-art research facility amid fenced dirt lots a few hundred yards from the Mission Bay canal. Bruce Conklin, a senior researcher in Gladstone's cardiovascular disease division, has been hard at work here with the help of CIRM grant money. His work offers evidence of where stem-cell research has gone since the fall of 2004: While Conklin is seeking to develop embryonic-stem-cell–derived therapies that could help those with heart disease, he is also still laboring to understand the cells' basic biological workings.
Conklin's lab is a long, open room with low ceilings. Informally divided by shelves and counters packed with cardboard boxes, bottles of solution, and lab-grade cleaning wipes, it resembles a Walgreens stockroom more than Hollywood images of austere research centers. "Molecular biology's a lot like cooking," the boyish-looking cardiologist says. At one end of the lab, a door opens into a small room dominated by glass-hooded SterilGARD III Advance machines, sterile workstations where stem cells can be developed and harvested. Chris Schlieve, a 24-year-old research associate wearing sterile green gloves and an eyebrow stud, sits at one such station. Working with a pipette, Schlieve teases at the edges of a culture of pluripotent stem cells, visible on his microscope's television-sized display as a grainy expanse resembling telescopic images of the Moon.
Much of the lab's work involves studying how these stem cells differentiate — that is, evolve and multiply — into heart cells.
The more general question of how stem cells form different tissues in the human body is vital, scientists believe, to the success of future cell therapies. The better researchers' grasp of cell differentiation, the less risk there is that implanted stem cells could get out of control and form tumors.
Upstairs from Conklin is the Gladstone Institute of Virology and Immunology. Here Warner Greene, its director, is trying to understand how to stabilize and regulate pluripotent stem cells' chaotic store of "jumping genes," so that the cells can be directed to form specific tissue types. Researchers like Greene effectively stand at the gateway for the use of pluripotent cells in humans: Their job is to know the cells well enough to ensure their safety.
It's a job, Greene says, that isn't complete yet. The challenge of harnessing pluripotent stem cells' random genetic capabilities is what has prevented their medical applications, while projects involving less malleable adult stem cells move ahead. Greene, for his part, has staked out a clear position on the need to hold the former category of cells back, for now, from clinical trials. "There's no way to hop over this basic biology," he said in an interview.
This view is shared by many other scientists who work with pluripotent stem cells. "There's more that we don't understand than we do," says Eric Rulifson, a researcher at the UCSF Diabetes Center. "None of this stuff works. There's no stem-cell therapy that works without causing harm, because we don't understand what stem cells do."
Basic research like that performed by these scientists has its advantages over work more directly aimed at producing results in the clinic. One is cost. Human clinical trials of cell therapies can cost hundreds of millions of dollars apiece. By contrast, lab experiments can be done for less than $1 million. Another and perhaps more significant benefit is those experiments' wide-ranging impact on the field. Studies involving, say, the stem cells found in adult human bones may tell you something about orthopedic medicine or joint repair; studies into the fundamental workings of an embryonic cell will tell you something about joints, as well as perhaps the liver, heart, and brain. "You really are dealing with the source material that could make anything," Conklin says. "As you go down the road toward these adult cells, it's unlikely that a cell that is making cartilage is going to help someone who has Parkinson's disease."
Conklin hopes himself to be part of a CIRM-funded team of scientists trying to prepare stem-cell–derived cardiac tissue for implantation into patients with heart disease. Yet he shares his colleagues' reservations about the agency's new emphasis on faster cures. His primary fear is less about dangerous therapies than about trials that simply don't pan out, or have implications for only narrow avenues of medical research. This is not an entirely disinterested perspective: He worries that funding for his work on pluripotent cells could dry out as CIRM concentrates on immediately applicable research. "The thing that everybody's worried about is cancer," he says. "I think that the more likely outcome is that it just won't work and we'll waste a lot of money.
"We all want the same thing — we want to see regenerative medicine work," he continues. "Although there's $2 billion left to give out, that's actually a very small amount of money. Now, if that's all spent on clinical trials that don't tell us anything because they don't work, that's a missed opportunity."
The most revolutionary recent discovery in stem-cell biology took place in the realm of basic science. In 2006, Japanese scientist Shinya Yamanaka, who now keeps lab space at the Gladstone Institutes, discovered that adult skin cells could be reprogrammed into the state of nearly infinite potential that characterizes embryonic cells. The resulting induced pluripotent stem (iPS) cell is now believed by many researchers to have therapeutic possibilities superior to those of human embryonic stem cells.
For one thing, iPS cells can be harvested from specific patients, minimizing the potential for immune-system rejection of foreign cells. Just as significantly, the cells obviate ethical questions surrounding the harvesting of tissue from destroyed human embryos. Clinical applications of iPS cells — which, with their broad potential for development and mutation, share the safety drawbacks of embryonic stem cells — are still years away. But they have some immediate uses: Conklin's lab, for instance, is working to develop lines of iPS cells that can differentiate into heart tissue.
From the standpoint of a research agency receiving public tax dollars, there is a downside to this kind of work: It makes no promises. So-called basic research into the science of stem cells involves the steady accrual of knowledge, much of which may never make its way beyond the syllabus of an advanced biology course. Whatever the voters who supported Prop. 71 think of the use of their money to support adult stem-cell cures for relatively pedestrian ailments, they would almost surely be angered if the ballot initiative's billions of dollars have bought, after a decade, only a sheaf of much-lauded studies in the journal Cell.
Even angrier, no doubt, would be the people who suffer from the diseases stem cells might one day cure. Their voices, more than any others, persuaded a majority of the state electorate to support Prop. 71. Today, those voices speak with decisiveness about the controversies surrounding the pace of research.
for the rest of the story: http://sfweekly.com/content/printVersion/1429758

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