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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 [of CIRM money] 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.