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Reprogramming the Debate
Tobias Brambrink sits at a microscope, staring at a plate coated with millions of specialized skin cells known as fibroblasts. He hopes to find a clump of cells that glow green, or even better, some cells that have the rounded shape of stem cells, rather than the elongated shape of fibroblasts. Brambrink, a postdoctoral researcher in Rudolf Jaenisch’s lab at the Whitehead Institute for Biomedical Research in Cambridge, MA, is searching for the genetic switches that control reprogramming – a poorly understood transformation that takes place during cloning, reverting an adult cell to its embryonic state.

All cells in an organism share the same genes, but the pattern of a cell’s gene activity determines whether it will become a stem cell or a differentiated cell. During reprogramming, some still-unknown factors in the egg turn off the genes that make a cell, say, a neuron and turn on the genes that are expressed in embryos. To uncover the genes controlling this conversion, Brambrink has engineered adult cells to express the genes that are selectively activated in eggs. If a particular gene expressed by one of these cells is crucial to the reprogramming process, it will activate genes that are known to be involved in the process’s later stages; those genes have been tagged with markers that make the cell glow green. In the best-case scenario, the activator gene might trigger reprogramming itself, creating a clump of stem cells where once sat differentiated fibroblasts.

Reprogramming cells in a dish would be a huge breakthrough for the field of therapeutic cloning. Once scientists understand the process, they can create new technologies to turn adult cells directly into stem cells. Such technologies would eliminate the ethical controversy surrounding embryonic stem cells, because they would not require the creation and destruction of human embryos. They would also eliminate the need for human eggs, which could make therapeutic cloning much more efficient and therefore more broadly useful. Such an advance could truly usher in a new era of regenerative medicine, where a tailored stem cell transplant is available to anyone who needs one.

Scientists have already shed some light on the reprogramming process. In a paper published in September, Rick Young, a biologist at Whitehead, and colleagues identified a set of genes that are kept inactive in undifferentiated stem cells. Researchers theorize that when these genes are turned on, they produce transcription factors that spur the cells along different developmental paths.

Scientists caution that a clear picture of reprogramming – one that would enable the production of stem cells without eggs – is likely decades away. However, the little known so far is already helping scientists develop new, less controversial techniques for creating stem cells. For example, scientists are searching for ways to create genetically altered embryos that no longer have the potential to develop into human beings, thus eliminating some of the ethical controversy surrounding nuclear-transfer research. Markus Grompe, director of the Oregon Stem Cell Center at Oregon Health and Science University in Portland, hopes to create such a technology by forcing donor cells to express genes normally found only in embryonic stem cells (see “10 Emerging Technologies: Nuclear Reprogramming,” March/April 2006).

In fact, nuclear transfer may turn out to be a transitional technology. But even if it is, and for all its controversy, it might still be vitally important as the key to developing newer technologies that are able to finally free embryonic stem cells from ethical quandaries. “Nuclear transfer is the only way we can currently do reprogramming. This is our model and our yardstick to learn what’s important,” says Whitehead’s Jaenisch. Adds Snyder, “If we don’t know how to do nuclear transfer, or we’re not allowed to do it, then this potentially debate-solving technique becomes impossible to pursue.”

Lanza is also working on new reprogramming technologies to get around the shortage of eggs. But like Snyder, he worries that too much focus on uncertain alternatives could derail progress on therapeutic cloning, which scientists know works. “Let’s develop all these technologies and see what works best,” he suggests. He adds that months and years of grappling with the ethical and legal issues surrounding stem cell research, rather than the science, have worn him down. But the thought of stem cell-based therapies pushes him to keep going. “I’ve often gone home and thrown up my hands. But then I say, We can’t give up that easily.”

Emily Singer is the biotechnology editor of Technology Review.

Sidebar: Overcoming Immunity
One of the biggest obstacles to stem cell-based therapies is the possibility of immune rejection, as can happen with donor kidneys. Patient-matched stem cells – derived from a patient-donated skin cell – could present a way around this problem. But as researchers have come to believe that cloning stem cells may be too inefficient for broad use, they have begun developing other ways to overcome immune rejection.

Rather than creating stem cell lines for every patient who needs them, says Stephen Minger, a stem cell scientist at King’s College London, we might do better to create 1,000 stem cell lines representing the most common immune profiles in the population. “You wouldn’t get a perfect match for everyone…but you would be close, and you might only need mild immunosuppression,” he says.

Scientists are also developing ways to use stem cells to deceive the immune system. “If you can knock out [immune response], it’s possible you can have cells sneak under the radar,” says Tim Kamp, a stem cell scientist at the University of Wisconsin-Madison. Preliminary research suggests that turning stem cells into a type of immune cell known as a dendritic cell can trick the host’s immune system into accepting other, related cells. If scientists made both immune cells and whatever cell type was needed for therapy from the same lines of stem cells, they might be able to inject both cell types into a patient without an immune response.

In some cases, doctors may not need to worry about immune rejection. “We’re starting to recognize that stem cells may be better tolerated by the immune system in some areas of the body than we expected,” says Evan Snyder, a neurologist at the Burnham Institute in La Jolla, CA. “Embryonic stem cells seem to be tolerated in the brain, even without immuno-suppression.”

Geron, a California-based biotechnology company developing embryonic-stem-cell therapies, is taking advantage of this fact to develop new treatments for spinal-cord injury. Scientists have spurred injured rats to walk again after injections of neural precursor cells derived from embryonic stem cells; Geron is seeking permission to start human clinical trials of a related procedure next year.

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