Stem-Cell Research: The Quest Resumes

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A year later, Yamanaka followed up his work by reporting success with the same four factors in turning back the clock on human skin cells. At about the same time, in Wisconsin, Thomson achieved the same feat using a different cocktail of genes. With those studies, what became known as induced pluripotent stem cells (iPS cells) were suddenly a reality. Never mind the frustratingly fickle process needed to create embryonic stem cells; this was something any molecular-biology graduate student could do. "We figured somebody would have success with reprogramming. We just thought that somebody would come along a generation from now," says Dr. David Scadden, Melton's co-director at HSCI. "Yamanaka threw a grenade at all of that, and now all of the doors are open."

Beyond Stem Cells
Melton, for one, isn't wasting any time before running through those doors. The iPS technology is the ultimate manufacturing process for cells; it is now possible for researchers to churn out unlimited quantities of a patient's stem cells, which can then be turned into any of the cells that the body might need to repair or replace.

Before that can happen, however, Melton wants to learn more about how diseases develop. And iPS cells make that possible too. For the very first time, he can watch Type 1 diabetes unfold in a petri dish as a patient's cells develop from their embryonic state into mature pancreatic cells. The same will be true for other diseases as well. "There is a good reason we don't have treatments for diseases like Parkinson's," says Melton. "That's because the only way science can study them is to wait until a patient appears in the office with symptoms. The cause could be long gone by then, and you're just seeing the end stages." No longer. Now the major steps in the disease process will be exposed, with each one a potential target for new drugs to treat what goes wrong. "This is a sea change in our thinking about developmental biology," says Dr. Arnold Kriegstein, director of the Institute for Regeneration Medicine at the University of California, San Francisco. "I consider it a real transformative moment in medicine."

The true power of reprogramming, however, does not stop with the stem cell. This summer, Melton flirted with the rules of biology once again when he generated another batch of history-making cells, switching one type of adult pancreatic cell, which does not produce insulin, to a type that does — without using stem cells at all. Why, he thought, do we need to erase a mature cell's entire genetic memory? If it's possible to reprogram cells back to the embryo, wouldn't it be more efficient in some cases to go back only part of the way and simply give them an extreme makeover? Using mouse cells, Melton did just that, creating the insulin-producing pancreatic cells known as islets. "The idea now is that you can view all cells, not just stem cells, as a potential therapeutic opportunity," says Scadden. "Every cell can be your source."

Realizing that potential — and with it, the prospect of successful treatments for conditions like Parkinson's or diabetes — may still be a few years away. Even iPS cells have yet to prove that they are a safe and suitable substitute for the diseased cells they might eventually replace in a patient. Ensuring their safety would require doing away with dangerous genes that can also cause cancer, as well as the retroviral carriers that Yamanaka originally used. Melton's team has already replaced two of the genes with chemicals, and he anticipates that the remaining ones will be swapped out in a few years. There are also hints that the iPS cells' short-circuited development makes them different in some ways from their embryonic counterparts. In mice, embryonic stem cells can generate a new mouse clone; iPS cells from the animals have so far stopped short of the same feat, aborting in midgestation, suggesting that some development cues may be missing. "It certainly makes me cautious," says Eggan.

Even if iPS cells do not prove as stable and as versatile as embryonic stem cells when they're transplanted into patients, they remain a powerful research tool. And if nothing else, they will have opened our eyes to the remarkable plasticity of biology and made possible new ways of thinking about repairing and replacing damaged tissues so we may consider not only treating but also curing disease. "It's a wonderful time," says Scadden. "Keep your seat belt on, because this ride is going to be wild."

For patients like Sam and Emma Melton, that ride carries with it the possibility of being free of the insulin pumps and injections they endure to keep their blood sugar under control. "I definitely think about how my life would be different if there is a cure," says Sam. His father is keenly aware that the ability of stem cells and reprogramming science to provide that cure is far from guaranteed. But his initial confidence in the power of the technology hasn't waned. "Everything we learned about stem cells tells us this was a really powerful approach," he says. "It would be a great shame if we let it wither and just go away." Melton, for one, is determined not to let that happen.

Science in Steps

A decade of conflicts and breakthroughs

1998
James Thomson, U of Wisconsin, isolates human embryonic stem cells

2001
President Bush restricts federal funding for research on human embryonic stem cells

2004
Douglas Melton of Harvard creates more than 70 embryonic-stem-cell lines using private funding and distributes free copies of the cells to researchers around the world

2006
Shinya Yamanaka, Kyoto University, turns back the clock on mouse skin cells to create the first induced pluripotent stem (iPS) cells, or stem cells made without the use of embryos. He uses only four genes, which are inserted into a skin cell's genome using retrovirus vectors

2007
Yamanaka and Thomson separately create the first human iPS cells

2008
July
Kevin Eggan at Harvard generates the first patient-specific cells from iPS cells — motor neurons from two elderly women with ALS

August
Melton bypasses stem cells altogether and transforms a type of mouse pancreatic cell that does not produce insulin into one that does

September
Konrad Hochedlinger at Harvard creates iPS cells in mice using the common-cold virus rather than retrovirus vectors — an important step in making the technology safer for human use

October
Melton's team makes human iPS cells by replacing two of the four genes, known to cause cancer, with chemicals. All four must be swapped out before iPS-generated cells can be transplanted into people

October
Yamanaka creates mouse iPS cells using safer plasmids of DNA instead of retrovirus vectors

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