西亚试剂： not even the dozen or so groups of scientists who intensiv

here is just one hitch. No one, not even the dozen or so groups of scientists who intensively study reprogramming, knows how it happens. They understand that differentiated cells go in, and pluripotent cells come out the other end, but what happens in between is one of biology's impenetrable black boxes. “We're throwing everything we've got at it,” says molecular biologist Knut Woltjen of the Center for iPS Cell Research and Application at Kyoto University in Japan. “It's still a really confusing process. It's very complicated, what we're doing.”

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One of the problems, stem-cell biologists say, is that their starting population contains a mix of cells, each in a slightly different molecular state. And the process for making iPS cells is currently inefficient and variable: only a tiny fraction end up fully reprogrammed and even these may differ from one another in subtle but important ways. What is more, the path to reprogramming may vary depending on the conditions under which cells are being grown, and from one lab to the next. This makes it difficult to compare experimental results, and it raises safety concerns should a mix of poorly characterized cells be used in the clinic.

But new techniques are starting to clarify the picture. By carrying out meticulous analyses of single cells and amassing reams of detailed molecular data, biologists are identifying a number of essential events that take place en route to a reprogrammed state. This week, the biggest such project — an international collaboration audaciously called Project Grandiose — unveiled its results2–6. The scientists involved used a battery of tests to take fine-scale snapshots of every stage of reprogramming — and in the process, revealed an alternative state of pluripotency. “It was the first high-resolution analysis of change in cell state over time,” says Andras Nagy, a stem-cell biologist at Mount Sinai Hospital in Toronto, Canada, who led the project. “I'm not shy about saying grandiose.”

“I'm not shy about saying grandiose.”
But there is more to do if scientists want to control the process well enough to generate therapeutic cells with ease. “Yes, we can make iPS cells and yes we can differentiate them, but I think we feel that we do not control them enough” says Jacob Hanna, a stem-cell biologist at the Weizmann Institute of Science in Rehovot, Israel. “Controlling cell behaviour at will is very cool. And the way to do it is to understand their molecular biology with great detail.”

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