Published online 5 March 2009 | Nature | doi:10.1038/news.2009.139

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Test tube disease models one step closer

Skin cells from Parkinson's patients transformed into tailor-made neurons.

neuronSkin cells from Parkinson's patients were transformed into neurons and reprogramming factors removed.Punchstock

Scientists trying to understand the causes of Parkinson's disease have made a significant step towards modelling the disease in the laboratory. The work signals progress towards the use of cell lines tailored to match the individual patient for the study of other diseases and possible treatments, say scientists. "This is elegant and powerful work and the future of stem-cell biology," said George Daley, a stem-cell researcher at Children's Hospital Boston in Massachusetts.

Parkinson's disease is caused by the death of particular neurons that make the brain chemical dopamine. In the new work, scientists made dopamine-producing neurons from so-called induced pluripotent stem cells, or iPS cells, which are reprogrammed adult cells. These cells have similar properties to embryonic stem cells, which researchers hope will become valuable tools in research and therapy because they can turn into all cell types of the body.

Scientists have previously used viruses to shuttle reprogramming factors into the genomes of adult cells to transform them into iPS cells (see 'Simple recipe gives adult cells embryonic powers'). In the new work, researchers performed this same step, but removed all remnants of the virus. They used an enzyme called Cre recombinase to cut the factors out of human cells once they were reprogrammed. For the first time, scientists transformed reprogrammed skin cells from patients with Parkinson's disease into neurons that are free of the factors used to reprogram the cells. This eliminates the risk that the reprogramming factors could trigger cancer1.

Other scientists earlier this week reported reprogramming mouse cells without using viruses, and then removing the factors from mouse cells. They also showed they had reprogrammed human cells, but did not show that the reprogramming factors had been removed (see 'Virus-free pluripotency for human cells').

The new work, led by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, shows strong evidence that the reprogramming factors were absent from the human reprogrammed cells. For instance, when DNA from the cells was amplified and checked for signs for the factors, they weren't there.

Factoring in differences

The study also sheds some light on the question of why iPS cells seem to behave subtly differently from embryonic stem cells — a phenomenon that has been noticed by many investigators: "There is so much anecdotal evidence out there that iPS cells are not the same," Jaenisch says.

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So his team analyzed gene expression in iPS cells before and after the reprogramming factors had been removed. The team compared the gene expression patterns to those seen in embryonic stem cells. Sure enough, the gene expression profile of the iPS cells lacking reprogramming factors was more similar to that of embryonic stem cells than to that of iPS cells with the factors. While 48 genes were expressed differently between the factor-free iPS cells and the embryonic stem cells, 271 genes differed between the factor-free iPS cells and the iPS cells that retained the factors.

"This gives you some hard data that they are really different, and yes, one has to worry about the [reprogramming] vectors," Jaenisch says.

There is still much work to do to perfect this and other reprogramming systems so that they are more efficient and lack all trace of manipulation, Jaenisch said. For instance, in the current work, a small piece of viral material was left behind in the genomes of the iPS cells after the reprogramming factors were removed. Removing all traces of the vectors that ferry reprogramming factors into cells is just one item on the ever-growing to-do list for scientists exploring the potential of these cells. 

  • References

    1. Soldner, F. et al. Cell 136, 964–977 (2009).
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