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Searching the brain of an Alzheimer’s patient for clues into the origin of the disease is like trying to find the cause of a plane crash in the wrecked aftermath. However, a recent breakthrough in stem-cell research could generate new cellular models that allow scientists to study disease with unprecedented accuracy, from its earliest inception to a cell’s final biochemical demise.

Last November, two groups of scientists announced that they had independently achieved one of the stem-cell field’s biggest goals: the ability to reprogram adult cells into embryonic-like stem cells without the need for human embryos. (See “Stem Cells without the Embryos.”) The findings garnered extensive media attention, largely because the new method obviated the need for human embryos, a major ethical minefield that has stymied research.

But scientists at stem-cell labs around the world are excited for another reason. The technique creates cells that are genetically matched to an individual, meaning that it’s now possible to create novel cell models that capture all the genetic quirks of complex diseases. “Being able to have human cells with human disease in a dish accessible for testing is a real boon to technology and to science,” says Evan Snyder, director of the Stem Cells and Regeneration Program at the Burnham Institute, in La Jolla, CA.

While animal models exist for many human diseases, they typically only incorporate certain aspects of the disease and can’t capture the complexity of human biology. In addition, some disorders known to have a significant genetic component, such as autism, have proved difficult to model in animals.

To reprogram cells, scientists from Wisconsin and Japan independently engineered skin cells to express four different genes known to be expressed in the developing embryo. For reasons not yet clear to scientists, this treatment turns back the developmental clock. The resulting cells are pluripotent, meaning that they can develop into any type of cell in the body, and they can apparently divide indefinitely in their undifferentiated state. The first two published studies on the new technique reprogrammed cells from a skin-cell line, while a third study, published last month, generated stem cells from the skin biopsy of a healthy volunteer.

No one has yet generated cell lines from a patient, although scientists have been talking about doing so for years. Previously, the only way to make such models for complex genetic diseases was through human therapeutic cloning, also known as nuclear transfer, which is fraught with technical and ethical issues and has not yet been achieved. (See “Stem Cells Reborn” and “The Real Stem Cell Hope.”) “Assuming that these procedures are as easy to do as it seems, it’s definitely more tractable than nuclear transfer,” says Snyder. His own lab is trying to generate such models, as is “probably everyone else you could call on your rolodex,” he says.

To generate a disease-specific cell model, scientists would take some cells from a patient with a particular disease and revert them to an embryonic state. The cells would then be prodded to develop into the tissue type damaged in that disease, such as dopamine neurons in Parkinson’s disease or blood cells in sickle-cell anemia. By comparing the differentiation process in cells derived from healthy and diseased people, scientists could observe how that disease unfolds at a cellular level. They could also use the cells to test drugs that might correct those biochemical abnormalities. “We want to use these cells to ask and answer questions that can’t be asked and answered any other way,” says M. William Lensch, a research scientist at the Harvard Stem Cell Institute and Children’s Hospital Boston.

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Credit: Jon Chase/Harvard News Office

Tagged: Biomedicine, stem cells, Alzheimer’s

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