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Patient-Matched Stem Cells

Scientists have created stem cells from an ALS patient using a new reprogramming method.
August 1, 2008

Stem cells derived from the skin of an 82-year-old patient with amyotrophic lateral sclerosis (ALS) could provide a novel model for studying the degenerative motor disease and for screening new treatment drugs; eventually, it could pave the way for cell-replacement therapies. The findings, published today online in Science, were made possible by new techniques to reprogram adult cells to become pluripotent–able to become any type of cell in the body.

Motor neurons: Scientists generated motor neurons (cell nuclei shown here in red), which are destroyed in amyotrophic lateral sclerosis (ALS), from stem cells created from a patient with the disease. The newly created cells should allow scientists to study the disease and screen new drugs. All neurons are marked in green.

Researchers have long wanted to make stem cells from actual patients to better understand the diseases from which they suffer. “Because the cells harbor genes that led to the disease in that patient, we might be able to use them in the laboratory to understand certain aspects of disease,” says Kevin Eggan, a stem-cell scientist at the Harvard Stem Cell Institute, who led part of the research.

To create the stem cells, researchers used a novel technique, recently developed by scientists in Japan, that doesn’t require human eggs or the creation or destruction of embryos, and thus bypasses major ethical and technical hurdles that have plagued the field of embryonic stem-cell research. Eggan’s team exposed the patient’s skin cells to four genetic factors found in the developing embryo. The procedure turned back the clock on the cells, triggering them to look and behave like embryonic stem cells.

While scientists had already used these reprogramming techniques to create stem cells from skin cells, this is the first time that these cells–called induced pluripotent stem cells, or IPS cells–have been generated from a patient. The ability to do so is key to creating models for studying complex genetic diseases, such as Alzheimer’s. The findings also confirm that it’s possible to use reprogramming techniques in older people and in those with a serious disease. “It was unclear if the fact that the patient had been sick for many years would interfere with our ability to reprogram [the cells],” says Eggan.

The researchers prodded the stem cells to differentiate into motor neurons by exposing them to another series of chemicals. Motor neurons are the primary cell type destroyed in ALS, a progressive neurodegenerative disease. While animal models of the disease exist, they can’t capture the complexity of human biology.

The new research allows scientists to generate an endless supply of motor neurons that are genetically identical to those of the cell donor, which should allow them to study the molecular events that trigger the disease. “Now we can see if they behave in a manner that mimics the disease,” says Chris Henderson, codirector of the Motor Neuron Center at Columbia University, in New York, who led part of the research. “For example, do they tend to die and degenerate in the culture dish? If so, we can try to understand more about the mechanism of degeneration.” Scientists also hope to use the cells to screen for new drugs that protect against neurodegeneration in ALS.

Diseased stem cells: Scientists generated a type of nerve cell called an astrocyte (shown here in red) from stem cells created from a patient with amyotrophic lateral sclerosis (ALS). Previous studies suggest that these cells play an important role in the progression of the motor neuron degeneration. The green cells are neurons, while the blue circles highlight cell nuclei.

“It is likely that this will be one of the most important uses of stem cells during the next 10 to 20 years,” said Ian Wilmut, director of the Scottish Centre for Regenerative Medicine, in Edinburgh, in an e-mail. Wilmut, best known for the cloning research that produced Dolly the sheep, was not involved in the current project but is pursuing a similar path.

Because the cells were created using genetic engineering, they are not suitable for therapeutic use. Scientists are now working on ways to reprogram cells using drugs rather than genes. However, therapies using IPS cells to replace the cells damaged in disease are likely years, if not decades, away.

The researchers haven’t yet studied the new motor neurons for signs of disease, but similar experiments in mice hint at the cells’ promise: mouse cells with a mutation in the same gene as that in the ALS patient seemed to reflect the disease. When differentiated into neurons and compared with neurons made from normal stem cells, those that carried the mutation didn’t survive as well as those that did not carry it, says Eggan, who is now using the cells to screen potential new drugs for ALS. “These approaches would be much more powerful if we could do them with actual patient cells,” he says.

The cells should also allow scientists to test specific theories of ALS. For example, in the mouse experiments, the researchers found that another type of neural cell, known as an astrocyte, seemed to produce a toxin that harmed motor neurons. “We’re curious to see if we can make astrocytes from stem cells and if they also have this toxic effect,” says Eggan.

The cell donor in this research has a rare, familial form of ALS linked to a specific genetic variation. Scientists are now trying to derive stem cells from a patient with the more-common sporadic form of ALS, as well as from a healthy control donor, in order to compare healthy and diseased cells.

Eggan first set out to create patient-specific stem cells more than two years ago using therapeutic cloning. In that technique, DNA from an adult cell is inserted into an egg whose DNA has been removed. The egg begins to develop as a normal embryo would, and scientists harvest stem cells after a few days. However, human eggs proved extremely hard to find: Eggan’s group, which is still pursuing cloning, has received eggs from only one donor to date. No one has yet produced stem cells from human therapeutic cloning.

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