Public Release:  Harvard-Columbia team creates neurons from ALS patient's skin cells

New key to understanding and treating ALS, and a step toward personalized regenerative medicine

Columbia University Medical Center

NEW YORK - Harvard and Columbia scientists have for the first time used a new technique to transform an ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease) patient's skin cells into motor neurons, a process that may be used in the future to create tailor-made cells to treat the debilitating disease. The research - led by Kevin Eggan, Ph.D. of the Harvard Stem Cell Institute - will be published July 31 in the online version of the journal Science.

This is the first time that skin cells from a chronically-ill patient have been reprogrammed into a stem cell-like state, and then coaxed into the specific cell types that would be needed to understand and treat the disease.

Though cell replacement therapies are probably still years away, the new cells will solve a problem that has hindered ALS research for years: the inability to study a patient's motor neurons in the laboratory.

ALS is caused by the degeneration and death of motor neurons, the nerve cells which convey nerve impulses from the spinal cord to each of the body's muscles. The death of motor neurons leads to paralysis of these muscles, including those involved in swallowing and breathing, and ultimately leads to death of the patient. The disease affects about 30,000 people in the United States.

"Up until now, it's been impossible to get access to the neurons affected by ALS and, although everyone was excited by the potential of the new technology, it was uncertain that we would be able to obtain them from patients' skin cells," says co-author Chris Henderson, Ph.D., professor of pathology, neurology and neuroscience, co-director of the Center for Motor Neuron Biology and Disease at Columbia, and senior scientific advisor of the Project A.L.S./ Jenifer Estess Laboratory for Stem Cell Research. "Our paper now shows that we can generate hundreds of millions of motor neurons that are genetically identical to a patient's own neurons. This will be an immense help as we try to uncover the mechanisms behind this disease and screen for drugs that can prolong life."

The motor neurons were created using a new technique that reprograms human adult skin cells into cells that resemble embryonic stem (ES) cells. The technique used to make these cells - called induced pluripotent stem (iPS) cells - was a major advance in the field that was first reported last November by researchers in Japan and Wisconsin. Those studies used skin cells from healthy adults, but it remained unknown whether iPS cells could be created with cells from chronically-ill patients and then transformed into neurons. The Columbia-Harvard team, in this paper, showed this was possible using an ALS patient's skin cells.

Columbia clinician-researchers Wendy Chung, M.D., Ph.D., Herbert Irving Assistant Professor of Pediatrics in Medicine, and Hiroshi Mitsumoto, M.D., D.Sc., the Wesley J. Howe Professor of Neurology at Columbia, obtained skin cells from an 82-year-old ALS patient. In the Project A.L.S. laboratory, Columbia researchers Dr. Henderson and Hynek Wichterle, Ph.D., assistant professor of pathology, and colleagues cultured the cells and contributed expertise needed for identifying iPS cell-derived motor neurons. Finally, Harvard researchers, led by Kevin Eggan of the Harvard Stem Cell Institute, successfully used the new technique to reprogram the skin cells into iPS cells and differentiate them into motor neurons.

Scientists had originally hoped to create neurons and other adult cells using "therapeutic cloning," in which DNA from a patient is inserted into a donated egg to create embryonic stem cells. That technique, however, has still not been successful in humans, and is also hindered by a shortage of donated eggs.

If the iPS technique holds its promise in producing neurons and other cells for research, it will probably replace the "therapeutic cloning" approach, Dr. Henderson says, but there are still lots of questions about the iPS-derived neurons.

"We don't know yet how similar they are to the motor neurons in ALS patients," he says. "While the cells exhibit many properties that are typical of motor neurons, we don't yet know whether they will be prone to degeneration that will allow us to mimic the disease in the culture dish and therefore to screen potential drugs."

Researchers at Columbia and Harvard are already collaborating to investigate the cells with the ultimate goal of determining how they differ from a healthy person's motor neurons.

"Project A.L.S. has always maintained that collaboration between scientists is the answer to understanding and treating this disease," Valerie Estess, founder and research director, Project A.L.S. "We are thrilled to have catalyzed the Harvard-Columbia collaboration that led to this discovery."

"Therapeutic use of the cells is probably a long way off," Dr. Henderson says. "Right now there are safety issues with iPS cells, including a risk of cancer. We also don't know how to reintroduce cells into a sick adult in a way that will be beneficial. All these hurdles need to be overcome first before we can think about using the cells to treat disease, but we can start immediately to evaluate them as a tool for drug discovery."

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The Columbia and Harvard researchers were supported by the Harvard Stem Cell Institute, Project A.L.S., the SMA Foundation, MDA Wings Over Wall Street, the Claire and Leonard Tow Charitable Foundation, the Spina, Drago and Bowen Families, Ride for Life and the New York Stem Cell Foundation.

*** Related Teleconference: A teleconference related to the forthcoming Science paper, "Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons," by Dr. Eggan and colleagues is planned for 12 noon, U.S. Eastern Time, Wednesday, 30 July. All information released during the teleconference will remain under embargo until 2:00 p.m. U.S. ET Thursday, July 31. NB: The teleconference will be recorded and posted on the web, and by calling in you are consenting to be recorded. Call in numbers are as follows: From the United States: 1-800-311-9410. From outside the United States: 1334-232-7224. The password is "stemcell"

The final roster of speakers has yet to be determined, but will at a minimum include Kevin Eggan of the Harvard Stem Cell Institute, and Chris Henderson of Columbia University. The embargoed press briefing is being organized by the Harvard Stem Cell Institute and Columbia University, in cooperation with Science ***

Columbia University Medical Center is home to the Eleanor and Lou Gehrig MDA/ALS Center, which cares for over 300 ALS patients each year, the Center for Motor Neuron Biology and Disease, with more than 40 scientists working to uncover the cause of ALS and other motor neuron diseases, and the Project A.L.S./Jenifer Estess/Laboratory for Stem Cell Research. In recent years, CUMC scientists have discovered that motor neurons may be degenerating in ALS in response to a toxin released by neighboring cells; developed ways to turn embryonic stem cells into motor neurons; and uncovered how motor neurons mature and find their way to their target muscles (most recently in a paper published this week in Cell by Thomas Jessell, Ph.D., the Claire Tow Professor of Neuroscience, Biochemistry & Molecular Biophysics and Investigator, Howard Hughes Medical Institute). This progress and the present article moves Columbia scientists and their colleagues closer to their long-term goal of finding a cure for this dreaded disease. Columbia University investigators in the Naomi Berrie Diabetes Center are also collaborating with Dr. Eggan and others in the Harvard Stem Cell Institute on similar experiments on skin cells taken from patients with diabetes. In January 2008, Columbia University received $2.5 million from New York State's Empire State Stem Cell Board, an agency created by the state legislature to support stem cell research.

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians & Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state, and one of the largest in the United States. For more information, please visit www.cumc.columbia.edu.

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