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ANNUAL REPORT 2002

Center for Neuroregeneration Research

Research shines light on Parkinson's and other brain disorders

To the untrained eye, the fluorescent green stain shining through a colony of stem cells-turned-neurons may look typical of what you see under a microscope. To scientists, however, it suggests a possible cure for Parkinson's disease.

Ole Isacson

Ole Isacson, Dr. Med Sci
Director of the Center for Neuroregeneration Research

"This was the first documentation of stem cell... correcting symptoms of Parkinson's disease in laboratory mice."

In 2002, the Center for Neuroregeneration Research at McLean Hospital demonstrated that the symptoms of Parkinson's disease could be reversed in animal models, an extraordinary breakthrough offering hope to millions who suffer from this debilitating disorder.

"This was the first demonstration of stem cells naturally becoming dopamine cells and correcting symptoms of Parkinson's disease in laboratory mice," says Center Director Ole Isacson, Dr. Med Sci. Embryonic stem cells are cells that have the potential to become any cell and tissue of the body.

Isacson's basic research, conducted over three years and published in 2002 in the prestigious Proceedings of the National Academy of Sciences, involves determining exactly how to trigger mouse embryonic stem cells so they will grow into the type of nerve cells that die in the brains of individuals with Parkinson's disease. These new cells produce dopamine, a brain chemical important in helping neurons communicate and allowing the body to move properly. Isacson's laboratory initially discovered that if you give stem cells no instruction at all, they will automatically become neurons.

Now, researchers at McLean, including Kwang-Soo Kim, PhD, are deciphering how to tell the stem cells to consistently produce very specific nerve cells.

"We have entered a phase of medicine in which we can look for cells that are desirable to treat people. I believe we can get the nerve cells that are therapeutically desirable for Parkinson's disease, and we will probably soon learn how to find cells for Huntington's disease and for ALS [amyotrophic lateral sclerosis], also known as Lou Gehrig's Disease," says Isacson.

Jim Finn

Since his ground-breaking surgery, Jim Finn, at his home in Newport, Rhode Island, can enjoy an old pastime: cooking.

James Finn of Newport, Rhode Island, is proof Isacson's team is on the right track. Six years ago, he had to crawl on his hands and knees to get from one room to another. His Parkinson's disease had progressed to the point he was about to commit suicide. Realizing Jim's desperation, Isacson asked him if he would be interested in participating in one of Isacson's earlier experiments: transplanting dopamine producing fetal pig cells into his brain. Six months later, Jim could walk with no assistance and even drive his cherished sports car.

Today, he is able to live independently and do just about everything. "Every day I wake up is amazing to me," says Jim.

Though Jim never experienced side effects, further research into this type of cross-species transplantation has revealed problems with cell rejection. Now the objective is to use same-species stem cells, rather than cells from other sources, to create therapeutic cells for testing.

Isacson is hopeful that continued success in animals will ultimately lead to helpful results in people.

"That's the dream: to first slow the progression of the disease and then to replace the cells that die," says Isacson.

'We're following what works'

It usually takes six weeks on medication before a person with depression or bipolar disorder feels better. The director of McLean's new Medication Development Laboratory, William Carlezon, PhD, says that's too long.

"We're trying to come up with medications that are totally unique, that work significantly better, faster, because they are more directed at the fundamental causes of these illnesses," he says.

Thanks to a $347,000 donation from the Stanley Foundation to McLean president and psychiatrist in chief Bruce Cohen, MD, PhD, Carlezon's work has begun.

"Here, we let our results direct us rather than worrying about whether a particular drug will be profitable or easy to market. We're following what works and tracking down the precise reason why it's working."

Already, Carlezon has discovered a possible new chemical link for depression: a gene called CREB. In the brain, CREB controls the activity of dynorphin, a chemical he calls the "evil cousin" of those that cause "runner's high."

Carlezon finds that dynorphin blockers show promise in his models, and he is confident his basic research will eventually lead to new and more effective therapies for a variety of complex psychiatric illnesses.