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Research
At St. Jude, even the most casual lunchtime conversations may produce ideas and discoveries about childhood illnesses—and some may have applications for adult disorders such as Parkinson’s disease.
What are you having for lunch today? For employees of St. Jude Children’s Research Hospital, an entrée in the hospital cafeteria may very well be accompanied by a side order of science. One recent gastronomic gathering at St. Jude ultimately yielded important research findings in two distinct disciplines.
When Katharine Sturm-Ramirez, PhD, joined Kennie Shephard, PhD, for lunch in the hospital’s Kay Kafe, a scientific discovery was the last thing on their minds. Sturm-Ramirez had spent the morning involved in influenza surveillance in the lab of internationally renowned flu researcher Robert Webster, PhD. In another part of the hospital, Shephard had been working on Parkinson’s disease research under the direction of developmental neurobiologist Richard Smeyne, PhD.
During lunch, the diners began to discuss the 1990 film Awakenings. Based on actual events, the movie chronicles the story of patients who survived a form of encephalitis that may have originated with the 1918 influenza pandemic. The patients suffer neurological symptoms similar to those of Parkinson’s disease. In the film, the individuals temporarily “awaken” from their catatonic state when a physician administers the drug L-dopa, which has long been used in Parkinson’s disease treatment.
“Later, Kennie came into my office and said, ‘You know, we could look to see whether influenza can affect Parkinson’s disease,’” Smeyne recalls.
Intrigued by the prospect, Smeyne and his lab teamed with Webster and his staff to determine whether survivors of H5N1 avian influenza might suffer from long-term neurological problems.
The results were as tantalizing to scientists as Beluga caviar is to an epicurean.
“We found that one strain of H5N1 absolutely does impact the nervous system,” Smeyne says. “It causes all kinds of pathology in the brain that you only see in Parkinson’s and Alzheimer’s diseases.”
The threat posed by other viruses, including the current H1N1 pandemic flu virus, is still being studied. Early indications are that the H1N1 pandemic strain carries a low neurologic risk.
At a recent meeting of the Michael J. Fox Foundation for Parkinson’s Research, Smeyne was encouraged by the response from the scientific community.
“People were saying that our work has shifted the entire paradigm of Parkinson’s disease and that now there is a major interest in whether viruses could cause neurological disease,” he says.
The influenza study is the latest in an impressive progression of courses served up in an environment where scientists with seemingly divergent interests collaborate on projects that have applications for pediatric catastrophic diseases.
Smeyne is accustomed to explaining why Parkinson’s—an incurable brain disorder that affects approximately 4.1 million American adults—is studied at St. Jude.
“While the hospital’s mission is to treat children, our research goals encompass basic developmental mechanisms that aren’t necessarily limited to childhood cancer,” he says. “The mechanisms that cause Parkinson’s offer us insight into a variety of diseases, as well as into pediatric and adult brain tumors.”
Parkinson’s disease occurs when nerve cells in a part of the brain called the substantia nigra are damaged or destroyed. These neurons normally produce a chemical called dopamine, which helps muscles function normally. Individuals with Parkinson’s disease experience tremors, muscular stiffness and other movement problems.
“The brain is a miraculous thing,” Smeyne says. “It has so much redundancy built in that you have to lose 70 percent of the neurons before you see your first, tiny symptom of Parkinson’s. That’s the great news. The bad news is there are not many neurons left to work with by the time you discover the disease.”
Smeyne and his colleagues are determined to find a way to stop the process before symptoms appear. “We are trying to develop a blood test to do that now,” he says.
During the past decade, Smeyne has emerged as a leading Parkinson’s expert. As a result of his investigations, Smeyne is convinced that both genetic and environmental factors play a role in the disease’s development.
In 2004, his lab demonstrated that sustained aerobic exercise prevented cell death in the substantia nigra of adult mice whose brains had undergone damage from molecules called free radicals.
Smeyne also found that a protein involved in the antioxidant response, called glutathione S-transferase pi (GST pi), also plays a key role in protecting these same dopamine neurons from environmental toxins or by other stressful conditions that can lead to the formation of free radicals. When GST pi is reduced or missing, the nerve cells can die or stop producing dopamine, resulting in the development of Parkinson’s disease.
Smeyne says his investigations into the effects of oxidative stress caused by free radicals are an integral part of the hospital’s mission.
“By studying Parkinson disease, we are learning more about free radical damage in the brain,” he explains.
“The concept and understanding of free radical damage is a basic biological process,” he continues. “For example, one mechanism in which chemotherapy works is by generating free radicals that then kill cancer cells. So, anything we learn studying the mechanism of free radical damage and detoxification in the brain could potentially be applied to the protocols we use to treat our patients.”
For decades, most school children have learned about the food pyramid, which helped them remember the basics of healthy eating. Smeyne uses a similar pyramid analogy to explain the importance of his work.
“Basic research is the base of everything we do,” he explains. “The patient is at the top of the pyramid. All the basic research leads up to translational research, which leads up to the patient. My research on Parkinson’s disease is sitting at the base. We are not working on childhood cancer, but we are learning about free radical biology; we are learning about neuroprotection; we are learning about all of these things that are basic biology.”
Then Smeyne offers the pièce de résistance: “Everything we learn about these molecular processes will eventually translate into therapy for patients.”
Reprinted from Promise Winter 2010
