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May 23, 2003

Land-grant site suits these health researchers

One of Ann Smiley-Oyen's (standing) research projects looks at how much Parkinson's patients can improve motor skills through practice. Photo by Bob Elbert.
by Debra Gibson
Vaclav and Jitka Ourednik quickly established themselves at Harvard University as noted neuroscientists. Already distinguished in Europe for their stem cell research, the Ouredniks soon garnered high-profile U.S. accolades, like the Michael J. Fox/Parkinson's Action Network Young Investigator Award.

So, after affiliations with some of the world's most prestigious medical institutions, the Czech natives decided to establish their own neuroscience laboratory -- at Iowa State University.

Like dozens of other ISU scientists, the Ouredniks are conducting human health research on a campus not particularly known for its medical specialties. Many cite the university's strengths in veterinary medicine, bioinformatics and plant sciences as their draw to this campus.

"While most stem cell research is being done at universities with medical schools, we are Ph.D.s, not M.D.s," Vaclav Ourednik said. "We believe stem cell research needs much more knowledge in how these cells work and differentiate and react to hosts, and that can be done in any biology department."

What else can be accomplished at a traditionally non-medical land-grant university? Take a look.

The brain beat
For more than 10 years, the Ouredniks, both associate professors of biomedical sciences, have been studying the brain's plasticity and regeneration, as well as neural transplantation. A diseased or injured brain has difficulty repairing itself; the use of stem cells from fetal tissue helps transfer the necessary material into the brain to aid its recovery.

But much is unknown about the stem cells themselves -- how they communicate with the original brain cells once transplantation occurs, what responses they may evoke in the host brain, their viability 20 years later.

"[Scientists] promise people we are very close to the miracles that will heal brain diseases," Jitka Ourednik said. "But I think we are far from that."

"It's important we slow down a bit from all the media-hyped science and get back to the basic research into these cells and tissues," her husband added.

Heather Greenlee is a fellow member of the biomedical sciences faculty who studies stem cells. Trained as a developmental neurobiologist, Greenlee pursues questions like "How does a neuron decide to become a neuron?" and "How does it become a specific type of neuron?" She also investigates how stem-cell related therapies target neurological diseases.

"In patients suffering with Alzheimer's disease," Greenlee explained, "the amyloid protein is toxic and builds up in the brain. We talk a lot about stem cell therapy for Alzheimer's patients -- but what happens to those stem cells when they encounter the toxic proteins? So far, I'm seeing that the stem cells don't like the amyloids much."

Greenlee also looks at how amyloids affect neurons and photoreceptors (cells in the eye that sense light). "Most blinding diseases, like macular degeneration, are a breakdown of the photoreceptors," Greenlee said. "We're hoping that the eye is another organ that is well-suited for stem cell therapy."

One of Greenlee's collaborators is Janice Buss, an associate professor of biochemistry, biophysics and molecular biology. In addition to their work on eye-related projects, the scientists have teamed with biomedical sciences professor Etsuro Uemura to study energy sources in brain cells. In particular, they are investigating how brain cells that are exposed to the protein amyloid Β-peptide, or AΒ, lose their ability to take in glucose, their sole energy source. This breakdown in energy resources may be an agent in causing Alzheimer's, as the resulting imbalance in the nerve cells can lead to memory loss and disorientation as the affected neurons die.

Buss became interested in her specialty when she realized "it was an opportunity to bring molecular insights into human disease. We have all kinds of drugs that target molecules, but you first have to understand the molecules. I want to make the discoveries that enable the people who ultimately make the drugs."

The Parkinson's pursuit
Parkinson's disease, among the most prevalent of adult neurological disorders, is another affliction studied by many ISU neuroscientists. The disease occurs when the portion of the brain that produces dopamine begins to degenerate. Dopamine is a chemical substance that allows humans to move smoothly. Parkinson's patients tend to move in a slower, more rigid manner, and often experience tremors or shakiness.

To better understand the disease, ISU has created the Parkinson's Disorder Research Program directed by Anumantha Kanthasamy, associate professor of biomedical sciences. In particular, Kanthasamy, a biochemist and toxicologist, studies how pesticides may attack and damage brain cells in the region that is specific to Parkinson's disease.

Though he previously conducted his research at a California medical school, Kanthasamy looks at ISU as a perfect fit for his studies.

"Because I'm working in an agricultural state, what I do has direct implications for the people of Iowa," he explained. "Once we know how these chemicals are killing cells, we can go back and devise strategies to prevent these diseases and aid in their treatments."

Until the day diseases like Parkinson's are eradicated, scientists like Ann Smiley-Oyen seeks ways to help patients cope with the symptoms. The assistant professor of health and human performance studies how two particular areas of the brain, the basal ganglia and the cerebellum, control the body's movements.

Specifically, her research looks at how these two brain regions contribute to motor learning and how intensive practice of repetitive motor skills can salvage those abilities in Parkinson's patients. Smiley-Oyen conducts a laboratory project on campus that tests Parkinson's patients on their abilities to perform such tasks as fastening buttons, intercepting a rolling ball, aiming toward targets and shifting their weight during controlled movements (similar to those practiced in tae kwan do). The project aims to see how much patients can improve skills through practice, and for how long those skills are retained.

"Medications can help people with Parkinson's," Smiley-Oyen said, "but there are negative side effects. I'm interested in how we can help improve their quality of life in ways other than pharmaceutical interventions."

It's all in the delivery
Nonetheless, how drugs are transported to cells is of significant interest to numerous ISU researchers. For instance, Victor Lin, an assistant professor of chemistry, works on materials that may deliver chemotherapy drugs more effectively. Currently, many such medications are delivered within biodegradable polymers that begin dissolving once they encounter water in a patient's body. If highly toxic anti-tumor drugs begin leaking before they reach cancerous cells, they also kill otherwise healthy ones, leading to such side effects as hair loss.

In Lin's research, the drugs are transported within a material he likens to "a tiny little sponge ball" that is itself surrounded by a chemical "cap," "like a rock that blocks these guys from leaking out," Lin said.

Specific chemicals released only by tumor cells would "unhinge" this cap and release the drug only into the diseased cells. Long-term, Lin, who received the National Science Foundation's Early Career Award last year, sees use of these materials for insulin implants that trigger the drug's release only when a diabetic's blood sugars reach a certain level.

Surya Mallapragada also is investigating new polymers for insulin delivery, but was sidetracked by the notion that the same polymers could be used in gene therapy for cancer patients. An associate professor of chemical engineering, Mallapragada has redirected some of her efforts to focus on delivering healthy genes to replace malfunctioning ones.

"Most gene therapy has used modified viruses to deliver the good genes," she explained. "But viruses could mutate and cause unexpected results. If these polymers are used, because they are fairly inert, they can hopefully successfully deliver these genes."

The polymers, which are both pH and temperature sensitive, may also function someday as "suicide genes" for cancer cells, forcing the damaged cells to self-destruct, Mallapragada said.

Her husband, Balaji Narasimhan, an assistant professor of chemical engineering, also investigates more efficient drug delivery systems via these biodegradable plastics. His research looks at single-dose vaccines that would administer, in a time-released system, all the drug needed to prevent diseases like tetanus or diptheria. Such deliveries would eliminate the need for booster shots and might significantly lower infant mortality rates in developing countries.

The antigens would be injected into the body encased in tiny spheres, one-millionth of a meter in diameter. The size and chemistry of these spheres would control when and how much antigen is released into the bloodstream.

The biomaterials Narasimhan uses have been approved by the U.S. Food and Drug Administration, but "we are a ways away from using these in human clinical trials," he said.

Back to basics
The health implications for sound nutrition and effective exercise have become standard newspaper fare. But long before the topics were trendy, numerous scientists on campus were studying these basics of longevity.

Diane Birt, for instance, has invested more than a quarter of a century in the study of dietary prevention of cancer. In particular, she investigates how plant components can offer protection, and how these components influence cell division in both normal and cancer cells. Birt, a professor and chairperson of food science and human nutrition, also heads ISU's Center for Research on Botanical Dietary Supplements, where studies are under way on two common herbs, echinacea and St. John's wort.

"I hope we can better define the herbs given to patients in clinical trials in the future," Birt said, "especially the factors that contribute to the greatest potential biological activity."

Elsewhere in Birt's department, associate professor D. Lee Alekel is launching a multi-center clinical trial that will test the effect of soy isoflavones on bone density in postmenopausal women. Isoflavones are compounds found in soybeans that behave like estrogen. More than 200 women in Iowa and California will participate in the three-year trial. Results from the study may aid in the prevention of osteoporosis, which is a prevalent consequence of menopause.

Across campus, Paddy Ekkekakis, assistant professor of health and human performance, is determining how people's emotions affect their ability to stick with an exercise program. In particular, he studies middle-aged women who are returning to the gym.

"When previously sedentary individuals first join exercise programs, they have to deal with negative feelings associated with exertion and fatigue," Ekkekakis said. "Professionals have traditionally recommended that they try not to think about it, think of these feelings as positive, convince themselves they can accomplish this or slow down when the negative feelings occur. It remains unknown whether these techniques are effective. We intend to answer these questions."

In the meantime, ISU researchers are examining how viruses evolve, persist and change. They are investigating the neurobiology of pain. Scientists are scrutinizing proteins that may help bodies fight infections, and how the brain stores memories, and whether exercise strengthens the immune system. All at a historically non-medical, land-grant institution, with many of these studies funded by the government's primary agency for medical research, the National Institutes of Health.

Here's to new traditions.

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