Pioneer in Progress against Parkinson's

Karen O'Malley, Ph.D., is ferreting out the facts about dopamine in leading-edge research

Karen O'Malley's Catholic girls' high school gave her a strong foundation in writing and literature but little career counseling or education in science. Her first attempt to get a Ph.D. landed her in the wrong field, and a brief stint in industry proved frustrating. But she eventually found her calling in neuroscience and the battle against Parkinson's disease, and now she is uncovering pathways that slay dopamine-producing cells in the brain.

When these cells die, hands shake, movements slow and other symptoms of the disorder follow. Between 1 million and 1.5 million Americans have Parkinson's, which is becoming more prevalent as the population ages.

"Karen's research is excellent in terms of the basic neuroscience, and it has clearly taken a direction that hopefully will lead to improved animal models for studying Parkinson's disease and eventually to more effective treatment of these important disorders," said David C. Van Essen, Ph.D., the Edison Professor of Neurobiology and head of the Department of Anatomy and Neurobiology.

Karen L. O'Malley, Ph.D., professor of neurobiology at the School of Medicine, became interested in science because her father was a science teacher. But as an undergraduate at California State University of Sonoma, she focused on environmental studies, which led her to Portland State University in Oregon. After a summer at a marine station in Charleston, Ore., however, she abandoned her doctoral studies for a master's degree. "I took a comparative physiology course in Charleston," she recalled, "and knew right away that more biochemically related research was what I really wanted to do."

In 1980, O'Malley obtained a Ph.D. from the University of Texas, Austin, by isolating and characterizing a small peptide from the brain that makes fat cells release some of their baggage. Such a molecule, if it could be turned into a drug, could be useful for treating obesity. "I learned many new techniques, as well as how to do research," she said. "But most importantly, I got very interested in factors that might be unique to the brain."

Isolating minute amounts of peptides from mountains of pig brains was very laborious, however, so O'Malley was delighted to read a 1979 paper in Nature by Stanley N. Cohen, the Stanford University researcher who co-invented DNA cloning in 1973. Cohen's group had cloned the gene for a precursor of several brain peptides. Once a gene is cloned, the corresponding peptide can be synthesized.

O'Malley applied for a fellowship in Cohen's lab, but she first spent six months studying molecular biology in a yeast lab in San Antonio, where her husband-to-be, Richard D. Todd, M.D., Ph.D., was finishing medical school. Todd now is the Blanche F. Ittleson Professor of Psychiatry, director of the Division of Child Psychiatry and professor of genetics here. The two married in 1980.

Cloning genes

When the couple arrived at Stanford, there was not yet space in Cohen's lab for O'Malley, who therefore began to work at Cetus, a biotech company Cohen had founded. Frustrated by publication constraints and bored with contract work, O'Malley quickly moved to Stanford. As a postdoctoral fellow in the lab of Laurence Kedes, O'Malley set out to clone genes for enzymes involved in the synthesis of catecholamines. This family of chemical messengers includes dopamine, the substance that is depleted in Parkinson's disease.

"It was a wonderful experience for me," O'Malley said. "Trying to understand how some of these molecules originated in the brain and how they might function seemed like a golden opportunity to move into an organ that had been inaccessible from a molecular standpoint up to that time."

Looking for a faculty position, O'Malley wasn't anxious to leave California. But a visit to Washington University changed her mind. "I felt that this was the best growing place for me because of the community of people interested in similar things and the depth of knowledge in neuroscience," she said.

In the ensuing years, she has focused largely on dopamine, uncovering factors that give certain cells in the base of the brain the unique ability to make this neurotransmitter. "Karen has become a recognized leader in the area of studying dopamine," Van Essen said. "Dopamine is important and has received a great deal of attention because it is implicated in affecting normal behavior and in a variety of clinical disorders. Karen has established a strong track record of studying the basic mechanisms of how dopamine is synthesized and studying the receptor molecules with which it interacts."

In the course of this work, O'Malley began to determine why dopamine-producing cells die in Parkinson's disease. To study the problem, she dissects out dopamine-making neurons from mouse or rat brains and cultures them in dishes. After exposing them to substances that cause Parkinson-like symptoms in animals, she examines the molecular consequences.

Her group has discovered that the two most commonly used toxins, 6-hydroxydopamine and a heroin metabolite called MPTP, kill these cells in different ways. Whereas 6-hydroxydopamine makes the cultured cells commit suicide, MPTP destroys the cells by a mechanism O'Malley's group is trying to define.

Her group currently is determining how free radical production and alterations in energy metabolism lead to cellular demise. She hopes to use this information to develop a realistic animal model for Parkinson's disease. "Our hope is that we will be able to identify the cause of cell death and suggest various ways to inhibit it and therefore to slow the progression of the disorder," O'Malley said.

When not in the lab, O'Malley is teaching the medical school's neuroscience course or participating in a course on research ethics. "In many cases, there is no consensus about what is right and wrong," she said. "So students need to think about the shades of gray and decide how they will respond when they face these issues."

She also is involved with the Academic Women's Network (AWN) at the medical school. "Having a critical mass of women is important because a single voice may not be heard as well," she explained.

Karen O'Malley enjoys some beach time with her daughter, Anne, and son, Lucas.

She is on AWN's mentoring committee, which tries to improve opportunities for female students and researchers. For example, the committee arranges seminars on topics of interest to trainees, such as improving public speaking or grant-writing skills. O'Malley also has been instrumental in arranging for the distinguished women who give the Mildred Trotter lectures to spend time afterwards discussing career issues in science.

One of O'Malley's two graduate students, Julia Lotharius, also is concerned about mentoring and helped found Women in Neuroscience at the medical school. From a survey she conducted a couple of years ago, she determined that graduate students would like more help, especially if they are women. "We would like to be sent to more meetings and introduced to more experts in our fields," Lotharius said.

Family time

"It was a very eye-opening experience to live in another country, struggle with another language and realize that things are not the same as in the United States," she said. "So that has been my long-term interest, and we try to go there at least every two or three years."

You can accomplish a lot in your career, but it is inevitable that you will have less time to be in the lab if you have children," she said. "But having a family is wonderful as well. There's a balance that you wouldn't otherwise get. So for us, it was worth doing."