Neuroscience research encompasses a wide range of scientific disciplines--molecular biology, biochemistry, physiology, imaging, and psychology, just to name a few--so it demands a penchant for interdisciplinary work. Below, we profile two top young researchers whose interdisciplinary training during their graduate studies has helped propel their careers in neuroscience forward.

Guinevere Eden: Reading Children
Guinevere Eden got her first exposure to interdisciplinary research as a graduate student at Oxford University in the U. K. Now an associate professor in pediatrics at Georgetown University Medical Center in Washington, D.C., and director of Georgetown's Center of the Study of Learning, Eden is investigating how children learn to read. In the process, she has managed to develop pediatric neuroscience imaging protocols.

Eden's interest in children's learning stems from her brother's difficulties at school due to his attention deficiency. At Oxford, she began her graduate studies under the tutelage of an advisor, John Stein, who studied animal models of human behavior. Stein had a strong reputation for his work in motor control and visually guided movements, but Eden was particularly attracted to his well-known program in dyslexia research.

In her first year, to help her pay to attend a conference in the U.S., Eden did a one-month fellowship at Wake Forest University in North Carolina with Frank Wood, who conducts longitudinal research studies of dyslexia. Besides being a research professor, Wood is a clinician who also worked directly with children in the study.

Intrigued by the research, Eden decided to split her time between Oxford and Wake Forest, where she studied children with dyslexia and children who read normally, collecting data on visual-spatial skills and temporal processing. The decision to spend time at Wake Forest created some tension between Eden and Stein--her advisor--but he eventually warmed to the idea: "I always came home with a big gift basket of data," she recalls.

The two research environments could not have been more different. "My former advisor at Oxford has a variety of interests, all very much based on animal models of how the brain is organized for skilled performance. My mentor at Wake Forest is a clinician who directly works with people with learning disabilities." The two environments were polar opposites, but the experiences were complimentary. "I split time between two labs studying dyslexia from very different angles. That's a good thing to do if you're working in a field that's very interdisciplinary."

After completing her Ph.D. in 1993, Eden began a postdoc at the intramural program at the National Institute of Health's Fogarty International Center and learned more about brain imaging, which she had been first exposed to at Wake Forest. Functional magnetic resonance imaging (fMRI) especially intrigued her. This technique measures changes in blood flow to the vasculature in the brain, highlighting regions of task-related activity.

After she accepted the associate professorship at Georgetown University in 1996, she continued her work with fMRI, but she also continued to work with the children involved in the Wake Forest longitudinal study. Many of the children she studied as a graduate student are now flown to Georgetown as young adults for ongoing studies. She continues to recruit new study participants, including children as young as six. The fMRI machine poses a challenge for the study of young subjects, because of the noise and because it requires the child to stay still in a confined space while performing a variety of tasks. Consequently, Eden and her colleagues have spent quite a bit of time developing protocols to calm fidgety children, protocols that include a mock-MRI scanner that children are allowed to climb on, and "lots of beanie babies," she says.

The work and patience paid off. Eden and her colleagues published the first-ever fMRI study of individuals with dyslexia ( Nature, 1996; 348: 66-69) and then the first imaging study of hyperlexia, in which a child with autism displays precocious reading ability ( Neuron, 2004; 41: 11-25). Eden's work suggests that hyperlexia and dyslexia are opposite extremes, neurologically speaking. People with hyperlexia show heightened activity in the left superior temporal cortex, which is associated with understanding the sounds of speech. Children with dyslexia show reduced activity in this region. Eden is also carrying on longitudinal studies, comparing brain images from children as they grow and gain reading proficiency, aiming to determine how brain activity changes with advancing skill ( Nature Neuroscience, 2003; 6:767-773).

Eden is also correlating the fMRI imaging with learning programs, looking for changes in fMRI images as children with reading disabilities improve their performance. Such imaging could eventually help diagnose dyslexia in young children; even better, Eden hopes that by studying subtle brain differences as children with and without dyslexia learn to read, fMRI could eventually help teachers target reading interventions.


Yimin Zou: Growing Nervous
After finishing his undergraduate degree in genetics at Fudan University in Shanghai, Yimin Zou came to the U.S. to study neuroscience. But the exchange program he was participating in limited him to just a few schools. He settled on the University of California (UC) at Davis and later moved to the University of California at San Diego. Because he lacked the connections needed to find a neuroscience advisor, he joined Kenneth R. Chien to study the genes that lead to the development of cardiac muscle.

As he learned the techniques of biochemistry and molecular biology--molecular cloning, protein expression and characterization, and in situ hybridization, among others--Zou never lost his desire to enter neuroscience. He read books about the field and attended neurobiology lectures at the nearby Salk and Scripps Institutes.

Today a rising star in neuroscience at the University of Chicago, Zou made a name for himself by being the first to discover the molecular signals that guide axons longitudinally along the spinal cord, toward or away from the brain.

In time, the techniques he honed studying heart development would serve him well. But after completing molecular cardiology Ph.D. in 1996, he had some catching up to do. He began by seeking a postdoc in neuroscience, eventually joining the lab of Marc Tessier-Lavigne at UC San Francisco. Tessier-Lavigne studies the molecular signals that provide directional guidance to axon growth in mice and rats. Zou's work focused on discovering the genes that coded for the signals, and the mechanisms of reading them. Zou was a fast study. "Molecular biologists can enter this field relatively quickly. It was not too hard to make that transition," recalls Zou. The work led quickly to a publication in Cell (2000; 102: 363-375).

In 2000, Zou moved to the University of Chicago, where he is currently an assistant professor of neurobiology, pharmacology, and physiology. Eager to establish himself, he chose a natural extension of the work he did with Tessier-Lavigne: identifying the molecular cues that guide axon growth toward and away from the brain. No such cues were known, but the problem had already attracted a number of research groups. It was a risky choice, Zou admits, but he was confident that the skills he had acquired and the model system he used would help him succeed. He chose to focus virtually his entire research effort on the problem.

The risk paid off. In Science (512 December, 2003; 302: 1984-1988) he described the first known longitudinal signals: Wnt proteins, which are known to regulate cell-cell interactions in embryonic development. Axons, he learned, respond to a concentration gradient of Wnt-4, growing toward the brain in the direction of increasing Wnt-4 concentration. The discovery opens up plenty of new avenues of research, including investigations into guidance mechanisms of other classes of axons along the longitudinal axis ( Nature Neuroscience, 2005; 8: 1151-1159) and axon regeneration following injury.

Zou credits his success to his single-minded focus and to the interdisciplinary approaches he used to studying the problem. His team performed embryology experiments, molecular cloning projects, and candidate gene studies, coming at the problem from several different angles at once. "You cannot do one project. You have to do a number of projects to try to get to the answer, hoping one of the approaches will work out," Zou advises.

Success, when it comes, is just the beginning. It's important to choose a project that will make a real contribution, Zou says, but also a project that can evolve. "When you have finished the first phase, the university will come to evaluate [your future prospects]. Your project has to have its own life."

References:

1) Abnormal processing of visual motion in dyslexia revealed by functional brain imaging. Eden, GF, et al. Nature, 1996; 348: 66-69.

2) The Neural Basis of Hyperlexic Reading: An fMRI Case Study. Turkeltaub, PE, et al. Neuron, 2004; 41: 11-25.

3) Development of neural mechanisms for reading. Turkeltaub, PE, et al. Nature Neuroscience, 2003; 6:767-773.

4) Squeezing Axons Out of the Gray Matter: A Role for Slit and Semaphorin Proteins from Midline and Ventral Spinal Cord. Zou, Y, et al. Cell, 2000; 102: 363-375.

5) Anterior-Posterior Guidance of Commissural Axons by Wnt-Frizzled Signaling. Lyuksyutova, AI, et al. Science, 12 December, 2003; 302: 1984-1988.

6) Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract. Liu, Y, et al. Nature Neuroscience, 2005; 8: 1151-1159.

Jim Kling is a freelance science and medical writer based in Bellingham, Washington.