A month before Christopher Walsh went to Bucknell University in Lewisburg, Pennsylvania, an acceptance into Honors Psychology 101 arrived in his mailbox. Walsh hadn't selected the course and knew nothing about psychology, but fortunately he decided to sign up. The teacher was Alan Leshner, who later directed the National Institute on Drug Abuse and now publishes the journal Science. "He got me really excited about neuroscience," says Walsh, who had gone to college with "no clue about what I wanted to do."
After Walsh's freshman year, his brother-in-law (a neurosurgical resident) found him a summer job at Columbia University's Neurological Institute of New York, working for neuroradiologist Sadek Hilal. The same summer, the institute acquired its first CT scanner. "I still remember Dr. Hilal holding up one of the pictures and saying, 'This is the future of neurology,'" Walsh recalls.
These two events were pivotal to his career, Walsh says. Today, he is an expert on the development of the cerebral cortex and the developmental missteps that produce mental retardation.
After Walsh graduated in chemistry in 1978, he entered the University of Chicago's M.D./Ph.D. program, interested in brain chemistry and disorders such as schizophrenia. But when he began to study brain development, he was struck by the similarity between the brain's physical structure and philosopher Immanuel Kant's ideas about the structure of perception, which he had encountered during a college course. "I became interested in the fact that the structure of consciousness is built out of biological nuts and bolts," Walsh explains.
Little was known about brain construction when Walsh became a postdoc at Harvard Medical School after completing his internship and residencies. Therefore, he decided to label cells in the developing brain to see where they ended up. At that time, it was thought that a dividing cell gave rise to a patch of similar cells that remained in that location, but that proved to be only partly true. "To my complete surprise, we saw some daughter cells being scattered as far as the eye could see," Walsh says.
Other scientists were skeptical of this finding, which Walsh and colleagues reported in Science in 1988. But over the next 10 years, the paper became very influential. Scientists now know that excitatory neurons cluster together during brain development but that inhibitory neurons migrate to other parts of the brain. "Nature has found it easier to make the inhibitory neurons for the entire forebrain in one place and then cause these cells to migrate far and wide than to form similar cell types in multiple places," Walsh says.
When Walsh established his own lab in 1993, he was unsure how to combine basic science with medicine. But after hearing a former professor's talk about an inherited brain malformation, Walsh decided to study human genetics. And he began to look for genes that affect neuronal migration.
By studying children who suffer from double cortex syndrome, in which an extraneous cortex forms beneath the cerebral cortex, his group discovered its first new gene for a human disease. Dubbed doublecortin, this gene encodes a signaling protein that structures the cellular skeleton of neurons. When it is faulty, neurons that should migrate long distances through the developing brain get stuck en route, forming the second cortex. The patients—usually girls because this recessive gene lies on the X chromosome—have epilepsy and mental retardation.
"This discovery was a major highlight for me because of the tremendous logic of genetics," Walsh says. "You focus on a disorder for a long period and then come up with a very simple explanation in terms of mutations in a specific gene." While it is difficult to envision therapies for gross malformations of the brain, Walsh adds, having a genetic diagnosis can help families decide whether to bear more children. "Having a disabled child is so defining for many families," he says. "To get an understanding of where the disorder came from—whether it is inherited or, more commonly, a spontaneous mutation—can be very useful."
Over the years, his group has discovered many more genes that affect neuronal migration and cause severe malformations when faulty. For example, they isolated a gene called ASPM, which controls brain size. When ASPM is mutated, the human brain grows to only about half its normal size. Walsh's group and others subsequently showed that this gene has changed markedly during primate evolution, as the brain has become bigger. Other interesting genes include PAK3, which Walsh's group discovered in 1998 in children with a disorder called X-linked nonspecific mental retardation. Walsh hopes this finding might one day lead to a therapy for such patients, who have well-formed brains. Other interests in the lab include rare but devastating brain conditions such as polymicrogyria, Joubert syndrome, schizencephaly, and Walker-Warburg syndrome. "Doing disease genetics gives you moments of discovery because you start with an inherited disorder, track the gene to a particular neighborhood of the genome, find the gene, and then determine the specific changes in that gene that result in the disorder."
Looking back over this work, Walsh is surprised by the number of things that can go wrong with brain development. "But the brain has 10,000 to 15,000 genes, and Nature has probably put them all there for good reason," he says. "We try very hard to categorize the disorders of kids as precisely as we can. Someday, I expect we will understand that, say, autism is hundreds of different disorders."
To better understand that complex disease, Walsh is collaborating with physicians in countries, such as Turkey and Saudi Arabia, where families are large and people often marry distant relatives, increasing the risk of genetic disease. He actively recruits collaborators at international scientific meetings, but sometimes finds them closer to home. He recently gave a talk at his alma mater on a malformation of the brain's right, but not left, hemisphere, which he had observed in one family. Afterward, a classmate from medical school said she was treating three siblings with the same condition, so two families are now available for study.
Differences between the right and left hemispheres have been one of Walsh's long-term interests. Although the left hemisphere is known to take charge of language, math, and logical thinking, leaving perception and artistic ability to the right hemisphere, the causes of this specialization are unknown. In 2005, Walsh's group took a fresh approach to this problem by studying gene expression in developing human brains. A surprisingly large number of genes was expressed at very different levels in the two hemispheres, they found. For example, a gene called LMO4 turned out to be very active in the developing right hemisphere but less so in the left. Although its exact function is unknown, the protein encoded by LMO4 appears to switch on panels of other genes, especially those that help connect the two hemispheres.
Walsh's world is now expanding beyond the brain, thanks to a new collaboration with geneticist and cardiologist Ming Hui Chen. Also on the Harvard faculty, Chen is Walsh's wife and the mother of their 9- and 12-year-old girls. Since some brain disorders include cardiac effects, the couple is studying filamin A, which has been implicated in neuronal migration. In December 2006, they reported that this protein is needed to establish junctions between cells in the developing heart and blood vessels. "Those moments of insight are one of the addictive things about genetics," Walsh says.