Christopher A. Walsh grew up in Cranford, New Jersey, the seventh of eight children. His mother was a math teacher, and his father, a transportation manager in New York City. Walsh enjoyed his science classes in high school, but he didn’t think of himself as “a science kid.” He did well enough academically, however, to skip his senior year, entering Bucknell University shortly after turning 17. “I had no clear idea what I would major in, but I was betting that college would be more fun than high school,” Walsh recalls. During his first year at Bucknell, he took two courses that had a profound impact on his future: organic chemistry and an honors psychology course taught by physiological psychologist Alan Leshner. Also influential was a summer internship at Columbia University doing medical research, where Walsh saw a grainy computed tomography (CT) image of the human brain. CT technology was then in its clinical infancy. “That was really exciting,” says Walsh. “I have pretty much been studying the chemistry of the brain ever since.”
After graduating from Bucknell, Walsh received a full scholarship to the University of Chicago’s dual MD/PhD program for physician-scientists. “I love taking care of patients, but I always felt that research is the thing that drives me more,” says Walsh. For his doctoral thesis, done under the guidance of physiologist and neuroanatomist Ray Guillery, Walsh described the timing and patterns involved in the formation of neurons in the retina. While engaged in that research, Walsh developed an expertise in the “birth-dating” of neurons—determining when neurons cease cell division during embryonic development. This research sparked Walsh’s lifelong interest in the relationship between neural development and genetics.
After receiving his PhD, Walsh moved to Boston, where he trained as a neurologist at Massachusetts General Hospital and then accepted a post-doctoral fellowship in the laboratory of geneticist Constance Cepko at Harvard Medical School. While there, Walsh pioneered ways of using barcoded retroviral markers to label and trace neural cells in the developing cerebral cortex of rats. This innovative technique quickly enabled him to make several fundamental—and unexpected—discoveries, including the finding that many neurons take unexpectedly long and winding migratory pathways in the developing cerebral cortex.
In 1993, Walsh joined the faculty at Harvard and set up his own laboratory, wanting to study the role of genetics in human neurological diseases but unsure of how to go about it. A few months later, at a medical conference in Venice, Italy, Walsh heard pediatric neurologist Peter Huttenlocher, who had been one of Walsh’s teachers at medical school, give a talk about a family with a multi-generational history of a rare inherited malformation of the cerebral cortex known as periventricular nodular heterotopia. “That was one of those momentary flashes of insight,” Walsh recalls. “I realized that this family had a mappable genetic mutation that I could study. As Peter spoke, I got so excited, I could feel my heart racing. I literally rushed up to him after the talk ended.”
Within five years of that serendipitous meeting, Walsh and Huttenlocher had mapped and cloned the gene—FLNA—responsible for periventricular nodular heterotopia. By that time, Walsh had also identified the gene—DCX— for another rare inherited neurological condition, “double cortex” syndrome. Mutations in both these genes result in abnormal neural migration during early development of the fetal brain. Encouraged by these successes, Walsh went on to identify genes for dozens of other inherited human disorders that affect the structure of the brain, including microcephaly (characterized by a head size that is much smaller than normal) and polymicrogyria (characterized by too many folds in the cerebral cortex), as well as for conditions that affect how the brain functions, but not its size or shape, such as certain types of epilepsy and autism spectrum disorders.
One of the key innovations Walsh used for this research—an approach that has since been adopted by many other laboratories—was to begin the search for the gene mutations by studying the genomes of consanguineous families with recessive genetic disorders. Children in such families have a greater chance of inheriting two mutated genes, thus making recessive genetic disorders easier to identify. Walsh worked with consanguineous families around the world, but particularly in the Middle East where marriages between cousins is a common social custom.
In recent years, Walsh has focused on the genomic diversity of neurons in the human brain, making paradigm-shifting findings. He pioneered the use of single-neuron genome sequencing to examine how somatic mosaic mutations (ones that occur after fertilization and that are present in some neurons but not in others) shape the cell lineage and fate of neurons. He demonstrated, for example, that certain somatic mutations can lead to focal epileptic disorders, while others can cause autism spectrum disorders. Walsh also made the groundbreaking discovery that a single neuron may carry more than 1,000 mutations that were not present in the fertilized egg—mutations that, amazingly, continue to accumulate throughout life, even in non-dividing neurons. That finding promises to help scientists better understand genetic forms of premature aging and neurological neurodegeneration.
Walsh is currently the Bullard Professor of Pediatrics and Neurology at Harvard Medical School and Chief of the Division of Genetics and Genomics at Boston Children’s Hospital and has been an Investigator of the Howard Hughes Medical Institute since 2002. Since 2017 he has also led the Allen Discovery Center for Human Brain Evolution in Boston. He has received numerous honors and awards for his research, including membership in the National Academy of Sciences, the American Academy of Arts and Sciences, and the National Academy of Medicine. Walsh lives in the Boston area with his wife, cardiologist Ming Hui Chen, MD, with whom he has collaborated on shared research interests, and in raising their two daughters.