Christopher A. Walsh, M.D., Ph.D.
The Walsh lab studies the development of the human cerebral cortex, from undifferentiated stem cells to mature neurons. Studies of families with genetic disorders of human brain development have allowed us to identify of dozens of genes essential for cortical development, and associated with conditions like epilepsy, intellectual disability and autism spectrum disorders. These genes control stem cell proliferation, resulting in a small brain; neuronal migration, resulting in a disorganized brain, and many other processes. Some of these genes essential for human cerebral cortical development were altered over the course of human evolution as well, helping to drive the unique features of the human brain.
More recently we have developed methods to sequence the genomes of single neurons in postmortem human brain, and have discovered that every neuron’s genome is unique, with hundreds of mutations distinguishing one neuron’s genome from the genome of the neuron next to it. For instance, mutations occur when the DNA is replicated with each cell division during development. These mutations form a permanent map of the lineage relationships of every cell in the brain (and the rest of the body for that matter). Occasionally, these “somatic” mutations--present in some but not all brain cells—damage an essential gene, creating risk for brain diseases. We have shown that clonal somatic mutations occurring during development play important roles in focal pediatric epilepsy, adult temporal lobe epilepsy, a subset of autism spectrum disorders and schizophrenia, and even in some age-related forms of neurodegeneration and dementia.
Surprisingly, the accumulation of somatic mutations does not stop when neurons withdraw from the cell cycle, which usually happens before birth. Instead, “private” somatic mutations—unique to just one neuron--continue to accumulate throughout life at a rate of about 20 new point mutations added each year, in a remarkably linear, “clock-like” fashion, by mechanisms that are still not completely understood. This highly linear accumulation of private mutations in human neurons is accelerated in all human degenerative disease that have been studied, including Alzheimer disease, Amyotrophic Lateral Sclerosis, Fronto-Temporal Lobe Dementia, and Chronic Traumatic Encephalopathy, brought on by playing American football. This suggests that the disease-related processes may cause neuronal degeneration by direct genotoxic damage and that somatic mutations may integrate disease risk mechanisms with age-related mechanisms.
Biosketch
Christopher A. Walsh is Bullard Professor of Pediatrics and Neurology at Harvard Medical School, Chief of the Division of Genetics and Genomics at Boston Children's Hospital, and an Investigator of the Howard Hughes Medical Institute. He completed his M.D. and Ph.D. degrees at the University of Chicago. After a neurology residency and chief residency at Massachusetts General Hospital, he completed a research fellowship in genetics at Harvard Medical School. His research has been recognized by the Perl-UNC Neuroscience award, the Gruber Neuroscience Prize, the Kavli Neuroscience Prize, and election to the National Academy of Medicine, the National Academy of Sciences, and the American Academy of Arts and Sciences.