CHRISTOPHER WALSH, MD, PHD
GENES AND THE CEREBRAL CORTEX
It was one of those moments that change your life. Christopher Walsh, a chemistry major at Bucknell University, happened to land a summer job working for the Chair of the Neuroradiology Department at Columbia University. (It helped that his brother-in-law was a neurosurgery resident at the time.)
One day, his boss told the young student that he had something to show him. “I vividly recall walking down to the basement of the Neurological Institute in New York. He showed me what now seems like a scratchy old Polaroid picture and said, ‘This is going to revolutionize our understanding of the human brain.’
“It was an image from one of the first computed tomography scanners, newly installed at Columbia. I had no idea then how significant this was. It is amazing that I happened to stumble across this incredible neurological event. I was just at the right place at the right time,” Dr. Walsh said.
Christopher Walsh, MD, PhD, is Bullard Professor of Neurology at Harvard Medical School and Beth Israel Deaconess Medical Center.
Dr. Walsh, who spoke on “Genes that Control the Shape and Size of the Human Cerebral Cortex” at the AAN Annual Meeting's Frontiers in Clinical Neuroscience Plenary Session, used the words “lucky” and “fortunate” a lot when talking about his career.
Another such stroke of luck had come along even before his job at Columbia. In his first year at Bucknell, he was invited to join an honors psychology seminar.
“I didn't know what it was, or how I got in, and I had only a vague idea of what psychology was, but since it was an honor, I thought I should do it.” His instructor in the seminar turned out to be no less an eminence than Alan Leschner, now the Editor of Science and the Chief of the National Institute on Drug Abuse.
“I had this amazing man as an instructor in freshman psychology with just 20 students. He was so smart and so energetic; he really got me excited about the brain and behavior and all these things I'd never thought about before.”
EXPOSURE TO NEUROANATO
His experiences at Columbia and with Dr. Leschner left Dr. Walsh certain that he wanted a career in medicine, and in some way related to the brain. This led him to a combined MD-PhD program at the University of Chicago, where luck was on his side again, pairing him with Rainer Guillery as a thesis advisor.
“Dr. Guillery got me interested in how the brain develops. It is such a tremendous mystery: these millions of cells have to form in the same order, with all this complex wiring, and suddenly the lights go on and you've got a mind there,” Dr. Walsh said. “That is the question I've been fascinated with ever since.”
But the fortunate encounters and partnerships weren't over yet. “How many major influences can you mention in one article?” Dr. Walsh laughed. In his case, the list might fill a Manhattan phone directory.
THINKING ABOUT GENETICS
Beginning his neurology residency at Massachusetts General Hospital in 1986, Dr. Walsh found himself engaged in a series of long, deep conversations with the then-head of the program, Joseph Martin, MD. Dr. Martin, now Dean of Harvard and then a major player in the genetic revolution in neurology, had just identified the Huntington disease gene with James Gusella, and he urged the young scientist to think genetically.
“I'd say to him, ‘I'm really interested in how the brain develops,’ and he'd say, ‘That really is a fascinating question. Can you relate it to genetics? That is the way that basic science gets tied to disease. It is the best basic science and the best disease-related research, all at the same time.’”
Dr. Walsh was intrigued, but not entirely convinced. “I thought it was really good advice, but I didn't see how it related to my scientific interests,” he said. “I couldn't see how I'd make that leap from my basic science interest in how the cerebral cortex gets put together to my clinical interests in neurology.”
But when he began setting up his own laboratory at Beth Israel Hospital in 1993, Dr. Martin's advice stuck with him. “I wanted to take a genetic approach to studying how the cerebral cortex develops, so I spent a weekend at the Jackson labs, where they have all these strains of mutant mice,” he recalled.
After 48 hours of staring at a roomful of microscope slides to find mice with mutations affecting the cerebral cortex, he left with just one mouse mutation that looked relevant. “I was very disappointed that there weren't a lot more. But I started working on that one mouse.”
And then the last piece of the puzzle fell into place at a conference in Venice. “One of my former teachers from the University of Chicago, Peter Huttenlocher, discussed a family with an inherited malformation of the cerebral cortex. In these patients, about half of the neurons that belong in the cerebral cortex are formed properly but end up in a totally wrong part of the brain,” Dr. Walsh said. “They have epilepsy, and surprisingly, most of them have normal intelligence, though occasionally they will be mildly cognitively impaired.”
Call it a light bulb, an epiphany, a magic moment. Whatever you call it, the result was that Christopher Walsh could barely wait until the end of the talk to literally run the 20 feet to the front of the room. “Here was the link between clinical neurology and basic biology I was looking for. My palms started sweating,” he said. “I thought, ‘Maybe I could map that gene.’ I was amazed when he wasn't collaborating with anyone else, and that he remembered me and was only too happy to work together.”
Dr. Walsh's partnership with Dr. Huttenlocher began just as the widespread use of magnetic resonance imaging (MRI) in clinical neurological practice was permeating the country – and the world. Here, he couldn't help talking about luck and fortune again.
“MRI has revolutionized our understanding of the human brain and how it is controlled by lots of genes, and it has made feasible the genetic analysis of mutations that cause specific abnormalities in the way the brain develops,” he said.
“Now we can do tremendously good genetics in humans, because of the Human Genome Project and the widespread use of MRI in clinical practice. We have the whole genome sequence, and we have the best possible way of finding out when a person has a mutation in the cortex: a phenotypic screen. In humans, our screen for abnormal phenotypes that have to do with the cerebral cortex is our life: work, play, school. We don't have to go looking for people with genetic abnormalities in how the brain develops – they come to us.”
HOPE FOR FUTURE
Do any of the genes involved in cerebral cortex formation, the ones that he talked about in his presentation, point toward treatments for these abnormalities? Dr. Walsh is optimistic, but realistic.
“Therapy is a tough one. I don't see us having the power to put things right in near future for many people with abnormal development of the brain. But in other patients, the brain seems to be put together normally, but its plasticity is hindered somehow. We call this ‘nonsyndromic mental retardation’ – when the brain looks fine, but they just have low IQ,” he said.
“There seem to be a large number of such conditions that are very hopeful for treatment, conditions for which we ought to be able to develop drugs in the not so long term. But I'm not trying to claim that all of these malformations are going to be treatable. Some will remain a fact of life to deal with and we'll try to prevent as much as possible with the availability of genetic testing.”