|An Interview with Christopher A. Walsh, M.D., Ph.D.|
Chief, Division of Genetics, Children’s Hospital Boston
Howard Hughes Medical Institute, Beth Israel Deaconess
Bullard Professor of Pediatrics and Neurology
Harvard Medical School
Q: Your research lab is focused on mostly rare genetic mutations that cause autism, epilepsy, mental retardation, and learning disabilities in children. What drives your interest in these genetic anomalies?
A: My interest is both scientific and medical. Human disorders of brain development, which these all are, highlight what I consider to be some of the great unanswered questions in the basic biology of the brain—what makes us human? What is the biological basis of language, intelligence, and social behavior? In my mind, we can only solve these basic biological problems by understanding this critical set of medical problems. As a neurologist I also happen to be excited by the possibility of contributing in some small way to understanding these medical conditions, since they represent a major burden of illness.
Q: What are the most common ways in which cortex development goes awry in humans? What are the therapeutic implications?
A: There are many rare disorders in which the human brain is obviously abnormal in its shape, size, or pattern of widespread connections. therapeutically, these conditions would appear to be the biggest challenge, since it seems that definitive treatment requires impossible amounts of change to the tissue of the brain.
On the other hand, the most common way in which development of the cortex goes awry is a brain that looks outwardly normal but does not function normally, resulting in mental retardation or autism. We had assumed for a long time that these latter disorders were also untreatable, since perhaps the “microstructure” of the brain was still impossibly abnormal, and even if we corrected the genetic defect, the brain would be permanently impaired. Much to everyone’s surprise and delight, recent work on animal models (from labs other than our own) has suggested that some mental retardation and autism syndromes (notably Rett syndrome and Fragile X syndrome) can be substantially reversed—even in a fully grown mouse brain—with the proper therapy, which might include replacing a [dysfunctioning] gene or otherwise compensating for it. As a neurologist, the prospect that genetic disorders may be subject to successful therapies guided by gene identification is tremendously hopeful, even if it only works for one or two genes.
Q: You’ve investigated how gene expression patterns differ between the left and right hemispheres, with an eye toward understanding whether such differences explain left-right specializations of the brain. What have you found so far?
A: The short answer is that we do not know for sure at this point [if left-right specializations are a result of differential gene expression]. We hope that this might be the case, and it is a reasonable hypothesis, but at this point it remains a hypothesis that needs to be rigorously tested. One of the genes that we found to be expressed more highly in the right hemisphere than the left hemisphere, called LMO4, appears to regulate the size of the sensory cortex in mice. This might suggest that left-right differences in the brain originate by slightly asymmetric “maps” of sensation or motor function in the two cerebral hemispheres.
We have also more recently identified a series of families in which several people share a malformation of the right cerebral hemisphere, but the left hemisphere looks normal.
Misfold: Polymicrogyria describes a condition in which at least one region of the brain’s cerebral cortex has too many folds (gyri) and the folds are smaller than normal. Polymicrogyria can occur focally or all over the brain. Walsh’s lab is trying to identify the genes that may be responsible for genetic forms of the condition to better understand the types of proteins that are important in brain development. (Image courtesy of Christopher Walsh, HHMI, Beth Israel Deaconess Medical Center)
We hope that understanding the gene that causes this condition will help us understand mechanisms of hemisphere-specific development.
Q: You have suggested that some genes that cause developmental brain disorders when mutated have likely been important to the evolutionary specializations of the human brain. What are some examples?
A: Several genes that cause developmental brain disorders appear to have been targets of evolution in the lineage leading from nonhuman primates to humans over the last two million or so years. And in some cases, the function of the gene—as elucidated by the details of the genetic disease—offers hypotheses about how the gene might have acted evolutionarily.
For example, Abnormal spindle microcephaly (ASPM) is a gene that is mutated in a human disease called microcephaly, in which the brain is greatly reduced in size and intelligence is low. ASPM seems to have undergone evolutionary changes in structure in parallel to the evolution of the large brain that distinguishes us from other primates (our brain is about twice as large as the chimp, our nearest relative). On the other hand, the evolutionary changes in ASPM seemed to stop about the time our brain became fixed at its present size, and so far there is no data that differences in ASPM between different humans account for any present-day differences between people.
We identified another gene, AHI1, that is mutated in Joubert syndrome, in which children have abnormal coordination, mental retardation, and other symptoms due to abnormal patterns of axon fiber connectivity in the brain. AHI1, like ASPM, shows evolutionary changes in gene structure in the lineage leading up to humans. We speculate that this evolutionary change in the gene accompanied changes in brain wiring, perhaps including those necessary for optimal motor coordination. But we do not yet know exactly how the evolutionary changes in gene structure map onto changes in gene function, and thence to changes in brain structure. That is for future work.
On the other hand, by no means are all human disease genes subject to evolutionary selection—in fact most are not. Evolutionary selection happened in many ways, not just by changes in a few disease genes. Nonetheless, it reminds us how some developmental brain disorders rob people of some of the most highly evolved human capabilities, such as language, speech, reading, and social activities. So it is not that surprising to see mechanistic links in a few instances.