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October 11, 2007
Joseph G. Gleeson, M.D.
Several years ago, Joseph Gleeson made what he calls a “major career decision” to begin traveling to the Middle East on a regular basis to directly examine, recruit, diagnose, and evaluate members of families that are affected by developmental brain disorders. In preparation for these trips, he and his clinical research coordinators typically spend an entire year identifying potential collaborators and key families to study.
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Joseph G. Gleeson, M.D.
University of California, San Diego School of Medicine
La Jolla, CA
Photo: Fred Greaves/PR Newswire, ©HHMI
A high-resolution photograph is available on request.
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Each year he travels to the Middle East for about a month, where he tries to visit five countries and meet with as many collaborating scientists as possible. His trips take him to destinations as diverse as Egypt, Kuwait, Morocco, Oman, Turkey, the United Arab Emirates, and Saudi Arabia. The trips are crucial for Gleeson's work in identifying genetic factors that are required for development of the human brain because collaborators working in these areas provide him with access to large families in which the parents are consanguineous (related by blood), a requirement for his studies.
Gleeson specializes in human diseases that show recessive patterns of inheritance. Recessive diseases are several times more common in the Middle East, possibly because of the degree of consanguinity among families there. For Gleeson and his colleagues, families in the Middle East, which often have 8 to 10 children, are ideal for mapping the genetic causes of brain disorders.
Gleeson has definite research goals as an HHMI investigator. He plans to leverage his work with Middle Eastern families to understand the genetics behind diseases with complex inheritance patterns, such as mental retardation, brain wiring defects, and epilepsy. By combining these studies with work in his laboratory and at the Center for Cerebellar Malformation at the University of California, San Diego (UCSD), Gleeson says, “Our goal is to identify one new disease gene each year.”
During his residency in pediatrics and subsequent clinical fellowship in neurology, Gleeson cared for many children with brain disorders caused by mutations in genes that direct brain development. “They came in with seizures, pneumonia, paralysis, and it was rewarding to make them feel better,” he recalls. “But you couldn't help wondering what was underlying these conditions and why so little was known about their causes.”
Rather than wondering, Gleeson decided to dedicate his career to finding out the causes of those conditions. He launched his research career focused on caring for and learning from patients with developmental brain disorders. Along the way, he trained as a postdoctoral fellow with Christopher A. Walsh (now an HHMI investigator) at Beth Israel Deaconess Medical Center before assuming his current positions in the Department of Neurosciences and as Director of the Neurogenetics Laboratory at the UCSD School of Medicine.
The problems Gleeson sees in the brains of patients he cares for in UCSD's Center for Cerebellar Malformation provide him with a better understanding of how particular genes contribute to the development of the human brain. He builds on these observations in the laboratory, using model organisms to understand the specific molecular mechanisms behind diseases he sees in patients.
These strategies, together with his work in the Middle East, have enabled Gleeson and his colleagues to identify several genetic mutations that lead to developmental brain disorders. Among them are the doublecortin (DCX) gene and its family member, doublecortin kinase-1 (DCK1), which are involved in several syndromes, including lissencephaly. Lissencephaly, or “smooth brain,” is a severe developmental brain disorder that causes epilepsy, mental retardation, and early death in children.
Gleeson and his colleagues cloned the DCX gene and showed that it was mutated in patients with lissencephaly. They found that the gene encodes a protein that helps neurons migrate to the cerebral cortex as the brain develops in the embryo. When the gene is mutated, “neurons end up trapped in the white matter of the brain instead of migrating into the gray matter where they belong,” Gleeson explains.
Doctors can now sequence the DCX gene to diagnose lissencephaly and a related disorder, double cortex syndrome, during prenatal care. Gleeson's research on DCX has also uncovered some of the basic biology of healthy brain development, revealing how cell structures rearrange themselves to allow neurons to migrate to their destinations. Another focus of Gleeson's lab is the genetics underlying Joubert syndrome, a developmental brain disorder—in which the midline of the cerebellum is actually missing—that affects about 1 in 10,000 children. The symptoms of Joubert syndrome range from mental retardation, seizures, and autism to kidney failure, blindness, breathing abnormalities, and extra toes and fingers.
“This study has been unbelievably fascinating and amazingly complex,” he says. “We thought it would be a single-gene disorder like X-linked lissencephaly, but there are six genes so far and undoubtedly will be many more.” Gleeson and his colleagues and collaborators discovered the first two genes involved in Joubert syndrome: AHI1 (Abelson Helper Integration-1) and CEP290 (Centrosome Protein-290). Both encode cytoskeletal proteins related to many of those the Gleeson lab has studied in other human diseases, illustrating the “perfect synergy between clinical and basic science” that Gleeson finds so appealing and challenging.
Gleeson sees tremendous opportunities ahead. He notes that only about 20 percent of genes expressed in the brain have known functions, and “clearly many have essential roles and cause disease when mutated. More than anything else, the complexity of our brain defines us as humans and separates us from other species,” Gleeson says. “I can't imagine being in any other field right now.”
Joseph Gleeson is Associate Professor of Neurosciences at the University of
California, San Diego, School of Medicine. He received his B.A. in chemistry from the University of California, San Diego, Revelle College and his M.D. from the University of Chicago Pritzker School of Medicine. Among his awards are the Klingenstein Award in the Neurosciences, a Searle Scholars Award, a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, and a Research Advocacy Award from the Joubert Syndrome Foundation.
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Jennifer Michalowski
