University of California, San Diego
Dr. Gleeson is also the Rady Auxilliary Chair of Neuroscience at Rady Children's Hospital, director of the Center for Brain Development at UCSD, and head of the Laboratory of Pediatric Brain Diseases at the Rockefeller University.
Developmental Brain Disorders
Joseph Gleeson has always been fascinated by how the human brain works and how it is uniquely structured to support higher cognitive function. During his clinical training at the University of Chicago, he became fascinated with conditions such as epilepsy, autism, and mental retardation. These cases, he believed, in which brain development goes awry, offered the opportunity to understand fundamental concepts of human cognition. To pursue this interest, Gleeson focused on child neurology, which allowed him to study genetic abnormalities or environmental influences that might cause the brain to develop or function incorrectly. If he could treat a child with a brain disorder, he believed, he could benefit the patient for his or her whole life.
There were, however, very few known causes of developmental brain disorders, and even fewer specific treatments when Gleeson finished his clinical training at Boston Children’s Hospital. This led him into the research lab at Harvard Medical School with Christopher Walsh. “The impact a doctor could have on one person," he says, "was far outweighed by the benefit one could have in the field of research, which could influence the way that other doctors practice.”
Since then, Gleeson has focused on identifying causes of a host of devastating neurological conditions affecting children. His research has identified more than 10 genes associated with brain development in humans. When mutated, these lead to a host of manifestations, such as autism and epilepsy. Gleeson's strategy, which continues to evolve, is to use a combination of careful assessments, brain MRI, and electrophysiology, in consultation with a team of international experts, to identify new types of neurological conditions. He then develops strategies to identify the molecular basis of these newly defined conditions.
Although the approach taken by Gleeson is straightforward, it is extremely demanding, requiring constant travel and coordination with a host of foreign collaborators. When Gleeson started his lab at the University of California, San Diego, he reasoned that the most likely places to find new neurological conditions to study was in the Middle East, North Africa, and Central Asia. Consanguinity rates in these regions average 30–60 percent, which is about 100 times more common than in the United States or Western Europe. The effect of these marriages is a doubling of the prevalence of inborn errors of development and metabolism in children. Gleeson realized that these populations, combined with the power of modern genetics, could help identify new causes of disease. The discoveries made in these isolated populations could then be applied to patients, not just in these populations but also in the United States and elsewhere to improve care.
Starting this project on a limited scale allowed Gleeson to set up collaborations with child neurologists, geneticists, and pediatricians across these regions. Successes in the lab led to further referrals from collaborating doctors, especially of unusual clinical cases. Despite the increased number of patients with a broad range of neurodevelopmental disorders, Gleeson personally evaluates patients enrolling in his study, looking for features shared with a previous case. It is these links between patients who might share common genetic elements that help drive his research program.
Gleeson now spends about one month per year traveling to remote sites to evaluate patients, meet with doctors, and share research findings. Recent changes in the political landscape have only made this work more challenging. “Even through these troubled times,” says Gleeson, “the local doctors and their staff dedicate their lives to helping treat these suffering patients.”
Since the introduction of new DNA-sequencing techniques, Gleeson, who initially focused on families with many similarly affected children, has changed his patient recruitment strategy dramatically. “The new sequencing techniques, with their ability to sequence the entire coding region of the genome in one fell swoop, hit just at the right time for us,” says Gleeson. “We had this enormous patient registry of both large and small families. For the first time we could make use of both to advance discovery.”
One of Gleeson's major contributions has been the discovery that the cellular skeleton contributes in important ways to neuronal function. He helped uncover the mechanism by which the folds develop in the cerebral cortex. More recently, he helped define a new class of disease, known as the ciliopathies, which affect many different organs in the body and are all due to the dysfunction of the cellular cilium. “The cilium is really the cell’s antenna,” says Gleeson. “It is one way the cell interprets the context of the signals with which it is constantly bombarded. Imagine if you suddenly smelled something burning but lacked the ability to detect the context. You wouldn’t know if someone had just put out a match or if the house were burning down. The cilium helps the cell understand the context of such signals, so that it can respond appropriately."
Some of the patients Gleeson has been studying, whose brain diseases are characterized by absence of part of the cerebellum, also have renal failure and blindness. The connection between renal disease and blindness had long been hypothesized to be due to disrupted cilia function, but the proof of this came from the identification of genes mutated in these conditions. Now, with more than a dozen genes that cause the brain disease known as Joubert syndrome and related disorders, Gleeson's lab is hot on the trail of fundamental mechanisms that might explain how cilia signal and how this signaling is critical for neuronal development.
Gleeson has set his sights on identifying most or all of the causes of developmental brain disorders. “Our goal is to understand all of the genetic contributions to brain assembly and function,” he says. “It is a field of limitless surprises and an opportunity to improve children’s health. I can’t imagine doing anything else.”
In July 2014 Gleeson moved from the University of California, San Diego to the Rockefeller University.