New faculty member uses genetic sequencing to investigate childhood brain disease

Joseph Gleeson, a neurogeneticist who hunts down genes responsible for devastating neurodevelopmental disorders, has joined The Rockefeller University and has established the Laboratory of Pediatric Brain Diseases. Gleeson, formerly a professor at the University of California, San Diego, is one of two mid-career scientists joining the university this summer.

Gleeson uses genetic sequencing to identify the causes of pediatric brain disease across its spectrum, including epilepsy, autism, intellectual disability and structural disorders.

“Joe is re-writing classical notions of brain diseases, revealing their true complexity, and in so doing he is making it possible to better diagnose and develop treatments for them,” says Marc Tessier-Lavigne, the university’s president. “His research is leading to a better understanding of how the human brain develops at the genetic level. We welcome him to Rockefeller and look forward to helping him build on his remarkable accomplishments.”

Because disorders caused by single-gene mutations are extremely scarce within the general population, Gleeson collaborates with physician-scientists in the Middle East, North Africa and Central Asia, where consanguineous marriage between relatives as close as first cousins is common, to recruit affected families. The practice of consanguineous marriage increases the frequency of genetic disorders, since related parents are more likely to share deleterious versions of the same gene. What’s more, researchers can easily track the disorder and the mutations within these highly susceptible families.

Gleeson travels extensively to evaluate patients, just returning from visits to Libya, Egypt, Saudi Arabia, Pakistan and Oman. These outreach efforts can be intense, with his team spending one to two days in each of a dozen or more cities, seeing up to a hundred patients in a day. “Dodging political conflict, communicable disease and war is a risk of the work. These patients and their families are desperate for some hope and some improvement in their lives,” Gleeson says.

Gleeson, who trained as a pediatric neurologist, wanted to do more for his patients with brain disorders, and his research is focused on delineating these conditions, and developing new treatments. Sequencing technology, with its ability to interpret the entire protein-coding region of a genome at once, as well as mouse, cell and other models of potential culprit mutations, are crucial tools for defining new causes of disease. And with them, he and colleagues have identified mutations that would otherwise be nearly impossible to pinpoint.

For example, within samples from families with children suffering from autism and seizures, Gleeson and colleagues identified a cause: a mutation in a gene, BCKDK, involved in essential amino acid metabolism. This discovery brought with it a promising treatment: replacing the depleted amino acids with a nutritional supplement.

“This newly defined disorder is part of a class of diseases we have discovered that have the potential for treatment, at least to some degree, by administering to patients something to replace a natural substance typically made by the body,” Gleeson says. “These discoveries suggest as-yet-undiscovered treatments exist for other disorders.”

When searching for the gene responsible for a disease, Gleeson uses genetic sequencing, an approach he adopted as a postdoc at Harvard Medical School hunting down the gene behind an abnormal brain development disorder called double cortex syndrome. At the time, in the late 1990s, the technology was just becoming available.

“It took us four years to find that gene. Now, we can find a gene in a day, and most days we find more than one!” Gleeson says. “With my arrival in New York City, collaboration with the New York Genome Center will give us access to even greater sequencing and analytical power.”

He hopes to see that power trained not only on the exome, which comprises protein-coding regions of the genome, but on a neglected part of it: DNA not directly responsible for producing protein. Currently, sequencing efforts generally focus only on the exome.

“There is a big move afloat to transition to whole genome sequencing where we sequence all three billion bases. The problem is that no one knows how to make sense of the ‘junk’ sequences. But I think our special families may afford us more power to investigate this part of the genome with colleagues at the Genome Center, Rockefeller and elsewhere,” Gleeson says.

Another shift in the future of sequencing will be toward the clinic, says Gleeson, who hopes to establish collaborations with neurodevelopmental specialists at city hospitals in order to obtain sequencing data. The audacious goal is to perform sequencing on every child admitted to the hospital with a brain disease. “This will accomplish two things: One, it will help us better diagnose patients, and two, it will help us rewrite medical textbook descriptions to be more driven by underlying causes than by signs and symptoms,” he says.