Brian O’Roak loves Gaelic football, a fast-paced game with 15 players; a round ball that can be carried, kicked or passed; and a bunch of complex rules. Which makes perfect sense when you discover that O’Roak has managed some of the most complicated studies of autism genetics to date, involving the sequencing and analysis of DNA samples from thousands of individuals. “I was looking for something that was really hard, but potentially with a path forward,” he says, recalling the moment in grad school when he decided to focus on autism research.
At Oregon Health and Science University (OHSU) in Portland, the 37-year-old assistant professor of molecular and medical genetics is still wrestling with big, complex challenges. Known for his pioneering work on the genetic risk factors for autism, a neurodevelopmental disorder that affects about 1 in 68 children, O’Roak is now investigating what those genes are doing as the brain develops. The ultimate goal? To devise gene therapies that could fix the mutations leading to autism and restore healthy brain development.
O’Roak’s work — for which he received the BRAINS (Biobehavioral Research Awards for Innovative New Scientists) young investigator award from the National Institute of Mental Health last fall — involves taking stem cells from human patients with autism and using new technology to coax them into becoming tiny brains-in-a-dish called organoids. O’Roak uses a 3D printer to create a scaffold on which the stem cells develop into brain-like structures in a petri dish. Watching these cells develop can provide clues to how a patient’s mutations affect the earliest stages of brain development.
“We can actually develop models in the lab that have the exact same genetic variants that are identified in individuals with autism,” O’Roak says, “and we can start to understand how those mutations affect the development of the human brain.”
For a kid who grew up in a small town in California’s Central Valley, aka America’s fruit basket, cutting-edge research wasn’t an obvious path. Raised by a single mom since second grade, O’Roak wasn’t exposed to advanced science until high school, when he became interested in biology and a teacher recommended a summer program sponsored by NASA at Southern University in Baton Rouge, Louisiana, where he worked with cells from genetically engineered obese mice.
Still unsure of what he wanted to study, O’Roak was invited to join the inaugural honors program class at Cal State Fresno, which came with a full scholarship. There, he found his way into a plant genetics and molecular biology lab (and started dating a fellow honors student who would become his wife).
From college he moved on to graduate school in genetics at Yale, completing a rotation with Matthew State, who was studying genetic mechanisms involved in psychiatric and neurodevelopmental disorders, including autism. “He [State] gave a really compelling case about how, even though neuropsychiatric or neurodevelopmental disorders were really complex, we could develop a strategy to identify risk genes that might actually let us start to unravel some of the complexities of these disorders,” O’Roak says.
Not surprisingly, he jumped into one of State’s most demanding projects. O’Roak identified individuals with autism but without any family history of the disorder, and he searched for novel mutations that had caused it to develop. Back in 2004, it wasn’t possible to sequence genes quickly and cheaply, so he looked for individuals with chromosomal abnormalities that were visible using a microscope.
Chris Mason, a postdoc in State’s lab who’s now a researcher at Weill Cornell Medicine, says of O’Roak was not only a good colleague for brainstorming about “pedigree analysis and complex genetic variation, but also complex hop variation in beer.” With his huge sideburns, rakish eyebrows and easy smile, O’Roak looks every bit the beer-brewing, football-playing weekend warrior, but during the week, says Mason, he’s a pioneering geneticist.
After finishing his Ph.D., O’Roak became a postdoctoral fellow at the University of Washington. As gene sequencing technology evolved, he used the faster method to sequence the exome — the part of the genome that codes for proteins — to identify new mutations (genetic aberrations not inherited from either parent) in children with autism. Raphael Bernier, a professor at UW, took note of O’Roak’s next-level analytic skills and was impressed that he could “work with such a massive data set,” synthesizing reams of minute details — “at such a quick pace.”
O’Roak is now marshaling those skills to help steer the largest genetic study of autism ever. OHSU is one of 25 clinical sites across the U.S. participating in SPARK, an initiative recruiting 50,000 families with autism to share genetic, behavioral and medical information with the goal of accelerating autism research. By dramatically increasing the sample size, “we think we can identify a lot of additional risk genes,” O’Roak says, while also identifying more common genetic variants that have weaker effects on autism risk.
But identifying the autism risk genes is just the beginning. “We’ve kind of just got the who in our story,” says O’Roak. “We still need to figure out the what,the where, the when and the why/how to make things better.”
Ultimately, O’Roak wants to figure out how the autism risk genes affect how the brain develops. Which brings us back to the brain organoids he’s been coaxing from stem cells of autistic patients. From these organoids, O’Roak can measure the gene activity in single cells to determine how a patient’s mutation changes the gene networks over time. He also plans to use the gene editing technology CRISPR to correct the mutation in the patient’s stem cells to see if that fixes the organoid’s growth — and points toward targeted treatments for autism.
Between his faculty responsibilities at OHSU, running a lab and parenting two young children, O’Roak is sprinting like the footballer he is. And still he finds time to make beer. In fact, Homebrew Con, a home brewers conference, came to Portland in June, and O’Roak competed in the national championship with his special home brew — the result, naturally, of a intensely complex process.
5 Questions for Brian O’Roak
What’s your favorite book? Adventures of Huckleberry Finn
What do you worry about? Too many things, but mostly about my kids and finding funds to support our lab.
What’s the one thing you can’t live without? Yeast. They make beer and bread.
Who’s your hero? Master Yoda
What’s one item on your bucket list? San Francisco Giants Fantasy Camp