This image shows a section of an organoid. Organoids are lab-grown tissues that model the human brain. A new study used brain organoids to probe key protein interactions that may be linked to profound autism.
Courtesy of the UCSF Quantitative Biosciences Institute
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Scientists have now gotten closer to understanding how gene mutations may lead some people to develop profound autism.
The clues, they say, lie in the murky space between genes and disease — where key proteins come together and interact.
A team of researchers from UC San Francisco mapped more than a thousand interactions between many proteins that come from certain autism risk genes. This molecular atlas, published in the journal Science, could point researchers toward new and promising treatments.
"It's an unprecedented resource for the field," says Dr. Daniel Geschwind, a professor of human genetics, neurology, and psychiatry at UCLA who was not involved with the study. "A lot of people interested in understanding autism and drug development are going to be using this."
For families affected by profound autism, it offers hope for eventual drug therapies. "This is the kind of scientific advance we have been waiting for and praying for," says Alison Singer, president of the nonprofit Autism Science Foundation, who has a daughter with severe cognitive impairment. "There's still a lot of work ahead, [but] this paper makes the path from genetic discovery to treatment much clearer."
The work builds on progress made in recent years to identify single genes that harbor mutations found in a subset of individuals with profound autism.
People with profound autism often live with severe intellectual disability and require around-the-clock care. They're nonverbal or minimally verbal, and often have serious medical conditions like epilepsy.
Pinning down the biology behind profound autism has always been a complicated endeavor — while both genes and environmental factors play a role, those factors can vary widely from person to person.
In the past decade or so, some genetics researchers have had remarkable success in identifying high-impact genetic differences in a subset of people with profound autism.
"They've discovered several hundred genes and corresponding mutations that are prevalent in [these] individuals," says Nevan Krogan, director of the Quantitative Biosciences Institute at UC San Francisco.
"But they kind of hit a wall," he added — because scientists haven't been able to turn those gene discoveries into many promising drugs and treatments.
"There was this huge missing piece," says Dr. Matthew State, a clinical psychiatrist and geneticist at UCSF: The genes serve as blueprints for making proteins that drive brain development, but researchers lacked visibility into how those proteins do the work.
State has been a pioneer in identifying high-risk genes, and the mutations in those genes, that are associated with profound autism. Krogan has been at the forefront of using new technology to look into protein interactions.
More than a decade ago, the two researchers were introduced by their mutual boss, the chancellor at UCSF, who encouraged them to collaborate. "[State] had the genes and the mutations. I had the technologies to look at the corresponding proteins," Krogan says.
