Largest ever ‘map’ of autism may hold clues for new targeted therapies - CNN

Using artificial intelligence and data on tiny brains grown in the lab, researchers have mapped out the ways in which certain genetic mutations that are associated with autism can rewire the brain and lead to the condition. The molecular map, published Thursday in the journal Science, could help inform more targeted therapies for autism.

“You need this insight to ultimately develop drugs, and we’ve generated a map now that is providing essentially the molecular underpinnings of autism and pointing us in a multitude of different directions for ultimate drug discovery,” said study author Dr. Nevan Krogan, professor at the University of California, San Francisco and senior investigator at the nonprofit Gladstone Institutes

“The hope would be at some point you’d be looking back and saying, ‘Ah, this map led to X, Y, and Z, and therefore we have now the first-ever treatment to autism.’ That’s the vision, and I believe that’s going to come to fruition at some point in the future,” Krogan said.

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For decades, developing effective treatments for autism has been a scientific puzzle.

Since there are more than 250 genes associated with autism spectrum disorder, finding a treatment that targets the genetic roots of the disorder is equivalent to seeking a single key for hundreds of different locks.

But now, the new study reveals how many of these diverse genetic mutations physically connect and rewire protein interactions in the developing brain, driving the emergence of autism. Proteins are molecules that physically build and help maintain the brain. So instead of needing hundreds of different drugs to target the genes themselves, scientists now have a blueprint to target the protein interactions instead.

“When you have the genes and the mutations, that’s just a list. That’s a parts list,” said Krogan, who also serves as director of the Quantitative Biosciences Institute at UCSF.

“What you need to do is have a wiring diagram of that parts list, and that’s where you need to go to the proteins and understand how the proteins talk to one another, and understand when you put a mutation in a protein, what does it do to the protein-protein interactions?” he said. “So, understanding that will point you down therapeutic roads that you just could not have ever imagined if you were simply just looking at the genes and the mutation.”

Krogan said that his colleagues and he already have three programs currently underway to develop potential new therapies, using insights from the new study.

To build the autism map, researchers from the University of California, San Francisco systematically mapped out how genetic mutations tied to autism may influence interactions between proteins in the brain. They found more than 1,800 protein-protein interactions tied to autism, among which 87% of those interactions had never been seen before.

The researchers created the map in the presence of the genetic mutations to understand how the proteins were “rewired” and then used an artificial intelligence system called AlphaFold to prioritize key mutations that were then studied in lab-grown brain organoids.

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“AI is allowing us to study proteins that we could never have even dreamed of even a couple of years ago, and it’s providing an unprecedented light being shone on autism, the underlying biology behind autism,” Krogan said.

The map is “the largest that has ever been done on autism,” he said. “It’s the largest map of its kind for any neuropsychiatric disorder, but it’s also the largest mutant map that’s ever been generated for any disease area.”

The new study “is really exciting in that it represents the most systematic protein-level view of autism risk we’ve had to date,” Fikri Birey, assistant professor in the Department of Human Genetics at Emory University School of Medicine, who was not involved in the study, wrote in an email.

“In the future, it may be possible to identify drugs that stabilize disrupted protein complexes or block pathological interactions, rather than trying to correct every individual autism-causing mutation,” Birey wrote, adding that the new study findings could help inform the disease-modeling research conducted in his own lab.

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