Scientists are getting a step closer to understanding exactly how autism develops in the brain – and what might work to treat it.
Using artificial intelligence and data on tiny brains grown in the lab, researchers have mapped out how 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. 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.
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.
This 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. 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? Understanding that will point you down therapeutic roads that you just could not have ever imagined if you were simply looking at the genes and the mutation.”
Building an autism map
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. 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.
The map is the largest that has ever been done on autism and 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.
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.
While the new study offers a map of molecular pathways through which autism may develop, it may not be definitive for every person with autism or every type of the disorder – as the study remains most directly relevant to people with profound autism, who account for about 30% of people with autism spectrum disorder, the ones that need 24-hour care,” Krogan said.
Findings on protein-protein interactions still could help inform other neuropsychiatric conditions too, including schizophrenia, obsessive-compulsive disorder and tic disorders, as well as other diseases including cancer.
Today’s study shows where different autism genes converge on shared biological pathways, and those shared pathways could ultimately give therapeutic targets relevant to much larger groups of autistic people, including people without an identified genetic cause. That is nothing short of a huge watershed moment for autism science.
For families of people with profound autism like mine, this is the kind of scientific advance we have been waiting for and praying for. Many people with profound autism have rare genetic variants and the promise of precision medicine has always been that understanding those variants would eventually allow us to move beyond treating symptoms and behaviors, and begin addressing the underlying biology. There is still a lot of work ahead and these discoveries today need to be translated into drug candidates and then tested for safety and effectiveness, but the path from genetic discovery to treatment has just become much clearer. Translating these kinds of discoveries into therapies is a long process. This study provides valuable insights into potential targets, but much more research is needed before these findings can lead to clinical applications.”