Scientists map key protein interactions linked with profound autism
Scientists have now gotten closer to understanding how gene mutations may lead some people to develop profound autism.
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mutations → map → autism
The clues, they say, lie in the murky space between genes and disease — where key proteins come together and interact.
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proteins → say → genes
A team of researchers from UC San Francisco mapped more than a thousand interactions between many proteins that come from certain autism risk genes.
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that → map → genes
This molecular atlas, published in the journal Science, could point researchers toward new and promising treatments.
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atlas → publish → 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.
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who → say → study
"A lot of people interested in understanding autism and drug development are going to be using this.
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lot → understand → this
For families affected by profound autism, it offers hope for eventual drug therapies.
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it → affect → 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.
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who → wait → impairment
"There's still a lot of work ahead, [but] this paper makes the path from genetic discovery to treatment much clearer."
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path → be → treatment
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.
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that → build → autism
People with profound autism often live with severe intellectual disability and require around-the-clock care.
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People → live → care
They're nonverbal or minimally verbal, and often have serious medical conditions like epilepsy.
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They → have → 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.
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factors → pin → 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.
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researchers → have → 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.
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Krogan → discover → 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.
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scientists → hit → drugs
"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.
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proteins → be → work
State has been a pioneer in identifying high-risk genes, and the mutations in those genes, that are associated with profound autism.
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that → identify → autism
Krogan has been at the forefront of using new technology to look into protein interactions.
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Krogan → use → interactions
More than a decade ago, the two researchers were introduced by their mutual boss, the chancellor at UCSF, who encouraged them to collaborate.
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who → introduce → them
"[State] had the genes and the mutations.
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State → have → genes
I had the technologies to look at the corresponding proteins," Krogan says.
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Krogan → have → proteins
They focused on filling a knowledge gap.
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They → focus → gap
"What we've been missing is the mechanistic understanding of how these mutations [on the genes] are seemingly resulting in autism," Krogan says.
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Krogan → miss → autism
"In order to understand that, you need to go to the proteins."
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you → understand → proteins
Proteins are the complex molecules that come together to build the body, based on instructions encoded in the genes.
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that → come → genes
"What makes an eye cell an eye cell, and a muscle a muscle, are the proteins and how they work together," State says.
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State → make → ?
In this case, the researchers wanted to find the molecular machinery of profound autism — to understand which proteins came from those high-risk autism genes, and how those proteins worked together.
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proteins → want → genes
The research was slow at first, but more recent advances in technology — including artificial intelligence — have sped things up.
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advances → include → things
To start, the researchers went on a "fishing expedition" for protein interactions.
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researchers → start → interactions
They chose 100 proteins from these high-risk autism genes, injected them into lab-grown cells, and then pulled them out, along with the additional proteins that attached to them.
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that → choose → them
Then, they used an AI system called AlphaFold, developed by Google DeepMind, to help determine which proteins in the clumps were directly touching.
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proteins → use → clumps
"Where AI is playing an important role is being predictive about who's talking to who," says Krogan.
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Krogan → play → who
"Sometimes they take years to figure out.
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they → take → years
Now, we can get these insights in an hour."
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we → get → hour
While imperfect, the system has worked well enough to save significant time and money, Krogan says.
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Krogan → work → time
Then, they wanted to see what happened to the proteins when the genes got tweaked.
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genes → want → proteins
They introduced mutations that appear in patients with profound autism, and assessed what changed.
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what → introduce → autism
"We broke the proteins in the way that they're broken in autism," says State.
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State → break → autism
"That allows us ultimately to answer the question of, when they're going wrong in autism, how are they going wrong?"
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they → allow → autism
…and 17 more, not listed.
The Aporia
