Uncovering environmental contributors to autism may also suggest ways to help autistic people live healthier lives.
In 1977, a small study of twins changed the course of autism research.
The study looked at 21 sets of twins in which at least one twin had autism. In all 10 pairs of fraternal twins, only one twin had autism. But in four of the 11 pairs of identical twins, both twins did. It was the first of many twin and family studies over the next two decades, all of which would confirm the strong role of genetics in autism. What remained unclear, however, was exactly what was inherited and how—questions the next generation of researchers were determined to answer.
As DNA sequencing technologies improved, geneticists began combing through the genomes of autistic individuals in search of specific genetic variants that were more common in people with the condition. While researchers found many commonly occurring genetic variants associated with the likelihood of an autism diagnosis and a handful of rare variants that caused autism, they could not explain all of autism risk with genetics.
DNA alone can’t explain why 1 in 36 American children have autism spectrum disorder, or why that number has skyrocketed in recent decades. Our genes cannot change so drastically in such a short period, says Heather Volk, PhD, MPH, an associate professor in Mental Health. Of course, doctors are now better at spotting autism. But something else may be going on.
“It has been difficult to find the culprits on both sides, genetics and environment, which are contributing to autism,” says Thomas Hartung, MD, PhD, a professor in Environmental Health and Engineering. “The two have to come together in this critical window of vulnerability in the developmental process, and that’s very hard to find.”
An ambitious new research endeavor—GEARs (Combining Advances in Genomics and Environmental Science to Accelerate Actionable Research and Practice in ASD)—aims to change this. Led by Volk and Christine Ladd-Acosta, PhD, at the Wendy Klag Center for Autism and Developmental Disabilities, the study will investigate how external factors such as pollution, maternal diet and medications, and social determinants impact neurodevelopment and autism symptoms.
Volk and Ladd-Acosta also aim to use their findings to improve the lives of people with autism—a plea they’ve heard from countless families in research projects they’ve conducted over the years.
“People with autism don’t just want to understand causes, they also want to understand the environmental factors they can identify and modify to make sure they’re achieving their best outcomes,” says Ladd-Acosta.
To autism researcher and self-advocate Zack Williams, an MD/PhD student at Vanderbilt University and member of the Klag Center’s Community Advisory Board, this combination of a focus on environmental factors and a drive to improve the lives of those with autism is what makes GEARs so important.
“It’s good to have intellectual exercises about risk factors to predict autism, but if you can’t do anything about it, that’s a lot less helpful,” says Williams.
All human traits are the result of interactions between genes and environment. A child who carries genes predisposing them to grow tall may still be of short stature if they don’t receive adequate nutrition. Similarly, a person with the inherited metabolic disorder phenylketonuria will suffer brain damage only if genetic factors (a mutation in the gene responsible for the metabolism of the amino acid phenylalanine) and environmental ones (a diet containing phenylalanine) combine. Remove the phenylalanine, and children with phenylketonuria develop normally.
“Autism is more complex than a single-gene disorder like phenylketonuria, but the principle remains the same,” says Brian Lee, PhD ’09, MHS ’06, an epidemiologist at the Drexel Dornsife School of Public Health.
The challenge was to identify the environmental risks as well as the genetic variations that make a person susceptible to them.
“The tools to understand genetics have gotten faster and cheaper and more accessible,” says Alycia Halladay, PhD, chief science officer at the Autism Science Foundation. “Technologies to understand environment haven’t been able to catch up. You can’t just take a blood sample and decide what all your exposures are.”
One complication is that “the environment” captures a broad range of factors that can include everything from pathogen exposure in utero to trauma, air quality, poverty, and a parent’s age. What’s more, many of these exposures are transient. No one would be able to describe the totality of their environmental exposures, both because we cannot remember all of them and because so many of them exist outside of our conscious awareness. Someone might know if they grew up near a freeway (and thus were exposed to higher levels of air pollution), but would they be able to quantify all the pesticides sprayed on their lawn or how many colds their mother had while pregnant? A prospective study involving annual blood draws, urine tests, and neuropsychological testing might help answer these questions—but would be expensive and time-consuming.
This left Ladd-Acosta and Volk in a quandary about how to study risk factors for autism and co-occurring problems like depression, anxiety, and sleep and gastrointestinal issues that couldn’t be found in DNA alone. And if they couldn’t identify these risks, they would have a hard time designing interventions to help people mitigate their impact.
What they needed was some way to tease apart the knotted threads—a way to identify specific environmental exposures and understand the mechanisms of how they might alter neurodevelopment based on a person’s genetics. They applied for an Autism Center of Excellence grant from the NIH, and in September 2022, the Wendy Klag Center and its GEARs study received an $11.7 million grant—one of nine awards funding these centers around the country.
GEARs won’t rely on epidemiology alone. Any connections that Volk and Ladd-Acosta may find through their epidemiological investigations will only be hypotheses; they can’t show how these elements impacted the brain’s function, nor can they indicate what happens as exposures are altered. So the pair teamed up with Hartung and Lena Smirnova, PhD, an assistant professor in EHE, to grow brain organoids—three-dimensional clusters of neurons that self-organize into a proto-brain. For this study, these organoids will be derived from samples of skin cells taken from individuals diagnosed with autism. Using the brain organoids, Hartung and Smirnova can see the impacts of varying exposures, and the timing of them, on neurodevelopment in autism—allowing them to test Volk and Ladd-Acosta’s hypotheses in the lab.
As part of the study, the GEARs team will leverage a wealth of neuropsychological test and clinical data from autism patients, as well as blood and urine samples. The Klag Center’s global connections mean that they will be able to use anonymized data from more than 175,000 participants from 18 research centers around the world. The data includes surveys about environmental exposures, medical chart data, and biological specimens for ’omics analysis. It will allow scientists to leverage deep biological analysis to understand how environmental exposures impacts neurodevelopment and autism symptoms in a range of different genetic backgrounds.
“I really can't imagine this study happening anywhere else,” says Halladay, due to the Klag Center’s ability to leverage both basic and clinical autism research.
During the first year or two of the GEARs study, while Volk and Ladd-Acosta are busy with their epidemiologic studies, Hartung and Smirnova will work to optimize their ability to grow and test brain organoids to better understand what’s happening at the cellular level. Key to this work is the development of control organoids derived both from autistic children and from neurotypical children to create a point of comparison for their experiments. Once potential environmental exposures are identified, Hartung and Smirnova will test how the amount and timing of an exposure affects organoid development. The process is painstaking and will take years, but Hartung says that by the end of the five-year GEARs grant, he hopes to have at least a few answers.
Volk hopes these findings will suggest environmental factors that can be modified to help people with autism live their healthiest lives now. For example, environmental factors could play a role in gastrointestinal problems or seizures experienced by many autistic people.
“If we can help figure out what triggers are for seizures, and it’s something common in the environment, and we’ve taken genetic background for those seizures into account, that might make a big difference,” says Volk. “If we know who might be more genetically susceptible or less genetically susceptible or have a certain pathway that doesn’t work as well as someone else’s, we could think about how different exposures could impact those groups differently.”
For Williams, that’s why GEARs is important not just to the scientific community, but to the autism community. The study goes beyond just trying to understand the cause of autism and is working toward improving the lives of autistic people.
“Whether or not someone is autistic is clearly not the only outcome that matters,” Williams says. “Gene-environment research could really explore developmental trajectories and how well someone does across the lifespan. That’s what GEARs cares a lot about.”