How organoids can help drive autism research forward

Researcher Lena Smirnova looked under the microscope at a cluster of cells. Though all together about the size of the eye of a house fly, the cells make a sizable contribution to our understanding of how environmental factors may contribute to autism, a condition that is now estimated to affect one in 44 children in the United States. 

In recent years, a growing number of studies have suggested that children who are exposed to common pesticides, either while in the womb or in the first year of life, may be more likely to develop autism. While it's still premature to say that pesticide exposure causes autism, alarm bells are ringing in the ears of environmental health experts about the dangers that pesticides might pose to brain development.

For a study published last year in Environmental Health Perspectives, Smirnova—a research associate in the university's Department of Environmental Health and Engineering—and a team of researchers turned to human-derived brain organoids, which are miniature brain models grown using stem cells. After about four weeks of growing mini brains in the lab, researchers added chlorpyrifos, a pesticide banned by the Environmental Protection Agency in August 2021, to the culture medium. They tracked the effect of chlorpyrifos on their mini brains, which had one copy of the CHD8 gene removed. Having just one copy of the gene instead of two can disrupt fetal development and is a known autism risk factor. But the researchers found that the combination of both the chemical and the genetic risk factor resulted in significantly higher rates of autism biomarkers in their cellular models.

For the first time, they were able to show that at least one environmental hazard can hit children with genetic risk factors for autism harder than most. The estimated rate of autism has been on the rise for years. In 2000, the CDC reported only about one in 150 children had the condition. The threefold increase in just a couple of decades has led researchers like Smirnova to suspect a combination of environmental and genetic risk factors is at play. 

Why don't we know more about what causes autism? "It's hard to get access to living human brain samples … [so] autism is very difficult to study," Smirnova says. Animal models are not ideal because they don't present autistic behaviors in the same way that humans do. And scientists couldn't conduct the study on humans because it's unethical to undergo research that may actually cause a person to contract a disease or disorder. So, the brain organoids, which originate from stem cells, helped the researchers avoid these potential pitfalls. "Only the stem cell technology has allowed us to really reproduce a developing brain," says Thomas Hartung, a professor in the Department of Environmental Health and Engineering who worked with Smirnova on the research. Johns Hopkins researchers, who were among the first to work with organoids, have also used them to study things like COVID-19 and antidepressant side effects. 

Smirnova and Hartung next plan to study arsenic and lead, and whether these chemicals might be associated with autism. They also plan to work with epidemiologists from the Bloomberg School's Wendy Klag Center for Autism and Developmental Disabilities to study the interaction between genes and environmental factors. Much about autism remains a mystery—is it several chemicals interacting with this one gene? Or is it one chemical interacting with several genes? It all needs to be explored. "This is the starting point now for intensifying the search for such combinations," Hartung says.