An associate professor at the University of North Texas is developing a new way to study genetic factors and environmental exposures that may affect early brain development in relation to autism.

“Once we develop these underlying technologies, then this approach could be applied to many other areas of biomedical research,” said Moo-Yeal Lee in the Department of Biomedical Engineering in the College of Engineering.

Lee is part of a three-person, multi-institutional team that also includes Xuexia Wang, professor of biostatistics at Florida International University, and Rebecca Schmidt, professor of public health sciences from UC Davis Health. The five-year project is funded by the National Institutes of Health, with $1.1 million of the grant going to UNT.

“One theory is that autism is caused by a genetic irregularity, but when we analyze patient data, only 10-20% of patients have a clear genetic irregularity,” Lee said. “Some researchers believe that exposure to environmental pollutions may play a role, or that autism may result from a combination of genetic factors and environmental toxicants.”

Each member of the team has a role in the project. Schmidt, who leads the human cohort and environmental epidemiology studies, collects biological samples from infants/children diagnosed with autism and their parents while Lee creates tiny, lab-grown brain tissues called organoids for study.

Lee will study brain organoids created from cells representing people with and without autism, including samples from individuals with known genetic irregularites and those without.

Researchers cannot ethically expose people to potentially harmful environmental chemicals to study their effects on brain development. Instead, Lee can expose the lab-grown brain tissue to those chemicals.

“We cannot expose people to these toxicants, but we can expose these organoids to them,” Lee said. “Then we can analyze how much brain development is disrupted when the cells are exposed to these chemicals.”

An important focus of the research is RNA, molecules that carry genetic instructions used to make proteins. Proteins carry out many of the functions within a cell. Lee is specifically studying an RNA modification called m6A, which plays an important role in brain development. He will collect data on how m6A is affected by exposure to different environmental toxicants.

“Once we have the patient cohort data and the organoid data, Wang will use machine learning to compare the two data sets and look for common factors,” Lee said. “This could help us a better understand the biological mechanisms associated with autism.”

Working with organoids also presents challenges. Because organoids do not have blood vessels to deliver oxygen to their cells, they must remain small enough to keep their central cells alive. They also require a steady supply of nutrients and oxygen. The organoids take at least two months to grow and can become too large to sustain if their growth is not carefully regulated.

“To uniformly generate these organoids, we use a special device that we invented in the lab called a pillar-perfusion plate,” Lee said. “It lets us control their growth to about one cubic millimeter while also allowing us to deliver oxygen and nutrients directly so we can maintain healthy, viable cells.”

Lee has one doctoral student working with him on the project as part of her thesis. She generates the organoids, exposes them to environmental toxicants and extracts the RNA to study their effects.

“With this project, we are developing a platform that can give researchers new tools to study how biological changes occur,” Lee said. “Ultimately, these tools could help researchers better understand the factors involved with autism.”