Dr. Donna Werling – Unraveling the Brain: Groundbreaking Research on Sex Differences and Autism

Donna Werling’s career path was illuminated by her personal experiences from a very young age. Her early role as a caregiver for her cousin with autism sparked an interest in understanding the human brain and its complexities, kickstarting her career in the field of neuroscience. Now an assistant professor of genetics at UW-Madison, Werling leads research focused on understanding sex differences in brain development, using cutting-edge genetic and experimental approaches to explore why neuropsychiatric conditions like autism affect males and females differently. 

Werling grew up in the Chicago suburbs, close to her extended family. Having a cousin who is on the autism spectrum and who also had epilepsy, Werling took on a caregiving role from a young age, even becoming trained to administer his therapy, which gave her close insight into the struggles he and his family faced while trying to improve his quality of life.

This exposure sparked Werling’s interest in neurological and developmental disabilities. “I got to see him grow up and see his trajectory and where he struggled with various topics. It was very intriguing to think about how his brain worked differently from other people’s brains,” Werling remembers. This interest ultimately led her to pursue a PhD in neuroscience at UCLA.

Werling completed her PhD at the Geschwind lab, which used functional genomics and bioinformatic approaches to understand the relationship between sex and genetic risk in ASD.. Following her PhD, she headed up the coast to UCSF, where she joined the State and Sanders labs for her post-doc. There, she continued studying developmental disorders with different genetic tools, specifically finding genes and variants that are associated with risk and then watching how those variants impacted brain development.

Following her post-doc, Werling found the perfect spot for her research here at UW-Madison’s Laboratory of Genetics, which she describes as a natural fit, “It’s great to be in a genetics department home but also be at such a big university where there are other subcommunities of people especially relevant for our lab, like the Waisman Center, which is a clinic and research center focused on understanding brain disorders with the focus on neurodevelopment.” In addition to being an Assistant Professor of Genetics, Werling is also a Waisman Center-affiliated investigator.

Research done in the Werling lab revolves around trying to understand how brain development differs in males and females and, within that understanding, identifying the mechanisms by which males and females have different susceptibilities for different neuropsychiatric diagnoses. The research has a particular focus on ASD due to its significant sex skew, with males being diagnosed four times more often than females. The goal is to identify sex differences between males and females and explore how these differences may manifest as risk factors for neuropsychiatric disorders.

The lab explores various dimensions of these manifestations including gene expression, cell types, hormonal influences, and brain regions affected by these disorders. Research methods include using genetic models of autism to identify mutations, then studying mouse models with those same mutations and watching how this affects their brain development. Also looking at how manipulating certain environmental exposures for the mice can cause changes in their brain development.

The Werling lab is unique in its use of computational and experimental aspects in its research projects. Using statistical analysis to look at genomic data sets, the lab can identify individual genes in the genome that are statistically associated with a risk for autism, thus allowing a genetic diagnosis to be made, which can benefit the individual and family of someone with a diagnosis. Following these genetic directions discovered in the analysis, the lab uses its experimental techniques, such as human and rodent models, to translate these findings into an understanding of the underlying mechanisms that drive sex differences in brain development. Werling emphasizes the importance of translating statistical findings into a mechanistic understanding stating, “Having both of those tactics under one roof is really powerful and we’re trying to make it work.”

Looking ahead to the future, a new research project is blooming in the Werling lab, where they are looking at parts of the brain that haven’t typically been studied regarding autism. Traditionally, the cortex of the brain is analyzed when looking at autism due to its cognitive, thinking, and executive functions, but this region hasn’t presented as many sex differences as expected. So, the lab is beginning to search for these differences in subcortical regions of the brain that typically have been overlooked regarding neuropsychiatric conditions since they fulfill more basic functions like feeding behavior, metabolism, and reproductive behavior. Werling believes that this new perspective on the brain, has the potential to uncover the reasoning behind the sex-differential phenomena that is observed in many neuropsychiatric disorders.

Werling’s journey from a family caregiver to a pioneering researcher in human genetics showcases how her personal experiences shaped her scientific career. Her lab at UW-Madison pushes the boundaries of our understanding of autism and other developmental disorders, not to find a “cure”, but rather to fill existing knowledge gaps and provide a more versatile toolbox to improve the quality of life for those who are seeking support with these diagnoses.