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Fall 2020

Living Science

Donna Werling stands outside the UW Genetics-Biotechnology Center. Photo by Michael P. King

 

When Donna Werling was growing up, she often babysat her younger cousin. He was diagnosed with an autism spectrum disorder when Werling was in high school, and, in addition to looking after him, she became part of his therapy team. She learned about several different types of behavioral therapy so she could strengthen his support system.

This was in the early 2000s, and the behavioral treatments Werling’s cousin was receiving were the standard for children with autism at the time. But after a string of weekly therapy sessions, she began to see they weren’t really working. She realized that if this was the best doctors could do for her cousin, then they truly didn’t know enough about the nature of autism.

Those insights marked a key turning point for Werling. She wanted to delve deeper, to understand what autism does at a biological level and how the brain of an autistic person develops. That desire stayed with her throughout her college career and into a neuroscience Ph.D. program at the University of California, Los Angeles. In October 2019, Werling became an assistant professor with the Department of Genetics, where she studies sex differential biology in brain development and how genes affect autism risk.

How did you make the turn from neuroscience to genetics?

During grad school I wound up — somewhat by accident — doing genetic research of autism. I had a project that didn’t work out, and, as a result, I had to change direction. My lab had access to a lot of genetic and genome-scale data that was relevant to autism. So I got to start looking at that data, learning the techniques from scratch.

I continued that work in my postdoctoral research, looking for genetic variants that are associated with risk for autism. I was trying to understand how genetic variants in the DNA sequence are related to gene expression changes and how those changes can inform us about what cell types or what processes in neurodevelopment are altered when you have an autism-associated mutation.

What is known about the genetic component of autism?

The autism research field has known for a long time — since the late ’70s — that genetics are involved in autism. When you look at cohorts of twins, you see that identical or monozygotic twins are much more likely to both have or not have autism. If you look at non-twin siblings, the rate of recurrence is between 10% and 20%. So the more of your genome you share with someone who has autism, the more likely you are to also have autism yourself.

Over the past decade, the field has made remarkable headway in identifying specific genes associated with risk. Scientists have been looking for de novo, or brand-new, mutations. These are not inherited from your mom or dad: They are just DNA replication mistakes that happen when any cell divides. We can find genes that have one of these de novo mutations in affected cases. But we almost never see the mutations in unaffected siblings or in people without autism. So that tells us that this gene is really important for development, and it is specifically associated with risk for autism.

If that gene is mutated, your chances of having autism may be fivefold, tenfold, fifteenfold above the normal expectation. We now have a list of 102 genes that are associated with autism risk.

How are sex differences between males and females related to autism?

Autism is among the most sex differentially skewed in terms of its prevalence. It’s four times more common in males than in females. Other conditions show a sex bias as well. Tourette syndrome is very male-biased. ADHD is male-biased. Major depression and generalized anxiety, those are female-skewed. And so, within the realm of neuropsychiatric disorders, there’s some component — I would hypothesize — of sex differential biology contributing to differences in risk.

The goal of my work is, if we can understand what the biological mechanisms are that are leading to these differences in prevalence, we might tap into a very potent pathway for developing treatments. Treatments could mimic or ramp up the biological processes associated with protection in the least affected sex or knock down the pathway that’s associated with risk in the more affected sex.

How does understanding genetic risk of autism lead to better treatments?

Many of the drugs used in the field of psychiatry were discovered by accident or a long time ago, and we’re lucky that they work in the way that they do. Autism has no therapeutics available to target autism-specific symptoms. We can give an antipsychotic to a patient with schizophrenia, and it will probably have effects on their psychosis symptoms. But we don’t have treatments to target the main defining symptoms of autism, specifically.

Right now, autism is defined by symptoms in two key domains. One is social communication that encompasses things like verbal language, perceiving facial expressions, and making friendships. The second symptom domain is restricted interests and repetitive behaviors, which can include things such as an intense interest in one topic or a motor movement such as rocking. Every individual has a different constellation of symptoms. We want to focus on these symptoms, and we would like to have some therapeutics to augment the efficacy of behavioral therapy too.

If we have a set of genes that we know are associated with risk for autism, we can use those genes as a place to start in terms of understanding biology. So, we can ask, do these  genes carry out similar functions, or do they carry out their major roles within the same cell type or at the same time in development? The hope is that we don’t have to design a drug for each of the 102 different conditions. Ideally, we can group these genes into sets that have similar functions, and then we can design drugs that change those specific pathways or functions. So maybe we don’t need 102 drugs, but five drugs or something to that effect. The major goal of these therapeutics would be to alleviate symptoms for patients seeking treatment and improve quality of life for people with autism and their families.

What made you want to study this field here at CALS and UW–Madison?

My Ph.D. is in neuroscience, and then I worked in a psychiatry department, so this is the first time that I’m sitting within a true genetics department and one that is not exclusively focused on human biology but also studies plants, microbes, yeast, and more. So even though that is the focus of my research and will continue to be, it’s exciting to be around labs and other faculty who are using different systems to ask very important questions that I haven’t had the chance to think about in a while.

The other thing that makes coming to the University of Wisconsin so exciting for me, working in this autism research space, is that just down the road is the Waisman Center. Waisman has been so well established in clinically facing research and research of specific neurodevelopmental syndromes related to autism, and autism itself, for a long, long time.

I’m excited to be here to bring this human genetics piece to that puzzle and to be complemented by people who are seeing patients day-to-day in the clinic or working on a mouse or cell system to understand biology. Now we can collectively span the range of research from seeing a human patient down to their DNA.

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