Where Nature Meets Nurture

Q & A with Dr. Lisa Stubbs: Where Nature Meets Nurture

“Do you believe in nature or nurture?” 

Instead of thinking of it as a binary, what if we examined the intersection where nature and nature collide?

PNRI’s Lisa Stubbs, PhD, studies the genetics of brain development. And how a person’s genetics might make a person more susceptible or resilient to stress-related diseases like type 2 diabetes or gestational diabetes—and neurological disorders like ADHD and autism. And to take it one step further: how stress influences genetics to impact health and behavior–exactly where nature and nurture collide. 

“Many people experience some level of depression, anxiety or hyperactivity,” Dr. Stubbs says. “But in one person, anxiety might be significant enough that they need to see a doctor, and someone else with anxiety may feel mostly okay but have a really hard time at parties. My lab is working to figure out the interplay between someone’s genes and their experiences to explain their reaction to stress.” 

We asked Dr. Stubbs about her exciting work unraveling the connections between stress and genetics. Here’s what she had to say. 

Q: What is the focus of your lab? 

In my career, I’ve worked in various areas related to developmental genetics, but my passion has always been neuroscience. My lab studies the master regulatory genes that have a big impact on brain development and how those genes, combined with environmental experiences, might make a person susceptible to or more resilient to developing certain disorders like autism or ADHD.

Some variants in master regulatory genes can cause very rare, serious diseases where children die in utero or at a very young age. But there are also variations in these genes that don’t cause serious health problems. We want to learn more about how those changes impact a person’s brain development, behavior, and overall health. Not just neurological health, but also how these genes interact with stress to cause a person to develop diseases like type 2 and gestational diabetes.

Through this work, I’ve recently become fascinated with the interplay of stress and genetics to influence brain development—more specifically: how stress and genetics affect pregnancy complications. The first area we are examining is how certain genes may protect highly stressed pregnant women or make them more susceptible to gestational diabetes.

As we know, maternal and newborn health in the United States is on a steep decline, especially in under-resourced communities, leaving vulnerable women and babies at risk. While we need to do better across all segments of society, communities of color suffer extreme disparities in adverse pregnancy events: preterm birth, gestational diabetes, preeclampsia, and life-threatening hemorrhage. Stress, especially chronic stress, is deeply implicated in these inequities. 

I came to PNRI because of my former collaborator and friend Dr. David J. Galas, and together, we launched our pilot: the Decoding Stress Project. This project brought together my expertise in genetics and brain development with David’s novel machine learning technologies. Unfortunately, David passed away before we received the first results of our pilot project. Now together with his widow, Diane Isonaka, and our dear friend Donna Russell of Precia Group, we are exploring the possibility of expanding upon this initial study to find protective genes that shield mothers from debilitating health effects from stress.

Our goal is to develop new diagnostics, treatments, and prevention to improve health and reduce these health disparities and their social and economic impacts. The pilot project examined a diverse sample of Black women from an under-resourced community in Baton Rouge, Louisiana. Our initial results identified a novel genetic factor that may shield some Black women from gestational diabetes (GDM); this novel gene is the first to be identified as relevant to GDM in the Black community. Its discovery highlights the potential for more inclusive personalized risk assessment and prevention.

Now my lab is exploring the possibility of an expanded scope. Our hope is that The Galas Project expands to 1,000 mothers and babies and focuses on understanding the interplay between stress and genetics to affect pregnancy outcomes, particularly among women who are underrepresented in research. From gestational diabetes to preterm birth, this research is pivotal to uncovering disparities and identifying solutions.

In my career, I have always welcomed a new challenge and sought out intriguing scientific puzzles. My lab is excited to embark on this research that could lead to personalized medicine that could literally save the lives of mothers and babies—and revolutionize how we think of who is “at-risk” of pregnancy complications.

Q: What sparked your interest in this work?

There is nothing more complex and fascinating to study than the human brain. Early in my career, I was on a research team conducting genetic analysis in mouse models. I became particularly interested in the ones that were modeling neurological disorders. Their genetics seemed to influence their behavior—some genetic changes made the mice frightened, while others made them aggressive. 

That’s what got me interested in how genes impact behavior and the intersection of genetics and environmental triggers could influence the development of autism or ADHD. 

And now with the possibility of The Galas Project, I’m excited to identify genes that can protect mothers from stress wreaking negative health effects on them or their child. We often think of genes as increasing our susceptibility to disease, but many of them are protective. If we can harness those protective genes, just think of how far we can go to prevent life-threatening pregnancy complications.

Q: What’s the most exciting thing happening in your lab right now?  

It’s thrilling that our initial results identified a novel genetic factor that may shield some Black women from gestational diabetes. This novel gene is the first to be identified as relevant to GDM in the Black community. My lab is excited to hopefully dive deeper into this work with The Galas Project.

This ambitious project starts with a network of partnering physicians and their patients in underserved urban and rural communities. All these patients are living under similar, stressful life conditions, and although many go on to have successful, uneventful pregnancies, the risk of pregnancy complications is particularly high. We will focus on clinics in the Precia Group network, led by Donna Russell. Precia specializes in women’s health research and collecting biological samples needed by the PNRI scientific team.  

My lab will develop genetic profiles, or genotypes, from the maternal blood samples, including women with pregnancy complications and normal pregnancy “controls.” As genetic profiles are developed, PNRI scientists will use Dr. Galas’ computational and novel statistical methods to identify genetic markers that are more prevalent (susceptibility factors) or less prevalent (protective factors) in the women with complicated pregnancies. These genetic studies will allow us to identify variant genes that make certain mothers especially susceptible, and others especially resilient, to certain types of pregnancy complications. Once validated, these new markers can be used in clinics to test women early in pregnancy to identify those who need to be specially monitored and preemptively treated before complications can begin.

The next step is that my lab and PNRI’s McLaughlin Lab will validate the candidate genes and investigate their biological functions, seeking to understand how the variant genes render their endangering or protective effects on prospective mothers. This understanding is the first step toward developing personalized treatments to prevent or mitigate the negative effects of pregnancy complications in a clinical setting.

Lastly, we will analyze the genetics of children from complicated pregnancies as well as their mothers, using cord blood collected at birth. Complicated pregnancies are dangerous for mothers and babies before and at birth. But even when babies are successfully delivered, both children and mothers in complicated pregnancies are left with a lifetime legacy of increased risk, developing physical and mental health disorders at markedly higher rates than other individuals. Our long-term goal will be to identify markers that contribute to these pernicious health issues, to identify the vulnerable mothers and children, and to improve the quality of their lives.

Q: How does working at an independent research institute benefit your work? 

I’ve worked in a government lab, a university, and now at PNRI, an independent genetics institute. I appreciate that PNRI’s mission is research and discovery for the greater good. This commitment gives us the freedom to ask innovative questions and follow where the science leads. As a result, we have the flexibility to be creative, explore new ideas, and tackle multiple important research questions at once. 

For instance, in addition to planning out The Galas Project, my lab is also pursuing research on variations of the AUTS2gene–a master regulatory gene that plays a role in autism, ADHD, epilepsy, and many other conditions. We’re still investigating this, but we believe that certain genetic variations might be linked to hyperactivity and anxiety. It could help explain why some people with autism are hypersensitive to things like light and sound—their brains get overstimulated because they have fewer inhibitory neurons telling the excitatory ones to calm down. 

At PNRI, this freedom to explore diverse scientific questions drives us towards exciting discoveries.

Q: Why is philanthropy important in your research? 

Because The Galas Project is exploring an entirely new area of research, we are reliant on private philanthropy to start this important project. I’m grateful to have an anonymous donor funding the pilot Decoding Stress Project, which yielded the important discovering of a novel genetic factor that may shield some Black women from gestational diabetes. Philanthropy is key to launching ambitious, new research questions and to gather the data needed to then apply for government funding. I’m so grateful that we have the private funds to plan this expanded project that could lead to an entirely new way to prevent and treat pregnancy complications for high-stressed communities.

Q: What do you like to do for fun? 

I am a bit of a nerd—I genuinely love reading and learning about the latest advances in science. I read the scientific literature outside my field for fun—and sometimes that has led to out-of-the-box ideas. I really love mentoring bright young scientists. I also love experimenting in the kitchen—unlike the lab you don’t really have to follow the recipes, just your taste buds, which fills me with a great sense of freedom and excitement. I love gardening and am trying to learn more about plant biology.  

Outdoors and nature have always been a passion of mine—it is what drew me to study biology—and I love biking, hiking, walking with my husband and our two dogs to explore the local terrain. My husband and I were both born in the Northwest but lived elsewhere for most of our adult lives, and we have a lot of catching up to do on the local culture, wildlife, and beautiful scenery. And I love being back home where I can spend more time getting to know my extended family again after many years away.

Dive Deeper

Dive deeper into Dr. Stubbs’ work by listening to her podcast episode “Demystifying Nature vs. Nurture.” Learn more about the Stubbs Lab and connect with PNRI to learn more.