Neurodegenerative diseases are often insidious, with patients showing symptoms suddenly and with little warning. The mechanisms of how this happens in the brain are still not fully known and effective treatments and cures have been elusive. For those who study these diseases and how the brain works, there are often more questions than answers.

Smita Saxena, PhD, is a lifelong learner who has dedicated her life to unraveling the circuitry of the brain and the diseases tied up in it, like amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). Inside Precision Medicine’s managing editor, Corinna Singleman, PhD, spoke with Saxena, a professor and researcher at NextGen Precision Health at the University of Missouri. They discussed Saxena’s path from a child fascinated with electrical circuits to becoming a renowned researcher who recently crossed an ocean to follow an opportunity to pursue her passion for neuroscience.

(The following interview has been edited for length and clarity.)

Q: What sparked your interest in neuroscience and can you describe your journey to date in reaching The University of Missouri?

Saxena: I was a curious kid, always the first to ask questions in school, and extremely fascinated by electrical gadgets, and even learned to repair them as a hobby.

I completed most of my studies in Switzerland, particularly at the University of Lausanne in the Lake Geneva region. It was an exciting time for neuroscience, as new genetic tools allowed researchers to explore neurons and cellular processes in ways that hadn’t been possible before.

During one of my courses, I worked with hippocampal neurons transfected with GFP, making them glow beautifully. The instructor explained, “These neurons control learning, memory, and personality.” I was intrigued by the idea that such tiny cells could shape who we are, how we learn, and store memories—that’s what drew me to neuroscience.

During my PhD, I wondered, “How do neurons communicate in circuits, and how does this affect disease?” Around the same time, my grandmother was diagnosed with dementia, prompting me to explore why there was no cure. This led me to study motor neuron diseases, focusing on how the nervous system develops pathology and how neural circuits might drive the pathological progression.

I came to realize how insidious neurodegenerative diseases can be, often progressing quietly before a diagnosis. That fueled my interest in continuing my work on neurodegeneration. I then competed for the Swiss National Science Professorship, which is a very competitive process. It’s awarded to scientists with great potential, and I was fortunate enough to receive it, which enabled me to start my own research group, where I began focusing on the neuronal circuits involved in neurodegeneration.

From there, new opportunities opened up, leading me to move to the U.S. It was a big challenge, transitioning from European to American academia, but in December 2023, I began my new role at the University of Missouri in the NextGen Precision Health Initiative.

Q: Can you describe the experience of moving from Switzerland to the US and the new role you are leading here at NextGen Precision Health?

Saxena: Taking risks is never easy, but they’re necessary if you want to grow and push your limits. I made the move to the U.S. because of the incredible opportunities NextGen Precision Health offers. The vision fascinated me.

What sets NextGen Precision Health initiative apart is the emphasis on bringing scientists and clinicians together under one roof, fostering collaboration to develop new therapies directly for patients. While there are many steps in the process, the idea is to stay connected—from research all the way to clinical application. It’s a forward-thinking, innovative, state-of-the-art environment where nothing happens in isolation, and you’re always grounded in the reality of patient care.

At NextGen, I’m able to do both translational and mechanistic disease research, exploring new compounds and gene therapies with the goal of turning them into real treatments. It’s a unique environment that supports building everything around you to make this vision a reality.

Q: What is the main focus of research in your lab?

Saxena: My lab uniquely integrates systems neuroscience and human cellular models to explore the complexities of brain diseases. We believe that these complexities arise from both deficits in neuronal network function and the vulnerability of individual neurons to neurodegenerative diseases.

We focus on how early signs of disease reflect network adaptations, examining the interplay between intrinsic neuronal vulnerability and neuronal network dynamics to better understand the underlying pathologies.

The most affected neurons will ultimately degenerate, but the network, which may be functioning sub-optimally, tries to adapt early on to maintain normal function. This adaptive capacity of the brain complicates early diagnosis, as it can compensate for the initial onset of disease by adjusting neuronal circuit functions.

We aim to understand how these early changes might drive pathology by using in vivo calcium imaging of the neuronal network, which is a readout for its activity status. By examining network function before disease symptoms appear, we can identify alterations that may occur in neurons that don’t degenerate immediately. These changes can disrupt the overall functioning of the neuronal network and, over time, may trigger or propagate pathology in more vulnerable neurons that are less able to adapt, ultimately leading to degeneration.

The second major approach that we have in the lab is to generate neurons and other brain cells, such as astrocytes and microglia, from patient fibroblasts in vitro. This allows us to investigate transcriptomic and proteomic changes at the patient level. Additionally, we perform drug screenings to identify compounds that may benefit these neurons, examining whether astrocytes contribute to toxicity through co-cultures derived from the same patient. We include healthy controls, typically unaffected siblings or parents, to reduce genetic heterogeneity and analyze their responses.

We categorize patients into “responders” and “non-responders” based on their reactions to specific therapies. While we’re still uncovering the mechanisms behind these classifications, this approach helps us identify targeted drug therapies tailored to the specific needs of each patient group.

Q: What do you foresee as the main challenges for precision medicine?

Establishing clear staging criteria is crucial, and I’m dedicated to this effort using patient-derived neurons and astrocytes to uncover why certain patients respond to specific therapies.

Saxena: One of the biggest challenges in precision medicine is understanding the mechanisms that drive neurodegenerative diseases. We’re still lacking critical insights into why pathologies occur, which complicates our ability to generate effective treatments from patient-derived neurons.

Another major hurdle is the grouping and staging of diseases. Many drug trials fail because patients with different disease stages and underlying mechanisms are grouped together, resulting in treatments that may only be partially effective. Establishing clear staging criteria is crucial, and I’m dedicated to this effort using patient-derived neurons and astrocytes to uncover why certain patients respond to specific therapies.

We need to explore whether the response is driven by disease mechanisms, genetic factors, lifestyle influences, or epigenetic aspects. Ultimately, the challenge in neurodegenerative diseases lies in developing predictive biomarkers and staging strategies that allow for precise therapeutic recommendations tailored to individual patients.

Q: Do you work with a very diverse patient pool?

Saxena: I believe our diverse patient pool is a significant asset. We bring samples from Europe, which is ethnically diverse, and now we’re also incorporating samples from Missouri, providing a broader perspective on disease phenotypes. We get patients’ samples in and can track when and where the disease was diagnosed and how the disease progressed. Because very often we take these patient samples, which are anonymized from databases where we do not know their natural history of when and how they were diagnosed, their socioeconomic background, their ethnicity, or the other things.  This layered complexity is essential for understanding disease mechanisms and responsiveness to specific drug targets.

The combination of European and U.S. samples creates a more heterogeneous patient population, allowing us to better stage diseases and identify potential therapeutic responses. It’s an exciting initiative, and I believe we’re making steady progress.

Q: So when you look back on your career trajectory to date, is there anything with the benefit of hindsight you may have done differently?

Saxena: So that’s a very, very neat question. As a scientist, I would not change anything. I do believe that I did the right choice because I see that what I’m doing impacts society. I see that there is a big need.

The advice I can give to young researchers and especially to female researchers is: “Go with your passion. Do what you love doing the best.”

Surround yourself with colleagues who are as excited and enthusiastic as you are, and I think that is the key. So do the thing you like to do. Be passionate about it.

Be resilient, Don’t give up. There will be hard times. I think being passionate and focused on the goal is the best thing you can do, and if it is science, go ahead. I know it’s not easy and it’s never going to be easy. But do it, give it a try, and go ahead with it. Take the challenge.

Q: What keeps you motivated in your neuroscience research and in your career in general?

Saxena: It is the belief that one day I can make a difference to patients suffering from motor neuron disease or any other neurodegenerative disease. That’s what keeps me going: not to forget the patients. You may have big publications, you may have great ideas, but don’t forget you’re doing it for the patients who really need it and who look to you for it.

Corinna Singleman joined the GEN and IPM teams in 2024 as a passionate science communicator. She earned her PhD in Biology from The Graduate Center, CUNY, studying the impacts of PCBs and TCDD contamination in the Hudson River on endangered Atlantic surgeon and zebrafish. Her strong educational background in STEM and continuous commitment to educating and informing a broad audience have equipped her with the ability to translate complex concepts into clear, accessible content. She uses this experience to bridge the ever-widening gap between the scientific community and the rest of the world by teaching, writing, and working on projects that directly impact others. Corinna is dedicated to promoting effective communication that fosters collaboration across diverse teams and organizations.