Kosaka Top Basic Science Abstract Finalist and SmartTots Investigator Interview: Xiaowen Bai, PhD

Anesthetic’s Adverse Effects on Human Cerebral Organoids: A Comprehensive Study from Molecules to Tissue

Abstract Presentation:

Kosaka Best Abstract Awards Session, Sunday, May 19, 2024, 7:00 am – 8:30 am PT, Columbia D, Hyatt Regency Seattle

For the past 15 years, Xiaowen Bai, PhD, an Associate Professor at the Medical College of Wisconsin, has investigated pediatric anesthetic neurotoxicity. Dr. Bai aims to advance the understanding of pediatric anesthesia’s adverse effects on neurodevelopment, with the ultimate goal to make it safer for children. During that time, scientific techniques have advanced significantly and the questions she seeks to answer have increasingly become more complex. However, these challenges have just made her more resolute in her journey to find these important solutions. Employing a multifaceted approach that leverages both animal models and cutting-edge in vitro systems like human stem cell-derived brain cells and organoids, Dr. Bai and her research team hope to pave the way for the development of therapeutic interventions and neuroprotective strategies. Noting the progress she has made thus far, Dr. Bai has been recognized as the Kosaka Top Basic Science Abstract Finalist from the over 500 abstracts accepted to the 2024 Annual Meeting, presented by IARS and SOCCA. She shared some of her initial findings during the Kosaka Best Abstract Awards Session on Sunday, May 19. In the following interview, she discusses how her research has evolved and how her initial results may transform patient care by minimizing the neurological risks associated with anesthesia, especially in the pediatric population.

1. For this research, you are…

Principal Investigator

2. What drew you to this area of research? Has it evolved since your initial research project?

I am deeply invested in pediatric anesthetic neurotoxicity research due to the substantial number of young and unborn children exposed to general anesthesia (GA) every year, which is necessitated by various medical procedures. The crux of my interest lies in the emerging evidence that points towards the developmental neurotoxicity of GAs. Early studies in animals have indicated potential acute neuronal damage and long-term cognitive impacts, which are findings increasingly supported by some human studies and meta-analyses. The FDA’s 2016 warning underscored the gravity of these effects, especially with prolonged or repeated exposure, and catalyzed further research into this critical issue. My research journey began with the urgent need to clarify the mechanisms by which GAs may cause such neurotoxicity and to explore possible preventive strategies.

Over the past 15 years, our work has evolved significantly. Initially focusing on 2D human neuron cultures and mouse models, we have progressed to more sophisticated and clinically relevant 3D human mini brains (also called cerebral organoids). Our investigations have broadened from examining the effects of ketamine to including other anesthetics such as propofol and sevoflurane. Mechanistically, our exploration has expanded from non-coding RNAs to examining the delicate balance between neuronal excitation and inhibition, as well as the critical role of mitochondria in neuronal signaling. This evolution reflects not only the advancements in scientific techniques but also the increasing complexity of questions we seek to answer.

3. What are the goals you most want to accomplish in your work with this research project?

The overarching goal of our research is to advance the understanding of pediatric anesthesia’s adverse effects on neurodevelopment, ultimately making it safer for children. To achieve this, we are employing a multifaceted approach that leverages both animal models and cutting-edge in vitro systems like human stem cell-derived brain cells and organoids.

Our specific aims are as follows:

1) Dissect pathological changes: We aim to meticulously categorize the age-specific, anesthetic-specific, and cell-specific pathological changes induced by anesthetics. This granular analysis is pivotal for identifying the vulnerable stages of development and the cellular processes most affected by anesthetic exposure.

2) Elucidate underlying mechanisms: By understanding the precise mechanisms through which anesthetics impact neurodevelopment, we can inform safer clinical practices and anesthesia guidelines. This involves exploring the molecular pathways and neural dynamics altered by anesthetic drugs.

3) Develop precision interventions: Using the insights gained, we plan to design targeted interventions that can mitigate the adverse effects of anesthesia. This may include the development of new drugs, anesthetic protocols, or timing strategies that minimize neurodevelopmental risks.

4) Create neuroprotective strategies: We are dedicated to developing strategies that not only intervene but also actively protect the developing brain. This could encompass pharmacological agents that bolster neural resilience during anesthetic exposure. By achieving these goals, we hope to fill critical knowledge gaps and translate our findings into clinical practices that safeguard the neurodevelopment of children undergoing anesthesia.

4. What is the potential impact of your research on the field of anesthesia and patient care?

The potential impact of our research on the field of anesthesia and patient care is substantial and multifaceted. Through rigorous experimentation, we provide direct evidence of anesthetic-induced brain injury in human brain cells and tissues. This not only underscores the urgency of our mission but also maps the landscape of injury, highlighting the when, how, and why behind these adverse effects. By elucidating the mechanisms of anesthetic-induced injury, our research paves the way for the development of therapeutic interventions and neuroprotective strategies. These strategies are poised to transform patient care by minimizing the neurological risks associated with anesthesia, especially in the pediatric population, whose developing brains are particularly susceptible. Furthermore, our work dissects the toxic effects of different anesthetic agents, allowing for a more informed selection of drugs based on their safety profile. This knowledge is invaluable for anesthesiologists as they tailor their approach to each individual patient, balancing the necessity of the procedure with the potential risks involved, ensuring that the administration of anesthesia is as safe as possible for all, especially our most vulnerable young patients.

5. What are the benefits of presenting your research at the IARS Annual Meeting?

Presenting our research at the IARS Annual Meeting offers an invaluable platform for disseminating our findings from stem cell-derived mini brains to a broader audience, especially physicians and researchers in anesthesiology.

The meeting facilitates several key benefits for our work:

1) Peer interaction: It provides a unique opportunity to engage with peers who are equally dedicated to advancing the field of anesthesiology. This exchange of ideas can foster collaborative efforts and provide new insights into our research methodologies and objectives.

2) Bridging bench to bedside: The IARS Annual Meeting is an ideal venue for transitioning research “from the bench to bedside.” It allows us to showcase how our lab-based discoveries have the potential to transform into clinical applications, potentially altering patient care protocols and improving outcomes.

3) Feedback from experts: Presenting to a knowledgeable audience enables us to receive critical feedback, which can refine our research direction and focus. Such expert critique is invaluable for ensuring that our work remains relevant and of high quality.

4) Visibility and impact: By highlighting our work in a high-profile setting, we raise awareness of the importance of investigating anesthetic-induced neurotoxicity, which can drive both funding and public interest towards this vital area of research. Collectively, by participating in the meeting, we aim not only to share our research but also to invite collaboration, foster innovation, and ultimately contribute to safer anesthetic practices.

6. Outside of your research, what might someone be surprised to learn about you?

Stepping out from the meticulous world of research, I immerse myself in hobbies that offer a striking counterpoint to the structured lab environment. My colleagues might find it unexpected that I hold a deep appreciation for the art of cinema, which provides a diverse palette of narratives and emotions. Reading is another cherished pastime, each book providing new insights that expand my perspective. Additionally, my enthusiasm extends to pickleball — a sport that brings both joy and a sense of community. As an avid gardener, I find a quiet satisfaction in the patient art of cultivating my garden, watching seeds grow into blossoms and fruits. This nurturing process is not only meditative but also a constant reminder to appreciate the journey as much as the destination.