In a recent webinar, Dr. Lena Smirnova discussed the role of brain microphysiological systems (bMPS) in improving in vitro neurotoxicity testing and disease modeling. Dr. Smirnova is an Assistant Professor at the Department of Environmental Health and Engineering at Johns Hopkins University's Bloomberg School of Public Health.
Dr. Smirnova's research focuses on developing human-relevant models to enhance chemical safety and drug testing, particularly for developmental neurotoxicity and disease modeling. She explained that bMPS are three-dimensional models—such as organoids, assembloids, and organ-on-chip platforms—derived from human induced pluripotent stem cells (iPSCs). These models aim to replicate the structure and function of the human brain by capturing features like network formation and cellular diversity.
According to Dr. Smirnova, these 3D models address some limitations associated with traditional two-dimensional cultures and animal studies by providing more physiologically relevant insights into human neurodevelopment and disease processes. She noted that animal models can be costly, time-consuming, and often fail to reflect human-specific biology: "For instance, a single Developmental Neurotoxicity (DNT) study in animals can cost over a million dollars and use more than a thousand rats." By contrast, bMPS enable higher-throughput testing while allowing researchers to study responses related to sex differences, genetics, immune function, as well as long-term or low-dose exposures.
The research team uses CRISPR/Cas9 gene editing technology to create fluorescent reporter lines for real-time tracking of specific cell populations or developmental events within these 3D systems. High-content imaging methods allow measurement of markers such as proliferation, apoptosis, and synaptogenesis across developmental timelines.
Dr. Smirnova described how her team studied the effects of environmental toxins like cadmium and chromium—both found in drinking water—and observed disrupted cell viability along with impaired neurite outgrowth in their models. Another experiment involving chronic exposure to low doses of domoic acid showed reduced network synchrony and plasticity even when cytotoxicity was not apparent.
She also introduced an "organic intelligence" concept that integrates bMPS with high-density microelectrode arrays and machine learning techniques: "This allows us to design open-loop and closed-loop experiments where brain organoids can be trained to recognize patterns or interact with simulated environments." The goal is to develop laboratory assays for cognitive functions similar to those tested in animal behavior studies.
Because bMPS are derived from donor-specific iPSCs, they can reflect biological differences based on sex or genetic variants linked with diseases. The integration of immune cells such as microglia enables exploration of neuroinflammatory mechanisms relevant for conditions like autism: "This opens up possibilities for precision medicine and targeted toxicology."
However, Dr. Smirnova acknowledged challenges including skilled handling requirements, lengthy differentiation protocols, variability among iPSC lines, adapting traditional assay endpoints for 3D contexts, and standardizing procedures across laboratories for improved reproducibility.
Interest is growing around incorporating bMPS into regulatory science frameworks; organizations such as the OECD have already adopted some in vitro methods for DNT testing. According to Dr. Smirnova: "The goal is to move toward harmonized validated platforms that deliver high-confidence data for chemical safety decisions while reducing reliance on animal studies."
She advised researchers interested in this field: "Invest in quality... Make sure you have the right tools and quality controls in place." Done correctly, she said bMPS provide a powerful means of studying human brain development and neurotoxicity under conditions more relevant than those offered by traditional models.
Dr. Lena Smirnova earned her PhD from Charité University in Berlin before completing postdoctoral training at Germany’s Federal Institute for Risk Assessment. She is a founding member and past-president of the International Microphysiological Systems Society and advocates advancing non-animal toxicology methods through interdisciplinary approaches combining neuroscience, stem cell biology, and toxicology.
