IMAG/MSM WG Multiscale Modeling and Viral Pandemics Zoom

December 11, 2025 at 10AM (EDT)

Job Berkhout, Utrecht Univ.
“Towards a Virtual Embryo: computational modeling of neural tube closure defects”
Neural tube closure is a critical morphogenetic event occurring early in development, between gestational days 23 and 30 in humans. Disruption of this process by genetic errors or exposure to toxic chemicals can result in severe neural tube defects (NTDs), such as spina bifida. NTDs are among the most prevalent human birth defects globally, with an estimated incidence of 20 per 10,000 live births. Predicting how chemical exposure impacts neural tube closure remains challenging due to limitations of traditional animal studies and the reductionist nature of in vitro alternatives. To support animal-free assessment of developmental toxicity, we developed a computational dynamic systems model of neural tube closure defects using CompuCell3D [Berkhout et al., 2025]. This model integrates a gene regulatory network with agent-based tissue modeling to enable probabilistic hazard assessment of NTDs caused by genetic disruption. To extend its application to chemical risk assessment, we incorporated experimental data from a zebrafish developmental toxicity study. Embryos were exposed to various toxicants and sampled at five timepoints spanning neurulation. RNA-seq was used to generate temporal gene expression profiles across doses. Differentially expressed genes were mapped to homologous human pathways represented in the model. These profiles were then used to adjust gene activity levels in silico, enabling prediction of chemical disruption on neural tube closure. These predictions were validated by morphological scoring of zebrafish embryos and aligned with developmental effects reported in epidemiological and animal studies. By integrating transcriptomics with a human-centric dynamic model, we demonstrate how in vitro data can drive probabilistic hazard assessment. This integrative, mechanistic, and human-relevant framework represents a powerful New Approach Method to predict developmental toxicity, reduce reliance on animal testing, and ultimately protect human health.