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Cells interact as dynamically evolving ecosystems. While recent single-cell and spatial multi-omics technologies quantify individual cell characteristics, predicting their evolution requires mathematical modeling. We propose a conceptual framework—a cell behavior hypothesis grammar—that uses natural language statements (cell rules) to create mathematical models. This enables systematic integration of biological knowledge and multi-omics data to generate in silico models, enabling virtual “thought experiments” that test and expand our understanding of multicellular systems and generate new testable hypotheses. This paper motivates and describes the grammar, offers a reference implementation, and demonstrates its use in developing both de novo mechanistic models and those informed by multi-omics data. We show its potential through examples in cancer and its broader applicability in simulating brain development. This approach bridges biological, clinical, and systems biology research for mathematical modeling at scale, allowing the community to predict emergent multicellular behavior. 

Modern agent-based models (ABM) and other simulation models require evaluation and testing of many different parameters. Managing that testing for large scale parameter sweeps (grid searches), as well as storing simulation data, requires multiple, potentially customizable steps that may vary across simulations. Furthermore, parameter testing, processing, and analysis are slowed if simulation and processing jobs cannot be shared across teammates or computational resources. While high-performance computing (HPC) has become increasingly available, models can often be tested faster with the use of multiple computers and HPC resources. To address these issues, we created the Distributed Automated Parameter Testing (DAPT) Python package. By hosting parameters in an online (and often free) “database”, multiple individuals can run parameter sets simultaneously in a distributed fashion, enabling ad hoc crowdsourcing of computational power. Combining this with a flexible, scriptable tool set, teams can evaluate models and assess their underlying hypotheses quickly. Here, we describe DAPT and provide an example demonstrating its use.