Human interpretable grammar encodes multicellular systems biology models to democratize virtual cell laboratories
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.
Authors
- Young Hwan Chang (ORCID: https://orcid.org/0000-0001-8764-1959)
- André Forjaz (ORCID: https://orcid.org/0009-0002-5115-2293)
- Denis Wirtz (ORCID: https://orcid.org/0000-0001-6147-3045)
- Elmar Bucher (ORCID: https://orcid.org/0000-0002-2929-2460)
- Neeha Zaidi (ORCID: https://orcid.org/0000-0002-0094-0049)
- Jacquelyn W. Zimmerman (ORCID: https://orcid.org/0000-0002-7775-2943)
- Fatemeh Shojaeian (ORCID: https://orcid.org/0000-0001-5972-9953)
- Aneequa Sundus (ORCID: https://orcid.org/0000-0001-6833-2341)
- Inês Godet (ORCID: https://orcid.org/0000-0002-4889-5144)
- Ashley Kiemen (ORCID: https://orcid.org/0000-0002-6281-2616)
- Jacob T. Mitchell (ORCID: https://orcid.org/0000-0002-5370-9692)
- Jacobo Solórzano (ORCID: https://orcid.org/0000-0003-1199-2239)
- Lisa M. Coussens (ORCID: https://orcid.org/0000-0003-2389-1865)
- Daniele M. Gilkes (ORCID: https://orcid.org/0000-0003-3984-9338)
- Eric Cramer (ORCID: https://orcid.org/0000-0003-2085-3679)
- Elana J. Fertig (ORCID: https://orcid.org/0000-0003-3204-342X)
- Michael Getz (ORCID: https://orcid.org/0000-0001-9886-8454)
- Joe W. Gray (ORCID: https://orcid.org/0000-0001-9225-6756)
- John Metzcar (ORCID: https://orcid.org/0000-0002-0142-0387)
- Laura DeLong Wood (ORCID: https://orcid.org/0000-0003-3096-652X)
- M. Booth (ORCID: https://orcid.org/0009-0003-4707-5640)
- Elizabeth M. Jaffee (ORCID: https://orcid.org/0000-0003-3841-6549)
- Heber L. Rocha (ORCID: https://orcid.org/0000-0002-5876-2644)
- Paul Macklin (ORCID: https://orcid.org/0000-0002-9925-0151)
- Melissa R. Lyman (ORCID: https://orcid.org/0000-0002-0091-0413)
- Randy Heiland (ORCID: https://orcid.org/0000-0002-7440-2905)
- Jeanette Johnson (ORCID: https://orcid.org/0000-0002-8268-5335)
- Pei-Hsun Wu (ORCID: https://orcid.org/0000-0002-7371-2960)
- Yoseph W. Dance (ORCID: https://orcid.org/0009-0003-0843-898X)
- Andrew D. Raddatz (ORCID: https://orcid.org/0000-0001-6096-0968)
- David G. DeNardo (ORCID: https://orcid.org/0000-0002-3655-5783)
- Jude M. Phillip (ORCID: https://orcid.org/0000-0002-2999-5254)
- Genevieve Stein-O’Brien (ORCID: https://orcid.org/0000-0001-8681-9110)
- Ian C. McLean (ORCID: https://orcid.org/0000-0003-2741-7941)
- Furkan Kurtoglu (ORCID: https://orcid.org/0000-0003-4547-1220)
- David Zhou (ORCID: https://orcid.org/0009-0006-3221-5307)
- Elizabeth D. Thompson (ORCID: https://orcid.org/0000-0001-9808-4991)
- Atul Deshpande (ORCID: https://orcid.org/0000-0001-5144-6924)
- Matthew Dunworth (ORCID: https://orcid.org/0000-0002-8852-169X)
- Luciane T. Kagohara (ORCID: https://orcid.org/0000-0003-1706-0950)
- Andrew J. Ewald (ORCID: https://orcid.org/0000-0002-1964-0740)
- Tamara Y. Lopez-Vidal (ORCID: https://orcid.org/0000-0003-0618-7008)
- Laura M. Heiser (ORCID: https://orcid.org/0000-0003-3330-0950)
- Daniel Bergman (ORCID: https://orcid.org/0000-0002-2166-6616)
- Yafei Wang (ORCID: https://orcid.org/0000-0001-6594-0608)
- Lei Zheng (ORCID: https://orcid.org/0000-0003-2326-9873)
- Zachary Nicholas (ORCID: https://orcid.org/0000-0002-7495-4080)
Institutions
- University of Maryland, Baltimore (US)
- Georgia Institute of Technology (US)
- Memorial Sloan Kettering Cancer Center (US)
- Johns Hopkins University (US)
- Emory University (US)
- Oregon Health & Science University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Washington University in St. Louis (US)
- Johns Hopkins Medicine (US)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- Indiana University Bloomington (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- University of Baltimore (US)
Publication Details
- Journal
- Cell
- Published
- 2025-07-26
- DOI
- https://doi.org/10.1016/j.cell.2025.06.048
- Citations
- 27
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 21.76