A reappraisal of how to build modular, reusable models of biological systems.
Open accessAbstract
Biological researchers increasingly rely on computational models to integrate biological systems knowledge, test hypotheses, and forecast system behavior.The expanding size of these models requires solutions for managing their complexity.Modularity, a time-tested design principle for managing complexity, can be applied within the biological modeling field to parallelize work, automate composition, and promote effective model sharing.As modelers of complex biological systems, we aim to apply modular production to accelerate our efforts and have therefore investigated several currently available approaches for modular modeling.We argue that some traditional features of modularity, in particular the isolation of a module's contents from the rest of the system, can impede model sharing and composition when applied within the context of biological simulation.Alternative approaches that can automatically interface model components based on the biological meaning of their contents (their semantics) avoid these limitations.Our conclusions have strategic implications for the design of systems biology, synthetic biology, and integrated physiological modeling technologies, as well as communitylevel model curation efforts.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Gene Ontology (GO) database and informatics resource
Gene Ontology Consortium (2003) · Nucleic Acids Research · doi:10.1093/nar/gkh036 · Cited by 4,533 · see citing works
Design Rules: The Power of Modularity
Baldwin, C. Y., & Clark, K. B. (2000) · doi:10.7551/mitpress/2366.001.0001 · Cited by 3,504 · see citing works
Parallel & distributed processing
Slusallek, P., Shirley, P. S., Mark, W. R., Stoll, G., & Wald, I. (2005) · ACM SIGGRAPH Conference (SIGGRAPH) · doi:10.1145/1198555.1198750 · Cited by 2,568 · see citing works
OWL Web Ontology Language Reference
Dean, M., Guus Schreiber, A., Bechhofer, S., van Harmelen, F., Hendler, J., Horrocks, I. R., MacGuinness, D., Patel‐Schneider, P. F., & Stein, L. A. (2004) · Data Archiving and Networked Services (DANS) · Cited by 2,394 · see citing works
A reference ontology for biomedical informatics: the Foundational Model of Anatomy
Rosse, C., & Mejino, J. L. (2003) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2003.11.007 · Cited by 1,167 · see citing works
ChEBI: a database and ontology for chemical entities of biological interest
Degtyarenko, K. N., de Matos, P., Ennis, M., Hastings, J., Zbinden, M., McNaught, A., Alcántara, R., Darsow, M., Guedj, M., & Ashburner, M. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm791 · Cited by 1,130 · see citing works
Le Novere, N. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkj092 · Cited by 762 · see citing works
NCI Thesaurus: A semantic model integrating cancer-related clinical and molecular information
Sioutos, N., de Coronado, S., Haber, M. W., Hartel, F. W., Shaiu, W.-L., & Wright, L. W. (2006) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2006.02.013 · Cited by 444 · see citing works
An Overview of CellML 1.1, a Biological Model Description Language
Cuellar, A. A., Lloyd, C. M., Nielsen, P. F., Bullivant, D. P., Nickerson, D. P., & Hunter, P. J. (2003) · SIMULATION · doi:10.1177/0037549703040939 · Cited by 345 · see citing works
Forty years of SNOMED: a literature review
Cornet, R., & de Keizer, N. F. (2008) · BMC Medical Informatics and Decision Making · doi:10.1186/1472-6947-8-s1-s2 · Cited by 301 · see citing works
A Reference Ontology for Bioinformatics: The Foundational Model of Anatomy
Rosse, C., & Mejino, J. L. V. (2003) · Cited by 196 · see citing works
TinkerCell: modular CAD tool for synthetic biology
Chandran, D., Bergmann, F., & Sauro, H. M. (2009) · Journal of Biological Engineering · doi:10.1186/1754-1611-3-19 · Cited by 184 · see citing works
Self-citationCellML and associated tools and techniques
Garny, A., Nickerson, D. P., Cooper, J., dos Santos, R. W., Miller, A. K., McKeever, S., Nielsen, P. M. F., & Hunter, P. J. (2008) · Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rsta.2008.0094 · Cited by 141 · see citing works
Antimony: a modular model definition language
Smith, L. P., Bergmann, F., Chandran, D., & Sauro, H. M. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp401 · Cited by 128 · see citing works
Self-citationAnnotation and merging of SBML models with semanticSBML
Krause, F., Uhlendorf, J., Lubitz, T., Schulz, M., Klipp, E., & Liebermeister, W. (2010) · Bioinform. · doi:10.1093/bioinformatics/btp642 · Cited by 108 · see citing works
Standard virtual biological parts: a repository of modular modeling components for synthetic biology
Cooling, M. T., Rouilly, V., Mısırlı, G., Lawson, J., Yu, T., Hallinan, J. S., & Wipat, A. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq063 · Cited by 93 · see citing works
Self-citationBioinformatics, multiscale modeling and the IUPS Physiome Project
Hunter, P. J., Crampin, E. J., & Nielsen, P. M. F. (2008) · Briefings in Bioinformatics · doi:10.1093/bib/bbn024 · Cited by 92 · see citing works
Multiple ontologies in action: Composite annotations for biosimulation models
Gennari, J. H., Neal, M. L., Galdzicki, M., & Cook, D. L. (2010) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2010.06.007 · Cited by 58 · see citing works
Self-citationCellular Open Resource (COR): current status and future directions
Garny, A., Noble, D., Hunter, P. J., & Kohl, P. K. (2009) · Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rsta.2008.0289 · Cited by 53 · see citing works
Multiscale Modeling and Data Integration in the Virtual Physiological Rat Project
Beard, D., Neal, M., Tabesh-Saleki, N., Thompson, C. T., Bassingtwaighte, J. B., Shimoyama, M., & Carlson, B. E. (2012) · Annals of Biomedical Engineering · doi:10.1007/s10439-012-0611-7 · Cited by 42 · see citing works
Self-citationPhysical Properties of Biological Entities: An Introduction to the Ontology of Physics for Biology
Cook, D. L., Bookstein, F. L., & Gennari, J. H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028708 · Cited by 37 · see citing works
Self-citationModular, semantics-based composition of biosimulation models
Neal, M. L. (2010) · ProQuest LLC eBooks · Cited by 7 · see citing works
Self-citationNeal, M. L., Cook, D. L., & Gennari, J. H. (2013) · Cited by 7 · see citing works
Self-citationA C library for retrieving specific reactions from the BioModels database
Neal, M. L., Galdzicki, M., Gallimore, J. T., & Sauro, H. M. (2013) · Bioinformatics · doi:10.1093/bioinformatics/btt567 · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
1 of the 25 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Immune digital twins for complex human pathologies: applications, limitations, and challenges
Niarakis, A., Laubenbacher, R., An, G. C., Ilan, Y., Fisher, J., Flobak, Å., Reiche, K., Martínez, M. R., Geris, L., Ladeira, L., et al. (2024) · npj Systems Biology and Applications · doi:10.1038/s41540-024-00450-5 · Cited by 104 · see citing works
Harmonizing semantic annotations for computational models in biology
Neal, M. L., König, M., Nickerson, D., Mısırlı, G., Kalbasi, R., Dräger, A., Atalag, K., Chelliah, V., Cooling, M. T., Cook, D. L., et al. (2019) · Briefings in Bioinformatics · doi:10.1093/bib/bby087 · Cited by 74 · see citing works
Self-citationA blueprint for human whole-cell modeling
Szigeti, B., Roth, Y. D., Sekar, J. A. P., Goldberg, A. P., Pochiraju, S. C., & Karr, J. R. (2018) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2017.10.005 · Cited by 72 · see citing works
Hierarchical bond graph modelling of biochemical networks
Gawthrop, P. J., Cursons, J., & Crampin, E. J. (2015) · Proceedings of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rspa.2015.0642 · Cited by 49 · see citing works
Data-Driven Modelling of Biological Multi-Scale Processes
Hasenauer, J., Jagiella, N., Hroß, S., & Theis, F. J. (2015) · Journal of Coupled Systems and Multiscale Dynamics · doi:10.1166/jcsmd.2015.1069 · Cited by 39 · see citing works
Modular bond‐graph modelling and analysis of biomolecular systems
Gawthrop, P. J., & Crampin, E. J. (2016) · IET Systems Biology · doi:10.1049/iet-syb.2015.0083 · Cited by 38 · see citing works
Kutumova, E. O., Akberdin, I. R., Kiselev, I. N., Sharipov, R., Egorova, V. S., Syrocheva, A. O., Parodi, A., Zamyatnin, A. A., & Kolpakov, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012560 · Cited by 38 · see citing works
Hunter, P. J. (2016) · IEEE Pulse · doi:10.1109/mpul.2016.2563841 · Cited by 34 · see citing works
Nickerson, D. P., Atalağ, K., de Bono, B., Geiger, J., Goble, C., Hollmann, S., Lonien, J., Müller, W., Regierer, B., Stanford, N., et al. (2016) · Interface Focus · doi:10.1098/rsfs.2015.0103 · Cited by 32 · see citing works
Modular assembly of dynamic models in systems biology
Pan, M., Gawthrop, P. J., Cursons, J., & Crampin, E. J. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1009513 · Cited by 32 · see citing works
Bond Graph Modeling of Chemiosmotic Biomolecular Energy Transduction
Gawthrop, P. J. (2017) · IEEE Transactions on NanoBioscience · doi:10.1109/tnb.2017.2674683 · Cited by 30 · see citing works
Towards integrative systems pharmacology models in oncology drug development
van Hasselt, J. G. C., & van der Graaf, P. H. (2015) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2015.06.004 · Cited by 31 · see citing works
Semantics-Based Composition of Integrated Cardiomyocyte Models Motivated by Real-World Use Cases
Neal, M. L., Carlson, B. E., Thompson, C. T., James, R. C., Kim, K., Tran, K., Crampin, E. J., Cook, D. L., & Gennari, J. H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0145621 · Cited by 25 · see citing works
Self-citationSemGen: a tool for semantics-based annotation and composition of biosimulation models
Neal, M. L., Thompson, C. T., Kim, K., James, R. C., Cook, D. L., Carlson, B. E., & Gennari, J. H. (2018) · Bioinformatics · doi:10.1093/bioinformatics/bty829 · Cited by 24 · see citing works
Self-citationModel annotation and discovery with the Physiome Model Repository
Sarwar, D. M., Kalbasi, R., Gennari, J. H., Carlson, B. E., Neal, M. L., de Bono, B., Atalağ, K., Hunter, P. J., & Nickerson, D. P. (2019) · BMC Bioinformatics · doi:10.1186/s12859-019-2987-y · Cited by 24 · see citing works
Self-citationWhere next for the reproducibility agenda in computational biology?
Lewis, J., Breeze, C. E., Charlesworth, J., Maclaren, O. J., & Cooper, J. (2016) · BMC Systems Biology · doi:10.1186/s12918-016-0288-x · Cited by 23 · see citing works
Recent advances in biomedical simulations: a manifesto for model engineering
Hellerstein, J. L., Gu, S., Choi, K., & Sauro, H. M. (2019) · F1000Research · doi:10.12688/f1000research.15997.1 · Cited by 20 · see citing works
Self-citationAkberdin, I. R., Kiselev, I. N., Pintus, S. S., Sharipov, R., Vertyshev, A. Y., Виноградова, О. Л., Викторович, П. Д., & Kolpakov, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910353 · Cited by 19 · see citing works
BrainSignals Revisited: Simplifying a Computational Model of Cerebral Physiology
Caldwell, M., Hapuarachchi, T., Highton, D., Elwell, C. E., Smith, M., & Tachtsidis, I. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126695 · Cited by 18 · see citing works
Kutumova, E., Kiselev, I., Sharipov, R., Lifshits, G., & Kolpakov, F. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.746300 · Cited by 16 · see citing works
Hierarchical semantic composition of biosimulation models using bond graphs
Shahidi, N., Pan, M., Safaei, S., Tran, K., Crampin, E. J., & Nickerson, D. P. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1008859 · Cited by 17 · see citing works
Analysing and simulating energy-based models in biology using BondGraphTools
Cudmore, P., Pan, M., Gawthrop, P. J., & Crampin, E. J. (2021) · The European Physical Journal E · doi:10.1140/epje/s10189-021-00152-4 · Cited by 17 · see citing works
Modular modelling with Physiome standards
Cooling, M. T., Nickerson, D. P., Nielsen, P. M. F., & Hunter, P. J. (2016) · The Journal of Physiology · doi:10.1113/jp272633 · Cited by 16 · see citing works
Self-citationSchölzel, C., Blesius, V., Ernst, G., & Dominik, A. (2021) · npj Systems Biology and Applications · doi:10.1038/s41540-021-00182-w · Cited by 15 · see citing works
Gawthrop, P. J., Pan, M., & Crampin, E. J. (2021) · Journal of The Royal Society Interface · doi:10.1098/rsif.2021.0478 · Cited by 15 · see citing works
ModelBricks—modules for reproducible modeling improving model annotation and provenance
Cowan, A. E., Mendes, P., & Blinov, M. L. (2019) · npj Systems Biology and Applications · doi:10.1038/s41540-019-0114-3 · Cited by 15 · see citing works
Network thermodynamics of biological systems: A bond graph approach
Gawthrop, P. J., & Pan, M. (2022) · Mathematical Biosciences · doi:10.1016/j.mbs.2022.108899 · Cited by 14 · see citing works
Peng, D., Warnke, T., Haack, F., & Uhrmacher, A. M. (2017) · SIMULATION · doi:10.1177/0037549717704314 · Cited by 14 · see citing works
Musculoskeletal Modelling and the Physiome Project
Fernandez, J. W., Zhang, J., Shim, V., Munro, J. T., Sartori, M., Besier, T., Lloyd, D., Nickerson, D., & Hunter, P. (2018) · Courses and lectures · doi:10.1007/978-3-319-58845-2_3 · Cited by 11 · see citing works
Gawthrop, P. J., Cudmore, P., & Crampin, E. J. (2020) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2020.110223 · Cited by 13 · see citing works
Open modeling and exchange (OMEX) metadata specification version 1.0
Neal, M. L., Gennari, J. H., Waltemath, D., Nickerson, D. P., & König, M. (2020) · Berichte aus der medizinischen Informatik und Bioinformatik/Journal of integrative bioinformatics · doi:10.1515/jib-2020-0020 · Cited by 12 · see citing works
Self-citationOMEX metadata specification (version 1.2)
Gennari, J. H., König, M., Misirli, G., Neal, M. L., Nickerson, D. P., & Waltemath, D. (2021) · Journal of Integrative Bioinformatics · doi:10.1515/jib-2021-0020 · Cited by 11 · see citing works
Self-citationEnergy-Based Modeling of the Feedback Control of Biomolecular Systems With Cyclic Flow Modulation
Gawthrop, P. J. (2021) · IEEE Transactions on NanoBioscience · doi:10.1109/tnb.2021.3058440 · Cited by 10 · see citing works
Schölzel, C., Blesius, V., Ernst, G., & Dominik, A. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2019.12.16.875260 · Cited by 9 · see citing works
From FAIR to CURE: guidelines for computational models of biological systems
Sauro, H. M., Agmon, E., Blinov, M., Gennari, J. H., Hellerstein, J. L., Heydarabadipour, A., Jardine, B. E., May, E., Nickerson, D., Smith, L. P., et al. (2026) · npj Systems Biology and Applications · doi:10.1038/s41540-026-00651-0 · Cited by 6 · see citing works
Self-citationA review of the diverse applications of bond graphs in biology and physiology
Ghazani, M. A., Pan, M., Tran, K., Rampadarath, A., & Nickerson, D. P. (2024) · Proceedings of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rspa.2023.0807 · Cited by 8 · see citing works
Flynn, A. J., Taksler, G. B., Caverly, T. J., Beck, A. W., Boisvert, P., Boonstra, P. S., Gittlen, N., Meng, G., Raths, B., & Friedman, C. P. (2022) · Learning Health Systems · doi:10.1002/lrh2.10325 · Cited by 6 · see citing works
A semantics, energy-based approach to automate biomodel composition
Shahidi, N., Pan, M., Tran, K., Crampin, E., & Nickerson, D. (2021) · bioRxiv · doi:10.1371/journal.pone.0269497 · Cited by 7 · see citing works
Gawthrop, P. J., Pan, M., & Crampin, E. J. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.24.436792 · Cited by 4 · see citing works
JigCell Model Connector: building large molecular network models from components
Jones, T. C., Hoops, S., Watson, L., Palmisano, A., Tyson, J., & Shaffer, C. (2018) · International Conference on Advances in System Simulation · doi:10.1177/0037549717754121 · Cited by 2 · see citing works
Waites, W., Mısırlı, G., Cavaliere, M., Vincent Danos, A., & Wipat, A. (2018) · ACS Synthetic Biology · doi:10.1021/acssynbio.8b00201 · Cited by 3 · see citing works
Challenges in horizontal model integration
Kolczyk, K., & Conradi, C. (2016) · BMC Systems Biology · doi:10.1186/s12918-016-0266-3 · Cited by 2 · see citing works
A Systems Biology Approach Towards a Comprehensive Understanding of Ferroptosis
Arbatskiy, M. S., Balandin, D. E., Akberdin, I. R., & Churov, A. V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111782 · Cited by 3 · see citing works
Evolvix BEST Names for semantic reproducibility across code2brain interfaces
Loewe, L., Scheuer, K. S., Keel, S. A., Vyas, V., Liblit, B., Hanlon, B. M., Ferris, M. C., Yin, J., Dutra, I., Pietsch, A., et al. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13192 · Cited by 1 · see citing works
CellML Model Discovery with the Physiome Model Repository
Sarwar, D. M., & Nickerson, D. P. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11681-2
The Perspective of Physiome Modelling in Systems Biology: New Horizon
Parvatikar, P., Bagali, S., Kanthe, P. S., Patil, A. V., & Das, K. K. (2023) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9789815165616123010008
How to stop worrying about model microfoundationality: lessons from multiscale cancer modeling
Neal, J. P. (2025) · Synthese · doi:10.1007/s11229-025-05344-5
Standardization and Modularity in Synthetic Biology
Israr, J., & Kumar, A. (2026) · Springer eBooks · doi:10.1007/978-981-95-3957-4_4
- Authors
- Neal, M. L., Cooling, M. T., Smith, L. P., Thompson, C. T., Sauro, H. M., Carlson, B. E., Cook, D. L., & Gennari, J. H.
- Affiliations
- University of Washington (US)
- University of Auckland (NZ)
- Medical College of Wisconsin (US)
- University of Michigan (US)
- Corresponding author
- Neal, Maxwell L.
- ORCID
- Venue
- PLoS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-10-02
- Volume
- 10
- Issue
- 10
- Pages
- e1003849
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC4183381
- OpenAlex
- W2016462601
- Cited by
- 49
- References
- 25
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 10 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 8 · 2015: 5
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Heart Association
- Royal Society
- European Commission (248502)
- Royal Society Te Apārangi (UOA1007)
- Maurice Wilkins Centre for Molecular Biodiscovery
- National Institutes of Health (GM094503)
- National Human Genome Research Institute (R42HG006737, R42-HG006737-03)
- National Institute of General Medical Sciences (R01-GM081070-06, P50GM094503, P50-GM094503-03, R01GM081070)
- U.S. National Library of Medicine (T15LM007442)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Social Sciences › Decision Sciences › Information Systems and Management › Scientific Computing and Data Management
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Modeling and Simulation Systems
- Keywords
- modular modeling, biological models, model reuse, model composition, model sharing, semantic interface, model curation, systems biology, synthetic biology, physiological modeling, model complexity
- MeSH terms
- Models, Biological, Software, Systems Biology, Metabolic Networks and Pathways
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
