Standards play an important role in Systems and Synthetic Biology. COMBINE (‘COmputational Modeling in BIology’ NEtwork) ,  is a formal entity that coordinates standards development in these fields of research, fosters and moderates discussions, designs and implements dissemination strategies, and organises two annual community meetings each year. HARMONY (Hackathons on Resources for Modeling in Biology) is a workshop and hackathon for the development of libraries, specifications and tool support. The COMBINE forum brings together experts from associated fields of research, discusses applications and further developments of COMBINE standards and hence offers a platform for communication between standards developers and users.
COMBINE describes itself as “…a network formed by the communities developing standards and formats to share computational models. Working together, it is expected that the federated projects will develop a set of interoperable standards covering all the aspects of computational modelling. Building on the experience of mature projects, which already have stable specifications, software support, user-base and community governance, COMBINE helps foster or support fledging efforts aimed at filling gaps or new needs” .
COMBINE standards and associated initiatives cover a range of topics, see Figure 1. COMBINE is an open initiative and everybody is invited to join. The COMBINE web site https://co.mbine.org/ and COMBINE-related publications , ,  provide more information. Please note that this editorial contains similar information to overviews in earlier special issues , , . We decided to give again a complete overview here as it helps the reader to find all information in one place.
COMBINE published the first collection of Systems and Synthetic Biology standards as a special issue of the Journal of Integrative Bioinformatics in 2015 . Since then a regular special issue of JIB provides updates to COMBINE standards. The latest update was published in 2018 . This special issue presents developments of standards and related initiatives in 2018/19.
2 Latest Versions of COMBINE Standards
When using and implementing COMBINE standards, please refer to the following specifications. Note: New specifications are highlighted with *NEW*.
2.1 Core Standards
2.1.1 BioPAX (Biological PAthway eXchange)
2.1.4 SBGN (Systems Biology Graphical Notation)
SBGN (Systems Biology Graphical Notation) , specifications are
*NEW* SBGN Process Description Level 1 Version 2  – which includes new developments such as the addition of equivalence operator, subunit, and annotation glyphs, modification to the usage of submaps, and updates to clarify the use of various glyphs;
SBGN Entity Relationship Level 1 Version 2.0 ;
SBGN Activity Flow Level 1 Version 1.2 .
2.1.5 SBML (Systems Biology Markup Language)
SBML (Systems Biology Markup Language) , specifications are
*NEW* SBML Level 3 Core, Version 2 Release 2  – which corrects some errors and clarifies some ambiguities discovered in Release 1. It defines validation rules that determine the validity of an SBML document and provides many examples of models in SBML form;
SBML Level 3 Core, Version 2 ;
SBML Level 3 Package: Flux Balance Constraints, Version 2 ;
SBML Level 3 Package: Hierarchical Model Composition, Version 1 ;
SBML Level 3 Package: Multistate, Multicomponent and Multicompartment Species, Version 1 Release 1 ;
SBML Level 3 Package: Render, Version 1, Release 1 ;
SBML Level 3 Package: Qualitative Models, Version 1 ;
SBML Level 3 Package: Layout, Version 1 ;
SBML Level 3 Package: Groups, Version 1 .
2.1.6 SBOL (Synthetic Biology Open Language)
SBOL (Synthetic Biology Open Language) , specifications are
*NEW* SBOL Version 2.3.0  – which includes representing sequence modifications such as insertion, deletion, and replacement, supporting organisation and attachment of experimental data derived from designs and describing numerical parameters of design elements. It includes specifying types of synthetic biology activities, unambiguous locations for sequences with multiple encodings, refinement of a number of validation rules, improved figures and examples, and clarification on issues related to the use of external ontology terms;
*NEW* SBOL Visual Version 2.1  – which extends the diagram syntax to include methods for showing modular structure and mappings between elements of a system, interactions arrows that can split or join, and new glyphs for indicating genomic context and for stop codons.
2.2 Associated Standards
Associated standards provide an additional layer of semantics to COMBINE representation formats. These are:
Identifiers.org URIs , community resources to provide persistent identification (no specification);
Systems Biology Ontology and Kinetic Simulation Algorithm Ontology  for controlled vocabularies and semantics in systems biology (no specification);
BioModels.net qualifiers  for representing relation between a model component and the resource used to annotate it (no specification).
Hucka M, Nickerson D P, Bader GD, Bergmann FT, Cooper J, Demir E, et al. Promoting coordinated development of community-based information standards for modeling in biology: the COMBINE initiative. Front Bioeng Biotechnol 2015;3:19. PubMedGoogle Scholar
Myers C, Bader G D, Gleeson P, Golebiewski M, Hucka M, Le Novère N, et al. A brief history of COMBINE. In: Proceedings of the 2017 Winter Simulation Conference. Piscataway, NJ, USA: IEEE Press, 2017:884–95. Google Scholar
Combine. 2017. http://co.mbine.org/. Accessed on 24/06/2019.
Waltemath D, Bergmann FT, Chaouiya C, Czauderna T, Gleeson P, Goble C, et al. Meeting report from the fourth meeting of the computational modeling in biology network (COMBINE). Stand Genomic Sci 2014;9:1285–301. CrossrefWeb of ScienceGoogle Scholar
Schreiber F, Bader GD, Gleeson P, Golebiewski M, Hucka M, Le Novère N, et al. Specifications of standards in systems and synthetic biology: status and developments in 2016. J Integr Bioinform 2016;13:289. PubMedGoogle Scholar
Schreiber F, Bader GD, Gleeson P, Golebiewski M, Hucka M, Keating SM, et al. Specifications of standards in systems and synthetic biology: status and developments in 2018. J Integr Bioinform 2018;15:0013. Google Scholar
BioPax. 2017. http://www.biopax.org/. Accessed on 24/06/2019.
Cannon RC, Gleeson P, Crook S, Ganapathy G, Marin B, Piasini E, Silver RA. LEMS: a language for expressing complex biological models in concise and hierarchical form and its use in underpinning NeuroML 2. Front Neurosci 2014;8:79. Google Scholar
Gleeson P, Crook S, Cannon RC, Hines ML, Billings GO, Farinella M, et al. NeuroML: a language for describing data driven models of neurons and networks with a high degree of biological detail. PLoS Comput Biol 2010;6:e1000815. CrossrefPubMedWeb of ScienceGoogle Scholar
Rougny A, Toure V, Moodie S, et al. Systems biology graphical notation: process description language level 1 version 2. J Integr Bioinform 2019;16:20190022. Google Scholar
Sorokin AA, Le Novère N, Luna A, Czauderna T, Demir E, Haw R, et al. Systems biology graphical notation: entity relationship language level 1 version 2. J Integr Bioinform 2015;12:264. PubMedGoogle Scholar
Hucka M, Finney A, Sauro HM, Bolouri H, Doyle JC, Kitano H, et al. The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 2003;19:524–31. PubMedCrossrefGoogle Scholar
Hucka M, Bergmann FT, Chaouiya C, Dräger A, Hoops S, Keating SM, et al. The systems biology markup language (SBML): language specification for level 3 version 2 core release 2. J Integr Bioinform 2019;16:20190021. Google Scholar
Hucka M, Bergmann FT, Dräger A, Hoops S, Keating SM, Le Novère N, et al. The systems biology markup language (SBML): language specification for level 3 version 2 core. J Integr Bioinform 2018;15:20170081. Google Scholar
Olivier BG, Bergmann FT. SBML level 3 package: flux balance constraints, version 2. J Integr Bioinform 2018;15:20170082. Google Scholar
Zhang F, Meier-Schellersheim M. SBML level 3 package: multistate, multicomponent and multicompartment species, version 1, release 1. J Integr Bioinform 2018;15:20170077. Google Scholar
Bergmann FT, Keating SM, Gauges R, Sahle S, Wengler K. SBML level 3 package: render, version 1, release 1. J Integr Bioinform 2018;15:20170078. Google Scholar
Chaouiya C, Keating SM, Bérenguier D, Naldi A, Thieffry D, van Iersel MP, et al. The systems biology markup language (SBML) level 3 package: qualitative models, version 1, release 1. J Integr Bioinform 2015;12:270. PubMedGoogle Scholar
Hucka M, Smith LP. The systems biology markup language (SBML) level 3 package: groups, version 1 release 1. J Integr Bioinform 2016;13:290. Google Scholar
Galdzicki M, Clancy KP, Oberortner E, Pocock M, Quinn JY, Rodriguez CA, et al. The synthetic biology open language (SBOL) provides a community standard for communicating designs in synthetic biology. Nat Biotechnol 2014;32:545–50. Web of ScienceCrossrefPubMedGoogle Scholar
Madsen C, Goni-Moreno A, Umesh P, Palchick Z, Roehner N, Atallah C, et al. Synthetic biology open language (SBOL) version 2.3. J Integr Bioinform 2019;16:20190025. Google Scholar
Madsen C, Goni-Moreno A, Palchick Z, Umesh P, Roehner N, Bartley B, et al. Synthetic biology open language visual (SBOL visual) version 2.1. J Integr Bioinform 2019;16:20180101. Google Scholar
Waltemath D, Adams R, Bergmann FT, Hucka M, Kolpakov F, Miller AK, et al. Reproducible computational biology experiments with SED-ML – the simulation experiment description markup language. BMC Systems Biology 2011;5:198. CrossrefWeb of SciencePubMedGoogle Scholar
Bergmann F, Cooper J, König M, Moraru I, Nickerson D, Novère NL, et al. Simulation experiment description markup language (SED-ML) level 1 version 3 (L1V3). J Integr Bioinform 2018;15:20170086. Google Scholar
Bergmann FT, Adams R, Moodie S, Cooper J, Glont M, Golebiewski M, et al. COMBINE archive and OMEX format: one file to share all information to reproduce a modeling project. BMC Bioinformatics 2014;15:369. PubMedCrossrefWeb of ScienceGoogle Scholar
Juty N, Le Novère N, Laibe C. Identifiers. org and miriam registry: community resources to provide persistent identification. Nucleic Acids Res 2012;40:D580–6. Google Scholar
Courtot M, Juty N, Knüpfer C, Waltemath D, Zhukova A, Drager A, et al. Controlled vocabularies and semantics in systems biology. Molecular Systems Biology 2011;7:543. PubMedWeb of ScienceGoogle Scholar
BioModels.net. 2017. http://co.mbine.org/standards/qualifiers. Accessed on 24/06/2019.
About the article
Published Online: 2019-07-13
Citation Information: Journal of Integrative Bioinformatics, Volume 16, Issue 2, 20190035, ISSN (Online) 1613-4516, DOI: https://doi.org/10.1515/jib-2019-0035.
© 2019, Falk Schreiber et al., published by Walter de Gruyter GmbH, Berlin/Boston. This work is licensed under the Creative Commons Attribution 4.0 Public License. BY 4.0