Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2019

Abstract This special issue of the Journal of Integrative Bioinformatics presents an overview of COMBINE standards and their latest specifications. The standards cover representation formats for computational modeling in synthetic and systems biology and include BioPAX, CellML, NeuroML, SBML, SBGN, SBOL and SED-ML. The articles in this issue contain updated specifications of SBGN Process Description Level 1 Version 2, SBML Level 3 Core Version 2 Release 2, SBOL Version 2.3.0, and SBOL Visual Version 2.1.


Introduction
Standards play an important role in Systems and Synthetic Biology. COMBINE ('COmputational Modeling in BIology' NEtwork) [1], [2] 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 COM-BINE 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" [3].
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 COMBINErelated publications [1], [2], [4] provide more information. Please note that this editorial contains similar information to overviews in earlier special issues [5], [6], [7]. 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 [5]. Since then a regular special issue of JIB provides updates to COMBINE standards. The latest update was published in 2018 [7]. This special issue presents developments of standards and related initiatives in 2018/19.

Latest Versions of COMBINE Standards
When using and implementing COMBINE standards, please refer to the following specifications. Note: New specifications are highlighted with *NEW*.

SBOL (Synthetic Biology Open Language)
SBOL (Synthetic Biology Open Language) [29], specifications are -*NEW* SBOL Version 2.3.0 [30] -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 [31] -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.

Associated Standards
Associated standards provide an additional layer of semantics to COMBINE representation formats. These are: -COMBINE Archive [34], specification is COMBINE Archive 1.0 [35]; -Identifiers.org URIs [36], community resources to provide persistent identification (no specification); -Systems Biology Ontology and Kinetic Simulation Algorithm Ontology [37] for controlled vocabularies and semantics in systems biology (no specification); -BioModels.net qualifiers [38] for representing relation between a model component and the resource used to annotate it (no specification).