Abstract (Expand)

The Computational Modeling in Biology Network (COMBINE) is an initiative to coordinate the development of community standards and formats in computational systems biology and related fields. This report summarizes the topics and activities of the fourth edition of the annual COMBINE meeting, held in Paris during September 16-20 2013, and attended by a total of 96 people. This edition pioneered a first day devoted to modeling approaches in biology, which attracted a broad audience of scientists thanks to a panel of renowned speakers. During subsequent days, discussions were held on many subjects including the introduction of new features in the various COMBINE standards, new software tools that use the standards, and outreach efforts. Significant emphasis went into work on extensions of the SBML format, and also into community-building. This year’s edition once again demonstrated that the COMBINE community is thriving, and still manages to help coordinate activities between different standards in computational systems biology.

Authors: Dagmar Waltemath, Frank T. Bergmann, Claudine Chaouiya, Tobias Czauderna, Padraig Gleeson, Carole Goble, Martin Golebiewski, Michael Hucka, Nick Juty, Olga Krebs, Nicolas Le Novère, Huaiyu Mi, Ion I. Moraru, Chris J. Myers, David Nickerson, Brett G. Olivier, Nicolas Rodriguez, Falk Schreiber, Lucian Smith, Fengkai Zhang, Eric Bonnet

Date Published: 15th Mar 2014

Journal: Stand. Genomic Sci.

Abstract (Expand)

Research in Systems Biology involves integrating data and knowledge about the dynamic processes in biological systems in order to understand and model them. Semantic web technologies should be ideal for exploring the complex networks of genes, proteins and metabolites that interact, but much of this data is not natively available to the semantic web. Data is typically collected and stored with free-text annotations in spreadsheets, many of which do not conform to existing metadata standards and are often not publically released. Along with initiatives to promote more data sharing, one of the main challenges is therefore to semantically annotate and extract this data so that it is available to the research community. Data annotation and curation are expensive and undervalued tasks that have enormous benefits to the discipline as a whole, but fewer benefits to the individual data producers. By embedding semantic annotation into spreadsheets, however, and automatically extracting this data into RDF at the time of repository submission, the process of producing standards-compliant data, that is available for semantic web querying, can be achieved without adding additional overheads to laboratory data management. This paper describes these strategies in the context of semantic data management in the SEEK. The SEEK is a web-based resource for sharing and exchanging Systems Biology data and models that is underpinned by the JERM ontology (Just Enough Results Model), which describes the relationships between data, models, protocols and experiments. The SEEK was originally developed for SysMO, a large European Systems Biology consortium studying micro-organisms, but it has since had widespread adoption across European Systems Biology.

Authors: None

Date Published: 2013

Journal: The Semantic Web – ISWC 2013

Abstract (Expand)

The increase in volume and complexity of biological data has led to increased requirements to reuse that data. Consistent and accurate metadata is essential for this task, creating new challenges in semantic data annotation and in the constriction of terminologies and ontologies used for annotation. The BioSharing community are developing standards and terminologies for annotation, which have been adopted across bioinformatics, but the real challenge is to make these standards accessible to laboratory scientists. Widespread adoption requires the provision of tools to assist scientists whilst reducing the complexities of working with semantics. This paper describes unobtrusive ‘stealthy’ methods for collecting standards compliant, semantically annotated data and for contributing to ontologies used for those annotations. Spreadsheets are ubiquitous in laboratory data management. Our spreadsheet-based RightField tool enables scientists to structure information and select ontology terms for annotation within spreadsheets, producing high quality, consistent data without changing common working practices. Furthermore, our Populous spreadsheet tool proves effective for gathering domain knowledge in the form of Web Ontology Language (OWL) ontologies. Such a corpus of structured and semantically enriched knowledge can be extracted in Resource Description Framework (RDF), providing further means for searching across the content and contributing to Open Linked Data (

Authors: Katy Wolstencroft, Stuart Owen, Matthew Horridge, Simon Jupp, Olga Krebs, Jacky Snoep, Franco Du Preez, Wolfgang Müller, Robert Stevens, Carole Goble

Date Published: 1st Oct 2012

Journal: Concurrency Computat.: Pract. Exper.

Abstract (Expand)

An existing detailed kinetic model for the steady-state behavior of yeast glycolysis was tested for its ability to simulate dynamic behavior. Using a small subset of experimental data, the original model was adapted by adjusting its parameter values in three optimization steps. Only small adaptations to the original model were required for realistic simulation of experimental data for limit-cycle oscillations. The greatest changes were required for parameter values for the phosphofructokinase reaction. The importance of ATP for the oscillatory mechanism and NAD(H) for inter-and intra-cellular communications and synchronization was evident in the optimization steps and simulation experiments. In an accompanying paper [du Preez F et al. (2012) FEBS J doi:10.1111/j.1742-4658.2012.08658.x], we validate the model for a wide variety of experiments on oscillatory yeast cells. The results are important for re-use of detailed kinetic models in modular modeling approaches and for approaches such as that used in the Silicon Cell initiative. Database The mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at

Authors: Franco Du Preez, David D van Niekerk, Bob Kooi, Johann M Rohwer, Jacky Snoep

Date Published: 21st Jun 2012

Journal: The FEBS journal

Abstract (Expand)

In an accompanying paper [du Preez et al., (2012) FEBS J doi: 10.1111/j.1742-4658.2012.08665.x], we adapt an existing kinetic model for steady-state yeast glycolysis to simulate limit-cycle oscillations. Here we validate the model by testing its capacity to simulate a wide range of experiments on dynamics of yeast glycolysis. In addition to its description of the oscillations of glycolytic intermediates in intact cells and the rapid synchronization observed when mixing out-of-phase oscillatory cell populations (see accompanying paper), the model was able to predict the Hopf bifurcation diagram with glucose as the bifurcation parameter (and one of the bifurcation points with cyanide as the bifurcation parameter), the glucose- and acetaldehyde-driven forced oscillations, glucose and acetaldehyde quenching, and cell-free extract oscillations (including complex oscillations and mixed-mode oscillations). Thus, the model was compliant, at least qualitatively, with the majority of available experimental data for glycolytic oscillations in yeast. To our knowledge, this is the first time that a model for yeast glycolysis has been tested against such a wide variety of independent data sets. Database The mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at

Authors: Franco Du Preez, David D van Niekerk, Jacky Snoep

Date Published: 13th Jun 2012

Journal: The FEBS journal

Abstract (Expand)

Encouraging more broad and inclusive data sharing in today's world will involve concerted community efforts to overcome technical barriers and human foibles. Vivien Marx investigates. (includess comments from Carole Goble, and mentions SysMO, SEEK and RightField).

Author: Vivien Marx

Date Published: 7th Jun 2012

Journal: Nat Biotechnol

Abstract (Expand)

Yeast glycolytic oscillations have been studied since the 1950s in cell-free extracts and intact cells. For intact cells, sustained oscillations have so far only been observed at the population level, i.e. for synchronized cultures at high biomass concentrations. Using optical tweezers to position yeast cells in a microfluidic chamber, we were able to observe sustained oscillations in individual isolated cells. Using a detailed kinetic model for the cellular reactions, we simulated the heterogeneity in the response of the individual cells, assuming small differences in a single internal parameter. This is the first time that sustained limit-cycle oscillations have been demonstrated in isolated yeast cells. Database The mathematical model described here has been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at free of charge.

Authors: Anna-Karin Gustavsson, David D van Niekerk, Caroline B Adiels, Franco Du Preez, Mattias Goksör, Jacky Snoep

Date Published: 23rd May 2012

Journal: The FEBS journal

Abstract (Expand)

To make full use of research data, the bioscience community needs to adopt technologies and reward mechanisms that support interoperability and promote the growth of an open 'data commoning' culture. Here we describe the prerequisites for data commoning and present an established and growing ecosystem of solutions using the shared 'Investigation-Study-Assay' framework to support that vision.

Authors: Susanna-Assunta Sansone, Philippe Rocca-Serra, Dawn Field, Eamonn Maguire, Chris Taylor, Oliver Hofmann, Hong Fang, Steffen Neumann, Weida Tong, Linda Amaral-Zettler, Kimberly Begley, Tim Booth, Lydie Bougueleret, Gully Burns, Brad Chapman, Tim Clark, Lee-Ann Coleman, Jay Copeland, Sudeshna Das, Antoine de Daruvar, Paula de Matos, Ian Dix, Scott Edmunds, Chris T Evelo, Mark J Forster, Pascale Gaudet, Jack Gilbert, Carole Goble, Julian L Griffin, Daniel Jacob, Jos Kleinjans, Lee Harland, Kenneth Haug, Henning Hermjakob, Shannan J Ho Sui, Alain Laederach, Shaoguang Liang, Stephen Marshall, Annette McGrath, Emily Merrill, Dorothy Reilly, Magali Roux, Caroline E Shamu, Catherine A Shang, Christoph Steinbeck, Anne Trefethen, Bryn Williams-Jones, Katy Wolstencroft, Ioannis Xenarios, Winston Hide

Date Published: 28th Jan 2012

Journal: Nat. Genet.

Abstract (Expand)

BACKGROUND: Ontologies are being developed for the life sciences to standardise the way we describe and interpret the wealth of data currently being generated. As more ontology based applications begin to emerge, tools are required that enable domain experts to contribute their knowledge to the growing pool of ontologies. There are many barriers that prevent domain experts engaging in the ontology development process and novel tools are needed to break down these barriers to engage a wider community of scientists. RESULTS: We present Populous, a tool for gathering content with which to construct an ontology. Domain experts need to add content, that is often repetitive in its form, but without having to tackle the underlying ontological representation. Populous presents users with a table based form in which columns are constrained to take values from particular ontologies. Populated tables are mapped to patterns that can then be used to automatically generate the ontology's content. These forms can be exported as spreadsheets, providing an interface that is much more familiar to many biologists. CONCLUSIONS: Populous's contribution is in the knowledge gathering stage of ontology development; it separates knowledge gathering from the conceptualisation and axiomatisation, as well as separating the user from the standard ontology authoring environments. Populous is by no means a replacement for standard ontology editing tools, but instead provides a useful platform for engaging a wider community of scientists in the mass production of ontology content.

Authors: Simon Jupp, Matthew Horridge, Luigi Iannone, Julie Klein, Stuart Owen, Joost Schanstra, Katy Wolstencroft, Robert Stevens

Date Published: 25th Jan 2012

Journal: BMC bioinformatics

Abstract (Expand)

The increasing use of computational simulation experiments to inform modern biological research creates new challenges to annotate, archive, share and reproduce such experiments. The recently published Minimum Information About a Simulation Experiment (MIASE) proposes a minimal set of information that should be provided to allow the reproduction of simulation experiments among users and software tools.

Authors: Dagmar Waltemath, Richard Adams, Frank T Bergmann, Michael Hucka, Fedor Kolpakov, Andrew K Miller, Ion I Moraru, David Nickerson, Sven Sahle, Jacky Snoep, Nicolas Le Novère

Date Published: 15th Dec 2011

Journal: BMC Syst Biol

Abstract (Expand)

Systems biology research is typically performed by multidisciplinary groups of scientists, often in large consortia and in distributed locations. The data generated in these projects tend to be heterogeneous and often involves high-throughput "omics" analyses. Models are developed iteratively from data generated in the projects and from the literature. Consequently, there is a growing requirement for exchanging experimental data, mathematical models, and scientific protocols between consortium members and a necessity to record and share the outcomes of experiments and the links between data and models. The overall output of a research consortium is also a valuable commodity in its own right. The research and associated data and models should eventually be available to the whole community for reuse and future analysis. The SEEK is an open-source, Web-based platform designed for the management and exchange of systems biology data and models. The SEEK was originally developed for the SysMO (systems biology of microorganisms) consortia, but the principles and objectives are applicable to any systems biology project. The SEEK provides an index of consortium resources and acts as gateway to other tools and services commonly used in the community. For example, the model simulation tool, JWS Online, has been integrated into the SEEK, and a plug-in to PubMed allows publications to be linked to supporting data and author profiles in the SEEK. The SEEK is a pragmatic solution to data management which encourages, but does not force, researchers to share and disseminate their data to community standard formats. It provides tools to assist with management and annotation as well as incentives and added value for following these recommendations. Data exchange and reuse rely on sufficient annotation, consistent metadata descriptions, and the use of standard exchange formats for models, data, and the experiments they are derived from. In this chapter, we present the SEEK platform, its functionalities, and the methods employed for lowering the barriers to adoption of standard formats. As the production of biological data continues to grow, in systems biology and in the life sciences in general, the need to record, manage, and exploit this wealth of information in the future is increasing. We promote the SEEK as a data and model management tool that can be adapted to the specific needs of a particular systems biology project.

Authors: None

Date Published: 29th Sep 2011

Journal: Meth. Enzymol.

Abstract (Expand)

One of the main pathways for the detoxification of reactive metabolites in the liver involves glutathione conjugation. Metabolic profiling studies have shown paradoxical responses in glutathione-related biochemical pathways. One of these is the increase in 5-oxoproline and ophthalmic acid concentrations with increased dosage of paracetamol. Experimental studies have thus far failed to resolve these paradoxes and the robustness of how these proposed biomarkers correlate with liver glutathione levels has been questioned. To better understand how these biomarkers behave in the glutathione system a kinetic model of this pathway was made. By using metabolic control analysis and by simulating biomarker levels under a variety of conditions, we found that 5-oxoproline and ophthalmic acid concentrations may not only depend on the glutathione but also on the methionine status of the cell. We show that neither of the two potential biomarkers are reliable on their own since they need additional information about the methionine status of the system to relate them uniquely to intracellular glutathione concentration. However, when both biomarkers are measured simultaneously a direct inference of the glutathione concentration can be made, irrespective of the methionine concentration in the system.

Authors: Suzanne Geenen, Franco Du Preez, Michael Reed, H Frederik Nijhout, J Gerry Kenna, Ian D Wilson, Hans Westerhoff, Jacky Snoep

Date Published: 24th Aug 2011

Journal: Eur J Pharm Sci

Abstract (Expand)

The development of disease may be characterized as a pathological shift of homeostasis; the main goal of contemporary drug treatment is, therefore, to return the pathological homeostasis back to the normal physiological range. From the view point of systems biology, homeostasis emerges from the interactions within the network of biomolecules (e.g. DNA, mRNA, proteins), and, hence, understanding how drugs impact upon the entire network should improve their efficacy at returning the network (body) to physiological homeostasis. Large, mechanism-based computer models, such as the anticipated human whole body models (silicon or virtual human), may help in the development of such network-targeting drugs. Using the philosophical concept of weak and strong emergence, we shall here take a more general look at the paradigm of network-targeting drugs, and propose our approaches to scale the strength of strong emergence. We apply these approaches to several biological examples and demonstrate their utility to reveal principles of bio-modeling. We discuss this in the perspective of building the silicon human.

Authors: Alexey Kolodkin, Fred C Boogerd, Nick Plant, Frank J Bruggeman, Valeri Goncharuk, Jeantine Lunshof, Rafael Moreno-Sanchez, Nilgun Yilmaz, Barbara M Bakker, Jacky Snoep, Rudi Balling, Hans Westerhoff

Date Published: 16th Jun 2011

Journal: Eur J Pharm Sci

Abstract (Expand)

MOTIVATION: In the Life Sciences, guidelines, checklists and ontologies describing what metadata is required for the interpretation and reuse of experimental data are emerging. Data producers, however, may have little experience in the use of such standards and require tools to support this form of data annotation. RESULTS: RightField is an open source application that provides a mechanism for embedding ontology annotation support for Life Science data in Excel spreadsheets. Individual cells, columns or rows can be restricted to particular ranges of allowed classes or instances from chosen ontologies. The RightField-enabled spreadsheet presents selected ontology terms to the users as a simple drop-down list, enabling scientists to consistently annotate their data. The result is 'semantic annotation by stealth', with an annotation process that is less error-prone, more efficient, and more consistent with community standards. Availability and implementation: RightField is open source under a BSD license and freely available from

Authors: Katy Wolstencroft, Stuart Owen, Matthew Horridge, Olga Krebs, Wolfgang Müller, Jacky Snoep, Franco Du Preez, Carole Goble

Date Published: 26th May 2011

Journal: Bioinformatics

Abstract (Expand)

This paper briefly describes the SABIO-RK database model for the storage of reaction kinetics information and the guidelines followed within the SABIO-RK project to annotate the kinetic data. Such annotations support the definition of cross links to other related databases and augment the semantics of the data stored in the database.

Authors: Isabel Rojas, Martin Golebiewski, Renate Kania, Olga Krebs, Saqib Mir, Andreas Weidemann, Ulrike Wittig

Date Published: 14th Sep 2007

Journal: In Silico Biol. (Gedrukt)

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