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COMBINE 2011 – coordination of systems biology standards

Systems biologists and bioinformaticians from all over the world met in the Heidelberg Institute for Theoretical Studies in early September 2011 with the aim of coordinating the various community standards and formats in systems biology and related fields. The “Computational Modelling in Biology Network” (COMBINE) aims to advance international understanding and cooperation in the field of systems biology.

The new HITS building and Villa Rainer in Heidelberg © Architektenkammer Baden-Württemberg

Directly after the 12th International Conference on Systems Biology in Mannheim and Heidelberg (see BIOPRO article entitled "Rückblick: ICSB 2011 oder mit Computermodellen Krankheiten besiegen?"), bioinformaticians and systems biologists from all over the world met in Heidelberg between 3rd and 7th September 2011 for a five-day workshop with the aim of coordinating the development and improvement of standards and formats for computer models of biological pathways, databases and visual representations. The Computational Modelling in Biology Network (COMBINE) 2011 meeting was held in the Studio Villa Bosch in Heidelberg. The meeting, which attracted around 80 scientists from all over the world, was organised by the Heidelberg Institute for Theoretical Studies (HITS gGmbH), a non-profit research institute of the Klaus Tschira Foundation focusing on basic research in the natural sciences, mathematics and computer sciences with the goal of strengthening data-driven science with computer methods, simulations and data management.

COMBINE 2011 was the second meeting organised by the international initiative COMBINE (“Computational Modelling in Biology Network”) which was established in Edinburgh in October 2010 and was designed to replace and to improve the interoperability of existing standards, including SBML (“Systems Biology Markup Language”), SEDML (“Simulation Experiment Description Markup Language), BioPAX (“Biological Pathway Exchange“) and SBGN (“Systems Biology Graphical Notation“), and contribute to closing gaps and advancing necessary new developments. The scientists present spent 20 hours discussing ways to ensure international understanding and cooperation in the field of systems biology. Dr. Nicolas Le Novère from the EBI (European Bioinformatics Institute, Cambridge, UK), who co-ordinates the COMBINE network with Dr. Gary Bader (University of Toronto, Canada) and Dr. Michael Hucka (Caltech, Pasadena, USA), highlighted in his welcome address that the initiative is not aimed at taking over the development of the standard formats, but to promote their interoperability and support necessary harmonisation processes.

A fragile situation

Nicolas Le Novère referred to the fragile situation of the development of systems biology standards; he explained that the processes depended to a large degree on the activity of individual scientists, the majority of whom were present at this year’s COMBINE meeting in the Studio Villa Bosch in Heidelberg. He expressed his belief that if certain key personalities were to disappear from the scene, the model systems would come to a standstill and disappear as well. He also pointed out that the financial resources, which come from many different sources that are often also linked to individuals and do not involve sufficient infrastructure measures, are at risk. Existing standards have been developed on the basis of completely different assumptions, approaches and goals – for example on the basis of implicit knowledge rather than on explicit, mathematically formulated knowledge.

Nicolas Le Novère called for common standards to be applied to the major data sources and to be compatible with computer models of biological systems. Many of these systems have been developed or advanced by participants of the HITS workshop. One of the latest software infrastructures used for the development and management of biological models is JUMMP (“Just a Model Management Platform”), which was announced at last year’s COMBINE meeting in Edinburgh and jointly presented by the German Cancer Research Center and the EBI early this year. COPASI (Complex Pathway Simulator), a software for the modelling, simulation and analysis of complex systems developed during a long-term collaborative project between Professor Dr. Ursula Kummer (BioQuant at the University of Heidelberg) and scientists from the Virginia Bioinformatics Institute (see BIOPRO article published on 4th December 2006), amongst others.

The Virtual Liver Network

Prof. Ursula Kummer from the Department of Modelling of Biological Processes at the University of Heidelberg located in the BioQuant Centre, was previously in charge of a group of researchers at EML Research (now HITS), and is now also involved in one of the most ambitious systems biology projects funded by the German Ministry of Education and Research (BMBF). The "Virtual Liver" project is focused on the development of a dynamic mathematical model that represents, rather than fully replicates, human liver physiology morphology and function, and integrates quantitative data from all levels or organisations, from sub-cellular levels to whole organs. While the predecessor project "HepatoSys" focused on the quantitative understanding of cellular processes in mammalian hepatocytes, the Virtual Liver project now focuses on the multi-scale representation of liver physiology in order to gain an understanding of the dynamics of liver function in normal and diseased states, generate experimentally testable hypotheses and generate simulations based on the knowledge of interactions between cells and metabolic pathways. This requires novel tools, processes and technologies to be developed and applied in systems biology research as well as in medical and pharmaceutical developments. The German Virtual Liver Network was established in 2010 and brings together 70 research groups across Germany. The network is being funded by the BMBF with around 43 million euros for a period of five years. In addition to BioQuant and HITS teams, the project also involves researchers from the German Cancer Research Center (DKFZ), the European Molecular Biology Laboratory (EMBL) and the Institute of Pathology at the University of Heidelberg.

Part of the network of NFκB-independent gene interactions associated with liver cancer. © DKFZ

The German Virtual Liver Network is setting new international standards with its worldwide unique computer model of a complete liver, the central metabolic organ in humans. The German government, which recognised the potential of systems biology and its application in university and non-university research at an early stage and introduced numerous systems biology funding measures, hopes that the Virtual Liver project will contribute to reinforcing the German lead in systems biology and related fields. In future, the German government will pool activities in systems biology under the programme "e:Bio - Innovations Competition Systems Biology", which was launched for the first time in 2010 (external link: https://www.gesundheitsindustrie-bw.debmbf.de/foerderungen/15679.php) with the aim of streamlining systems biology research and better exploiting the effects arising from synergy.

From microscope to mathematical models

The keynote lectures by Michael White (University of Manchester, UK) and Dr. Peer Bork (EMBL) were the highlights of the recent COMBINE workshop. Prof. White, who established the Centre for Cell Imaging at the University of Liverpool, which is equipped with state-of-the-art light microscopes, presented high-resolution images of labelled live cells and observations of individual live cells to illustrate how the transcription factor NFκB (NF-kappaB), which plays a key role in processes such as cell division, apoptosis, inflammation and cancer, oscillates between cytoplasm and cell nucleus and how these oscillations affect the transcription of specific genes. These results provided new insights into NFκB-dependent signalling cascades and cellular processes. Mathematical models are being developed in order to analyse interactions occurring between the individual components of these signalling pathways (including the tumour necrosis factor TNFα and the enzyme IKK (IκB kinase)) as well as to make predictions on the effects of heterogeneous signalling in cells. White and his team have received funding from the BBSRC, one of the most important life sciences funding institutions in Great Britain, as part of the BBSRC’s new comprehensive systems biology funding programme (SABR, “systems approach to biological research”) to continue their research into the dynamics and function of the NFκB signalling system.

Dr. Peer Bork, Senior Group Leader and Joint Coordinator of the Structural and Computational Biology Unit, EMBL, Heidelberg. © EMBL

Dr. Peer Bork, who gave a keynote lecture during the conference dinner, is one of the best known German bioinformaticians in the world. According to ISI (now Thomson Reuters Web of Knowledge), Bork is the most-cited European researcher in the field of molecular biology and genetics, based on figures from the last ten years. Only recently, Bork's paper about the effect of the microbiome (the entirety of microorganisms) of the human destine on human health published in the renowned journal "Cell" received great attention. However, scientists at the COMBINE workshop were mainly interested in Bork's contributions to the development of methods in bioinformatics and systems biology. One of Bork's tools is STRING, a database of known and predicted protein-protein interactions. At present, the database contains more than 5.2 million proteins from more than 1100 organisms. Another tool is STITCH, a "search tool for interactions of chemicals". STITCH contains the interactions of more than 74,000 low-molecular chemical molecules and millions of proteins in 630 organisms. In 2008, Bork and his team published iPath ("Interactive Pathway Explorer"), a Web-based tool for the visualisation, analysis and customisation of the various metabolic pathway maps that provides an overview of the entire metabolism in biological systems. The recently published iPath2.0 version also provides global overview maps of the biosynthesis of secondary metabolites and a selection of important regulatory pathways. iPath therefore provides a general overview of the protein functions in a genome or metagenome.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/combine-2011-coordination-of-systems-biology-standards