Chemical Biology is a rather young interdisciplinary research field1 following a chemistry-driven approach to investigating biology. Chemical entities are introduced into biological systems such as bacteria, cells, tissue, or small model organisms in the form of modified building blocks, tags, enzyme substrates or ligands (binders); these chemical tools then affect the function of cellular target molecules to become activated, inhibited, or labelled for pull down, for detection, or for in situ visualisation.2-4 Many fundamental questions about the molecular mechanisms that underlie biological processes can be addressed advantageously – and sometimes exclusively – by using chemical tools.5
Need for a European Infrastructure
One major route for the discovery of bioactive substances is the systematic empirical screening of large compound collections with dedicated bioassays designed to respond with a robust signal to an anticipated biological activity. The screening provides hit compounds as entry points for further modification by chemists towards useful tools and potential candidates for products. This approach, typical of industry, is technically and logistically rather demanding with respect to the necessary storage and maintenance of a compound collection (several hundred thousand substances), as well as rapid testing with reasonable effort and the necessary reliability. It requires large, dedicated facilities with expensive investments and experienced personnel. Meanwhile, some academic institutions have established such high-tech screening facilities to support interdisciplinary research projects between chemists and biologists. However, these facilities serve mainly their local or national communities, due to limited resources. Linking these facilities within a truly pan-European network, similar to the Molecular Libraries Program (MLP) of the NIH in the US, generates the critical mass to cost-efficiently develop novel tools to the maximal benefit of the scientific community.
The European Strategy Forum on Research Infrastructures (ESFRI)
“The competitive and open access to high quality Research Infrastructures” was recognized vital for developing the European Research Area (ERA).6 Therefore ESFRI was set up in 2002 by the EU Competitiveness Council and the research ministers of the European member states as a meeting of senior representatives for informal consultations on strategic issues related to research infrastructures.7 In 2004 ESFRI received the mandate to develop a European Strategic Roadmap for Research Infrastructures which shall describe the needs for the next 10 to 20 years and identify vital new European research infrastructures in all fields of research. 1000 high-level experts from all Member and Associated States were involved in a bottom-up selection process. The first roadmap was published in October 2006, updated in 2008 and 2010.
The FMP in Berlin, node of the German ChemBioNet and national open access screening platform, submitted a proposal for a European-type ChemBioNet named EU-OPENSCREEN which was included on the ESFRI roadmap in 2008. Since then, ChemBioNet has served as a model for the building of national networks in other European countries; several of them are now on their respective national roadmaps for research infrastructures. EU-OPENSCREEN is currently in its Preparatory Phase Project, funded by the European Commission with 3.7 million Euros. The infrastructure will be fully operational from 2015 onwards.
Concept of the infrastructure
EU-OPENSCREEN is a distributed network that will involve Europe’s leading compound screening sites including expert chemistry and biology groups, to provide to users from academia and SMEs access to their cutting-edge technologies, services and resources required for the discovery and characterisation of biologically active substances. It brings together a multitude of academic groups, thereby integrating the individual biological, chemical and technological expertise only available at these local sites.
The screening sites jointly use one European compound collection. This European Chemical Biology Library (ECBL) will be built on the expert knowledge of European chemists and will be profiled against hundreds of assays. It will be composed of proprietary compounds collected from European chemists and selected commercial compounds to optimally serve the research community and its needs. This compound collection will be managed (incl. storage, QC, distribution of compounds to the service sites) centrally in one Compound Collection Management Facility (CCMF).
EU-OPENSCREEN adopts an open-access poli-cy to support maximal data dissemination and publication, where the same rules will apply to users from academia and SMEs alike. EU-OPENSCREEN’s European Chemical Biology Database (ECBD) will contain validated output from screening centres in a public and pre-release form. It serves as a web portal with search and analysis capabilities and is an environment designed to ensure maximal availability, reuse and analysis of data.
EU-OPENSCREEN will select projects according to scientific novelty and excellence. It will support these projects through assay development, screening and follow-up chemical optimisation as well as biological validation. High quality bioactive tool compounds shall be made openly available to the community.
EU-OPENSCREEN´s service portfolio
Exploring the secrets of life
EU-OPENSCREEN has no bias towards target families, biological topics or models. The chemical tools developed within EU-OPENSCREEN will support a wider use of the pharmacological approach to biology and help to enter new fields beyond the parent themes of pharmacology, human and veterinary medicine, and toxicology. EU-OPENSCREEN explicitly advocates wide-ranging projects that will encourage cross-fertilisation between disciplines and, thus, increase our knowledge base. By utilising chemical tools, new opportunities are opened in systems and network biology (directed and selective perturbation of signalling pathways), structural biology (atomic resolution of compound-target interactions), chronobiology (modulation of biological rhythms), plant biology8-9 (response of wild or crop plants to environmental and agricultural substances), chemical ecology (chemical communication between species), and many more.
EU-OPENSCEEN builds on national networks in 14 European countries and their expert facilities. Currently, 21 institutions are partners in the EU-OPENSCREEN preparatory phase project: Austria – Centre for Molecular Medicine Vienna; Czech Rep. – Inst. Molecular Genetics Prague; Denmark – DTU Copenhagen; EMBL-European Bioinformatics Inst. (EMBL-EBI); Finland – Finnish Inst. for Molecular Medicine Helsinki; France – CNRS; Germany – Leibniz Institute für Molekulare Pharmakologie (FMP), Helmholtz Centre for Infection Research (HZI), Max-Delbrück-Centre for Molecular Medicine (MDC), BMBF, Leibniz Association, Helmholtz Association; Italy – CISI Milan, IRBM Rome; The Netherlands – National Cancer Inst. Amsterdam; Norway – Univ. Oslo; Poland – IMB Lodz; Spain – Barcelona Science Parc; Sweden – Univ. Umeå; Belgium – VIB Ghent; Romania – Inst. Chemistry Timisoara;
Interested institutions: Estonia – Tartu Univ.; Greece – BRFAA Athens; Univ. Ioannina; Hungary – Univ. Budapest; Israel – Weizmann Inst. Rehovot; Portugal – Univ. Lisbon; Switzerland – EPFL Lausanne; UK – Univ. Dundee, Univ. Cambridge.
- Bucci et al. (2010) A decade of chemical biology. Nature Chemical Biology 6: 847-53.
- Mitchison TJ (1994) Towards a pharmacological genetics. Chem Biol 1: 3-6.
- Stockwell BR (2001) Chemical genetics: ligand-based discovery of gene function, Nature Rev Genet 1: 116-125.
- Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999) Small Molecule Inhibitor of Mitotic Spindle Bipolarity Identified in a Phenotype-Based Screen. Science 286: 971-974.
- Schreiber SL (2003) The small-molecule approach to biology: Chemical genetics and diversity-oriented organic synthesis make possible the systematic exploration of biology. Chem & Eng News 81: 51-61.
- ESFRI Biological & Medical Sciences Thematic Working Group Report 2010,
- Ward E and Bernasconi P (1999) Target-based discovery of crop protection chemicals. Nat Biotechnol 17: 618-619.
- Tóth R and van der Hoorn RAL (2009) Trends in Plant Science 15: 81-8.