The Warwick Systems Biology Centre (WSB) represents an £11m investment by the University of Warwick to create an autonomous centre to capitalise on strengths in multidisciplinary research. We combine experimental and mathematical approaches, focusing on linking models with the huge volume and diversity of contemporary cellular and molecular data; such as that coming from high-throughput, genome-wide and imaging technologies. Our aim is to improve understanding of complex biological systems so that a broad range of biological and medical priorities, such as disease mechanisms, pharmaceutical drug discovery, drug target validation, and challenges in horticulture and agriculture, can be addressed.

Systems biology involves developing the understanding of a biological system through the mathematical and computational modelling of the interactions of components of the system, leading to the expression of this understanding in qualitative and quantitative terms. A key feature that distinguishes the modern approach to Systems Biology is the aim of linking modelling with the huge volume and diversity of contemporary cellular and molecular data such as that coming from high-throughput, genome-wide and imaging technologies. Understanding of complex biological processes will allow us to tackle many important problems and will be crucial in addressing an enormously broad range of biological and medical priorities such as disease mechanisms, pharmaceutical drug discovery, drug target validation, and horticulture and agriculture.

The Warwick Systems Biology Centre (WSB) was founded in 2004/5 by the University of Warwick to build on its strengths in multidisciplinary research, the mathematical and physical sciences and the life sciences. This initial investment funded the appointment of 11 new staff, purpose-designed accommodation and a substantial amount of experimental and computing equipment. Several further staff with interests in Systems Biology have since been appointed throughout the University. The Centre is an autonomous institute and has joint staff with the Medical School, the School of Life Sciences and the Mathematics Department. It also has particularly strong links to the Departments of Chemistry, Physics and Statistics. It moved into its own new accommodation in Summer 2006. The Centre's director is Professor David Rand.

One of the Centre’s unique selling points is the strength and breadth of the mathematical, statistical and bioinformatics skills that it brings to bear on its biological projects. Such skills are key to SB because many SB projects present mathematical challenges that are at the cutting-edge and many biological projects produce data that needs sophisticated mathematical analysis and modelling that often requires the development of new statistical tools. WSB’s scientific programme is built around a number of substantial projects in addition to the individual research programmes of its staff and collaborators. A very broad range of biological systems are covered from the molecular level to the whole organism and we use and develop tools for a very extensive set of data types. Areas where such cross-cutting dry technology has been developed include network reconstruction, imaging, transcriptional dynamics, promoter analysis, model analysis and experimental optimisation.

The Centre has a three person bioinformatics support group that comprises a senior bioinformatics software engineer (Jay Moore), and two junior bioinformaticians (Clare Boddington and currently being appointed). In addition, there is a combined systems administrator and scientific programmer (Paul Brown). These people support databases & data management, data capture & basic processing, and pipelines and workflows for processing complex data such as ChIP-seq and microarray time series. In addition, they interface to our research projects and the associated postdocs, and provide support for advanced analysis, the creation of user-friendly and web-based tools, and scientific and systems computing.

Plants & crops
There is very active area for us and within Warwick there is substantial SB grant funding in this area particularly in plant stress (e.g. PRESTA, >£5m), the circadian clock and root nodulation. Plans for developing this area further are well-advanced. An important development will be the extension of a SB approach to crops to connect models and data at the network level to crop models and to deal with multiple genes. Outside Warwick there are strong collaborations with European groups (notably to develop biological technology) and with other UK groups (e.g. Nottingham, Edinburgh, York, Exeter, Essex and through the £5m ROBuST project).

Medical
There are particularly strong joint research programmes with WMS in the areas of reproductive health, metabolic medicine such as diabetes and obesity, stress in vascular medicine and nutrition. Collaborations with groups outside of Warwick includes a £5.4m SABR project on NF-kappaB signalling led by Mike White and on the dry side David Rand, a Wellcome programme grant to study the 4-d transcriptional dynamics of prolactin in the pituitary, a £3m BBSRC LoLa grant (co-I Hugo van den Berg) with immunologists in Cardiff to accomplish full characterization of the agonists of T cell receptors, and a cross-Europe ERASysBio+ project on the chronobiology of cancer (co-coordinator David Rand). Jointly with WMS we are building a substantial collaboration with the Liverpool School of Tropical Medicine in a number of high-impact areas of common interest e.g. Red blood cell - Endothelium adhesion and signalling, drug design, insecticide transport and resistance, and modelling of the electron transport chain and related metabolism.

Core Biology
Within Warwick there are an increasing number of collaborations with the Biomedical Cell Biology Group in WMS for example with the Centre for Mechanochemical Cell Biology in the area of systems biology of the dynamic microtubule end complex and with the lab of Graham Ladds studying G-protein signalling and also determinants of cell polarity. Modelling of cellular motility and actin pattern formation has been a recent theme of work by Till Bretschneider and Nigel Burroughs. Till Bretschneider has a number of other collaborations with leading groups in the area of cell polarity and actin-myosin cytoskeleton organisation and reorganization. He is PI on BBSRC grant “A 3D-perspective on neutrophil migration” with leading biochemists from the Babraham Institute and with CI Weijer (Dundee) he has a Wellcome funded project on chemotactic cell sorting during development.
There is an increasing interest in applying systems biology ideas to biotechnology and Nigel Burroughs in a member of a UK-US team funded by the NSF and BBSRC working on a multi-tiered approach to generating increased carbon dioxide for photosynthesis. We see this as a jumping-off point for a development of a programme of applications of synthetic biology and metabolic engineering to bioenergy.
In Neuroscience, WSB has actively contributed to interdisciplinary neuroscience which is very active at Warwick. In particular, it facilitates communications across the campus, has financially supported annual summer meetings and Magnus Richardson and Yulia Timofeeva (Complexity) recently organized a highly successful international conference Dendrites, Neurones and Networks. In am ongoing grant funded collaboration Richardson and Mark Wall (School of Life Sciences) aim to considerably increase experimental capacity at Warwick with a key aim over the next 5 years to make Warwick a leading centre in the empirically driven modelling and theory of spatial effects in the neocortex. Other ongoing collaborations include joint projects with Bruno Frenguelli (Life Sciences) on epilepsy prediction, with Anatoly Shmygol (WMS) on intercellular calcium dynamics, and a multi-disciplinary imaging project led by Matthew Turner (Physics) and James Covington (Engineering).
In Microbiology, there the immediate aim is to follow up the c€4.5m SysMO grant Global metabolic switching in Streptomyces coelicolor (led by Liz Wellington) to determine the utilisation networks of phosphate, carbon and nitrogen, from environment monitoring through to their impact on the secondary metabolism profiles.

Cross-cutting dry technology
A distinguishing characteristic of the Warwick Centre is its focus on using its mathematical and statistical skills to develop tools for the analysis of data and models. Areas where we have developed such tools include:
¥ imaging: e.g. tools for tracking cells (Bretschneider & Du), reconstructing membranes etc from z-stacks (Burroughs), high resolution tracking of cell membrane dynamics in moving cells (Bretschneider), ...
¥ transcription: e.g. tools for reconstructing transcriptional dynamics from imaging data (Rand) (subject of recent high-impact PLoS Biology paper)
¥ genomics: e.g. tools for clustering (Wild), locating differential gene expression (Wild), network reconstruction (Burroughs, Wild), ChIP-seq analysis (Ott), switch tool to identify key events in time-series (Rand, Finkenstadt)...
¥ proteomics: e.g. protein structure prediction, David Wild is PI on a £200k grant Analysing Protein Energetics with Statistical Machine Learning
¥ other bioinformatics: e.g. APPLES (Ott) (integrated set of tools for analysis of regulatory regions and transcription factor binding sites)
¥ model analysis: e.g. theory package for global sensitivity analysis (Rand & Paul Brown); experimental optimisation package (Rand & Paul Brown);
Our ability to develop such tools is key to our attractiveness for collaborations and developing these tools is at the heart of our plans.

Further information about the Centre can be obtained from Professor David Rand (d.a.rand@warwick.ac.uk).

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