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Informatics challenges in systems biology. Douglas Kell School of Chemistry, University of Manchester, MANCHESTER M60 1QD, U.K. dbk@man.ac.uk http://dbk.ch.umist.ac.uk/ http://www.mib.ac.uk. “Biology is an informational science” Lee Hood, Director, Institute for Systems Biology, Seattle.
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Informatics challenges in systems biology Douglas Kell School of Chemistry, University of Manchester, MANCHESTER M60 1QD, U.K.dbk@man.ac.uk http://dbk.ch.umist.ac.uk/ http://www.mib.ac.uk
“Biology is an informational science”Lee Hood, Director, Institute for Systems Biology, Seattle.
HYPOTHESIS/ ANALYSIS/ DEDUCTION SYNTHESIS/ INDUCTION dB The cycle of knowledge ‘KNOWLEDGE/ RULES OBSERVATIONS / DATA
Timeline • Pre-genomics Post-genomics/ functional genomics Systems Biology • Organismal Cellular Molecular Systems
The Manchester Interdisciplinary Biocentre (2005-) Postdoc and studentship positions available MIB
The MIB model - a major international research centre - a partner to the disciplines - parallel to schools/faculties - one of a number of expected IRCs Chemistry Chem. Eng. Maths/ Computing Biology MIB Medicine/ Pharmacy http://www.mib.ac.uk Physics Engineering Mat. Sci. MIB
Summary of NF-kB – 3 steps • NF-B is a nuclear transcription factor and is held inactive in the cytoplasm of non-stimulated cell by three IB isoforms • During cell stimulation, the IKK complex is activated, leading to phosphorylation and ubiquitination (and removal) of the IB proteins. • Free NF-B translocates to the Nucleus, activating genes including IB. IB& - are synthesised at a steady rate, allowing for complex temporal control of NF-B activation involving negative feedback (2) (1) (3)
The model has 64 unidirectional reactions & 26 variables Violet red circles = IB-NF-B cytoplasmic reactions; Blue Arrows and circles = Nuclear Transport; Magenta Arrows and Pink circles = IB mRNA synthesis (including transcription, translation and degradation); Black Arrows and white circles = IB-NF-B nuclear reactions; Light Green Arrows and circles = IB Phosphorylation and Degradation reactions; Brown Arrows and brown circles = Bimolecular IKK- IB and tri-molecular IKK- IB-NF-B; Yellow Arrows and circles = IKK slow adaptation coefficient
Main areas of informatics challenges • Data and model storage and standards – including new kinds of data • Forward modelling • Inverse modelling • Data mining
Data and model storage and standards – including new kinds of data • Existing data standards/models and dB are not vertically integrated; MaxD (transcriptome), PEDRo (proteome), ArMet (metabolome) • All relate to variables, not parameters (which are more important for SB) • Models – SBML (http://sbml.org) • Create, edit, visualise, disseminate, analyse, compare with each other and with experimental data, mine • Potentially large and novel datasets e.g. of cellular images
“Real” oscillations of GFP-NFkBn observed microscopically with labelled IkBa and NFkB Nelson et al 2004 Science 306, 704-8 NB we measure individual cells, not ensembles
The timing and amount of oscillations depend strongly on the type of stimulation (various amounts and times of TNFa, different individual cells) Nelson et al 2004
Forward modelling Running a forward ODE model is comparatively easy e.g. with Gepasi (Mendes & Kell, Bioinformatics (1998) 14, 869-883). PDEs are much harder computationally
After pre-equilibration for 2000s, IKK is ‘added’ at 0.1 mM IKK NFkBn
Largest sensitivity values for each reaction (D100%)(Ihekwaba et al., Systems Biology 1, 93-103 (2004)
Mathematical challenge is the Inverse Problem – work out the system that gave THIS time series
Disease diagnosis by GC-tof- MS – look for metabolites that discriminate ‘cases’ from ‘controls’ IF 403 < 0.035 AND (IF 415 < 0.001 OR IF 427 > 0.001) THEN disease IF 403 > 0.015 AND (IF 415 <0.012) THEN disease
Conclusion • (Systems) Biology is an informational science • At least 4 main areas where informatics is central • Many new and interesting challenges for integrating data and models to achieve a true systems understanding • Huge potential scientific (and indeed commercial) pay-offs