Emeritus Professor of Cardiovascular Physiology, Department of Physiology, Anatomy and Genetics, Oxford University, UK
Author of the book The Music of Life
Title: Differential and Integral views of gene-phenotype relations: a systems biological insight
Abstract: This lecture uses an integrative systems biological view of the relationship between genotypes and phenotypes to clarify some conceptual problems in biological debates about causality. The differential (gene-centric) view is incomplete in a sense analogous to using differentiation without integration in mathematics. Differences in genotype are frequently not reflected in significant differences in phenotype as they are buffered by networks of molecular interactions capable of substituting an alternative pathway to achieve a given phenotype characteristic when one pathway is removed. Those networks integrate the influences of many genes on each phenotype so that the effect of a modification in DNA depends on the context in which it occurs. Mathematical modelling of these interactions can help to understand the mechanisms of buffering and the contextual-dependence of phenotypic outcome, and so to represent correctly and quantitatively the relations between genomes and phenotypes. By incorporating all the causal factors in generating a phenotype, this approach also highlights the role of non-DNA forms of inheritance, and of the interactions at multiple levels.
Chair in Cardiac Biophysics and Systems Biology, NHLI, Imperial College, London, UK
Title: Systems Biology of the Heart: Hype or Hope
Abstract: 'Systems Biology' has developed into an omni-present term, used as a strategic concept, research direction, funding priority, or as a label which - at least occasionally - is employed in the absence of much thought about its meaning. It may not come as a surprise, therefore, that a concise definition of the term that would be generally acceptable remains elusive. This lecture will briefly explore the concept of a system, highlight systems research as an approach, and apply this approach to cardiac biology. In the process, challenges and opportunity of interdigitating 'wet' and 'dry' studies into biological structure and function, from sub-cellular levels to clinical relevance, will be illustrated, followed by a praise of failure.
Kohl P, Crampin E, Quinn TA & Noble D. Systems biology: an approach. Nature CPT 2010/88:25–33. [http://www.ncbi.nlm.nih.gov/pubmed/20531468]
Quinn TA, Kohl P. Systems biology of the heart: hype or hope? Ann N Y Acad Sci 2011/1245:40-43.[http://www.ncbi.nlm.nih.gov/pubmed/22211976]
Deputy Director of Systems Biology Ireland, Dublin, Republic of Ireland.
Title: Signalling ballet in four dimensions
Abstract: The advancements in "omics" (proteomics, genomics, and metabolomics) technologies have yielded large inventories of genes, transcripts, proteins, and metabolites. The challenge is to find out how these entities work together to regulate cellular responses to external and internal cues. Computational models provide insight into the intricate relationship between stimuli and responses, revealing mechanisms that enable networks to amplify signals and reduce noise and generate discontinuous bistable dynamics or oscillations. In this talk, we review experimental and theoretical progress towards better understanding how the cellular functions are encoded by the spatiotemporal dynamics of downstream signalling networks. We focus on how cellular networks integrate the temporal and spatial information to determine specific biological outcomes, and how the designed features of the networks specify biological decisions.
Kholodenko, B. N., Hancock, J. F. & Kolch, W. (2010) Signalling ballet in space and time. Nat Rev Mol Cell Biol. 11, 414-426.
Nakakuki, T., Birtwistle, M. R., Saeki, Y., Yumoto, N., Ide, K., Nagashima, T., Brusch, L., Ogunnaike, B. A., Okada-Hatakeyama, M. & Kholodenko, B. N. (2010) Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics, Cell. 141, 884-896.
Nguyen, L. K., Munoz-Garcia, J., Maccario, H., Ciechanover, A., Kolch, W. & Kholodenko, B. N. (2011) Switches, Excitable Responses and Oscillations in the Ring1B/Bmi1 Ubiquitination System, PLoS Comput Biol. 7, e1002317.
Tsyganov, M. A., Kolch, W. & Kholodenko, B. N. (2012) The topology design principles that determine the spatiotemporal dynamics of G-protein cascades, Molecular BioSystems. 8, 730-43.
Kholodenko, B., Yaffe, M. B. & Kolch, W. (2012) Computational approaches for analysing information flow in biological networks, Sci Signal. 5, re1.