The group tries to understand how cellular and molecular systems interpret signals from their environment and adapt their behaviour as a consequence. We use detailed and quantitative computational models and simulations to reproduce and study cellular and molecular processes. The group also participates to the development of community tools and services that facilitate research in computational systems biology. Since the group moved at the Babraham Institute in October 2012, its activity has unfolded along four parallel though cross-fertilizing themes.
1) Molecular basis of neuronal signalling: The group is partner of several collaborations aiming at understanding synaptic transmission at a systems level. They include the European projects SynSys, studying the molecular networks underpinning synaptic function, and AgedBrainSYSBIO, using GWAS, protein interaction networks and pathway modelling to better understand late onset Alzheimer's disease. We develop structural models of dynamic macromolecular assemblies and chemical kinetic models of transduction pathways. To link biochemical pathways and neuronal function, the group created hybrid models of entire neurons, linking signalling and electrical behaviour through event driven synchronizations (e.g. Mattioni & Le Novère 2013 PloS ONE).
2) Cross-talks between MAPK, Calcium and phosphoinositide signallings: We believe intracellular signalling is largely made of "vertical" kinase cascades cross-linked by horizontal phosphatases modulations. Accordingly, we are trying to understand the connections of the pathways listed above, key in regulating synaptic plasticity and extensively studied in the signalling ISP and elsewhere in the institute. We have put a particular emphasis on the calcium/calmodulin target, the modulation of ERK phosphorylation, and the fine regulation of PIP3 levels upon perturbations. We have for instance shown that the balance of CaMKII and calcineurin activation in the neurons depend on calcium signals amplitude, frequency and duration (Stefan et al 2008 PNAS, Li et al 2012. PloS ONE). Within the framework of the Signalling Institute Strategic Programme, and a BBSRC/Astrazeneca funded collaboration with Phil Hawkins and Len Stephens, are analysis and modelling the effects of PIP3 signalling perturbations More information
3) Large scale model development: With the development of vast curated pathway databases and the availability of omics datasets, it has become possible to generate mathematical models of large cellular systems. The group is at the core of partnership developing standard formats and related technology to enable data and model integration. We recently participated to the construction of the entire human metabolic network, and the subsequent modelling of 65 cell-types (Thiele et al Nat Biotechnol). In order to facilitate future efforts, the group coordinated the automated production of mathematical models of metabolic networks and signalling pathways, resulting in 140000 (unparametrised) models ( Büchel et al).
4) Ageing and stem cells: Regulation of autophagy has been shown to be key in maintaining healthy ageing, extending life-span, and has been proposed as a path to correct mysfolded proteins disorders such as Alzheimer's disease. We are developing a research program to understand the formation of autophagosome in collaboration with the group of Nick Ktistakis. Autophagy is also a key component of the models we are developing for the AgedBrainSYSBIO project.
Regenerative medicine is one promising way for fighting ageing. Stem Cells, embryonic or induced, will be key to those efforts. The group intend to focus a large part of its efforts in that direction in the future.