1. University of Sheffield www.dcs.shef.ac.uk/~rod/ Modelling Tissue Development Rod Smallwood, Mike Holcombe, Sheila Mac Neil, Rod Hose, Richard Clayton (University of Sheffield), Jenny Southgate (University of York)

2. University of Sheffield www.dcs.shef.ac.uk/~rod/ The social behaviour of cells How do these individual cells … … assemble into this complex tissue?

3. University of Sheffield www.dcs.shef.ac.uk/~rod/ Building an integrative systems biology: the Human Physiome Project The aim of the Human Physiome Project is to provide a “quantitative description of physiological dynamics and functional behaviour of the intact organism” it is overseen by the Physiome and Bioengineering Committee of the IUPS (International Union of Physiological Sciences) projects include the Cardiome (heart), the Endotheliome (lining of blood vessels), Micro-circulation … … and the Epitheliome – computational modelling of the social behaviour of (epithelial) cells

4. University of Sheffield www.dcs.shef.ac.uk/~rod/ Where does cell modelling fit into the Physiome Project? Hunter P, Robbins P, Noble D (2002) The IUPS human physiome project. Eur J Physiol 445 1-9 Social model of cell Cellular tissue 10 -5 m The Epitheliome

5. University of Sheffield www.dcs.shef.ac.uk/~rod/ The social life of the cell is important! Essential step from single-cell to multi-cellular organisms Tissues and organs are self-assembling systems No organising principle above the level of a single cell –so order is an emergent property of cellular interaction This is a salient feature of biological systems - order emerges as the result of the interaction of large numbers of complex entities Courtesy of Sheila Mac Neil, Sheffield

6. University of Sheffield www.dcs.shef.ac.uk/~rod/ What are the drivers? Screening for epithelial cancers Contraction of skin grafts Wound healing Courtesy of Dawn Walker & Sheila Mac Neil, Sheffield

7. University of Sheffield www.dcs.shef.ac.uk/~rod/ What are the common features? Self assembly/disassembly Forces between cells Cell motility Cell signalling as a result of mechanical forces Only an empirical understanding of the processes –e.g. differentiation at an air- liquid interface Courtesy of Sheila Mac Neil, Sheffield

8. University of Sheffield www.dcs.shef.ac.uk/~rod/ From ants to epithelium Existing models of tissue are either descriptive or derive function from structure –need a predictive model, not a descriptive model –in advance of healing, there is no structure in a wound, so need to develop structure from function What paradigm can we use to model self-assembly of large numbers of very complex entities? The basic idea came from work on the social behaviour of ants – we are interested in the social behaviour of cells Two key insights were essential –a mechanism for integrating cellular biology into the ‘social model’ –linking the ‘social model’ to a physical model of the tissue behaviour Courtesy of Francis Ratnieks, Sheffield

9. University of Sheffield www.dcs.shef.ac.uk/~rod/ Simulation of monolayer growth NO. CELLS ITERATION NUMBER Physiological Ca 2+ (2 mM) Low Ca 2+ (0.09 mM) Ca 2+ = 2mM Ca 2+ = 0.09mM

10. University of Sheffield www.dcs.shef.ac.uk/~rod/ in silico wound healing Physiological Ca 2+ (2mM) Low Ca 2+ (0.09mM)

11. University of Sheffield www.dcs.shef.ac.uk/~rod/ in vitro wound healing Low Ca 2+ Physiological Ca 2+ (Cell movie from Gemma Hill, Jack Birch Unit for Molecular Carcinogenesis, University of York)

12. University of Sheffield www.dcs.shef.ac.uk/~rod/ Major challenges Developing a ‘realistic’ physical model that is computationally tractable for ~10 6 cells Deciding what is important - sparseness (parsimony) Linking individual cell dynamics to a continuum model of tissue –how does stress at the tissue level affect mechano-transduction at the cytoskeletal level –how is the signalling resulting from a wound related to cellular-level response Comparing tissue growth in vitro and in silico –how do we validate the computational model Balaban et al 2001 Nature Cell Biology 3 466

13. University of Sheffield www.dcs.shef.ac.uk/~rod/ Summary We have developed a proof-of-concept model of the social behaviour of cells The model shows similar behaviour to urothelial cells grown in vitro In principle, the model: –can incorporate the biological mechanisms which control cell behaviour –can be scaled up to realistic numbers of cells In practice, sparseness will be essential! The model is changing biologists’ thinking and driving biological experiments Strong validation is essential

14. University of Sheffield www.dcs.shef.ac.uk/~rod/ Acknowledgements Cell biology: Jenny Southgate (York) Sheila Mac Neil Eva Qwarnstrom Modelling: Mike Holcombe Dawn Walker Steven Wood Engineering: Rod Hose Peter Hunter (Auckland) Funding: Engineering & Physical Sciences Research Council (EPSRC) Higher Education Funding Council for England (HEFCE)

15. University of Sheffield www.dcs.shef.ac.uk/~rod/