1. Agent-based methods for translational cancer multilevel modelling Sylvia Nagl PhD Cancer Systems Science & Biomedical Informatics UCL Cancer Institute London

2. Main points of the talk Potential of agent-based modelling Systems biology perspective on large cell network simulation A new synergy between modelling and wet biology

3. Hanahan and Weinberg (2000) Cell 100:57-70 The hallmarks of cancer

4. Systems biology and medicine Diseases are abnormal perturbations of biological networks - through defects in molecular mechanisms or environmental stimuli Therapies are the interventions needed to restore networks to their normal states

5. Butcher et al. (2004) Nature Biotechnology 22:1253 Modelling challenge: genome to phenotype extended genotype elementary phenotype

6. Systems biology and medicine Fundamental question of where function lies within a cell –distributed (networks of interacting molecules) –hierarchical network motifs and modules complex network connecting modules A globalist view of the dynamics of (large) cell networks is therefore needed cell and tissue levels cell networks molecular interactions (molecular dynamics) E-science }

7. Systems biology and cancer Given the many components of functional modules, there are different paths to disease-inducing systems failure A multitude of ways to ‘solve’ the problems of achieving a survival advantage in cancer cells Each patient’s cancer cells evolve through an independent set of genomic lesions and selective environments - a fundamental reason for differences in survival and treatment response

8. Likelihood of cancer cell death in response to DNA damaging drugs and radiotherapy DNA damage response network Supporting treatment optimisation in the individual patient

9. Agent-based modelling Agent based model Simulation A1A2 A1 Ai A2 One-to-one mapping of cell components to computational agents Agents at multiple levels: Protein, network motif, module (organelle, cell …) Interaction rules Translates wealth of molecular knowledge into component-based models Patient-specific molecular data ?

10. TF1 S1 S2 SN TF2 TFm Signal-genetic network Environment Transcription factors Genes DNA damage Changes in genome activation

11. TF1 S1 S2 SN TF2 TFm Signal-genetic network Environment Transcription factors Genes Agent-based modelling: ‘Agent’ (protein, motif, module) => behaviour rules Kinetics/step function/Boolean variables scale up to large networks

12. Challenge: Emergence Coherent behaviour of cells emerges from interactions between a large number of system components – proliferation, cell death, resistance to drugs ‘Computational’ definition of emergence: Unspecified properties and behaviours arise from interaction between agents rather than as a consequence of a single agent’s actions Methods for analysis needed e.g. for therapy target discovery

13. Detecting event patterns in time A simple event is a state transition due to a rule execution A complex event is made up of a set of interrelated simple events Classification of complex events in a simulation allows one to discover associations between processes at different levels Published formalism available at www.cs.ucl.ac.uk/staff/C.Chen/research.html

14. Linking network simulations to integrated cell behaviour requires knowledge external to the simulation, the question of ‘biological meaning’ Challenge: ‘the gap’

15. A new synergy Data generation is still largely motivated by a non-systems-based research paradigm Systems biologists then seek to use these data to build and validate models of systems – with difficulties We need to rethink the relationship between experiment and modelling –both need to proceed within a complex systems framework –new kinds of experiments needed to investigate multi-level relationships in the wet system e. g., global signal network states need to be matched to cell- level phenotypic measurements over time and under a range of conditions E-science systems modelling and experiment need to complement and synergise

16. Acknowledgements Nuno Rocha Nene (CoMPLEX PhD programme) Chih-Chun Chen (interdisciplinary EPSRC DTA awards) CR UK, Department of Health Published formalism available at www.cs.ucl.ac.uk/staff/C.Chen/research.html www.cs.ucl.ac.uk/staff/C.Chen/research.html Decision support tool for ABM techniques www.abmsystemsbiology.info www.abmsystemsbiology.info My email: s.nagl@ucl.ac.uk