1. The Context of Systems Biology Michele Griffa Dept. of Physics, Polytechnic of Torino michele.griffa@polito.it The Role of Mathematical Modeling and Numerical Simulation in the Systems Biology Era Workshop Bioindustry Park of Canavese, Colleretto Giacosa February 28 th, 2006

2. t 2000 Institute for Systems Biology, Seattle (www.systemsbiology.org)www.systemsbiology.org Leroy Hood “The HGP has given us a parts list. The next step is to capture the information from all the elements in a biological system: DNA, proteins, cells, tissues and organs, and then create new mathematical models that will represent the relationships between them” The Economist Technology Quaterly, september 17-23 2005 system-level understanding grounded in molecular-level one function and dynamics understanding of a whole biosystem prediction and control since ‘950s General Systems Theory (von Bertalanffy, 1967) Biological Cybernetics (Wiener/Rosenbluth) Automata Theory (von Neumann) Compartmental models in Physiology Biochemical oscillators since ‘910s Concept of Homeostasys (Cannon) Predator- Prey Dynamics (Volterra/Lotka) Systems Biology: history of a grand challenge

3. t 1990s: a leap forward Post Genomic Era high throughput tools developed for genomes sequencing theory, modelling, computational power (hardware, algorithms) microtechs, total analysis-on- one device databases, WWW access and data mining networks paradigms 1 gene 1 protein gene regulatory networks transcriptional pathways metabolic pathways Systems Biology approach needed !

4. Systems Biology: goals Biosystems structure: components modules that implement functions interplay between modules, relationships between components networks of gene interactions biochemical pathways mechanisms through which such interactions modulate physical properties of intracellular and multicellular structures whole-biosystem dynamics: how a whole-system behaves over time under various (boundary) conditions control of the system  robustness (evolutionary) design: how to construct or modify biosystems having desired properties

5. Multi-Scale Modeling of the Heart, from Genes to Cells to the Whole-Organ: an example of Systems Biology-like result 1952: Hodgkin/Huxley’s model, study of the dynamical behaviour of the voltage dependent conductivity of a nerve cell membrane for Na + and K + ions, prediction of the dynamics of action potential and of axon conduction in giant squibb. electrophysiological activity of miocytes (oscillators models) emergence of synchronization in sets of coupled non-linear oscillators (pacemakers cell population dynamics, Winfree, 1980s) genetic mutations, protein expression and cardiac sodium channel dynamic behaviour (Clancy, Rudy, 1999) propagation of action potential wavefield in excitable media (incorporation of cellular models into whole-organ ones) mechanical-electrical feedback (how the contraction of the heart influences its electrical conduction properties) blood fluid dynamics around cardiac valves surfaces (immerse boundary methods for the solution of PDEs problems involving dynamic fluid-structure interaction, McQueen/Peskin, 1980s)

6. Multi-Scale Modeling of the Heart, from Genes to Cells to the Whole-Organ Spread of the electrical activation potential wavefield in an anatomically detailed cardiac model (P. Kohl et al., Philos. Trans. R. Soc. London Ser. A 358, 579, 2000) red: activation potential wavefront; blue: endocardial surface Transmural pressure on coronary vessels from the myocardial stress (dark blue=0 press., red=peak press.) (N.P. Smith, G.S. Kassab, Philos. Trans. R. Soc. London Ser. A 359, 1315, 2001) end-diastoleearly systolelate systole

7. Systems Biology: a knowledge-management goal ! large-scale measurements collection large-scale data/knowledge sharing modeling and simulation Integration and Scaling of Knowledge, Information, Data, Models, Simulation Tools: Integrative Biology ! KEGG ( www.genome.ad.jp ) www.genome.ad.jp STKE ( www.stke.org ) www.stke.org Alliance for Cellular Signaling ( www.signaling-gateway.org ) www.signaling-gateway.org BioCyc ( www.biocyc.org ) www.biocyc.org BIND (www.bind.ca/Action?pg=0)www.bind.ca/Action?pg=0 R-DBMS, WWW data and text mining Semantic Web (XML-enabled techs) SBML ( www.sbml.org ) www.sbml.org CellML ( www.cellml.org ) www.cellml.org BioUML ( www.biouml.org ) www.biouml.org BioSpice ( https://community.biospice.org ) https://community.biospice.org XML-based computer readable model definition languages; toolboxes for analysis, synthesis and simulation;

8. The Context of Systems Biology Michele Griffa Dept. of Physics, Polytechnic of Torino michele.griffa@polito.it The Role of Mathematical Modeling and Numerical Simulation in the Systems Biology Era Workshop Bioindustry Park of Canavese, Colleretto Giacosa February 28 th, 2006