1. Mathematical Comments on Systems Biology: examples and questions Elisabeth Pécou Institut de Mathématiques de Bourgogne (U. de Bourgogne) and Centro de Modelamiento Matemático (U. de Chile)

2. Biomolecular Systems Genes, proteins, metabolites,… Activation, inhibition, chemical transformations, signal transduction,… INTERACTION GRAPH (gene networks, metabolic pathways,…) Adaptability, evolvability, robustness, social behaviour,…

3. Example: Morphogenetic movments in Dictyostelium amoebae A few cells start to produce periodic cAMP pulses which are detected, amplified and relayed by surrounding cells, forming spiral waves. Dictyostelium cells move by chemotaxis toward increasing cAMP concentration and then aggregate to form a mound. Copyright, M.J. Grimson & R.L. Blanton

4. Systems Biology Theory Understand the emerging properties, like self-organization, of complex biomolecular systems.

5. A fundamental system behaviour: switching Switching implies that the underlying dynamical systems has two stationary stable states.

6. Interaction graph

7. Thomas-Soulé Theorem If a system admits more than one non degenerate stationary states on an open domain, then at least one of its local interaction graphs has a positive circuit. Example: in the domain ]0,+  [x]0,+  [x]r,+  [, the Lorenz system has at most one stationary state.

8. Switching occurs by bifurcation Discontinuous experimental « curve » Equilibrium curve: the 0-level curve of the vector-field p c is a saddle-node bifurcation point

9. Hysteresis effect: « irreversibility » « Irreversibility »: when the parameter decreases under p c no jump occurs. This criterion distinguishes switch phenomena from simple shifts. SHIFT SWITCH

10. Example: Genetic Toggle Switch (Gardner, Cantor, Collins) Synthetic gene regulatory network of two genes, negatively interacting on each others (cooperative repression) which exhibits bistability for a wide range of parameter values.

11. Perspectives Bistability is at the basis of cell differenciation or cancer proliferation. Work remains to be done to understand how multistability is effectively achieved in those cases and how to control the process at the system level. Successful construction of synthetic genetic networks open the doors to an infinite range of applications in therapeutic strategies and in industrial processes.

12. Homeostasis, another fundamental system behaviour A biological system is open. It exchanges matter, energy and information with its environment. Homeostasis is the capacity of a system to maintain constancy even in the face of changing environment (Claude Bernard, Walter Cannon).

13. Mathematical homeostasis Existence of a stable equilibrium state or a stable periodic orbit with small amplitude. Negative loop in the interaction graph: necessary condition for homeostasis. Weakness: the definition does not take into consideration changes in the environment.

14. Copper homeostasis in Enterococcus hirae* Cu essential micronutrient, toxic at high concentration.  Necessity of a tight regulation. Homeostasis of Cu in E. hirae involves the cop operon ( see M.Solioz and coworkers ). *joint work with A. Maass, D. Remenik, J. Briche, and M. Gonzalez (2005)

15. cop operon of E. hirae

16. The biological model Virtual variable (Cu) int ; Assume all copper needs are fulfilled Thus, the criterion for homeostasis reads: (Cu) int  0 ( at equilibrium )

17. The mathematical model Model of a population of identical cells. Mass-action kinetics, except passive uptake and outake, modelled by threshold functions (either non linear sigmoidal, or piecewise constant). Four classes of models, according to:  Expelled copper is immediatly recycled or not;  Timescales are taken onto account either by a time delay in transcription or by the introducing mRNAs as variables.

18. The equations

19. Results: Existence of equilibrium Theorem: for any values of the parameters,and any external point source of copper, the system admits an equilibrium state for which (Cu) int =0 Mathematical homeostasis condition is satisfied. The stationary state does not depend on the source of copper. Cu int Cu ext

20. SBMLSim: Simulation tool SBMLSim: MATLAB program which presents a graphical user interface, solving and plotting the solutions of the differential system. It allows the user to easily change the parameters and initial conditions. The input are standard SBML files which can be generated by Cell designer. http://www.dim.uchile.cl/SBMLSim

22. Transient dynamics Internal copper reaches a maximum and then decreases toward 0. The parameters which influence the maximum value are the uptake velocity and the transcription velocity. Changing k A Changing C A

23. Sources On Dictyostelium S. Sawai, P.Thomason, E. Cox, Nature 433 (2005) E. Palsson, E. Cox, P.N.A.S. 93(1997) On bistability and positive feedback loops C. Soulé, ComplexUs 1 (2003) J.Monod, F. Jacob, Cold Spring Harbor Symp Quant. Biol. 26 (1961). J. Ferrell, Cur. Op.Chem.Biol. 6 (2002). The genetic toggle switch T. Gardner, C. Cantor, J. Collins, Nature 403 (2000) Homeostasis E. Pécou, A. Maass, D. Remenik, J. Briche, M. Gonzalez (2005) « A mathematical model for copper homeostasis in Enterococcus Hirae » D. remenik, A. Maass, E. Pécou, J. Briche, M. Gonzalez (2005) « SBMLSim: a Matlab GUI for simulating SBML models ».