1. BIOLOGICAL SYSTEMS SIMULATIONS BASED ON NEGATIVE FEEDBACK EUROPEAN UNION EUROPEAN REGIONAL DEVELOPMENT FUND The work was co-funded by the European Regional Development Fund as part of the Innovative Economy program. Jakub Wach 3, Marian Bubak 1,3, Leszek Konieczny 2, Irena Roterman-Konieczna 2 1 AGH University of Science and Technology, Department of Computer Science, Kraków, Poland 2 Jagiellonian University, Department of Bioinformatics and Telemedicine, Kraków, Poland 3 Academic Computer Centre Cyfronet AGH, Kraków, Poland http://dice.cyfronet.pl

2. PROBLEM DESCRIPTION Biological system  Anything alive (enzyme, virus, cell, ….)  Mulitple levels – from a single enzyme to whole organism Need for simulation  Novel treatments  Insight into details (structure and function preciction) Existing simulation methods  Approximate (based on PDEs)  Precise (Stanford cell model)

3. NFS APPROACH The idea  L. Konieczny, I. Roterman, P. Spolnik : “Systems biology”  Model function, not structure  Use negative-feedback systems (NFSs), simplest regulator as building blocks Negative Feedback System  Effector  Delivers a product  Output regulated by Receptor  Receptor  Delivers signal regulating Effector  Signal output is regulated by product level

4. NFS APPROACH - SYSTEMS  Biological system – composition of building blocks  Organized Systems – OS – composition of connected NFSs

5. OS - COOPERATION  Cooperation connection  Product of one NFS is substrate of another one  Receptor is not aware of the change – it’s a local (Effector) relation  Example – enzymatic cascade, where one enzyme delivers substrate to another, e.g. glycolysis

6. OS - COORDINATION  Coordiation connection  One NFS can change regulation threshold of another NFS  Whole NFS is affected – it’s a global (Receptor) relation  Example – allosteric control of enzymes

7. OS – HIERARCHY  Component hierarchy  One NFS can be coupled with a Receptor  Higher – level NFS is created this way  Multiple „nesting” levels possible  Example – hormonal regulation

8. APPLICATION  Multiple modules available  Implements OS model with all of the relations  Allows both bounded (cooperation) and unbounded (unlimited source) NFSs  Allows space-time constraints by introducing delay parameter  Simple iterative simulation algorithm  Sophisticated, real product diffusion model http://crick.cm-uj.krakow.pl:8080/nfs/

9. APPLICATION - PLAYGROUND  JSON definition of an OS  Graphical parameters editor

10. APPLICATION - PLAYGROUND  Real time OS model visualization in SVG (already presented)  Simulation run results charts  Archivable and exportable

11. APPLICATION - MANAGEMENT  Provides exercise management  Allows for creating, editing and deleting exercises  Allows for user (student) assignment  Allows date / time constraints for exercises  Provides task management  Allows for OS definition for a task  User can add name and description for a task

12. WORKFLOW INTEGRATION  Models can be very complex, even for typical scenarios  Hundreds of parameters for optimization  Search for appropriate structure and values