1. Design Principles in Biology: a consequence of evolution and natural selection Rui Alves University of Lleida ralves@cmb.udl.es

2. Climbing down mount improbable Overtime, edged stones would accumulate on the slope. Smooth, round, stones accumulate at the bottom. Design Principles: - Smooth, roundish rocks roll down the mountain. - Edged, flat, rocks don’t.

3. Design principles in molecular biology Similarly, if a topology or set of parameters can be shown to create a molecular network that functionally outperforms all other possible alternatives in a given set of conditions, one can talk about a design principle for the system under those conditions. [sensu engineering]

4. Index of talk How to identify design principles in molecular networks Design principles in: – Gene expression – Metabolic networks – Signal transduction – Development Design principles, what are they good for? Summary

5. First step, define the alternatives Gene Regulator + Gene Regulator _ X0X1X2X3

6. First step, define the alternatives X0X1X2X3 X3 t How strong should the feedback be?

7. Then, create models for each alternative Gene Regulator + Gene Regulator _

8. Then, create models for each alternative X0X1X2X3

9. Characterization of network behavior Biological functional effectiveness criteria for the network. Alternative designs X1 … Xj … … Mathematical models Enforce mathematical controls before analyzing model behavior Comparison of behavior between networks

10. Index of talk How to identify design principles in molecular networks Design principles in: – Gene expression – Metabolic networks – Signal transduction – Development Design principles, what are they good for? Summary

11. The demand theory for gene expression Are there situations where positive regulation of gene expression outperforms negative regulation of gene expression and vice versa? Gene Regulator + Gene Regulator _

12. Regulating gene expression has principles Positive regulator: – More effective when gene product in demand for large fraction of life cycle. – Less noise sensitive if signal is low. Negative regulator: – More effective when gene product in demand for small fraction of life cycle. – Less noise sensitive if signal is high. Gene Regulator + Gene Regulator _ Genetics 149:1665; PNAS 103:3999; PNAS 104:7151;Nature 405: 590

13. Glycogen Trehalose Regulating gene expression has principles

14. Design principles in development

16. Index of talk How to identify design principles Design principles in: – Gene expression – Metabolic networks – Signal transduction – Development Design principles, what are they good for? Summary

17. Negative overall feedback is a design principle in metabolic biosynthesis X0X1X2X3 Negative overall feedback: – More effective in coupling production to demand. – More robust to fluctuations. Bioinformatics 16:786; Biophysical J. 79:2290

18. Index of talk How to identify design principles Design principles in: – Gene expression – Metabolic networks – Signal transduction – Development Design principles, what are they good for? Summary

19. Bifunctional sensors can be a design principle in signal transduction Bifunctional sensor: – Performs best against cross talk Independent deactivator: – Better integrator of signals Mol. Microbiol. 48:25; Mol. Microbiol. 68: 1196 Signal Sensor Efector Deactivator Effect

20. Index of talk How to identify design principles Design principles in: – Gene expression – Metabolic networks – Signal transduction – Development Design principles, what are they good for? Summary

21. Gene Regulator _ Design principles in development Gene Regulator + High demand, low signal Signal + High demand, high signal Low demand, high signal Low demand, low signal Signal _ Genetics 149:1665; PNAS 103:3999; PNAS 104:7151;Nature 405: 590

22. Index of talk How to identify design principles Design principles in: – Gene expression – Metabolic networks – Signal transduction – Development Design principles, what are they good for? Summary

23. Biological design principles are good to understand why biology works as it does Biological design principles may connect molecular determinants to functional effectiveness. Heat shock Expression of important genes time Growth rate time BMC Bioinformatics 7:184

24. Underlying assumption Evolution of molecular networks can be treated as modules. Work in the group of Uri Alon suggests that – networks evolving to meet simultaneous goals evolve in a modular fashion – Networks evolving to meet a single goal evolve globally Modularity seems like a reasonable first assumption PNAS 102:13773; PLOS Comp Biol 4:e1000206;BMC Evol biol 7: 169

25. The good news about function Sometimes, you get stuff for free!!! For example: – networks that are responsive to signals, just because they are responsive may have inbuilt buffering of noise. – Functions that are associated with marginally stable proteins are favored because due to the large dimensions of sequence space most randomly selected sequences have a structure that is marginally stable. PNAS 100:14463; PNAS 103:6435; Proteins 46:105

26. How can biological design principles be applied? Design of molecular circuits with specific behaviors!! Stable Systems Unstable systems Oscilations Bistable systems Cell 113: 597; PLoS Comput Biol. 5:e1000319; PNAS 106: 6435

27. Index of talk How to identify design principles Design principles in: – Gene expression – Metabolic networks – Signal transduction – Development Design principles, what are they good for? Summary

28. Design principles can be found in molecular networks. Such principles can sometimes be connected to selection for function effectiveness. Even in the absence of such a connection, if they are valid they can be used to build biological circuits with specific behaviors.

29. Acknowledgments Mike Savageau Albert Sorribas Armindo Salvador Oleg Igoshin Programa Ramon y Cajal MCyT MCyT FCT NIH