Design Principles in Biology :

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

2. Climbingdownmount improbable • Overtime, edgedstoneswould accumulateontheslope. • Smooth, round, stones accumulate at the bottom. DesignPrinciples: - Smooth, roundishrocks roll downthemountain. - Edged, flat, rocksdon’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 Regulator Regulator _ + Gene Gene X0 X1 X2 X3 X0 X1 X2 X3

6. First step, define the alternatives X3 X0 X1 X2 X3 How strong should the feedback be? t

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

8. Then, create models for each alternative X0 X1 X2 X3 X0 X1 X2 X3

9. Characterization of networkbehavior Biological functional effectiveness criteria for the network. Alternativedesigns … Comparison of behaviorbetweennetworks X1 … Xj … X1 … Xj … Mathematical models Enforce mathematical controls before analyzing model behavior

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 Regulator Regulator _ • Are there situations where positive regulation of gene expression outperforms negative regulation of gene expression and vice versa? + Gene Gene

12. Regulating gene expression has principles Regulator Regulator _ • 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 Gene Genetics 149:1665; PNAS 103:3999; PNAS 104:7151;Nature405: 590

13. Glycogen Trehalose Regulating gene expression has principles

14. Design principles in development

15. 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 • Negative overall feedback: • More effective in coupling production to demand. • More robust to fluctuations. X0 X1 X2 X3 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 Signal Sensor Sensor Efector Deactivator Efector Effect • Bifunctional sensor: • Performs best against cross talk • Independent deactivator: • Better integrator of signals Mol. Microbiol. 48:25; Mol. Microbiol. 68: 1196

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. Design principles in development Regulator Regulator _ Signal Highdemand, lowsignal + Signal _ Gene Gene + Highdemand, highsignal Lowdemand, lowsignal Lowdemand, highsignal 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. Expression of important genes Heat shock Growthrate time 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 CompBiol 4:e1000206;BMC Evolbiol7: 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!! Bistablesystems Unstablesystems StableSystems Oscilations Cell 113: 597; PLoSComputBiol. 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. Summary • 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 Programa Ramon y CajalMCyT MCyT FCT NIH Mike Savageau Albert Sorribas Armindo Salvador Oleg Igoshin