Prof. Peter Csermely and the LINK-Group Semmelweis University, Budapest, Hungary

1. Crisis responses and crisis management What can we learn from biological networks? www.linkgroup.huinfo@linkgroup.hu Prof. Peter Csermelyand the LINK-GroupSemmelweis University, Budapest, Hungary

2. How can we learn from biological networks? • Networks have general properties • small-worldness • hubs (scale-free degree distribution) • nested hierarchy • stabilization by weak links Karinthy, 1929 Watts & Strogatz, 1998 Barabasi & Albert, 1999 Csermely, 2004; 2009 • Generality of network properties offers • utilization of billion-years crisis experience • judgment of importance • innovation-transfer across different layers of complexity

3. ecosystem, market, climate • slower recovery from perturbations • increased self-similarity of behaviour • increased variance of fluctuation-patterns • Nature 461:53 Crisis-prevention in different systems:example to break conceptual barriers Aging is an early warning signal of a critical transition: death • Prevention: elements • with less predictable behaviour • omnivores, top-predators • market gurus • stem cells Farkas et al., Science Signaling 4:pt3

4. Creative nodes: life-insurance of complex systems Creative:few links to hubs, unexpected re-routing, flexible, unpredictable Distributor:hub, specialized to signal distribution, predictable Problem solver:specialized to a task, predictable change of roles Csermely, Nature 454:5 TiBS 33:569 TiBS 35:539

5. The creative person has an insatiable appetite to discover new and new network environments The creative person is a network-entrepreneur in a Schumpeterian sense

6. For this the creative person needs a continuous refocusing in the social categories (dimensions) • By this refocusing the creative person • understands others better • let others know her/his values better • connects isolated people • and exponentially enriches her/himself. • Moreover: this is a self-amplifying circle.

7. A creative person always lets others go to the centre – to remain free Detoxifying protein • Creative amino acids • centre of residue-network • in structural holes • Creative proteins • stress proteins • signaling switches • Creative cells • stem cells • our brain detoxification drug-binding Csermely, Nature 454:5 TiBS 33:569 TiBS 35:539 • Creative persons • firms • societies mobile

8. Network changes in cellular crisisa short intro to the messy life of cells • networks: • STRING 7 • (5329/190018) • BioGRID • (5329/91749) • Ekman • (2444/6271) stressed protein weight resting protein weight mRNA expression multiplication multiplication continuous weights discrete weights average average resting link-weight stressed link-weight unique stress average stress • weights: • equal units • proteins • (Nature 441:840) • mRNA-s • (Cell 95:717) 13 stress conditions, 65 experiments (Gasch et al, Mol. Biol. Cell 11:4241) 6 stress conditions, 32 experiments (Causton et al, Mol. Biol. Cell 12:323) analysis of overlapping network modules:ModuLand method Mihalik & Csermely PLoS Comput. Biol. 7:e1002187

9. The ModuLand method family detects overlapping network communities community landscape community centrality: a measure of the influence of all other nodes influence zones of all nodes/links communities as landscape hills network hierachy available as a Cytoscape plug-in shows the centre of modules too! Kovacs et al, PLoS ONE 5:e12528 www.linkgroup.hu/modules.php network of network scientists; Newman PRE 74:036104

10. Community centrality reflectsnode-(link)-importance in crisis-survival protein synthesis energy distribution community centrality protein degradation energy distribution • yeast protein-protein interaction • network: 5223 nodes, 44314 links • stress: 15 min 37°C heat shock • link-weight changes: mRNA • expression level changes survival processes Mihalik & Csermely PLoS Comput. Biol. 7:e1002187

11. Changes of yeast interactome in crisis:a model of systems level adaptation • BioGrid yeast interactome: • 5223 nodes, 44314 links • stress: 15 min 37°C heat shock • + Gasch et al. MBC 11:4241 • link-weight changes: mRNA • expression level changes • Stressed yeast cell: • nodes belong to less modules • modules have less intensive contacts • smaller overlaps between modules, • more condensed modules Mihalik & Csermely PLoS Comput. Biol. 7:e1002187

12. cell death network desintegration creative elements* • increased network flexibility • spared links • noise and damage localization • modular independence:larger • response-space and better conflict • management Crisis survival: creative elements Consequences of network crisis stress *Schumpeterian creative destruction Szalay et al, FEBS Lett. 581:3675; Palotai et al. IUBMB Life 60:10 Mihalik and Csermely PLoS Comput. Biol. 7:e1002187

13. Bacteria living in a variable environment have more separate network modules more separate modules metabolic networks of 117 bacteria Parter, Kashtan & Alon BMC Evol. Biol. 7:169 larger environmental variability

14. Bacteria living in a variable environment have more separate network modules community landscapes (red/yellow: tops) Szalay-Bekő et al. arxiv.org/1111.3033 Multimodular metabolic network of the free livingE. coli Single major core of the metabolic network of the symbiontBuchnera

15. Telecommunication network modules become more cohesive in social crisis cohesive modules phone call intensity diffuse modules more than 10 million people Bagrow, Wang & Barabasi PLoS ONE 6:e17680 time in crisis we call our mother and not a distant friend… Vassy, Wang, Barabasi & Csermely in preparation

16. Generality: emergence of two phenotypes • ecosystems: food limitation see otters, patchiness in drought • brain:modular reorganization in learning • social networks:broker stress, Schumpeterian creative destruction • Haldane & May: US Volcker Rule separates bank system modules Topological phase transitions reflect the overlap-decrease at one level higher network diameter degrees of freedom Physica A 334:583 Csermely: Weak Links stress assembly > disassembly disassembly > assembly

17. Bateson et al. Nature 430:419 Janos Kornai: Thoughts about capitalism (in Hungarian, in preparation in English) Society: large: capitalism small: socialism surplus and shortage economies Metabolism: large: rapid, overspending small: slow, ‘thrifty’ ‘overeating’ society: diabetes Many resources: large phenotypefew resources: small phenotype

18. 5% of phenotypes can be reached stress, crisis ‘small’ ‘balanced’ ‘large’ + + possibility of adaptation + + effect of adaptation Low adaptation potential of ‘small’ and large’ phenotypes all phenotypes can be reached Draghi, Parsons, Wagner & Plotkin, Nature 463:353

19. Community rearrangements may be a general mechanism of system level adaptation 2. A network component of evolvability? ‘small’ ‘balanced’ ‘large’ + + possibility of adaptation + + effect of adaptation stress, crisis Take-home messages Biological networks offer the experience of billion years in crisis-survival 1.

20. Acknowledgments Robin Palotai Ágoston Mihalik Stress Peter Csermely: Weak Links Springer, 2009 potential new collaborators Aging Zsolt Vassy Shijun Wang ModuLand Games István A. Kovács Gábor I. Simkó Máté Szalay-Bekő Marcell Stippinger available free: Google-books www.linkgroup.huinfo@linkgroup.hu András London

21. Influence zones using the NodeLand method starting node influence zones community-44: 1127 schoolchildren, 5096 friendships; Add-Health