1. L. ARAVIND National Center for Biotechnology Information Apprehending Life’s complexity: Making and communicating biological discoveries

2. We are becoming meme and teme machines ! It is all about replicators: biological and otherwise The good old genes Memes Temes

4. The two philosophies in biology Natural history: discovery of new forms, cataloguing and classification Hypothesis-> attempt at falsification->paradigms: Popper’s world view Largely a history of clash or neglect

8. Getting behind biological clocks, photodetectors and oxygen sensors Regulation of circadian rhythms in animals Periodic growth and sporulation in fungi Light regulated expression of photosynthetic pigments Oxygen-seeking behavior in aerobic bacteria A master regulator of the clock the period protein (per) WC-1 and WC-2 two light sensory regulators of gene-expression in Neurospora BAT a regulator of photosynthetic pigment expression The aerotaxis receptor of E.coli and other bacteria

11. Overview of biological complexity Discovery and classification of domains Mesoscopic Characterization of biological functional systems Function prediction & classification Microscopic Computational analysis of whole biological systems or networks Reconstructing organismal biology and whole ecosystems Macroscopic Evolutionary trajectories: Genomes to Biology

12. Eukaryotic signaling proteins show non-linear scaling with proteome size… However, major superfamilies of signaling proteins show largely linear trends: invention of many lineage-specific systems independent of the large superfamilies Deviations point to important functional adaptations: convergent evolution of LRR+kinase architectures

13. (Prolyl hydroxylases) Rs Pbcv1 Dm Arabidopsis Drosophila Lineage specific expansion of a domain family Definition: The increase in numbers of a domain in particular lineage with respect to its number in sister reference lineage Homo

14. Section of the contextual network for the Ub pathway LF LF WLM UB WLM PUG WLM UB LF LF WLM WLM PNGase Thioredoxin PAW PNGase PAW PUG UBA PUG PPPDE PUL DOMAIN Thioredoxin PPPDE UB OTU-DUB UB C 2 H 2 OTU-DUB UB Asp Protease UBA Thioredoxin X UBX UBX Thioredoxin ZZ finger UBA PUL DOMAIN WD40 LF LF LF LF LF Calpain A 2 0 Z n F UB/ UBX UBCH LF C 2 H 2 - U An1 ZnF OTU-DUB PNGase RAB-GEF PUL DOMAIN Thioredoxin PPPDE Asp Protease PAW ZZ finger WLM (metallopeptidase) Yif1 TM TM TM TM TM // RAB WD40 Calpain E2 // UBA * * Predicted DUB * * * * *

16. Biology of Networks Nodes Links Interaction A B Network Proteins Physical Interaction Protein-Protein A B Protein Interaction Metabolites Enzymatic conversion Protein-Metabolite A B Metabolic Transcription factor Target genes Transcriptional Interaction Protein-DNA A B Transcriptional

17. 112 TFs 711 TGs 1295 Interactions E. coli transcriptional regulatory network Small-scale biochemical experiments Large-scale ChIP-chip experiments and genetic deletion and over-expression data 157 TFs 4410TGs 12873 Interactions Datasets Yeast transcriptional regulatory network

18. Scale-free structure Presence of few nodes with many links and many nodes with few links Transcriptional networks are scale-free Scale free structure provides robustness to the system Albert & Barabasi, Rev Mod Phys (2002) N (k)  k  1

19. Crp NarL Crp NarL E. coli H. influenzae B. pertussis NarL Crp Regulatory hubs which are condition specific can be either lost or replaced The same protein in organisms living in different lifestyles may confer different adaptive value. Hence it may emerge as a regulatory hub in the organism to which it confers high adaptive value and not in the others Different proteins should emerge as hubs in organisms with different lifestyle

20. Apprehending the diversity of eukaryotes “ crown group” Most studied “ microbial eukaryotes” Most diverse and prevalent animals fungi Slime molds plants Chlorophytes rhodophytes diatoms Heteroloboseans parbasalids Diplomonads Euglenozoa ciliates Apicomplexans

21. Some notable associations that might favor inter-eukaryotic gene flow Primary endosymbiosis with cyanobacterium Secondary endosymbiosis with different plant lineages Plant lineages Karyoklepty (e.g. ciliates) Endosymbiosis Engulfment Parasitic nucleus Nuclear invasion Karyoparasitism (e.g. Rhodophytes) Endoparasitism (e.g. apicomplexa)

26. Conclusions Given the “special” interests: 1)Journals and publishers 2)Evaluation of scientists by host institutions 3)Triaging scientific publications 4)Allocating Funds for Biological research 5) Need to bar crackpots Given the competition: 1)Blogs 2)Wikis 3)Open access, open peer-review etc. 4)The ubiquity of the internet 5) The drive from the memes and temes! Will out of the box thinking help?