1. Source Bohringer-Mannheim

2. The History of Biological Networks Structures Strings, Physical Structures,…. Networks: Objects with relationships or discrete transformation Pattern and Form Dynamics The Fundamental Problem: To use observations: expression levels enzyme concentrations metabolite concentrations ……. To infer underlying network, its structure, dynamics, evolution, function and interactions SP I2I2 I4I4 I3I3 I1I1

3. The Origins of Metabolic Research Louis Pasteur 1822-95 1840s - the first edge!! Justus von Liebig (1803-73) in the 1840s studied the conversion of malic acid to fumaric acid. Emil Hermann Fischer 1852-1919 NP1902 1890s - Fischer structure and conversion of sugars 1860s - Pasteur studies fermentation Hans Buchner (1850-1902) Eduard Buchner 1860-1917 NP 1907 1897 - Edvard Buchner showed that fermentation could occur in cell free extracts +

4. Hans Adolf Krebs 1900-1981 NP1953 Melvin Calvin 1911-97 NP 61 1945 Norman H. Horowitz First Model of Metabolic Evolution. 1926 Kluyver & Donker's "unity of biochemistry" principle 1930-40s Krebs characterizes citric acid cycle 1930-40s Calvin characterizes carbon path in photosynthesis 1910s-20s - Michaelis,Menten (1913) - Briggs,Haldane (1925) studies rate laws for simple enzymatic reaction (simplified). E S P

5. Jacques Monod 1910 -76 NP1965 François Jacob 1920- NP1965 AB AB mRNA Factor A Factor B protein mRNA promoter Gene 1961 The Operon model of Gene Regulation 1964 Goodwin First mathematical analysis of Operon model of Gene

6. Stuart KauffmanMichael Savageau X 0 ' =  0 X 0 g00 X 1 g01 -  0 X 0 h00 X 1 h01 X 1 ' =  1 X 0 g10 X 1 g11 -  1 X 0 h10 X 1 h11 X0X0 X1X1 1969- exploration of the dynamics of Boolean Networks 1969- Biochemical Systems Theory Gene 2 Gene 3 Gene 4 Gene n Gene 1 Time 1 Time 2Time 3Time T mRNA Factor C Factor B mRNA Factor A Remade from Somogyi & Sniegoski,96. F2

7. 1995:Arkin, McAdams, Ross: Stochastic Models of Gene Regulation Reinhart Heinrich Henrik Kacser 1918-95 1973-4..: First articles on MCA - metabolic control analysis From Fell Two classes of theorems Control Summation Connectivity P1P1 S1S1 P2P2 E, protein mRNA promoter Gene

8. 1995-2005 Kinetic Model Fitting Westerhoff The phenotype of a network (Omholt, Plathe, …) Network Comparison: Labeling of edges/nodes (homology) Spatial Information Network inference Designed/Evolved Network Modularity Robustness Evolvability Integration of Networks Designed Networks. Metabolic Pathways, Flux Analysis and Genome Annotation SP I2I2 I4I4 I3I3 I1I1 Palsson Schilling Fell Schuster

9. Biological cellular and supra-cellular Networks Neural Networks Immunological Networks Cellular Disease Networks Genealogical Networks Above the Cell Non-biological Networks Social Networks The Internet Collaboration Networks Semantic Networks Publications and references Biological sub-cellular Networks Signal Transduction Networks Protein Interaction Networks Alternative Splicing Graph

10. Today’s Schedule 1.00pm Jotun Hein:Introduction and Biology of Networks 1.20pm Chris Holmes: Inference of Networks 1.35pm Andrea Rocco: Modelling structure and function in complex networks 1.50pm Gesine Reinert: Statistics for small-world networks 2.10pm Michael Stumpf: Comparative Biology of Networks 2.25-2.45pm mini-BREAK 2.45pm Imre Vastrik:The Reactome 3.15 pm Hector Keun:Metabonomics and modeling metabolic networks. 3.45-4.15pm maxi-BREAK 4.15 pm Philip Bang: Machine Learning for Systems Biology 4.45pm Gail Preston:Evolutionary Modelling of Nitrogen Metabolism in Pseudomonas 5.05–5.20pm Neil Johnson:Complex Agent-Based Dynamical Networks