1. Lecture # 1 The Grand Schema of Things

2. Outline 1.The grand scheme of things 2.Some features of genome-scale science 3.The systems biology paradigm 4.Building foundations 5.Where does (Molecular) Systems Biology fit in to biological hierarchy

3. THE GRAND SCHEMA OF SCIENCE How does systems biology fit in?

4. Gregor Mendel (1822-1884) Established the existence of discrete inherited elements, now called genes, that determined organism form and function (i.e., the phenotype) The genotype/phenotype relationship becomes a fundamental concept in biology

5. Fast Forward to the 1950s: genes and human disease Linus Pauling: Hemoglobin and Sickle-cell anemia Monogeneic traits can be easily traced – about 150-200 that can be tested for However, most traits are polygeneic and complex

6. Fast Forward to 1995: birth of the genome era Whole genome sequences become available “All” genetic elements in a genome can be identified and characterized – in principle but in practice 2/3 Genome scale science enabled Craig Venter

7. Putting the Pieces Together: Genome-scale Network Reconstructions, 1997-2000 Organism-specific genome- scale metabolic networks – E. coli, H. influenzae, H. pylori The first high throughput in silico biologists Christophe Schilling Jeremy Edwards

8. Extended to Eukaryotes (2001-03) Yeast, w/Jens Nielsen Lab Iman Famili/Jochen Forster

9. Global Metabolic Map Comprehensively represents known reactions in human cells Pathways (98) Reactions (3,311) Compounds (2,712) Human metabolism: RECON 1 (2005-07) Genes (1,496) Transcripts (1,905) Proteins (2,004) Compartments (7)

10. Network reconstruction is a BiGG knowledge base Conversion of knowledge into mathematical format Birth of genome-scale (metabolic) systems biology Puts a mechanistic basis for the genotype-phenotype relationship Dual causality needs to be accounted for – different than physics a 100 years ago Stoichiometric Matrix S = reaction metabolite Network map Mathematical representation

11. CONCEPTS IN GENOME-SCALE SCIENCE Mechanistic genotype-phenotype relationships

12. Nature Biotechnology, 18:1147, 2000 Molecular to Systems Biology

13. Pathway in the Context of a System Examining the Properties of an Individual Pathway L-serine Biosynthesis Methanosarcina barkeri metabolism

14. The intracellular environment is crowed and interconnected placing severe constraints on achievable physiological states

15. Hierarchy in systems biology Systems biology: emphasis on modules and understanding of how coherent physiological functions arise from the totality of molecular components Biological causation; genome-scale changes and description of 1000’s of variables. Network and econometric type analysis methods Charles Darwin (1809-1882) Chemical causation: Can apply P/C laws and get causality on a small scale Ludwig Boltzmann (1844- 1906)

16. Building the G/P-relationship: integrated network reconstructions conceptual M Matrix E Matrix O Matrix OME Matrix ME Matrix Meta- structure operational

17. Reconstruction is iterative: History of the E. coli Metabolic Reconstruction Adam Feist Jeff Orth Ines Thiele Jennie Reed Jay Keasling Amit Varma Jeremy Edwards

18. THE SYSTEMS BIOLOGY PARADIGM

19. Systems Biology Paradigm: components -> networks -> computational models -> phenotypes Palsson,BO; Systems Biology, Cambridge University Press 2006

20. Data types -- 211 Reconstruction– 211/212 In silico analysis– 212/213 Tailoring to tissues Drug response phenotypes SMILEY Adaptive evolution Disease progression Differentiation Synthetic Biology Metabolic Engineering Our Systems Biology Series

21. BUILDING FOUNDATIONS Towards ‘principles’for molecular biology on genome scale

22. Emerging Axioms of COBRA Axiom #1: All cellular functions are based on chemistry. Axiom #2: Annotated genome sequences along with experimental data enable the reconstruction of genome-scale metabolic networks. Axiom #3: Cells function in a context-specific manner. Axiom #4: Cells operate under a series of constraints. Axiom #5: Mass (and energy) is conserved. Axiom #6: Cells evolve under a selection pressure in a given environment. This statement has implicit optimality principles built into it FEMS, 583:3900, 2009

23. WHERE IN THE BIOLOGICAL HIERARCHY IS (MOLECULAR) SYSTEMS BIOLOGY?

24. Biological Scales and Systems Analysis Courtesy of Vito Quaranta, MD; Vanderbilt University, Nashville, TN Molecular systems biology ecology physiology immunology

25. Multi-scale view of E. coli colonycellnucleoidmacromolecule

26. Summary Genes are quanta of inherited information These quanta influence the functions of organisms The genotype-phenotype relationship is foundational to biology Monogenic diseases/traits can easily be traced Most traits are poly-genic Full sequencing of genomes gave us the possibility to enumerate all the genes that make up an organism Systems biology rose to meet the challenge of figuring out how all genes and the biochemical properties of the gene products come together to produce organism functions The (metabolic) genotype-phenotype relationship now has a mechanistic basis! Fundamentals of the field are emerging