Lecture # 1

1. Lecture # 1 The Grand Schema of Things

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

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

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 Jeremy Edwards Christophe Schilling

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 Reactions (3,311) Pathways (98) Genes (1,496) Transcripts (1,905) Proteins (2,004) Human metabolism: RECON 1 (2005-07) Compounds (2,712) Compartments (7)

10. Stoichiometric Matrix reaction metabolite S = • 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 Mathematical representation Network map

11. Mechanistic genotype-phenotype relationships Concepts in genome-scale science

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

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

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

15. Hierarchy in systems biology Chemical causation: Can apply P/C laws and get causality on a small scale Ludwig Boltzmann (1844-1906) Charles Darwin (1809-1882) 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

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

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

18. The Systems Biology Paradigm

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

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

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

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 ecology physiology immunology Molecular systems biology Courtesy of Vito Quaranta, MD; Vanderbilt University, Nashville, TN

25. Multi-scale view of E. coli colony cell nucleoid macromolecule

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