Lecture # 1

Lecture # 1

The Grand Schema of Things

Outline

1. The grand scheme of things2. Some features of genome-scale science3. The systems biology paradigm4. Building foundations5. Where does (Molecular) Systems Biology fit

in to biological hierarchy

THE GRAND SCHEMA OF SCIENCEHow does systems biology fit in?

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

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

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

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

Extended to Eukaryotes (2001-03)

• Yeast, w/Jens Nielsen Lab • Iman Famili/Jochen Forster

Global Metabolic MapComprehensively 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)

• 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

Network map Mathematical representation

Concepts in genome-scale scienceMechanistic genotype-phenotype relationships

Nature Biotechnology, 18:1147, 2000

Molecular to Systems Biology

Pathway in the Context of a System

Examining the Properties of an Individual Pathway

L-serine Biosynthesis

Methanosarcina barkeri metabolism

The intracellular environment is

crowed and interconnected placing severe constraints on

achievable physiological

states

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)

Building the G/P-relationship: integrated network reconstructions

conceptual

M Matrix

E Matrix

O Matrix

OME Matrix

MEMatrixMeta-

structure

operational

Reconstruction is iterative:History of the E. coli Metabolic Reconstruction

Adam Feist Jeff Orth Ines ThieleJennie ReedJay KeaslingAmit Varma Jeremy Edwards

The Systems Biology Paradigm

Systems Biology Paradigm:components -> networks -> computational models -> phenotypes

Palsson,BO; Systems Biology, Cambridge University Press 2006

Data types -- 211

Reconstruction– 211/212

In silico analysis– 212/213

Tailoring to tissuesDrug response

phenotypes

SMILEY

Adaptive evolutionDisease progression

Differentiation

Synthetic BiologyMetabolic Engineering

Our Systems Biology Series

BUILDING FOUNDATIONSTowards ‘principles’for molecular biology on genome scale

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

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

Biological Scales and Systems Analysis

Courtesy of Vito Quaranta, MD; Vanderbilt University, Nashville, TN

Molecular systems biology

ecology

physiology

immunology

Multi-scale view of E. coli

colony cell nucleoid macromolecule

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