Download (molecular) systems biology?

Lecture # 1
The Grand Schema of Things
Outline
1.
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5.
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
How does systems biology fit in?
THE GRAND SCHEMA OF SCIENCE
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
Craig Venter
• 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
Putting the Pieces Together:
Genome-scale Network Reconstructions, 1997-2000
Christophe Schilling
• Organism-specific genomescale metabolic networks
– E. coli, H. influenzae, H. pylori
• The first high throughput in
silico biologists
Jeremy Edwards
Extended to Eukaryotes (2001-03)
• Yeast, w/Jens Nielsen Lab
• Iman Famili/Jochen Forster
Human metabolism: RECON 1 (2005-07)
Global Metabolic Map
Comprehensively represents
known reactions in human cells
Compounds
Reactions (3,311)
(2,712)
Pathways (98)
Genes (1,496)
Transcripts (1,905)
Proteins (2,004)
Compartments (7)
Network map
Mathematical representation
Stoichiometric Matrix
reaction
metabolite
S=
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•
•
•
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
Mechanistic genotype-phenotype relationships
CONCEPTS IN GENOME-SCALE
SCIENCE
Molecular to Systems Biology
Nature Biotechnology, 18:1147, 2000
Pathway in the Context of a System
Methanosarcina barkeri metabolism
Examining the Properties of an
Individual Pathway
L-serine Biosynthesis
The intracellular
environment is
crowed and
interconnected
placing severe
constraints on
achievable
physiological
states
Hierarchy in systems biology
Chemical causation:
Can apply P/C laws
and get causality on
a small scale
Ludwig Boltzmann (18441906)
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)
Building the G/P-relationship:
integrated network reconstructions
conceptual
operational
M Matrix
Metastructure
E Matrix
O Matrix
ME
Matrix
OME
Matrix
Reconstruction is iterative:
History of the E. coli Metabolic Reconstruction
Amit Varma
Jay Keasling
Jeremy Edwards
Jennie Reed
Adam Feist
Jeff Orth
Ines Thiele
THE SYSTEMS BIOLOGY PARADIGM
Systems Biology Paradigm:
components -> networks -> computational models -> phenotypes
Palsson,BO; Systems Biology, Cambridge University Press 2006
Our Systems Biology Series
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
Towards ‘principles’for molecular biology on genome scale
BUILDING FOUNDATIONS
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
ecology
physiology
immunology
Molecular systems biology
Courtesy of Vito Quaranta, MD; Vanderbilt University, Nashville, TN
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