Systems Biology Lecture 1 - Bioinformatics Institute€¦ · The genesis of systems biology 1940s:...
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Transcript of Systems Biology Lecture 1 - Bioinformatics Institute€¦ · The genesis of systems biology 1940s:...
Historical context
1900 1950 2000
Dominantapproach
Focus ofstudy
Paradigmaticdiscovery
Limitationsof approach
Physiology
Functioning oforgans andmetabolism
Homeostasis
Inability to identify /modify cellularcomponents
Molecular biology
Identification andfunctioning of cellularcomponents
DNA discovery, Wholegenome Sequencing
Inability to explain howcomponents interact toproduce phenotype
N.Chomsky. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004
2000 10-15 years ? Another 10-15years or more
We know geneproducts of majorpathways
Identify all theinteractions amongproteins in the pathway
Quantitativeunderstandingof biology. Major“how and why”questions resolved
Future timeline
N.Chomsky. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004
The genesis of systems biology
1940s: Nobert Wiener - Father of Cybernetics
1960s, 70s: Biochemical system theory, Metabolic control theory
Mid 1990s: Systems Biology - Leroy Hood
Defintion and complexity• Systems Biology is defined by assays, data types, global assays and
the types of data integrations
• Hypothesis drivenGlobalQuantitativeIntegrativeIterativeDynamicMultiscaleCross-disciplinary
Leroy Hood. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004
Bottomline: System is really where you draw the box !
Levels of biological complexity
- DNA- RNA- Proteins- Protein-protein & protein DNA Interactions- Pathways- Networks- Cells & tissue- Organs & Systems- Organisms- Population- Ecology
Fundamental ConceptsWhat is :
system
model
modeling
Simulation
Validation
What is a:
steppathpathwayNetwork?
Step: 1 reaction eventPath: 1 entry, 1 exitPathway: 1 entry, 1-many exitsNetwork: many entries, many exits
Measure-ment
Experi-mentation
Comput-ationalmodeling
My initiation into Systems BiologyThe E-Cell System
E4P
PGI PFK
GLCtr
ATP
GLC
ADP G6P
GLC
ATP ADP
F6P ALD
DHAP
TPI
GAPDHGA3P
DPGM
2,3DPG
1,3DPG PGK
DPGase
Pi
NAD NADHPi
3PG PGM 2PG
ATPADP ADP ATP
PEPEN PK
ATP
ADP
ATPaseLDH
PYRtr
LACtr
Glycolysis
NADNADH
PYR
LAC
PYR
LAC
G6PDH
HKFDP
GL6P
6PGLase
NADPGSH
GO6P
GSSGR
6PGODH
Ru5PCO2
NADPH GSSG
GSHox
X5PX5PI
TK1
TK2
TA
S7P
R5PI
Pentose phosphate pathway
AMP
ATPR5P
PRPP
ADE
PRPPsyn
PiPi
PiPi
ADPRT AMP
AMPDA
PRM
APK AK
AMPase
PiIMP
Pi
ADO
ADA
INO
PNPase
HGPRT
R1PPi
HX
IMPase
HXtr
HX
Nucleotide metabolism
CAH
HCO3
H+
H+
CO2
HCO3
Na/K Pump
K+K+
Na+Na+
ATP
ADP
K+
K+Na+
Na+
ADE
ADE
ADEtr
Membranetransport
mOsm VOL
mOsm VOL
Donnan ratio
H+
Why is it difficult to model cellular transactions?• Qualitative biology
• Inaccuracy of data
• Incompleteness of data
• Memory
• Sensing
• Feedback
• Communication
• Toggle switches (feedback loops +/-),amplifiers, resistors and oscillators,bistable states, unstable states, attractors,hysteresis?
• Where do cells derive their robustnessfrom?
Sci.Am. Jan2004 issue
Problem What we understand…
Biological chemistry,Transmission of genetic information
What we don’t understand ?
Biological complexity
The best non-living equivalent of life(for in-silico modeling)
Emergent phenomena
Heavy usage of mathematics !Mathematics: Usually approach driven, not problem driven
From fusion to confusioncomputational & Intellectual
Assuming 5 parameters / protein30,000 genes = 150,000 parameters space (PS)Cell physiology = 1 point in this PS
Dynamics of regulation
Change 1 point in PS
5000 genes respondEquivalent to 25000 parameters change
Q1: How do cells find safe paths betweencontinuously changing physiological states ?
Q2: Hidden Laws of Biological Complexity ?
Unanswered questions
Q1. What are the initial and boundaryconditions in biological systems ?
Q2: Is there a broader set of primitivesone can use in biology?
Q3. Can a simple rule give rise tocomplex biological patterns ?
Q4. How are networks generated frommolecular interactions?
Q5. Rules that generate a combination ofscale-free / modular network ?
Q7: The big one: How do organismshandle information 6 orders ofmagnitude apart ?
The why files ?
Q1.Why model pathways,networks, cells and tissues ?
Q2: Has Systems Biologygone far beyond its intendedmeaning ?
Q3: Experimental SystemsBiology vs. ComputationalSystems Biology
Challenges Requirements
• Number ofcomponents -enormous
• Rules of howthey fit together ?
• Principles of complexand robust behavior
• Biology
• Math
• Comp Science
• Physics
• Engineering
Training new breed ofbiologists whounderstand non-biological concepts !!
3 billion years of metabolism and1 billion year of Cell biology
1986-2003: 3500 fold HTS
2003 - 2013: 3500 more !
Leroy Hood. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004
Systems Biology is NOT a subculture of Mathematical Biosciences !
Biological knowledge
Validated model
Conceptual Model
Makepredictions
Explain non-intuitivephenomenon
Use model fordiagnosticpurposes
Analytical Model
Computer simulation
Rate EquationsConstraintsGuess missing parametersAdd lots of assumptions !
Match in-silico & in-vivo
Revise
OurModelingstrategy
Reading materialLeroy Hood GroupDrug Discov Today. 2003 May 15;8(10):436-8.
Mech Ageing Dev. 2003 Jan;124(1):9-16.
Nature. 2003 Jan 23;421(6921):444-8. Review
Annu Rev Genomics Hum Genet. 2001;2:343-72. Review.
Tomita Group - JapanE-Cell publication: Bioinformatics (1999) 15(1): 72-84.
BIIArtificial Life and Robotics (2002) 6: 99-107.
Complex Systems Science in Biomedicine (Kluver, in press)
Encyclopedia of Molecular cell biology and Molecular Medicine (Wiley-Verlag)
The Ecell Book. Kluver-Landes
Bioessays. 2004 Jan;26(1):68-72.
OthersDe Jong. J Comput Biol. 2002;9(1):67-103.
Hoefstadt et al. In Silico Biol. 1998;1(1):39-53.
Caltech group: Bioinformatics. 2003 Mar 1;19(4):524-31.