Download Systems Biology Lecture 1

Systems Biology Lecture 1
history, introduction and definitions
Pawan Dhar
Historical context
1900
1950
Dominant
approach
2000
Physiology
Molecular biology
Focus of
study
Functioning of
organs and
metabolism
Identification and
functioning of cellular
components
Paradigmatic
discovery
Homeostasis
DNA discovery, Whole
genome Sequencing
Limitations
of approach
Inability to identify /
modify cellular
components
Inability to explain how
components interact to
produce phenotype
N.Chomsky. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004
Future timeline
10-15 years ?
2000
We know gene
products of major
pathways
Identify all the
interactions among
proteins in the pathway
Another 10-15
years or more
Quantitative
understanding
of biology. Major
“how and why”
questions resolved
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 driven
Global
Quantitative
Integrative
Iterative
Dynamic
Multiscale
Cross-disciplinary
Levels of biological complexity
- DNA
- RNA
- Proteins
- Protein-protein &
protein DNA Interactions
- Pathways
- Networks
- Cells & tissue
- Organs & Systems
- Organisms
- Population
- Ecology
Bottomline: System is really where you draw the box !
Leroy Hood. Systems Biology Meeting, MIT, Boston Jan 8-9, 2004
Fundamental Concepts
What is a:
What is :
system
model
modeling
Simulation
Validation
step
path
pathway
Network?
Experimentation
Measurement
Computational
modeling
Step: 1 reaction event
Path: 1 entry, 1 exit
Pathway: 1 entry, 1-many exits
Network: many entries, many exits
My initiation into Systems Biology
The E-Cell System
GLC
Glycolysis
GLCtr
ADP
DPGase
DPGM
ADP
ATP
ATP
2,3DPG
DHAP
GLC
Pi
TPI
HK
G6P
PGI
PFK
F6P
FDP
ALD
NADP
TK2
GSH
G6PDH
GA3P GAPDH 1,3DPG PGK
Pi
NAD NADH ADP
HCO 3
CAH
H+
CO 2
6PGODH
TK1
GSSG
ATP
H+
R5PI
CO 2
Pentose phosphate
pathway
NADH
LAC
LACtr
NAD
AMPase
IMP
R5P
HGPRT
PRM
Pi
R1P
ADO
Pi
ADA
IMPase
PRPPsyn
X5P
LDH
ATPase
AMP
Pi Pi
AMP
Ru5P
X5PI
PYR
K+
PRPP
NADPH
LAC
ADP
AK
Pi Pi AMPDA
S7P
GO6P
PYRtr
PK
ATP
ADPRT
TA
GSHox
PEP
ATP
APK
ADE
GSSGR
EN
2PG
ADP
ATP
E4P
6PGLase
PYR
PGM
H+
GL6P
HCO3
3PG
INO
K+
Pi
ADP
ADE
Na+
ADEtr
VOL
HXtr
ADE
HX
mOsm
VOL
K+
Na/K Pump
HX
mOsm
Na+
ATP
PNPase
Nucleotide
metabolism
Donnan
ratio
K+
Na+
Membrane
transport
Na+
Where are
we now ?
Grid version released in
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 robustness
from?
Sci.Am. Jan
2004 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 confusion
computational & Intellectual
Assuming 5 parameters / protein
30,000 genes = 150,000 parameters space (PS)
Cell physiology = 1 point in this PS
Dynamics of regulation
Change 1 point in PS
5000 genes respond
Equivalent to 25000 parameters change
Q1: How do cells find safe paths between
continuously changing physiological states ?
Q2: Hidden Laws of Biological Complexity ?
The why files ?
Q1.Why model pathways,
networks, cells and tissues ?
Q2: Has Systems Biology
gone far beyond its intended
meaning ?
Q3: Experimental Systems
Biology vs. Computational
Systems Biology
Unanswered questions
Q1. What are the initial and boundary
conditions in biological systems ?
Q2: Is there a broader set of primitives
one can use in biology?
Q3. Can a simple rule give rise to
complex biological patterns ?
Q4. How are networks generated from
molecular interactions?
Q5. Rules that generate a combination of
scale-free / modular network ?
Q7: The big one: How do organisms
handle information 6 orders of
magnitude apart ?
Challenges
•
Number of
components enormous
•
Rules of how
they fit together ?
•
Principles of complex
and robust behavior
Requirements
•
•
•
•
•
Biology
Math
Comp Science
Physics
Engineering
Training new breed of
biologists who
understand nonbiological concepts !!
Systems Biology is NOT a subculture of Mathematical Biosciences !
3 billion years of metabolism
and
1 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
Biological knowledge
Our
Modeling
strategy
Conceptual Model
Analytical Model
Revise
Computer simulation
Rate Equations
Constraints
Guess missing parameters
Add lots of assumptions !
Match in-silico
& in-vivo
Validated model
Use model for
diagnostic
purposes
Make
predictions
Explain nonintuitive
phenomenon
t
a
D
a
M
Classic
State-ofthe-art
o
l
e
d
Wish list
Reading material
Leroy Hood Group
Drug 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 - Japan
E-Cell publication: Bioinformatics (1999) 15(1): 72-84.
BII
Artificial 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.
Others
De 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.