Introduction to Systems Biology

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Introduction to Systems Biology

• Lecture 1 Jan-Feb 04
• Dr. Eduardo Mendoza
• Physics Department
• Mathematics Department Center for
  NanoScience
• University of the Philippines
  Ludwig-Maximilians-University
• Diliman Munich, Germany
• eduardom_at_math.upd.edu.ph
  Eduardo.Mendoza_at_physik.uni-muenchen.de

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Some systems biology surprises
Surprise No.1 Systems biology and the origin
of life !
Primordial Systems Biology Doron Lancet, Ron
Kafri, Arren Bar-Even, and Barak Shenhav Crown
Human Genome Center, Dept. of Molecular Genetics,
Weizmann Institute of Science, Rehovot 76100,
Israel
A widespread notion is that life arose from a
single molecular replicator, probably a
self-copying polynucleotide. We present an
alternative view, envisioning the spontaneous
formation of micelle-like molecular assemblies,
within which every compound has multiple
recognition and catalysis partners.
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Surprising?...
IAS Center for Systems Biology
Systems Biology Short Course Control and
Dynamical SystemsMay 21-24
UCSB To Be a Pioneer in Systems Biology Novel
Gift from Professor and Spouse will Build Centers
of Excellence Across the DisciplinesMay 13, 2003

etc...
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Surprise No. 2 Harvard Medical Schools Approach
Nature Oct 2
First entirely new HMS department in 20 years
HMS plans to recruit 20 faculty members for the
new department
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Topics

• What is and why systems biology?
• Systems biology as an integrative framework
• Measurement challenges for system
  discovery/modeling
• Computational challenges need for software
  standards and platforms
• Key trend focus on motifs and modules
• Understanding the chemotaxis module
• Characteristics of eukaryotic chemotaxis
• A microfluidics-based approach for chemotaxis
  experiments
• Modeling eukaryotic chemotaxis
• The modular design hypothesis some perspectives

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What is Systems Biology?

• This emerging paradigm aims at systems-level
  understanding and requires a set of principles
  and methodologies that links the behaviors of
  molecules to systems characteristics and
  functions (H. Kitano, ICSB 2000)
• Current primary focus is the cell but the
  perspective needs to be extended to tissues,
  organs, organisms, populations, ecosystems,..

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What Data is Needed to Specify a Single
Eukaryotic Cell?

• Macromolecules
• 5 Billion Proteins
• 5,000 to 10,000 different species
• 1 meter of DNA with Several Billion bases
• 60 Million tRNAs
• 700,000 mRNAs
• Organelles
• 4 Million Ribosomes
• 30,000 Proteasomes
• Dozens of Mitochondria
• Chemical Pathways
• Vast numbers
• Tightly coupled
• Is a Virtual Cell Possible?

www.people.virginia.edu/rjh9u/cell1.html
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A simpler view ...
just for fun ?
courtesy of scholars of the (elite) German
National Academic Foundation...
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A systems biology view...

Lifes Complexity Pyramid (Oltvai-Barabasi,
Science 10/25/02)
System
Functional Modules
Building Blocks
Components
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Biology Mini-review Eukaryotic Gene Expression
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Systems approaches are not new...

• A few systems thinkers in biology and related
  fields
• Systems Physiology
• J. Cannon (30s) homeostasis
• W. McCullough (50s)
• H. Maturana
• Systems Ecology
• H.T. Odum
• Cybernetics and (complex) systems theory
• N. Wiener (50s)
• L. V. Bertalanffy (60s)
• H. Atlan
• J.G. Miller
• ....

• but (due to the progress in molecular
  biology) is now defining a NEW PARADIGM for
  bioscientific and biomedical research
• Other names
• Network Biology
• Integrative Biology
• Quantitative Biology
• Predictive Biology

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A major paradigm today the system is a
network...
Science, Sep 26
Spring 02
Fall 02
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Bio-Map
A.L.Barabasi
NETWORK BIOLOGY
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Systems Biology is an integrative approach

• it seeks to integrate
• levels (of structure and scale)
• process phases (the many omics)
• experiment and modeling/computational work
• scientific disciplines (multi-disciplinary)
• to achieve quantitative experimental results and
• to build predictive models/simulation
  environments

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4 Key Areas - 4 Key Activities

• Key Areas
• Systems structures topology of networks (genetic
  regulatory, signal transduction, metabolic
  pathways,..), parameters, constraints
• Systems dynamics eg stability analysis,
  sensitivity analysis, bifurcation analysis
• Control methods eg identifying feedback
  mechanisms for minimizing malfunction
  (robustness)
• Design methods modify, construct biosystems with
  desired properties
• (H. Kitano, Science, Mar 02)

• Key Activities
• Systems simulation (Influence analysis)
• Systems reasoning

• Systems modeling

• Systems discovery (Systems Inference,
  Reverse Engineering)

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A biologists vision
Nobel Laureate Sydney Brenner, a professor of
biology at the Salk Institute, told participants
that he envisioned a time whenjust as the
National Academy of Sciences no longer has a
section for molecular biology because every
biologist is essentially a molecular
biologisteveryone is a computational
biologist. (The Scientist, Nov 12)
Friday, November 7,2003 Biology Keynote
Address Computational Models of Biological
Processes Sydney Brenner, D.Phil
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Measurement challenges for Systems Biology

• Requires high quality data as reference point for
  modeling simulation (in small and large
  experiments!)
• Measurement process needs to be
• comprehensive (wrt factors, time series,
  features)
• Quantitatively accurate
• Systematic
• Next generation of experimental systems
  (microfluid systems, nanotechnology,
  femtochemistry,..) and supporting software
• ? More challenging for experimental biologists!

(T. Ideker et al)
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Fast growing interest

• The Institute for Systems Biology, Caltech and
  the University of California Los Angeles have
  recently established a NanoSystems Biology
  Alliance (NSBA).
• The current tools used in systems biology are
  large, expensive, labor intensive,
  time-consuming, and require a significant amount
  of cells for analysis. However, newly developed
  nanotechnologies have the potential to vastly
  increase the efficiency of a systems analysis at
  all levels.

"The Tiny Toolkit"   Nature 424, 10 (1 May
2003)  
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Computational challenges for Systems Biology

• Develop approaches for large complex systems
  encompassing multiple scales (in space and time)
  and with highly diversified components
• Establish "systems engineering-oriented" ways of
  collaboration among modelers, including use of
  standards and platforms for data schemes and
  software tools used

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Example of an Emerging Standard SBML

• Language for representation and exchange of
  biochemical network models
• Main benefits
• Enable use of multiple tools
• Enable models to be shared and published
• Ensure survival of models beyond the lifetime of
  the software used to create them
• Key characteristics
• Releases community driven (sbml-discuss list,
  Software Platfoms for Systems Biology forum)
• Based on XML ( further XML-based standards like
  MathML)
• Support by 35 modeling/simulation tools

Check www.sbml.org
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SBML 2 Model Definition
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Example of an SBML-based platform DARPA
BioSPICE

• BioSPICE Mission provide bio-scientists a
  standard, scalable and easy-to-use modeling and
  simulation environment (as open source software)
• model library
• simulation environment with links to relevant
  databases
• user interface and data visualization tools
• Testing and validation of the models using a
  range of cell experiments

• SPICE
• Originally Simulation Program for Integrated
  Circuit Evaluation
• DARPA Simulation Program for Intra-Cell
  Evaluation
• DARPA Bio-Computing Project
• initiated Fall 01 (50m)
• 2 Parts DNA Computing and BioSPICE (bigger)

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• .

Check https//community.biospice.org
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Key trend focus on motifs and modules

Lifes Complexity Pyramid (Oltvai-Barabasi,
Science 10/25/02)
System
Growing focus
Functional Modules
Building Blocks
Components
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Network Motifs

• Network motifs
• are small subnetworks (max 5 nodes?)
• perform specific information processing tasks (
  natural circuits)
• repeat (in a statistically significant way)
• are (probably) evolutionarily conserved
• are analogous to protein motifs

• Monod-Jacob (1961)
• It is obvious from the analysis of these
  bacterial genetic regulatory mechanisms that
  their known elements could be connected into a
  variety of circuits endowed with any desired
  degree of stability.

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Motif examples

• Feedfoward Loop
• A regulator that controls a second Regulator
• and together they bind a common target gene
• Function
• A switch for rejecting transient
• input

Biphasic amplitude filters
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Motif classes (1)
D.Wolf, A. Arkin
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Motif classes (2)
D.Wolf, A. Arkin
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A programmatic call by cell biologists
(Nature, Dec 99)
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Reinforcing the modular view

• Currently
• Cancer Research UK
• Medicine Nobel 01

Nature, Aug 03
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What are (functional) modules?

• Diverse characteristics proposed
• chemically isolated
• operating on different time or spatial scales
• robust
• independently controlled
• significant biological function
• evolutionarily conserved
• clustered in the graph theory sense
• ...
• any combination of the above

Biochemistry Biophysics
Control Engineering
Biology
Mathematics
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Bacterial chemotaxis model
Barkai-Leibler Model Refinement (Almogy et al
12/01)
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Integral Feedback mechanism in bacterial
chemotaxis (Yi et al 2000)
This could be a protein network motif !
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Subsystem focus the novelty of Systems Biology?

• Hans V. Westerhoff (Amsterdam)
• "Systems biology is not the biology of systems,"
  he emphasizes. Instead, he says, it is the region
  between the individual components and the system,
  which is why it's new.
• "It's those new properties that arise when you
  go from the molecule to the system," he says.
  "It's different from physiology or holism, which
  study the entire system. It's different from
  reductionist things like molecular biology, which
  only studies the molecules. It's the in-between."

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Eukaryotic Chemotaxis Examples

• Polarization of neutrophil (a-d)
• Axons navigating in developing nervous system (e)
• Yeast budding and mating (f)
• Dicty forming multicellular aggregates (g)

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Introducing Dicty (www.dictybase.org)
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Dicty chemotaxis (video)
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Chemotaxis Pathways in Dictyostelium
(Kimmel-Parent, Science June 03)
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Rädler Lab Activities (1) Microfluidics allows
for quantitative gradient variation
Experiment (S. Thunnessen, S. Kempter) Slime mold
(Dictyostelium discoideum) chemotaxis
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Vision Dynamic Systems Response
output
input
c1, c2, c3, ... D1, D2, D3, ...
oscillating cAMP gradient
Cell reaction CRAC polarization Arp 2/3 F/G
actin ...
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Initial steps gradient sensing (Weiner Apr 02)
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Very rough submodule architecture
Cell Movement
Cell Orientation
Cell Protrusion
Gradient Sensing
Receptor submodule
Cell Adhesion
Polarization
Cell Retraction
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Levchenko-Iglesias Model (Jan 02)
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Levchenko-Iglesias Model (Jan 02)
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Compartmentalized S-System (joint with T.
Bretschneider)

• Approach
• Use classical activator-inhibitor model to
• simplify
• Model diffusion by compartmentalizing
• ? GMA model
• Use recasting algorithm to obtain S-System

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Compartmentalized GMA

• Differential equations
• X1' kAA X12 (1.0 - alphaX2g) kA - kAm
  X1 kcAMP XcAMPl
• X2' -kIm X2 kAI X1 D(X4-X2)
• X3' kAA X32 (1.0 - alphaX4g) kA - kAm
  X3 kcAMP XcAMPr
• X4' -kIm X4 kAI X3 D(X2-X4)
• X5' kAC X1 - kCm X5
• X6' kAC X3 - kCm X6

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Modular Design Hypothesis (1)
Science, Sep 26

• Although Nature is more of a tinkerer (F.
  Jacob), biological networks share structural
  principles with engineered systems, e.g.
• Modularity
• Robustness
• Use of recurring circuit elements

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Modularity vs. Non-Modularity
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(Part of) Sea Urchin GRN for development
Hood-Galas Nature, Jan 23 03
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Modular Design Hypothesis (2)

• We suspect that animal GRNs are modular in
  structure in that there is an enumerably small
  set of GRN building blocks from which larger
  GRNs are constructed. It is likely that larger
  modules will be hierarchichally built up from
  combinations of smaller ones
• Some building blocks are
• Single and two-gene feedback loops (for ensuring
  unidirectional progress of developmental
  processes)
• Positive feedback (community effect) between
  genes in different cells (ensure that all cells
  within a territory adopt the same fate)
• Repression gene cascades (define sharp spatial
  boundaries between cells of different future
  territories)

H.Bolouri, E.Davidson, BioEssays Dec 02
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Research _at_ Harvard Bauer Center (1)

• NIGMS Center of Excellence for Modular design in
  Living Systems (9/03, 15 million)
• Projects initiated
• Computational approaches to identifying modules
  and predicting their behavior (A. Regev)
• Theoretical analysis of functional modules (D.
  Fisher)
• Robustness and evolvability in simple synthetic
  modules (M. Elowitz, Caltech)

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Harvard Bauer Center (2)

• Module Classes (in D. Fishers project)
• Modules that perform Boolean (logical) functions
  (eg set of genes controlling Drosophila embryo)
• Modules that measure environmental parameters (eg
  chemotaxis modules)
• Modules that provide quantitative control of a
  biological process (eg set of proteins that
  control assembly of a mitotic spindle of a
  certain length

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Example Drosophila segment polarity GRN
(Albert-Othmer 03)
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Harvard Bauer Center (3)

• Experimental projects initiated
• Dissecting and evolving the mating module of
  budding yeast (A. Murray)
• Optical methods for monitoring protein
  phosphorylation in living cells (K. Thorn)
• Regulation and integration in bacterial cells (M.
  Laub) (genetic modules in cell cycle)
• The stress response, a universal integrating
  module (O. Rando)
• Inter-module integration plasticity and
  robustness in brain and behavior (H. Hofmann)

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Motifs vs. modules
But is the difference really clear?

• Motifs
• small
• Repeated (significantly)
• information processing task
• evolutionarily conserved

• Modules
• large(r)
• Overlapping
• Significant biological function
• evolutionarily conserved

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Are (circadian) clocks motifs ?
or modules?
Roenneberg-Merrow
Model complexity
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Motifs and modules many open questions
challenges

• Partial list (Wolf-Arkin)
• Establishing (or disproving) the engineering
  (circuit) metaphor (eg are there motifs unknown
  to engineering lexicon?)
• Rigorous definitions of motif and module
• Extending homology concepts to motifs and modules
• Consistent theories of network evolution
• Establishing parameter regimes for motif behavior
• Experimental measurement of dynamics in single
  cells
• ...

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Thanks for your attention !
MSBF

• Questions?