Genetic Regulatory Networks and Systems Biology

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Gene(tic) Regulatory Networks and 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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Topics

• Genetic vs. Gene(tic) Regulatory Networks
• GRNs in the Systems Biology Context
• Network motifs
• Cell Biology from molecular to modular
• Papers for presentation

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1. Genetic vs. Gene(tic) Regulatory Networks

• Variations of genetic network concept
• Noveen 1998 an association of many genes which
• interact with each other in cascades or parallel
  pathways and
• achieve a specific function or various functions
  through such interactions
• Note interactions allow adjustment of gene
  expression or function thru activation/inhibition
  of transcription, translation or
  post-translational modifications
• Wagner 2001 a group of genes in which
  individual genes change the activity of other
  genes
• Note activity changes changes in gene
  expression on mRNA or protein level (methylation
  state, phosphorylation state or alternative
  splicing)

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Genetic Networks variations (2)

• Dhaeseleer 2000
• Focuses on transcriptome level ? higher level
  interactions (rather than biochemical mechanísms)
• Need to integrate gene expression data with
  information sources

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Gene(tic) regulatory networks

• GRN defined as networks of regulatory
  interactions between DNA, RNA, proteins and small
  moleculesDEJO02
• Also called transcriptional regulatory networks
• (Classical) GRN Example 1 lac operon in E.coli
• GRN Example 2 Drosophila segment polarity
• GRN Example 3 Sea Urchin Endoderm Development
• GRN Example 4 RNA interference

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GRN Example 1 The lac Operon
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Example 2 Drosophila segment polarity GRN
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Example 3 (Part of) Sea Urchin GRN for
development
Hood-Galas Nature, Jan 23 03
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RNAi (RNA Interference) Nature July 25 02
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Bio-Map
NETWORK BIOLOGY
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Terminology

• Biochemical processes mediate the interaction of
  cells with their environment and are responsible
  for most of the information processing inside the
  cell. Networks of interacting proteins underlie
  many of these processes. Three major types of
  biochemical processes are distinguished
• Metabolic pathways are sequences of chemical
  reactions, each catalyzed by an enzymes, where
  certain product molecules are formed from other
  small substrates. Metabolites are usually small
  molecules while enzymes are proteins.
• Signal transduction networks are pathways of
  molecular interactions that provide communication
  between the cell membrane and intracellular
  end-points, leading to some change in the cell.
  Signals are transduced by modification of one
  proteins activity or location by another
  protein.
• Gene regulation circuits determine whether or
  not a particular gene is expressed at any
  particular time. Transcription factors, proteins
  that promote or repress transcription, either
  directly or indirectly bind regulatory DNA
  elements.
• Metabolic, transduction and regulatory circuits
  are interleaved and integrated. For example, gene
  regulation circuits are fed by external signals
  transmitted by signal transduction pathways.

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Two main problems/challenges (Altman)
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2. GRNs in the Systems Biology Context

• What is Systems Biology?
• This emerging paradigm aims at systems-level
  understanding which requires a set of
  principles and methodologies that links the
  behaviors of molecules to systems characteristics
  and functions (H. Kitano, ICSB 2000)
• Primary focus is the cell, but from there
  extensible to organs, organisms, ecosystems,..
• Other names Integrative (whole-istic) Biology,
  Quantitative Biology, Predictive Biology, Network
  Biology,...

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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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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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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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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 _at_ first look 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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Why Systems Biology? (2)

• J.B.Martin (Dean, HMS) It is worrying that we
  do not understand how most drugs work and
  essential that we in detail how both genetic
  mutations and the environment contribute to
  disease
• M. Kirschner (cell biologist) We need to build
  on the foundation of molecular biology to
  construct an understanding of the architecture
  of the cell and how cells cooperate across organ
  systems with a predictive model of physiology as
  the ultimate goal.

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Why Systems Biology? (3)

• Major challenges of Cell Biology (B. Alberts, Sep
  01)
• Graduate from cartoons to a real understanding of
  each protein machine
• Completely understand one type of cell
• Understand how cells make decisions in complex
  environments, such as in a multicellular organism
• Understand how cells organize,and reorganize,
  their internal space
• Decipher the pathways by which cells and other
  organisms evolved on the earth
• Use our increasingly profound understanding of
  biology to design intelligent strategies to
  understand diseases

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Why Systems Biology? (4)

• The vision of the Institute of Systems Biology
  (ISB)
• use systems approaches to enable in the next
  10-15 years predictive, preventive and
  personalized medicine

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Systems Biology and D3(D3 Drug Discovery and
Development)
The vision

• Modeling and simulation
• can reduce the number of clinical trials that
  have to be performed on real human beings
• can be used to design better trials once a drug
  is ready for testing in man

The Physiome Project a worldwide effort to
define the physiome by developing databases and
models which will facilitate the understanding
of the integrative functions of cells, organs
and organisms.
Currently

• def.Physiome is the quantitative
• and integrated description of the
• functional behavior of the physiological
• state of an individual or species.

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Modeling/Simulation Potential in Life Sciences

• Large IT investments expected
• Experts believe bioinformatics (incl
  modeling/simulation) has the potential to reduce
• the annual cost of developing a new drug by 33,
  and
• the time taken for drug discovery by 30.
• IT-related spending to rise from 12 b (01) to
  30 b (06)
• Emerging standards and platforms SBML, BioSPICE

• Pharma sector challenges
• Steeply rising costs for new drugs .8 b (01) ?
  1.6 b (06)
• 15 years average for a new drug (in addition 1
  in 5 drugs risk failure in human clinical trials)
  
• 35 drugs with 73 b global sales face US patent
  expiration between 2002 and 2007

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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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Modeling/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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Modtech diversity to match bio-complexity

• Graphs (directed and undirected)
• Bayesian networks
• Boolean, generalized logical networks, polynomial
  models
• Nonlinear ODEs (ordinary differential equations)
• Special cases S-Systems, GMA Systems, pieceweise
  linear, qualitative
• PDEs (partial differential equations) and other
  spatially distributed models
• Stochastic master equations
• Rule-based formalisms
• Petri nets, transformational grammars, process
  algebras,.

Modtech Modeling techniques
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Choosing the right Modtech
Source DEJO02
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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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3. 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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4. 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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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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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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Papers for presentation

• Group 1 (2 members, Feb 12/17)
• J. Heidel, J. Maloney, C. Farrow Finding Cycles
  in Synchronous Boolean Networks with Applications
  to Biochemical Systems (preprint, 37 pp)
• Group 2 (2 members, Feb 17/19)
• R. Laubenbacher, B. Pareigis Finite Dynamical
  Systems, Adv. In Applied Math. 26 (2001), 14 pp

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Thanks for your attention !

• Questions?