Introduction To System Biology Lecture1

Introduction to System Biology
Dr. Carlo Cosentino

School of Computer and Biomedical Engineering
Department of Experimental and Clinical Medicine
Università degli Studi Magna Graecia
Catanzaro, Italy
carlo.cosentino@unicz.it
http://bioingegneria.unicz.it/~cosentino
Dr. Carlo Cosentino 1 Carnegie Mellon University, Pittsburgh, 2008

Outline of the Lectures
Ó Introduction to Systems Biology

Ô Basic Principles
Ô Biology in a nutshell
Ô Getting experimental data
Ó Modeling biochemical reactions
Ô Deterministic Models
Ô Stochastic Models
Ó Biological Networks
Ô Types of biological networks
Ô Dynamical models of biological networks
Ô Inference of biological networks
Ó Analysis and Simulation of Biological Systems
Ô A case-study: The cell cycle
Ô Modeling the cell cycle
Ô Analysis of biological models
Ô Software tools

Introduction to System Biology
Ó Basic Principles
Ó Biology in a nutshell
Ó Experimental Techniques

What is Systems Biology?
Ó Systems biology is concerned with the study of biological functions and

mechanisms, underpinning inter- and intra-cellular dynamical networks, by
means of signal- and system-oriented approaches
Ó “Life is an emergent, rather than an immanent and inherent, property of matter.

Although it arises from the material world, it cannot be reduced to it” (E. Schrödinger)
Ó “Science is built up of facts, as a house is with stones. But a collection of facts is no more a
science than a heap of stones is a house” (H. Poincaré)

Systems Biology Approach
Ó A systems biology approach means

Ô Investigating the components of cellular networks and their interactions
Ô Applying experimental high-throughput and whole-genome techniques
Ô Integrating computational and theoretical methods with experimental
efforts

An Iterative Approach
Experiments
Data
Handling
Modeling

Main Related Disciplines
Ó Biology!
Ó Biotechnology
Ó Mathematics and Statistics
Ó Physics and Chemistry
Ó Information Science
Ó Engineering (Biomedical, Chemical, Computer, Systems & Control,

Electronic)
Ó …

Foundations
Ó Improved biological knowledge with the prospect of utilization in

biotechnology and health care
Ó New experimental techniques in genomics and proteomics
Ó Classical mathematical modeling of biological processes
Ó Computer power for simulation of complex systems
Ó Storage and retrieval capability in large databases and data mining

techniques
Ó Internet as the medium for the widespread availability from multiple sources
of knowledge

Goals
Ó Models to unveil mechanisms causing alterated phenotypes and devise novel

therapies and drugs
Ó Predictive tools to design cells with desired properties cheaply and reliably
Ó Individualized and predictive medicine

Models are not Real, though Reality can be
Modeled
Ó In almost any case, models are only rough representations of their biological
counterparts
Ó Nevertheless, models enable to

Ô Elucidate network properties
Ô Check the reliability of basic assumptions
Ô Uncover lack of knowledge and requirements for clarification
Ô Create large repository of current knowledge, formalized in a non-
ambiguous way and including quantitative data

What is a Model?
Ó It depends on whom you ask…

Ô Genetist: the mouse family Ts65DN serves as a model for human
trisomy 21
Ô Chemist: a reaction network, described by dots (for metabolites) and
arrows (for reactions)
Ô Mathematician/Engineer: the same reaction network can be modeled by
a system of nonlinear ODEs
Ó Abstract representation of objects or processes that explains features of

these objects or processes

Mathematical Models
Ó Biological processes can be described in mathematical terms, however

Ô A biological object can be investigated by means of different
experimental methods
Ô Each biological process can be described through different
(mathematical) models
Ô The choice of a mathematical model or an algorithm depends on the
problem, the purpose, and the intention of the investigator
Ô Modeling has to reflect essential properties of the system: Different
models may highlight different aspects of the same instance

Model Development
Ó Formulation of the problem:

Ô Identify the specific questions that shall be answered, along with
background, problem and hypotheses
Ó Available Knowledge:
Ô Check and collect quantitative and structural knowledge
Õ Components of the system
Õ Interaction map and kind of interactions
Õ Experimental results with respect to phenotypic responses against different
stimuli (gene knockout, RNAi, environmental conditions)

Model Development (cont’d)
Ó Selection of model structure:

Ô Level of description (atomistic, molecular, cellular, physiological)
Ô Deterministic or stochastic model
Ô Discrete or continuous variables
Ô Static, dynamical, spatio-temporal dynamical
Ó Robustness/Sensitivity Analysis:
Ô Test the dependence of the system behavior on changes of the
parameters
Õ Numerical simulations
Õ Bifurcation analysis

Model Development (cont’d)
Ó Experimental Tests
Ô Hypotheses driven
Ô Choice of parameters to be measured, different types of experiments,
number of samples and repetitions, …
Ó Assessment of the agreement and divergences between experimental results

and model behavior
Ó Iterative refinement of the hypotheses (and of the model)

Data Integration
Ó Observation of biological phenomena is restricted to the granularity and

precision of the available experimental techniques
Ó A strong impulse to the development of a systematic approach in the last

years has been given by the new high-throughput biotechnologies
Ô Sequencing of human and other genomes (genomics)
Ô Monitoring genome expression (transcriptomics)
Ô Discovering protein-protein and -DNA interactions (proteomics)
Ó Different types of information need to be integrated

Issues in Data Integration
Ó Data representation and storage:

Ô (too) Many databases (GO, KEGG, PDB, Reactome…)
Ô XML-like annotation languages (SBML, CellML)
Ó Information retrieval
Ô Tools for retrieving information from multiple remote DBs
Ó Data correlation
Ô Find the correlation between phenotypes and genomic/proteomic
profiles
Ô Statistics, data mining, pattern analysis, clustering, PCA, …

Interdisciplinary Information Exchange
Ó The interdisciplinary nature of systems biology requires the exchange of

information among scientists from different fields
Ó Mathematical formulas have to be made understandable for biologists
Ó People acquainted with the rigid rules of mathematics and computers have
to understand the diversity of biological objects and the uncertainty in the
outcome of experiments

Outline
Ó Basic principles
Ó Experimental techniques

Branches of Biology
Ó Biology is the science that deals with living organisms and their
interrelationships between each other and their environment in light of the
evolutionary origin
Ô Biochemistry
Ô Molecular biology
Ô Genetics
Ô Physiology
Ô Morphology
Ô Cytology
Ô Ecology
Ô…

Prokaryotes and Eukaryotes

Model Organisms

Structure of the (Animal) Cell
Nelson, Cox, Lehninger Principles of Biochemistry

Composition and Sizes of Biological Objects
Ó Biological compounds are prevalently composed of four basic components:

C, N, O, H
Ó Many compounds are made out of a set of few repeated basic blocks
(nucleic acids, polypeptides, polymers)

Biomolecules Classifications
Ó Biomolecules can be divided into four families

Ô Carbohydrates (energy storage)
Ô Lipids (structure, signaling)
Ô Proteins (catalysis, regulation, signaling, structure and support)
Ô Nucleic acids (Information coding, regulation)
Ó Each family has multiple functions (e.g. RNAs are coding polymers, but can
also have regulatory functions, whereas some lipids act as hormones, i.e.
signals)
Ó Most molecules are made up of sub-complexes belonging to different

families

Nucleic Acids
Ó Nucleic acids are polymers built up of covalently bound mononucleotides, they

comprise DNA and RNA
Ó DNA contains coding sequences (genes) for proteins and RNAs and non-coding
sequences
Ó Nucleotides are also important in energy

transfer in a multitude of reactions (e.g.
ATP – ADP)
Ó Some nucleotides also serve as signaling

packets (e.g. cAMP)

Central Dogma of Molecular Biology
Lodish et al, Molecular Cell Biology

Transcription and Translation
Ó Through alternative splicing, the same coding region can produce more than
one protein

Structure of Proteins
Ó Proteins consist of one or more polypeptides
Ó Each peptide is composed of covalently linked amino acids, chosen from a

set of 20 different ones

Structure of Proteins (cont’d)
Ó The functioning of a protein is strictly dependent on its three-dimensional

structure
Ó Chemical modifications (e.g. phosphorylation) can induce relevant

conformational changes, exposing or hiding the active sites
Ó On the other hand, environmental changes (e.g. pH, temperature) or

endogenous alterations (e.g. genetic mutations) usually modify the protein
structure, hindering its correct functioning

The Cytoskeleton
Ó Translocation of compounds is an important mechanism, though it cannot

be described by standard diffusion processes

Combinatorial Regulation
Ó Genes expression is regulated via adjacent transcription-control regions in a

combinatorial way
Ó Only a subset of the whole genome is expressed at a particular time or in a

specific cell type
Lodish et al, Molecular Cell Biology

Biosignaling: Membrane Receptors

Outline
Ó Basic Principles
Ó Experimental Techniques

Getting Experimental Data
Ó Systems scientists are typically not concerned about the difficult and often
indirect processes by which biological relationships and interactions are
identified
Ó It is worth having a glimpse at the basic techniques used in experimental

biology
Ó Two main issues arise when using experimental techniques:

Ô How to get quantitative data out of experiments designed to give
qualitative answers
Ô How to get time-sampled (synchronized) measurements of many
biological objects (possibly cheaply and in a suitable time)

Gel Electrophoresis
Ó Both nucleic acids and proteins are electrically charge, thus they can be
separated by applying electrical fields
Ó While the negative charge of DNA is proportional to the length of the

fragment under consideration, for proteins the charge distribution is much
more involved and case-specific
Ó By using sodium dodecyl sulfate (SDS) it is possible to confer to a protein a

negative charge that is proportional to the number of its amino acids

Gel Electrophoresis
Ó SDS-PAGE does not provide absolute quantitative data, rather it can be

used for relative measurements
Ó The samples have to be purified before measurement (at least in one-

dimensional GE)

Hybridization and Blotting
Ó Hybridization techniques are based on the specific recognition of a probe

and target molecule
Ó Used to selectively visualize only the molecules of interest in a complex

mixture
Ó It can be applied both to DNA (Southern Blotting) and to mRNA samples

(Northern Blotting)
Ó In the case of protein it is not possible to exploit hybridization, hence it is

necessary to use a specific antibody for the protein of interest

Western Blotting (Immunoblotting)
Ó Measurements of intracellular protein concentration

Yeast Two-Hybrid (Y2H)
Ó Two-hybrid screening is used to determine protein – protein and protein –

DNA interactions
Ó The protein to be tested are hybridized with two fragments of a

transcription factor
Ó The TF interacts with the upstream activation site (UAS), activating the
reported gene

DNA Microarrays
Ó DNA chips, also called DNA microarrays, are a recently developed method
for the high-throughput analysis of gene expression
Ó Instead of looking at the expression of a single gene, microarrays allow one

to monitor the expression of several thousand genes in a single experiment,
resulting in a global picture of cellular activity
Ó Hence they represent a key tool for implementing a systems biology

approach

Single Feature
Image courtesy of Affymetrix, Inc.

Probes Hybridization

Hybridized DNA Visualization

Time-Course Experimental Data
Ó Microarrays enable to derive time-course experimental data, with a desired

sampling time
Rustici et al, Nature Genetics 36(8), 2004

Protein Microarrays
Ó The function of a gene is realized by the coded protein, not by its mRNA
Ó This fact addresses a main flaw in the DNA microarray approach
Ó Solution: protein microarrays! Unfortunately…

Ô Proteins are not as uniform as DNA
Ô It is not (yet) possible to generate the amount of recombinant protein
needed for high-throughput experiments
Ô Optimal interaction conditions (in terms of temperature, ionic strenght,
pH) are largely varying among proteins
Ó Nonetheless, research on protein chips is rapidly progressing

ChIP on Chip
Ó Chromatin Immuno–Precipitation is used to discover transcription factors

(protein-DNA interactions)

Mass Spectrometry
Ó Mass spectrometry is used to identify unknown compounds and quantify

known compounds in a solution
Ô A small sample of compounds is ionized, usually to cations by loss of an
electron
Ô The ions are sorted and separated according to their mass and charge
Ô The separated ions are then detected and tallied, and the results are
displayed on a chart

RNA Interference (RNAi)
Ó Used for transiently down – regulating arbitrary genes

References
Ó Klipp et al, Systems Biology in Practice, Wiley-VCH, 2005
Ó DL Nelson, MM Cox, Lehninger Principles of Biochemistry, WH Freeman, 2004
Ó Lodish et al, Molecular Cell Biology, WH Freeman, 2007

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Introduction to System Biology

Dr. Carlo Cosentino

Dr. Carlo Cosentino 1 Carnegie Mellon University, Pittsburgh, 2008

Ó Introduction to Systems Biology

Dr. Carlo Cosentino 2 Carnegie Mellon University, Pittsburgh, 2008

Dr. Carlo Cosentino 3 Carnegie Mellon University, Pittsburgh, 2008

Ó Systems biology is concerned with the study of biological functions and

Ó “Life is an emergent, rather than an immanent and inherent, property of matter.

Dr. Carlo Cosentino 4 Carnegie Mellon University, Pittsburgh, 2008

Ó A systems biology approach means

Dr. Carlo Cosentino 5 Carnegie Mellon University, Pittsburgh, 2008

Dr. Carlo Cosentino 6 Carnegie Mellon University, Pittsburgh, 2008

Ó Mathematics and Statistics

Ó Physics and Chemistry

Ó Engineering (Biomedical, Chemical, Computer, Systems & Control,

Dr. Carlo Cosentino 7 Carnegie Mellon University, Pittsburgh, 2008

Ó Improved biological knowledge with the prospect of utilization in

Ó New experimental techniques in genomics and proteomics

Ó Classical mathematical modeling of biological processes

Ó Computer power for simulation of complex systems

Ó Storage and retrieval capability in large databases and data mining

Dr. Carlo Cosentino 8 Carnegie Mellon University, Pittsburgh, 2008

Ó Models to unveil mechanisms causing alterated phenotypes and devise novel

Ó Individualized and predictive medicine

Dr. Carlo Cosentino 9 Carnegie Mellon University, Pittsburgh, 2008

Ó Nevertheless, models enable to

Dr. Carlo Cosentino 10 Carnegie Mellon University, Pittsburgh, 2008

Ó It depends on whom you ask…

Ó Abstract representation of objects or processes that explains features of

Dr. Carlo Cosentino 11 Carnegie Mellon University, Pittsburgh, 2008

Ó Biological processes can be described in mathematical terms, however

Dr. Carlo Cosentino 12 Carnegie Mellon University, Pittsburgh, 2008

Ó Formulation of the problem:

Dr. Carlo Cosentino 13 Carnegie Mellon University, Pittsburgh, 2008

Ó Selection of model structure:

Dr. Carlo Cosentino 14 Carnegie Mellon University, Pittsburgh, 2008

Ó Assessment of the agreement and divergences between experimental results

Ó Iterative refinement of the hypotheses (and of the model)

Dr. Carlo Cosentino 15 Carnegie Mellon University, Pittsburgh, 2008

Ó Observation of biological phenomena is restricted to the granularity and

Ó A strong impulse to the development of a systematic approach in the last

Ó Different types of information need to be integrated

Dr. Carlo Cosentino 16 Carnegie Mellon University, Pittsburgh, 2008

Ó Data representation and storage:

Dr. Carlo Cosentino 17 Carnegie Mellon University, Pittsburgh, 2008

Ó The interdisciplinary nature of systems biology requires the exchange of

Ó Mathematical formulas have to be made understandable for biologists

Dr. Carlo Cosentino 18 Carnegie Mellon University, Pittsburgh, 2008

Dr. Carlo Cosentino 19 Carnegie Mellon University, Pittsburgh, 2008

Dr. Carlo Cosentino 20 Carnegie Mellon University, Pittsburgh, 2008

Dr. Carlo Cosentino 21 Carnegie Mellon University, Pittsburgh, 2008

Dr. Carlo Cosentino 22 Carnegie Mellon University, Pittsburgh, 2008

Nelson, Cox, Lehninger Principles of Biochemistry

Dr. Carlo Cosentino 23 Carnegie Mellon University, Pittsburgh, 2008

Ó Biological compounds are prevalently composed of four basic components:

Dr. Carlo Cosentino 24 Carnegie Mellon University, Pittsburgh, 2008

Ó Biomolecules can be divided into four families

Ó Most molecules are made up of sub-complexes belonging to different

Dr. Carlo Cosentino 25 Carnegie Mellon University, Pittsburgh, 2008

Ó Nucleic acids are polymers built up of covalently bound mononucleotides, they

Ó Nucleotides are also important in energy

Ó Some nucleotides also serve as signaling