Cell Functions

Dynamic Systems
in Molecular & Cell Biology
Olaf Wolkenhauer
Growth

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Differentiation
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Gene expression

Apoptosis
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Key cellular processes and the network concept

Metabolism

Proliferation

Examples of signaling pathways

Cell signalling

Pathway, Network
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How do I model and simulate a system?

Biological Complexity: Nonlinear Dynamics

S=8
S=14

0.6

0.5

0.3

Machine-learning
Clustering and Classification

0.3
0.2

0.2

0.1

0.1
0
0

Statistics and Probability Theory

0.4

0.4

R(t)
R(t)

R(t)
R(t)

0.5

10

15
time t

20

0
0

25

time t

10

Dynamical Systems Theory

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ODE-based mechanistic modeling

Stochastic modeling & simulation

0.5
0.5

Response RSS

R(t)

0.4
0.3
0.2
0.1
0
0

0.4

Simulation/Agent-based modeling

0.3

Logical Representations

0.2
Scrit
0.1

4
time t

0
0

10

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Signal S

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Kinds of Modeling

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Kinds of modeling (contd)

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There is nothing more practical than a good theory!

Mechanistic Modeling

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Interaction networks - Biochemical Reaction Networks

Why model?

Enzymatic Reaction as a Template:

Explain (very distinct from predict!)

Guide data collection
Illuminate core dynamics
Suggest dynamical analogies
Discover new questions
Promote scientific habit of mind
Bound outcomes to plausible ranges
Illuminate core uncertainties
Formulate hypotheses
Reveal simplicity in complexity

Biochemical equation:

SBGN:

Ren Magritte: La Clairvoyance, 1936

cf. JM Epstein JASSS 11 (4) 2008

Modelling is a means for theorizing: We construct and analyse models

in order to formulate hypotheses about general law-like (organising) principles.
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Enzyme Kinetic Reactions

Enzymatic Reaction as a Template:

Kinetic Rate Equations:

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Enzyme Kinetic Reactions

Elementary Reactions
Monomolecular Reaction:

Enzymatic Reaction as a Template:

Kinetic Rate Equations:

Bimolecular Reaction:

Reversible Reaction:

Conservation laws:

Quasi steady state assumption:

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Derivation of the Michaelis-Menten Equation

Deriving the Michaelis-Menten Equation

Quasi steady state assumption:

Michaelis-Menten Equation:

Limiting Rate:

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Deriving the Michaelis-Menten Equation

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From reactions to networks

Michaelis-Menten Equation:

Dimensionless Representation (Activity):

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A generic signaling network

A generic signaling network

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The Systems (Biology) Approach

frequency)

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Rss+

R"
S+

R"

Observa(ons+
Experiments+

Hypothesis+

dR
= k0E * (R)+ k1S k2R
! dt

Modeling+

Contextual*
Assump/ons**

S+

Claim+

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Rebu>al+
Understanding+

Simula(on+
Analyses+

t+

Predic'ons+

Explana(on+
Concepts+

Narra/ve*

R+
E*+

S+

E+
e.g.+Feedback+regula(on,+Bistability+

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Learning Outcomes
Cellular functions (cell growth, proliferation, differentiation and apoptosis are
dynamical systems.
The notion of a pathway/network is used to represent intracellular interactions.
The mechanisms, feedback loops in particular, determine the dynamic behavior of
the system.
Interaction networks can be modeled as biochemical reaction networks.
Ordinary differential equations are frequently employed to simulate such networks.
More complex networks can be broken down into basic elements, modeled in terms
of elementary reactions.
The vast majority of cellular reactions can be represented as a kind of enzyme
kinetic reaction (facilitated reaction)

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The prototype enzymatic reactions can be modelled with four ODEs.

Conservation laws and steady-state assumptions allow us to simplify these equations
into the Michaelis-Menten equation.
When modelling and simulating cellular processes, we must be aware of the
assumptions we make.
Modeling and simulation serves several purposes (see list).
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