CLASS 19
IDC 401:
THEORETICAL BIOLOGY
Instructor: SOMDATTA SINHA
Email: ssinha@[Link]
Modelling Genetic Regulatory Circuits
&
Simple Biochemical Pathways
Class 19 Sep 9, 2025
Cellular functions are controlled by networks of
biochemical reactions Class19
Sep 9, 2025
LinkDB: database of link information
Class 19 Sep 9, 2025
EXPECTATIONS FROM THEORETICAL STUDIES
Identification of common features
in different pathways
Identification of differences in similar pathways
in different organisms
functional implications
Predict new behaviour
Design new pathways
Correct pathological states
Molecular Biology, Genetics, Biochemistry, Mathematics, Statistics,
Databases, Visualisation, Network Theory, Computational methods
Class 19 Sep 9, 2025
BIOCHEMICAL PATHWAYS ARE SEQUENTIAL REACTIONS
Information for short and long range regulation is transferred
primarily through feedback and feed-forward loops
Cellular behaviour is the emergent property of many complex biochemical
reactions networked through feedback/feed-forward processes with
overlapping and wide-ranging time scales
Biochemical details of each pathway may be different, but they possess
certain general features which can be described using the rules of chemical
kinetics.
The resultant dynamics underlie different functional behaviour
Stability – Homeostasis
Multistability – Ability to operate on alternative conditions
Threshold Sensitivity – Switching behaviour
Oscillatory – Rhythmic and cyclic processes
Chaotic – Bursting activity & irregular behaviour
Transient processes – Stochastic phenomena and spatial waves
Generality in dynamics across a large variety of biochemical
processes allow theoretical studies to be functionally meaningful & useful.
Class 19 Sep 9, 2025
MODELLING BIOCHEMICAL PATHWAYS
Three complementary approaches
REVERSE ENGINEERING LARGE NETWORKS
Model existing pathways based on Construction & analysis of
information derived from – functionally related
• Genome sequences pathways from large scale
• Protein sequences gene expression and
protein interaction data
• Biochemical & Genetic information
using network theory
FORWARD ENGINEERING ‘Rational Network
Design’
All designs that are not physically
forbidden are realizable, Artificial genetic and
but not all realizable designs are enzymatic networks with
functionally effective specific properties
(in relation to context and constraints constructed based on
of the system and environment). mathematical models
Class 19
Sep 9, 2025
MODELS OF MOLECULAR COMPUTING
Implementing a complex decision process with
multiple input cues using logic.
‘when gene A is active AND gene B is inactive
AND gene C is mutated → generate the effect’
Class 19 Sep 9, 2025
Forward Engineering of gene circuits
(Rational Network Design, Synthetic Biology)
Construction of desired network with specific properties predicted
from mathematical models using knowledge from biochemistry,
molecular biology, and genetics.
Boolean/Logical Circuits in Biology :
Organisms take decisions based on input signals
and give a binary (0/1) response in some cases.
Repressor
RNAP Inducer Jacob & Monod Model of the
prokaryotic operon (1961)
J. Mol. Biol., 3 (1961), pp. 318-356
Gene A Gene B Nobel Prize in 1965
Promoter Operator
“It is obvious from analysis of these [bacterial genetic regulatory]
mechanisms that their known elements could be connected into a wide
variety of ‘circuits’ endowed with any desired degree of stability”
Class 19 Sep 9, 2025
Basic digital circuits:
A A A
And C Or C Nand C
B B B
A B C A B C A B C
0 0 0 0 0 0 0 0 1
0 1 0 0 1 1 0 1 1
1 0 0 1 0 1 1 0 1
1 1 1 1 1 1 1 1 0
Digital genetic circuit: A repressible system –The NOT gate:
If repressor is input and
the gene product is output,
then if repressor is 1, gene product is 0
and vice versa.....
the input is inverted.
Class 19
Sep 9, 2025
Genetic Circuit Engineering Paradigm
Design - Simulate - Implement & Test
A basic assumption underlying such ‘synthetic’ biology
The properties of individual genetic components can be
used to understand and quantitatively predict circuit-level
behaviour.
“ Rational Network Design ” can -
a) engineer new cellular behaviour, and
b) improve understanding of naturally occurring networks.
DESIGN PRINCIPLES
Class 19
Sep 9, 2025
George Boole (1815 –1864) was an
English mathematician, educator,
philosopher and logician.
He worked in the fields of differential
equations and algebraic logic, and is
best known as the author of The Laws
of Thought (1854) which contains
Boolean algebra.
Boolean logic is credited with laying the
foundations for the information age.
Boolean algebra is named after him, as is the crater Boole on the Moon. The
keyword Bool represents a Boolean data-type in many programming languages,
though Pascal and Java, among others, both use the full name Boolean.
The library, underground lecture theatre complex and the Boole Centre for
Research in Informatics at University College Cork are named in his honour. A road
called Boole Heights in Bracknell, Berkshire is named after him.
Class 19 Sep 9, 2025
Logic Functions/Gates:
Mappings between multiple inputs and a single output,
where both the inputs and the output
can only take values of
0 and 1 false and true
• NOT is a horizontal bar above the number
_
0=1
_
1=0
• OR is a plus • AND is multiplication
0+0 = 0 0*0 = 0
0+1 = 1 0*1 = 0
1+0 = 1 1*0 = 0
1+1 = 1 1*1 = 1
Class 19
Sep 9, 2025
Buffer
• A buffer is a gate with the function F = X: X F
• In terms of Boolean function, a buffer is
the same as a connection
• Not
• And
Basic logic
• Or gates
• Nand
• Nor
Class 19 Sep 9,
2025
NAND Gate
• For three inputs (x, y, z), the basic NAND gate has the
following symbol : (NAND) - AND-Invert
X
Y F( X , Y, Z ) = X×Y×Z
Z
• NAND represents NOT AND, i. e., the AND function
with a NOT applied. The symbol shown is an AND-
Invert. The small circle (“bubble”) represents the
invert function.
Class 19 Sep 9, 2025
NOR Gate
• NOR represents NOT – OR
i.e., the OR function with a NOT applied.
• The basic NOR gate has the following symbol, for 3
inputs (x, y, z):
– OR-Invert (NOR) - The small circle (“bubble”)
represents the invert function.
X
Y F(X, Y, Z) = X +Y+ Z
Z
Class 19 Sep 9, 2025
TRUTH TABLES
A repressible system –The NOT gate: If repressor is input and
the gene product is output,
then if repressor is 1, gene product is 0
and vice versa.....
the input is inverted.
Class 19 Sep 9, 2025
Logic circuits:
Specific arrangements of logic gates (chemical
reactions) that can compute specific logic
functions.
Write the circuits for the following Boolean algebraic
expressions
__
a) x+y
x
x x+y
y
Class 19 Sep 9, 2025
• Find the output of the following circuit
x x+y
y (x+y)y
y y
• Answer: (x+y)y
Class 19 Sep 9, 2025
• The circuits for the following Boolean algebraic
expression:
_______
(x+y)x
x x+y
x+y (x+y)x
y
Class 19 Sep 9, 2025
Gene Regulatory Networks
• Gene regulatory networks (GRNs) are the
on-off switches of a cell operating at the
gene level.
• Two genes are connected if the expression
of one gene modulates expression of
another one by either activation or
inhibition
Class 19 Sep 9, 2025
Class 19 Sep 9, 2025
Sources: [Link]
Simplified Representation of GRN
• A gene regulatory network can be represented by a directed
graph;
w Node represents a gene;
w Directed edge stands for the
modulation (regulation) of one
node by another:
e.g. arrow from gene X to
gene Y means gene X affects
expression of gene Y
Class 19 Sep 9, 2025
Modeling Gene Regulatory Networks
• Linear Model
• Bayesian Networks
• Differential Equations
• Boolean Network
• Boolean Network
Originally introduced by Kauffman (1969)
– Boolean network is a kind of Graph
§ G(V, F) – V is a set of nodes ( genes ) as x1 , x2, …, xn
F is a list of Boolean functions f(x1 , x2, …, xn)
– Gene expression is quantized to only two level:
1 (On) and 0 (OFF)
– Every function has the result value of each node;
Class 19 Sep 9, 2025
Basic Structure of Boolean Networks
1 means active/expressed
A B 0 means inactive/unexpressed
Boolean function
A B X
0 0 0
0 1 0
1 0 0
X
1 1 1
Two genes (A and B) together regulate gene X
In principle, any number of “input” genes are possible.
Positive/negative feedbacks are also common.
Class 19 Sep 9, 2025
g3
g2 g1
Class 19 Sep 9, 2025
*
Truth Table
Boolean Network
Class 19 Sep 9, 2025
State Transition Graphs
Steady State Behaviour
Non-linear Phenomenon
Periodic behaviour
Behaviour of a single
Logical States
gene g1 for the
logical states (0,1,0) or
(0,1,1):
Transition States
Class 19 Sep 9, 2025
• At Initial states ->
g1 = 0 , g2 = 1, g3 = 0
Class 19 Sep 9,
2025