Design Principles in Biology:
a consequence of evolution and natural selection
Rui Alves
University of Lleida
ralves@cmb.udl.es
Climbing down mount improbable
• Overtime, edged stones would
accumulate on the slope.
• Smooth, round, stones
accumulate at the
bottom.
Design Principles:
- Smooth, roundish rocks roll down
the mountain.
- Edged, flat, rocks don’t.
Design principles in molecular biology
• Similarly, if a topology or set of parameters
can be shown to create a molecular network
that functionally outperforms all other
possible alternatives in a given set of
conditions, one can talk about a design
principle for the system under those
conditions.
[sensu engineering]
Index of talk
• How to identify design principles in molecular
networks
• Design principles in:
– Gene expression
– Metabolic networks
– Signal transduction
– Development
• Design principles, what are they good for?
• Summary
First step, define the alternatives
Regulator
Regulator
_
+
Gene
Gene
X0
X1
X2
X3
X0
X1
X2
X3
First step, define the alternatives
X3
t
How strong should the feedback be?
X0
X1
X2
X3
Then, create models for each alternative
Regulator
Regulator
_
+
Gene
Gene
Then, create models for each alternative
X0
X0
X1
X1
X2
X2
X3
X3
Biological functional effectiveness
criteria for the network.
X1
X1
…
…
Xj
…
Xj
…
Characterization of network behavior
…
Alternative designs
Mathematical models
Comparison of behavior between networks
Enforce mathematical controls
before analyzing model behavior
Index of talk
• How to identify design principles in molecular
networks
• Design principles in:
– Gene expression
– Metabolic networks
– Signal transduction
– Development
• Design principles, what are they good for?
• Summary
The demand theory for gene expression
Regulator
Regulator
_
+
Gene
Gene
• Are there situations where positive regulation
of gene expression outperforms negative
regulation of gene expression and vice versa?
Regulating gene expression has principles
Regulator
Regulator
_
+
Gene
Gene
• Positive regulator:
– More effective when gene product in demand for large
fraction of life cycle.
– Less noise sensitive if signal is low.
• Negative regulator:
– More effective when gene product in demand for small
fraction of life cycle.
– Less noise sensitive if signal is high.
Genetics 149:1665; PNAS 103:3999; PNAS 104:7151;Nature 405: 590
4
6 4
2
4 2
0
2 0
0
Regulating gene expression has principles
PFK
TPS
TPS
PYK
TDH
PYK
20
c)
16
14
GLK
12
(d)
Glycogen
Trehalose
TDH
18
16
14
G6PDH
10
8
8
6
6
4
4
2
2
0
0
TDH
GLK
12
10
PFK
PYK
HXT
20
18
PDH
PFK
TDH
PYK
HXT
PF
TPS
PFK
PYK
TDH
Design principles in development
Design principles in development
Index of talk
• How to identify design principles
• Design principles in:
– Gene expression
– Metabolic networks
– Signal transduction
– Development
• Design principles, what are they good for?
• Summary
Negative overall feedback is a design principle in
metabolic biosynthesis
X0
X1
X2
X3
• Negative overall feedback:
– More effective in coupling production to demand.
– More robust to fluctuations.
Bioinformatics 16:786; Biophysical J. 79:2290
Index of talk
• How to identify design principles
• Design principles in:
– Gene expression
– Metabolic networks
– Signal transduction
– Development
• Design principles, what are they good for?
• Summary
Bifunctional sensors can be a design principle in
signal transduction
Signal
Sensor
Effect
Efector
Efector
Deactivator
• Bifunctional sensor:
– Performs best against cross talk
• Independent deactivator:
– Better integrator of signals
Mol. Microbiol. 48:25; Mol. Microbiol. 68: 1196
Index of talk
• How to identify design principles
• Design principles in:
– Gene expression
– Metabolic networks
– Signal transduction
– Development
• Design principles, what are they good for?
• Summary
Design principles in development
High demand, low signal
Signal
Signal
+
_
Regulator
Low demand, low signal
_
+
High demand, high signal
Gene
Low demand, high signal
Genetics 149:1665; PNAS 103:3999; PNAS 104:7151;Nature 405: 590
Index of talk
• How to identify design principles
• Design principles in:
– Gene expression
– Metabolic networks
– Signal transduction
– Development
• Design principles, what are they good for?
• Summary
Biological design principles are good to
understand why biology works as it does
Growth rate
Heat
shock
Expression of
important genes
• Biological design principles may connect
molecular determinants to functional
effectiveness.
time
BMC Bioinformatics 7:184
time
Underlying assumption
• Evolution of molecular networks can be
treated as modules.
• Work in the group of Uri Alon suggests that
– networks evolving to meet simultaneous goals
evolve in a modular fashion
– Networks evolving to meet a single goal evolve
globally
• Modularity seems like a reasonable first
assumption
PNAS 102:13773; PLOS Comp Biol 4:e1000206;BMC Evol biol 7: 169
The good news about function
• Sometimes, you get stuff for free!!!
• For example:
– networks that are responsive to signals, just because
they are responsive may have inbuilt buffering of
noise.
– Functions that are associated with marginally stable
proteins are favored because due to the large
dimensions of sequence space most randomly
selected sequences have a structure that is marginally
stable.
PNAS 100:14463; PNAS 103:6435; Proteins 46:105
How can biological design principles be
applied?
• Design of molecular circuits with specific
behaviors!!
Bistable
systems
Stable
Systems
Oscilations
Cell 113: 597; PLoS Comput Biol. 5:e1000319; PNAS 106: 6435
Unstable
systems
Index of talk
• How to identify design principles
• Design principles in:
– Gene expression
– Metabolic networks
– Signal transduction
– Development
• Design principles, what are they good for?
• Summary
Summary
• Design principles can be found in molecular
networks.
• Such principles can sometimes be connected
to selection for function effectiveness.
• Even in the absence of such a connection, if
they are valid they can be used to build
biological circuits with specific behaviors.
Acknowledgments
Mike Savageau
Albert Sorribas
Armindo Salvador
Oleg Igoshin
Programa Ramon y
Cajal MCyT
MCyT
FCT
NIH