Design Principles in Biology:

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



Gene

Regulator

+

Gene

Regulator

_

X0


X1


X2


X3

X0


X1


X2


X3

First step, define the alternatives



X0


X1


X2


X3

X3

t

How strong should the feedback be?

Then, create models for each alternative



Gene

Regulator

+

Gene

Regulator

_

Then, create models for each alternative



X0


X1


X2


X3

X0


X1


X2


X3








Characterization

of
network

behavior

Biological functional effectiveness
criteria for the network
.








Alternative

designs

X1 …
Xj

…

X1 …
Xj

…

…

Mathematical models






Enforce mathematical controls
before analyzing model behavior








Comparison

of
behavior

between

networks

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


•
Are there situations where positive regulation
of gene expression outperforms negative
regulation of gene expression and vice versa?

Gene

Regulator

+

Gene

Regulator

_

Regulating gene expression has principles

•
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.


Gene

Regulator

+

Gene

Regulator

_

Genetics

149:1665; PNAS 103:3999; PNAS 104:7151;
Nature

405
: 590

Glycogen
Trehalose

Regulating gene expression has principles

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



•
Bifunctional

sensor:

–
Performs best against cross talk

•
Independent deactivator:

–
Better integrator of signals


Mol.
Microbiol
. 48:25; Mol.
Microbiol
. 68: 1196

Signal

Sensor

Sensor

Efector

Efector

Deactivator

Effect

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


Gene

Regulator

_

Design principles in development

Gene

Regulator

+

High

demand
,
low

signal

Signal

+

High

demand
,
high

signal

Low

demand
,
high

signal

Low

demand
,
low

signal

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

•
Biological design principles may connect
molecular determinants to functional
effectiveness.

Heat

shock

Expression

of
important

genes

time

Growth

rate

time

BMC
Bioinformatics

7:184

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!!

Stable

Systems

Unstable

systems

Oscilations

Bistable

systems

Cell

113: 597;
PLoS

Comput

Biol
. 5:e1000319; PNAS 106: 6435

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