Design Principles in Biology:

a consequence of evolution and natural selection

Rui AlvesUniversity of Lleidaralves@cmb.udl.es

Climbing down mount improbable

• Overtime, edged stones would accumulate on the slope.

• Smooth, round, stonesaccumulate 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

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20HXT

GLK

PFK

TDHPYK

TPS

G6PDH

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20HXT

GLK

PFK

TDHPYK

TPS

G6PDH

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20HXT

GLK

PFK

TDHPYK

TPS

G6PDH

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20HXT

GLK

PFK

TDHPYK

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G6PDH

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20HXT

GLK

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TDHPYK

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G6PDH

(a) (b)

(c) (d)

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

SensorSensor

EfectorEfectorDeactivator

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

Expr

essi

on o

f im

port

ant g

enes

time

Gro

wth

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

assumptionPNAS 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 SavageauAlbert SorribasArmindo SalvadorOleg Igoshin

Programa Ramon y Cajal MCyT

MCyTFCTNIH