Evolutionarymodelsofconflictandcooperation

May13,2010JoaoXavier

Evolutionarycooperationiscentraltoalllife

•  Whyevolutionarycooperationisimportant•  Simpledefinitions:

– Evolution– Fitness– Socialinteractions

•  Mathematicalmodelsof‘socialevolution’•  Cooperationandconflictinmicrobialpathogens

•  Cooperationandconflictincancer

Evolutionisthechangeofgenefrequencywithinapopulation

Fourmechanisms:•  Mutation

•  Naturalselection•  Drift(“geneticdrift”,or“randomdrift”)

•  Migration

Δt

(onegeneration)

Fitnessisaquantitativemeasureofnaturalselection

TheabsolutefitnessofgenotypeYis

W(Y) =

Thechangeinfrequencyis

p = p’ = Y

Y+B

Y’

Y’+B’

Y’

Y

Higherfitnesscanleadtogenotypefixation

Explicit solution of long-term consequences

Evolutionary dynamics

p

t

p=1 (fixation)

Dynamicsequationprovidesevolutionarytrajectory

Evolutionary dynamics

p'

p

p = 1 (fixation)

0

1

0 1 p0

p1

Dynamicsequationprovidesevolutionarytrajectory

Evolutionary dynamics

p'

p

p = 0 (extinction)

p0

0

1

0 1

Fitnesscanbe‘contextdependent’

p'

p

Example:Cancercellsthathaveresistancetoadrug,butthatgrowworsethansensitivecellsintheabsenceofdrug

Context:Nodrug

p'

p

Context:Drugpresent

Fitnessisoften‘frequencydependent’WhenW(Y) andW(B) arenotconstants,butratherafunctionofp

p'

Equilibrium (p*) p

COOPERATIONISACENTRALTHEMEINTHEHISTORYOFLIFE

Biologicalorganizationgrowsoncooperation

Traitscanbeclassifiedaccordingtotheir‘social’effects

AnindividualcarryingoutasocialtraitisanactorTheindividualaffectedbythattraitistherecipient

Positive Negative

PositiveMutualbenefit Selfishness

NegativeAltruism Spite

Effectonrecipient

Effectonactor

Cooperation Competition

West,S.A.,Griffin,A.S.,Gardner,A.&Diggle,S.P.(2006)Socialevolutiontheoryformicroorganisms.NatureReviewsMicrobiology4,597‐607.

‘Publicgood’cooperationisanexampleofaltruism

Example:

• Cancercellssecreteametalloproteinasethatiscostlytosynthesize(reducesgrowthrate)

• Metalloproteinasedegradeextracellularmatrixandallowcellstoproliferatebetter

Cooperatorsonly(Lowmixing)

“Publicgood”

W(C) = W0 – C + B Basalfitness

Costofsynthesis

Benefitfrominvasion

Adefinitionof‘publicgood’fromeconomics

• Isavailabletoallindividualswithinpopulation• Iscostlytoproduce

Incentiveto‘cheat’

Purepopulationofcooperators

Purepopulationof‘cheaters’

Cheatersdorelativelybetter,butattheexpenseofthewholegroup

Mix

“Publicgood”

Cheatersdobetterthancooperatorsbyexploitinga“publicgood”

Prisoner’sdilemma:afundamentalproblemingametheory

PrisonerB

Cooperate Defect

Cooperate

Defect

Eachserves6month

Prison

erA

A:10yearsB:goesfree

A:goesfreeB:10years

A:5yearsB:5years

Prisoner’sdilemma:Ametaphorinevolutionarytheory

Payoffmatrix:

Cooperator Defector

Cooperator

Defector

b‐c,b‐c b/2–c,b/2

0,0b/2,b/2‐c

Key:b‐benefitfromcooperationc‐costofcooperation

NowakMA(2006).“EvolutionaryDynamics:ExploringtheEquationsofLife.”HarvardUniversityPress.

Evolutionarygamesarebasedonpair‐wiseinteractions

Cooperator Cooperator

DefectorDefector

Cooperator Defector

Evolutionarytheorycanexplaintheevolutionofcooperation

•  Kinselection:r>c/b(risrelatedness)

•  Directreciprocity:w>c/b(wischanceofrepeatedencounter)

•  Indirectreciprocity:q>c/b(qisprobabilityofknowingreputation)

•  Networkreciprocity:b/c>k(kisaveragenumberofneighbors)

•  Groupselection:b/c>1+(n/m)(nisgroupsize,misnumberofgroups)

Interactionsarerandom

InteractionsarestructuredProblem:Rulesderivedfromgametheoryassumepair‐wiseinteractionsInteractionsamongcellsareseldompairwise

Fiverulesofcooperation(Nowak2006Science)

Diffusiblepublicgoodscanevolveinspatiallystructuredpopulations

Nadelletal,FEMSMicRev,2009

Mix

ed

S

tru

ctu

red

Bacteriarelyonmulticellulartraits

What prevents evolutionary cheating?

Cooperator

“Public good”

"cheater"

+

• Strength by numbers

• Secretion of virulence factors

• Biofilm formation

• Quorum sensing

Cellsinbiofilmsareembeddedinamatrixofextracellularpolymericsubstances

Bacteria (red) and glycoconjugate matrix (green). Courtesy T. Neu, UFZ Germany.

100µm

Biofilmdynamicsemergefrominteractionsamongcells

1 cell

growth division

1. Growth 2. Division 3. Spreading

2 cells

start

end

Gradientsproduceheterogeneousgrowth

Gradients of oxygen concentration

Solid substratum

Biofilm

Liquid

x

y

Diffusion Reaction

Vertical cross-section through biofilm

Xavier and Foster, PNAS (2007)

Boundarylayeratconstantdistancefrombiofilm

Liquid in boundary layer

Producersandcheaterscompetewithinthebiofilm

With oxygen gradients OFF “cheaters” win

Xavier and Foster, PNAS (2007)

Xavier and Foster, PNAS (2007)

WithoxygengradientsON“cheaters”lose

Low

er p

olym

er d

ensi

ty

Xavier and Foster, PNAS (2007)

Extracellularpolymerscanworkasacompetitivetrait

Cooperative trait

Open to exploitation

Competitive trait

Benefit own lineage

Xavier and Foster, PNAS (2007)

Swarming:collectivemotilityinPseudomonasaeruginosa

Swarming:collectivemotilityinPseudomonasaeruginosa

Pseudomonasaeruginosa‐amodelforbacterialpathogenesis‐

•  Sequencedgenomes•  Non‐redundantlibrariesoftransposonmutants•  AffymetricGeneChipmicroarrays

•  Itisanopportunisticpathogen

•  Formsbiofilmsincysticfibrosislungsthatarehardtotreatwithantibiotics

Swarmingbenefitsthecolonybutrequiresbiosurfactantsynthesisbycells

Whatpreventsevolutionarycheating?

Biosurfactantsynthesisiswellcharacterized

Wild-type

rhlA-

(Non-cooperator)

Glucose‐6‐phosphate

Glucose‐1‐phosphate

dTDP‐D‐glucose

dTDP‐6‐deoxy‐D‐4‐hexulose

dTDP‐6‐deoxy‐L‐lyxo‐4‐hexulose

dTDP‐L‐rhamnose

Acyl‐ACP‐Ketocyl‐ACP

‐Hydroxyacyl‐ACP Enoyl‐ACP

3‐(3‐hydroxyalkanoyloxy)alkanoates(HAAs)

Di‐rhamnolipids

Mono‐rhamnolipids

typeIIfattyacidcycle(FASII)

RhlA

RhlB

RhlC

Differentgenotypesaredistinguishableusingneutralcolors

GFP RFP mix

GFP RFP mix

ce

lls in

co

lon

y

2x10 10

1x10 10

Biosurfactantsarea“publicgood”

Biosurfactantsecretionisuncheatable

•  Non‐cooperatorsdobetterthanwhenalone…

•  Not enough to distinguish who wins, WT or rhlA-

•  …but at expense of wild-type

Measured relative fitness:

0.990.05

Reporterfusionsallowmonitoringgeneexpressiondynamics

[h]

rhlAB expression ON rhlAB expression OFF

P. aeruginosa PA14 rhlAB-GFP

Quorumsensingisnecessaryyetnotsufficient

[h]

Low density

rhlAB ON

rhlAB OFF

High density

Expressionofbiosurfactantsynthesisisfavoredatlowernitrogensourcelevels

Carbon source: Glycerol (C3H5(OH)3) Nitrogen source: (NH4)2SO4

rhlAregulationensuresmetabolicprudence

N N C

C C

C

C

Medium both carbon and nitrogen but

carbon is in excess

C C

C

C C

Cells grow while there’s

nitrogen…

C

C

…then use excess carbon to secrete

rhamnolipids

InduciblerhlABbypassesmetabolicprudencemechanism

No inducer (behaves like non-

cooperator)

Inducer present (strict cooperator)

Biosurfactantsecretioninstrictcooperatorischeatable

Day1 Day2 Day3 Day4

Summary•  Bacteriarelyonmulticellulartraitsformanytasks

•  Multicellularcooperativetraitsareopentoexploitation…

•  …andthereforemusthaveevolvedwithmechanismsforrobustness

•  Wecanfindthemechanismsstabilizingbacterialmulticellularity:

–  Physicalorbiologicalmechanismssettingpopulationsstructure

– Molecularmechanisms(metabolicprudence,quorumsensing,more?)

•  Canleadtonewtherapies

Cancerisadiseaseofclonalevolutionwithinthebody

Nowell. "Clonal evolution of tumor-cell populations" (1976) Science

Cancooperationevolvedenovoincancerprogression?

HanahanandWeinenberg(2000)“Thehallmarksofcancer”

Hypothesis:Ifsomeofthese“hallmarks”are

cooperative(benefitothercells)lineage

complementationcangreatlyspeedupthe

appearanceofmalignancy

HanahanandWeinenberg(2000)

“Thehallmarksofcancer”Sixtraitsnecessarytolead

aneoplasmtocancermalignancy

Cell‐cellcommunicationbetweencancerandtumor‐associatedmacrophages

WithJohannaJoyce(MSKCCCancerBiology&Genetics)