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Essay

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One of the organizing principlesof life on Earth is that cellscooperate. This is evident in

the case of multicellular organisms,from nematodes to humans, but italso appears to apply widely amongsingle-celled organisms such asbacteria, fungi, and amoeba. In manycases, the label single-celled applies

to only part of the life cycle of theseorganisms. For example, the modelamoebaDictyostelium discodiumis single-celled under conditions of nutritionalabundance, but upon starvation, itcommunicates to form aggregates thatsubsequently pass through multicellularstages of slug and fruiting body.Indeed, in light of recent discoveriesof communication among bacteriaand the importance and prevalenceof bacterial biofilms, single-celledmay turn out to be a misnomereven for these organisms. Here we

highlight some of the better-studiedexamples of cooperation amongmicroorganisms and attempt to identifysome of the important questions inthis emerging field. Understandingcooperation among microorganismspresents conceptual and mathematicalchallenges at the interface ofevolutionary biology and the theory ofemergent properties of independentagents, two of the most exciting areasin modern mathematical biology.

Most of the best-studied cases ofcooperation among microorganisms

concern intraspecies cooperation. Anexample of this is quorum sensingamong bacteria, in which cells produce,secrete, and detect small molecules,called autoinducers. At high enoughautoinducer concentrations (highcell densities), the bacteria enter anew mode of existence characterized

by expression of genes associatedwith collective behaviors that are best

carried out in concerted fashion bymany cells [1]. These behaviors includethe formation of protective biofilms,the expression of virulence factors toattack a host, the production of light,the establishment of competence toexchange DNA (a bacterial form ofsexual recombination), and manyothers. The signaling pathway for oneof the better- studied quorum-sensingcircuits, that ofVibrio cholerae, thehuman pathogen, is shown in Figure 1.

Another well-studied example ofintraspecies cooperation concerns the

cyanobacterium Anabaena, which growsin long chains, in which approximatelyone cell out of ten differentiates into aheterocyst that provides fixed nitrogenfor the neighboring cells (Figure 2)[2].Dictyosteliumis probably the most-studied model for cooperation amongeukaryotic microorganisms, but even inthe nonmotile eukaryote Saccharomycescerevisiae, hyphal growth (that is,filamentous growth) can be viewed as acooperative mechanism for foraging.

Cooperation between differentmicroorganism species is much less

understood, or studied, partially forpractical reasons, but also because theubiquity of communication amongmicroorganisms has only recently beenappreciated. Nevertheless, it has beenclear for many years that bacteria form

Cooperation among MicroorganismsNed S. Wingreen, Simon A. Levin*

Series Editor: Simon Levin, Princeton University,United States of America

Citation: Wingreen NS, Levin SA (2006) Cooperationamong microorganisms. PLoS Biol 4(9): e299. DOI:10.1371/journal.pbio.0040299

DOI: 10.1371/journal.pbio.0040299

Copyright: 2006 Wingreen and Levin. This is anopen-access article distributed under the termsof the Creative Commons Attribution License,which permits unrestricted use, distribution, andreproduction in any medium, provided the originalauthor and source are credited.

Ned S. Wingreen is Professor in the Department ofMolecular Biology, Princeton University, Princeton,New Jersey, United States. Simon A. Levin is Professorin the Department of Ecology and EvolutionaryBiology, Princeton University, Princeton, New Jersey,United States.

* To whom correspondence should be addressed.E-mail: slevin@princeton.edu

Essays articulate a specific perspective on a topic of

broad interest to scientists.

DOI: 10.1371/journal.pbio.0040299.g001

Figure 1. Quorum-Sensing Circuit of the Bacterial Pathogen Vibrio choleraeRed arrows indicate phosphoryl-group transfer [1].(Figure: Matthew B. Neiditch, Princeton University, Princeton, New Jersey, United States)

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biofilms on many surfaces (includinghuman teeth, artificial joints, andorgans, as well as on the surfacesand in the roots of plants, includingcrops) that consist of large consortiaof different organisms. Moreover,it is clear that, far from being a caseof pure Darwinian competition,interactions among these species

and with eukaryotic hosts may bemutually beneficial. A recent case inpoint is the discovery of a mutualisticinteraction of four bacterial specieswith the tomato plant (M. del Gallo,personal communication). Rather thancompeting, the four species coexistand strongly promote plant growthby fixing nitrogen, providing growthhormones, and preventing hostilebacterial species from growing. Toothbiofilms have been shown to consist ofstable consortia of hundreds of distinctspecies, and bacterial mats are believedto consist of even larger numbersof species, in dynamic equilibriumamong themselves, and with multiplebacterial viruses. Interest in bacterialcooperation has been spurred by thediscovery that one of the autoinducers,named AI-2 (a furanone), is producedby a wide variety of bacteria, includingmost known human pathogens, andit may be one of a class of universalinterspecies communication molecules[3,4].

These examples highlight the

range of behaviors that could betermed cooperation. Cooperativebehaviors include complex socialinteractions such as division of laborand mutualism in providing shelter,foraging, reproduction, and dispersal[5]. The examples also highlightthe importance of communicationin adjusting group behavior toenvironmental circumstances andpopulation density. Cooperationalso has its discontents, and there isgrowing interest in the role and fateof cheaters among microorganisms.

There is some evidence as well forpolice, particularly in the contextof bacterial-host interactions, inwhich host systems favor the growthof symbiotic bacteria but discouragegrowth of noncooperative, butotherwise identical, cells [6,7]. For arecent review of communication inbacteria that highlights these issues, see[8].

Understanding how cooperationarose and is maintained, particularly

among large numbers of species,presents a challenge for practitionersof both molecular biology andevolutionary biology, as well asfor theorists. Is cooperation bestunderstood as the convergence of theimmediate self-interest of multipleparties? Or can evolution lead to stablecases of short-term altruistic behavior,providing long-term benefit for all?These questions have been central inevolutionary biology since the timeof Darwin, who regarded apparentlyaltruistic behavior as a challenge forhis theory. Especially puzzling was theextreme levels of cooperation andaltruism, termed eusociality, in thehaplodiploid insects and termites.

J. B. S. Haldane elucidated afundamental principle underlyingapparent altruistic behavior when hesaid that he would lay down his lifeto save two brothers or eight cousins,reflecting the one-half and one-eighthof his genes he shared with each,respectively. William D. Hamiltonformalized these notions in his theoryof kin selection, pointing out thatthe enhanced genetic relatedness ofhaplodiploid sisters, who share three-quarters of their genes, facilitatesaltruism in the haplodiploid species.

Subsequent work has shown that kinselection can also work effectivelyunder conditions of low relatednessand, furthermore, is not even necessaryfor cooperative behavior to arise.Cooperation can similarly be facilitatedamong unrelated individuals, forexample, when the spatial range ofinteractions is restricted. Kin selectionmay play a role when limited spatialrange is involved, but it is not essential[9]. On the other hand, a limited range

of spatial interactions is no guaranteeof cooperation; it can just as well leadto spite and selfish behavior, as in theproduction of allelopathic substancesin microorganisms and plants [10]. Forreviews of the selective mechanismsleading to cooperation and altruism,see [1113].

The challenges in understanding

cooperation and how it becomesreinforced over evolutionary timeto produce stable mutualisms andeven multicellularity is at the core ofunderstanding biology. It is key tounderstanding how complexity aroseevolutionarily, how organisms bandtogether and profit from collectivedecision making, and how populationsof diverse organisms interact to produceself-reinforcing networks of mutualbenefit. It is also key to understandingthe maintenance of ecologicalcommunities and patterns of nutrientcycling. The mathematical approachesof the past provide a foundation, butnew mathematical techniques drawnfrom such diverse subjects as dynamicalgame theory and spatial stochasticprocesses will be needed to lay bare theessential truths. Considerable progresshas been made in the past few years indeveloping the relevant mathematics,and we are at the threshold of dramaticadvances in our understanding ofcooperative behavior, one of the centraland fundamental issues in biology.

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DOI: 10.1371/journal.pbio.0040299.g002

Figure 2. Heterocyst Differentiation inAnabaena sp. UTCC-426(Photograph: Mary Olaveson, University of

Toronto Scarborough, Toronto, Ontario,Canada)

Acknowledgments

Funding. We are pleased to acknowledgethe support of the Defense AdvancedResearch Projects Agency under grant 344-4065 to Princeton University.

Competing interests. The authors havedeclared that no competing interests exist.

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