A Symbiotic View of Life: We Have Never Been Individuals

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A Symbiotic View Of Life: We Have Never Been Individuals

Scott F. Gilbert Swarthmore College, [email protected]

J. Sapp

A. I. Tauber

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Recommended Citation Scott F. Gilbert, J. Sapp, and A. I. Tauber. (2012). "A Symbiotic View Of Life: We Have Never Been Individuals". Quarterly Review Of Biology. Volume 87, Issue 4. 325-341. DOI: 10.1086/668166 https://works.swarthmore.edu/fac-biology/165

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A Symbiotic View of Life: We Have Never Been Individuals Author(s): Scott F. Gilbert, Jan Sapp and Alfred I. Tauber Source: The Quarterly Review of Biology, Vol. 87, No. 4 (December 2012), pp. 325-341 Published by: The University of Chicago Press Stable URL: http://www.jstor.org/stable/10.1086/668166 . Accessed: 14/08/2015 15:20

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This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions Volume 87, No. 4 THE QUARTERLY REVIEW OF BIOLOGY December 2012

A SYMBIOTIC VIEW OF LIFE: WE HAVE NEVER BEEN INDIVIDUALS

Scott F. Gilbert Department of Biology, Swarthmore College Swarthmore, Pennsylvania 19081 USA Biotechnology Institute, University of Helsinki 00014 Helsinki, Finland e-mail: [email protected]

Jan Sapp Department of Biology, York University Toronto, Ontario M3J 1P3 Canada e-mail: [email protected]

Alfred I. Tauber Department of Philosophy, Boston University Boston, Massachusetts 02215 USA e-mail: [email protected]

keywords symbionts, symbiosis, individuality, evolution, holobiont

abstract The notion of the “biological individual” is crucial to studies of genetics, immunology, evolution, development, anatomy, and physiology. Each of these biological subdisciplines has a specific conception of individuality, which has historically provided conceptual contexts for integrating newly acquired data. During the past decade, nucleic acid analysis, especially genomic sequencing and high-throughput RNA techniques, has challenged each of these disciplinary definitions by finding significant interactions of animals and plants with symbiotic microorganisms that disrupt the boundaries that heretofore had characterized the biological individual. Animals cannot be considered individuals by anatomical or physiological criteria because a diversity of symbionts are both present and functional in completing metabolic pathways and serving other physiological functions. Simi- larly, these new studies have shown that animal development is incomplete without symbionts. Symbionts also constitute a second mode of genetic inheritance, providing selectable genetic variation for natural selection. The immune system also develops, in part, in dialogue with symbionts and

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thereby functions as a mechanism for integrating microbes into the animal-cell community. Recogniz- ing the “holobiont”—the multicellular eukaryote plus its colonies of persistent symbionts—as a critically important unit of anatomy, development, physiology, immunology, and evolution opens up new investigative avenues and conceptually challenges the ways in which the biological subdisciplines have heretofore characterized living entities.

N THE EARLY modern period, mirroring ceptions of the planet’s biosphere. They have Ithe appearance of the independent citizen, not only revealed a microbial world of much the notion of the autonomous individual agent deeper diversity than previously imagined, but framed a biology that was organized around also a world of complex and intermingled rela- the study of particulate, interacting, living enti- tionships—not only among microbes, but also ties (Taylor 1989). Anatomical, physiological, between microscopic and macroscopic life and developmental criteria were conceived (Gordon 2012). These discoveries have pro- solely in terms of individuals, and the Darwin- foundly challenged the generally accepted ian view of life regarded aggregates of individ- view of “individuals.” Symbiosis is becoming a uals of common ancestry as identifiable units core principle of contemporary biology, and it in competition with one another. With the un- is replacing an essentialist conception of “indi- derstanding that plants and animals are com- viduality” with a conception congruent with prised of living “cells,” a new orientation the larger systems approach now pushing the quickly developed concerning the integration life sciences in diverse directions. These find- of physiological processes and anatomic units, ings lead us into directions that transcend the but still these cells were understood as agents self/nonself, subject/object dichotomies that in constructing and sustaining a singular or- have characterized Western thought (Tauber ganism that would in turn maintain its auton- 2008a,b). omy and integrity. Only with the emergence of This reorientation is not new for the micro- ecology in the second half of the 19th century bial or botanical sciences. In the world of pro- did organic systems—comprised of individu- tists, hereditary symbiosis, the inheritance of als in cooperative and competitive relation- acquired symbionts is legion. In the microbial ships—complement the individual-based world, “you are what you eat” can be taken conceptions of the life sciences. literally. In botanical science, the concept of The development of such complex formu- the autonomous individual has also been lations of individuals and systems depends on challenged by discoveries concerning rhizo- myriad factors, of which technology constitutes bia, mycorrhizae, and endocytic fungae. a major component in the characterization Nonetheless, zoologists long subscribed to a process. We perceive only that part of nature more individualist conception of the organ- that our technologies permit and, so too, our ism, since the role of microbial symbionts theories about nature are highly constrained had been more difficult to document in an- by what our technologies enable us to observe. imal evolution (Sapp 1994, 2002, 2009). We But theory and technology act on each other report here that the zoological sciences are reciprocally: we construct those technologies also finding that animals are composites of that we think are important for examining a many species living, developing, and evolv- particular perspective of nature. The developing together. The discovery of symbiosis ment of the microscope, for example, revealed throughout the animal kingdom is funda- the hitherto invisible microbial world of bacte- mentally transforming the classical concep- ria, protists, and fungi; and the descendants tion of an insular individuality into one in of that instrument further allowed the disco- which interactive relationships among spe- very of subcellular organelles, viruses, and cies blurs the boundaries of the organism macromolecules. New technologies such as and obscures the notion of essential identity. polymerase chain reaction, high-throughput Our aims in this overview are to: outline RNA analysis, and next generation sequencing the data demonstrating that animals are continue to dramatically transform our con- symbiotic complexes of many species living

This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions December 2012SYMBIOTIC VIEW OF LIFE 327 together; demonstrate how a thoroughly resides). When this symbiosis is broken by a symbiotic perspective opens important ar- prolonged increase in sea-surface tempera- eas of research and offers fundamentally tures, corals “bleach.” They lose their algal sym- new conceptions of the organism; and ex- bionts and die. Similarly, the entity we call a plore what this new evidence means for cow is an organism whose complex ecosystem biology, medicine, and for the conserva- of gut symbionts—a diverse community of cel- tion of biodiversity. lulose-digesting bacteria, ciliated protists, and anaerobic fungi—informs its specialized anat- Criteria for Individuality omy, defines its plant-digesting physiology, reg- ulates its behaviors, and ultimately determines What would biological science be if symbio- its evolution (Kamra 2005). sis were seen as the rule, not the exception? In addition to the mitochondrial vestiges What scientific questions would become para- of ancient symbiosis, thousands of bacterial mount and how might this change our view of “species” (themselves genetic composites) life if intimate cooperation between species live in intimate association with our own were a fundamental feature of evolution? What eukaryotic cells. Estimates that 90% of the could “individual selection” mean if all organ- cells that comprise our bodies are bacterial isms were chimeric, and there were no real (Bäckhed et al. 2005; Ley et al. 2006) belie monogenetic individuals? any simple anatomical understanding of There are many ways in which the term individual identity. Metagenomic sequenc- “individual” is used in biology. Individuals ing (Qin et al. 2010) has shown that each can be defined anatomically, embryologi- human gut has entered into a persistent part- cally, physiologically, immunologically, ge- nership with over 150 species of bacteria, netically, or evolutionarily (see Geddes and and that the human species maintains about Mitchell 1911; Clarke 2010; Nyhart and Lid- 1000 major bacteria groups in our gut micro- gard 2011). These conceptions, though, are biome. The gene set contained by this sym- not wholly independent of one another. Nor biotic metagenome is about 150 times larger have these definitions of individuality often than that of the human eukaryotic genome. been explicitly articulated as such. Indeed, And this does not include the symbionts of even in biology today there is a dearth of human airways, skin, mouth, or reproductive definition in what constitutes the individual orifices. organism. Still, definitions are implied, and Mastotermes darwiniensis, a termite of north- each stems from the common tenet of ge- ern Australia, may claim the title of “poster nomic individuality: one genome/one or- organism” for the chimeric individual. The ganism. As such, all classical conceptions of worker termites eat trees and entire homes, individuality are called into question by evi- digesting the cellulose in their guts and con- dence of all-pervading symbiosis. structing elaborate subterranean nests. But as Lewis Thomas (1974) and Lynn Margulis and Anatomical Individuality Dorion Sagan (2001) have asked: What consti- Anatomically, the individual animal is re- tutes the individual organism? How can a garded as a structured whole. Yet, data from worker termite be considered an individual PCR show that the cells and bodies of animals when it is the hive that is the reproductive unit are shared with numerous “species” of bacteria of the species, and the worker cannot even and other microbes. In some sponges, nearly digest cellulose without its gut symbiont, Mix- 40% of the volume of the organism is com- otricha paradoxa, which is itself a genetic comprised of bacteria, which contribute signifi- posite of at least five other species? Neither cantly to host metabolism (Taylor et al. 2007). humans, nor any other organism, can be re- The algal symbiont, Symbiodinium, provides up garded as individuals by anatomical criteria. To to 60% of the nutrients needed by its host coral capture this complexity, the term “holobiont” (the term “host” is used here in the classical has been introduced as the anatomical term sense to denote the larger, eukaryotic, multi- that describes the integrated organism com- cellular organism in which the “symbiont” prised of both host elements and persistent

This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions 328 THE QUARTERLY REVIEW OF BIOLOGY Volume 87 populations of symbionts (Rosenberg et al. ment of particular organs is predicated on 2007). chemical signals from symbionts (Douglas 1988, 2010). For example, the ovaries of Developmental Individuality the parasitoid wasp, Asobara, undergo apo- The developmental view of animal individual- ptosis if signals from their Wolbachia symbi- ity was originally proposed by Thomas Huxley onts are lacking (Pannebakker et al. 2007). in his published lecture, “Upon Animal Indi- And the newborn of the squid Euprymna viduality” (Huxley 1852). A variant of the ana- scolopes lacks a light organ, which is devel- tomical version of biological individuality, the oped in cooperation between the squid individual animal proposed here is understood and the luminescent bacteria (Vibrio fisheri) to be that which proceeds from ovum to ovum. absorbed by its ventral epithelium (McFall- Yet, this view of life is belied by evidence that Ngai et al. 2012). Without the bacteria, the what we understand to be the “individual” de- organ does not develop. velops as consortia of animal cells and mi- In “germ-free” asymbiotic mice, the de- crobes (McFall-Ngai 2002; Gilbert and Epel velopment of the immune system and the 2009; Fraune and Bosch 2010; Pradeu 2011). digestive system cannot be completed with- Indeed, the development of both vertebrates out gut bacteria (Ley et al. 2006, 2008; Lee and invertebrates (especially larval and postem- and Mazmanian 2010). Rather, these mice bryonic development) is predicated on inti- have insufficient intestinal capillaries, poorly mate relations with microbes. developed or absent gut-associated lymphoid In some instances, the symbiosis may be par- tissue, and a diminished T-cell repertoire asitic, one organism benefiting at the expense that gives them an immunodeficiency syn- of another. For example, the development of drome (Stappenbeck et al. 2002; Rhee et al. the European blue butterfly Maculinea arion 2004; Niess et al. 2008; Duan et al. 2010). In requires that the female lays her eggs on thyme zebrafish, microbes regulate (through the plants. The larvae, however, do not eat thyme, canonical Wnt pathway) the normal prolifer- but drop to the ground, where they produce a ation of the intestinal stem cells. Without mixture of volatile chemicals mimicking the these microbes, the intestinal epithelium has smell of the larvae of the ant species Myrmica fewer cells, and it lacks goblet cells, entroen- sabuleti. Patrolling Myrmicae mistake the but- docrine cells, and the characteristic intesti- terfly larva as one of their own, and carry it into nal brush border enzymes (Rawls et al. 2004; the ant nest. Once in the nest with the ant Bates et al. 2006). larvae, the caterpillar is fed by the workers, Microbial symbionts appear to be a nor- eventually eating young ants until it is ready to mal and necessary part of the life cycle of pupate. It undergoes metamorphosis in the all mammals, which acquire the microbes ant colony and emerges as an adult (Thomas as soon as the amnion breaks or when in- 1995; Nash et al. 2008). This type of life-cycle fants suckle or hug. The microbes colonize symbiosis occurs throughout marine inverte- the guts and induce appropriate gene ex- brates, where larvae require cues, often from pression in the intestine of the newborn their food sources, in regard to where and (Hooper et al. 2001). In the developing when to settle and undergo metamorphosis. guts of mice and zebrafish, hundreds of The importance of symbiotic organisms genes are activated by bacterial symbionts for the completion of host life cycles is also (Hooper et al. 2001; Rawls et al. 2004). The evident in parasitic worms, where bacteria coevolution of mammals and their gut bacteria are crucial for embryogenesis and molting has in effect resulted in the “outsourcing” of (Hoerauf et al. 2003; Coulibaly et al. 2009) developmental signals from animal cells to mi- and in salamander development, where crobial symbionts. Thus, the symbionts are in- symbiotic algae on the egg jelly produce tegrated into the normal networks of animal the oxygen necessary for the survival of the development, interacting with the eukaryotic spotted salamander embryos (Olivier and cells of their “host” (Gilbert 2001, 2003; McFall- Moon 2010; Kerney et al. 2011). Ngai 2002). Development then becomes a In numerous organisms, the develop- matter of interspecies communication. We are

This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions December 2012SYMBIOTIC VIEW OF LIFE 329 not individuals from the viewpoint of develop- causing “germs” defined the antagonistic view mental biology. that microbes were “the enemy of man.” Current molecular biological research has Physiological Individuality underscored how symbionts can become part Since the classical writings of Henri Milne- of an obligatorily integrated commonality Edwards (1827) and Rudolf Leuckart (1851), (MacDonald et al. 2011; Vogel and Moran the physiological view of animal individuality re- 2011). For example, the “genome” of the gards the organism as comprised of parts that mealy bug Planococcus is the product of a cooperate for the good of the whole. Complex- nested symbiosis: animal cells harbor the be- ity of animal organization is accompanied by taproteobacterium Tremblaya princeps, which the increasing division of labor among or- in turn harbor a gammaproteobacte- gans, a concept derived from Adam Smith’s rium, provisionally named Moranella en- conception that socioeconomic progress in dobia. The synthesis of amino acids appears to complex societies results from the division of be coordinated between these two microbes labor (Limoges 1994). In the post-Darwinian and the host. Three of the enzymes needed for era, this individualistic view of the organism phenylalanine biosynthesis are encoded by the extended to the organization of the cell, as Moranella bacterium, five other enzymes are well as projected onto the organism formed encoded by the Tremblya bacterium, and a fi- by intercellular relations. Accordingly, all com- nal enzyme in this pathway is encoded by the plex organization resulted from the struggle insect (McCutcheon and von Dihlen 2011). for existence, providing an ever-increasing in- Note, the genomes of all three organisms have tegration through a division of labor (Sapp been altered through this symbiosis. Such met- 1994, 2003). A common assumption underlays agenomic sequencing has demonstrated the this classical conception, namely, that each or- importance of microbes in insect physiological ganism is derived from one germplasm, the systems (Va´squez et al. 2012; Weiss et al. 2012). zygote. Microbial symbiosis also has been dem- Yet, far removed from this classical con- onstrated in vertebrate physiology. Lipid ception, a small but growing body of evi- metabolism, the detoxification of xenobiotics, dence accumulated, which reveals that this regulation of colonic pH, vitamin synthesis, physiological division of labor could also and intestinal permeability are each biological be accomplished by different species living functions provided to the holobiont by bacte- together, as exemplified by the discoveries, ria (Nicholson et al. 2012). Specific bacteria in the latter 19th century, of the duality of also induce the formation of regulatory T-lym- lichens, of fungi living in the roots of or- phocytes that suppress potentially dangerous chids and forest trees, of nitrogen-fixing immune responses that can cause inflamma- bacteria in root nodules of legumes, and of tory bowel disease (Mazmanian et al. 2008; algae living inside the cells of translucent Chow et al. 2010). The role of symbiotic mi- cnidarians. Later, in the early 20th century, crobes in mammalian disease prevention is findings that microbes inherited through well recognized today (Mazmanian et al. 2008; the eggs of insects caused morphological Lee and Mazmanian 2010; Ballal et al. 2011), changes with no apparent pathogenic effects and new metagenomic sequencing continues on their host further suggested how organ- to provide new insights into the relationships isms living in close proximity shared their between human physiological states and the respective physiologies (Buchner 1965; Sapp microbial populations found in humans 1994). (Turnbaugh and Gordon 2009; Greenblum et Still, evidence of such intimate microbial al. 2012). And there is reciprocity. The com- interactions, especially with animals, was rela- mon gut symbiont Bacteroides thetaiotaomicron tively scarce, and the evidence for the life- induces angiogenin-4 gene expression in the giving properties of microbial infections could intestinal Paneth cell. This protein functions to not compete with the great success and impor- produce new blood vessels. But it is also a bac- tance of the germ theory of disease. Indeed, teriocidal factor against Listeria, the major com- the view of microbial infections as disease- petitor of Bacteroides and a gut pathogen (Cash

This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions 330 THE QUARTERLY REVIEW OF BIOLOGY Volume 87 et al. 2006). From these examples, we may con- that might stabilize a community. Recent stud- clude that on classical physiological grounds, ies in Drosophila, for instance, demonstrate that animals are not individuals. the symbionts (not alleles of nuclear genes) provide important pheromonal cues necessary Genetic Individuality for mating preference (Sharon et al. 2010). The classical genetic conception of the in- Symbionts can therefore provide selectable al- dividual is rooted in sex and based on the in- lelic variation such that the entire group—the heritance of the chromosomal complement holobiont—is the selectable entity rather than acquired at fertilization. That conception of either host or symbiont alone (see Zilber- the genetic individual, at the basis of the Weis- Rosenberg and Rosenberg 2008; Gilbert et al. mannian biology of the 19th and 20th centu- 2010). Thus, microbes provide a second hered- ries (Weismann 1893), was fortified by classi- itary system that enables holobiont survival cal Mendelian genetics and later came to and selection. Indeed, as the mealy bug ex- include the mitochondrial chromosome as ample mentioned earlier demonstrates, ge- well (Chapman et al. 1982; Avise 1991). In nomes evolve in such a manner that they population genetics, this genetic identity su- need their partners to achieve complex ge- persedes all others, as it is postulated to con- netic integration. None of the three species tain the allelic variations that are the bases of in that symbiosis has a “complete” genome. phenotypic variation. It is the holobiont that does. We are not The one-genome/one-organism doctrine of individuals by genetic criteria. classical genetics has been eclipsed by studies of hereditary symbiosis. Microbial symbionts Immune Individuality form a second type of genetic inheritance The “immune self” model of individua- (Moran 2007; Gilbert 2011). Arthropods often lity, first proposed by Sir McFarlane Burnet acquire their symbionts vertically though the (Burnet and Fenner 1949), portrays the im- maternal germline as well as horizontally from mune system as a defensive network against a the environment. Mammals obtain them hostile exterior world. The immune individual through the maternal reproductive tract and rejects anything that is not “self.” Indeed, the from the mutual licking and grooming follow- discipline of immunology has been called “the ing birth. The microbial symbionts represent science of self/non-self discrimination” (Klein diverse genomes; and those genomes can also 1982). In this view, the immune system is a be coselected together with the genome of defensive “weaponry,” evolved to protect the their host. In aphids, symbiotic bacteria pro- body against threats from pathogenic agents: vide selectable allelic variation (thermotoler- worms, protists, fungi, bacteria, and viruses. Ac- ance, color, parasitoid resistance) that enable cordingly, if it were not for the immune system, some hosts to persist better under different opportunistic infections would prevail (as they environmental conditions (Dunbar et al. 2007; do in cases of immune deficiencies) and the Tsuchida et al. 2010). There is also allelic vari- organism would perish. ation in the human microbiome. The genes of In a fascinating inversion of this view of life, Bacteroides plebeius differ in different human however, recent studies have shown that an populations. The Japanese strain contains at individual’s immune system is in part created least two genes (horizontally transferred from a by the resident microbiome. In vertebrates, the marine relative) that enable the bacteria to gut-associated lymphoid tissue is specified and metabolize complex sugars, such as those organized by bacterial symbionts (Rhee et al. found in seaweeds (Heheman et al. 2010). In- 2004; Lanning et al. 2005). The immune sys- deed, the Human Microbiome Project (Turn- tem does not function properly and its reper- baugh et al. 2007) has applied ecological toire is significantly reduced when symbiotic metagenomics to explore the microbial microbes are absent in the gut (see Lee and world within the human species. Mazmanian 2010; Round et al. 2010). Simi- The evolutionary importance of microbial larly, Hill et al. (2012) have shown that micro- symbionts goes well beyond increasing the fit- bial symbionts provide developmental signals ness of hosts or providing hereditable variation that limit the proliferation of basophil progen-

This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions December 2012SYMBIOTIC VIEW OF LIFE 331 itor cells and thereby prevent basophil-induced ants Hamiltonella result from the incorporation allergic responses. Lee and Mazmanian con- of a specific lysogenic bacteriophage within the clude, “multiple populations of intestinal im- bacterial genome. The aphid must be infected mune cells require the microbiota for their with Hamiltonella, and the Hamiltonella must be development and their function” (2010:1768). infected by phage APSE-3. As Oliver et al. This ability of symbionts to condition and (2009) write, “In our system, the evolutionary promote the immune capacities of the holo- interests of phages, bacterial symbionts, and biont is not exclusive to vertebrates. In several aphids are all aligned against the parasitoid insect species, bacteria of the genus Wolbachia wasp that threatens them all. The phage is im- appear to play an important role in antiviral plicated in conferring protection to the aphid protection (Teixeira et al. 2008; Moreira et and thus contributes to the spread and main- al. 2009; Hanson et al. 2011). In plants, en- tenance of H. defensa in natural A. pisum pop- dophytes, the diverse and widespread fungi ulations” (Oliver et al. 2009:994). But there is a that live out most of their life cycle in plant cost to the host in having this beneficial pro- tissue, provide enhanced pathogen immu- tection, for in the absence of parasitoid infec- nity to their host; they can also ward off her- tion, those aphids carrying the bacteria with bivores, among other benefits (Herre et al. lysogenic phage are not as fecund as those 2007). Thus, immune systems are created, in lacking them. Similarly, a tradeoff occurs in part, by microbial symbionts. We will return aphids that carry the thermotolerant genetic to these newer concepts of immunity below, variants of Buchnera, i.e., while more heat resis- in a discussion of how the holobiont commu- tant, they have less fecundity at milder temper- nity can be an evolutionarily viable “individ- atures than their sisters whose bacteria lack the ual.” functional allele for the heat-shock protein. However, the population as a whole can survive Evolutionary Individuality: The hot weather, which would otherwise prevent Revised Immune Individual reproduction. Biological individuality has also been de- This symbiotic relationship appears to fined evolutionarily, as that which can be fulfill the criteria for group selection: al- selected (see Maynard Smith and Szath- leles can spread throughout a population ma´ry 1995; Michod and Roze 1997; Okasha because of the benefits they bestow on 2006). Usually, these individuals are genes groups, irrespective of the alleles’ effect on or monogenomic organisms. But, from the the fitness of individuals within that group. above discussion, it is evident that organisms Except, in this case, the beneficial alleles are anatomically, physiologically, developmen- are genetic variations in bacterial symbionts, tally, genetically, and immunologically multi- which provide their hosts with a second genomic and multispecies complexes. Can it source of inherited selectable variation. be that organisms are selected as multigenomic We are not genetic or anatomical individ- associations? Is the fittest in life’s struggle the uals; and if there is no “individual organ- multispecies group, and not an individual of a ism,” what remains of classic notions of single species in that group? “individual selection”? An instructive example comes from studies This moves the biological discussion of sym- of the pea aphid, Acyrthosiphon pisum and the biotic associations into the venerable con- several species of bacteria that live in its cells: ception of “group selection,” so abhorrent to variants of Buchnera provide the aphid with neo-Darwinian sensibilities, and so denigrated thermotolerance (at the expense of fecundity by sociobiologists’ conceptions based on game at normal temperatures; Dunbar et al. 2007); theory. Most discussions of group selection Rickettsiella provides color change, turning ge- (see Williams 1966; Lewontin 1970; Hull 1980; netically red aphids green through the synthe- Keller 1999) are not germane here, because sis of quinones (Tsuchida et al. 2010); and they assume that the group in question is com- some variants of Hamiltonella provide immunity posed of a single species. However, one im- against parasitoid wasp infection (Oliver et al. portant concern is relevant: cheaters. The 2009). But in the last case, the protective vari- major problem for all group selection theo-

This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions 332 THE QUARTERLY REVIEW OF BIOLOGY Volume 87 ries (and the groups, themselves) are poten- that have similarly evaded the immune- tial “cheaters,” those lower-level parts of the enforced social modes of conformity (Hoshi group that would proclaim their own auton- and Medzhitov 2012). Most Neisseria species, omy and that would multiply at the expense for instance, can become symbionts. The two of the others. As Stearns has pointed out, pathogenic Neisseria species that will not be “conflicts within lower levels and between part of the symbiotic community (N. gonor- lower and higher levels must be suppressed rhoeae and N. meningitidis) have escaped the or otherwise resolved” (2007:2275). social control of the holobiont by circum- This problem of cheaters, it has been ar- venting the immune system (Mulks and gued, has rendered many models of group Plaut 1978; Welsch and Ram 2008). selection mathematically untenable (see Keller In some cases, the internal immune surveil- 1999; Leigh 2010; Eldakar and Wilson 2011). lance of symbionts can actually be observed. In The problem of “cheaters” then has to be insects, symbionts are sequestered in bacteria- solved in such a way that associates in a sym- bearing host cells, called the bacteriocytes, biotic relationship are under the social con- which, in some species, cluster together to trol of the whole, the holobiont. This strong form a bacteriome (Buchner 1965). In weevils, socializing and unifying force is found in the antimicrobial peptide coleoptericin-A selec- immune system, and there we find a solution tively targets endosymbionts within the bacte- to the problem of cheaters in a symbiotic riocytes and inhibits their cell division (Login complex. et al. 2011). If the synthesis of this peptide is The immune system may be formulated as blocked, the bacteria escape from the bacterio- having two “limbs”: an outward-looking limb cytes and spread into the insect tissues. Here, it that defines the organism as that which is to seems that the coevolution of host and symbi- be protected from foreign pathogens, and ont has enabled the immune system to facili- an inward-looking arm that looks for poten- tate the endosymbiotic relationship. In squids tial dangers arising from within the organism (McFall-Ngai et al. 2010) and mammals itself (see Burnet and Fenner 1949; Tauber (Hooper et al. 2012), elements of the host im- 2000, 2009; Ulvestad 2007; Eberl 2010; Pra- mune system have been co-opted to support deu 2010). This dualistic vision was the original the colonization, limitation, and persistence of conception of Metchnikoff at the end of the symbiotic bacteria within the host. 19th century. He regarded immunity as a gen- Medzhitov et al. (2012) have discussed “dis- eral physiology of inflammation, which in- ease tolerance” as a strategy whereby the defen- cluded repair, surveillance for effete, dying, sive factors are minimalized to prevent damage and cancer cells, as well as responsibility for the to the infected organism. However, what we defense against invading pathogens (Tauber suggest is not merely “tolerance” toward mi- 1994). This larger, systemic understanding crobes, but active recruitment of symbiotic bac- thus places defensive properties as only part of teria by the immune system. Peterson et al. a continuous negotiation of numerous interac- show that IgA, in addition to its well-known tions between the organism and its biotic envi- role in attacking polio virus and other patho- ronment—both “internal” and “external” gens, plays a “critical role in establishing a sus- (Ulvestad 2007; Tauber 2008a,b). tainable host-microbial relationship” (2007: If the immune system serves as the critical 328). Similarly, these Peyer’s Patch antibodies, gendarmerie keeping the animal and microbial which are essential in fighting opportunistic cells together, then to obey the immune system pathogens, appear to be involved in “the cre- is to become a citizen of the holobiont. To ation of an optimal symbiotic environment on escape immune control is to become a patho- the interior of the PPs” (Obata et al. 2010: gen or a cancer. In cancer, such autonomously 7419). Even the Toll-like receptors that medi- proliferating (lower-level) cells must escape the ate innate immunity are utilized by Bacteroides innate, acquired, and anoikis-mediated im- to establish a host-commensal relationship. mune systems of the host in order to survive The ability of symbiotic bacteria to use the (Hanahan and Weinberg 2011; Buchheit et al. innate and acquired immunity pathways to 2012). Infections are those microbes that initiate symbioses has led Round et al. (2011)

This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions December 2012SYMBIOTIC VIEW OF LIFE 333 to conclude that “the immune system can several symbioses. Suggestions that their nu- discriminate between pathogens and the mi- clei, mitochondria, and chloroplasts originated crobiota through recognition of symbiotic bac- from ancient symbioses had been repeatedly terial molecules in a process that engenders postulated throughout the 20th century, but commensal colonization” (Round et al. they were dismissed and ridiculed in so much 2011:974). To use an anthropomorphic anal- as they conflicted with the main tenets of clas- ogy, the immune system is not merely the sical biology (Sapp 1994). The tipping point body’s “armed forces.” It is also the “passport occurred in the 1960s when mitochondria and control” that has evolved to recognize and chloroplasts were shown to possess their own welcome those organisms that help the body. genes and their own translation machinery. Thus, the immune system looks inward, in And with that discovery, symbiosis in the origin surveillance, to monitor potential microbial of the eukaryotic cell was brought to the fore of cheaters. The “defensive” role of immunity, so cell biology (Sagan 1967; Margulis 1970, 1981). prominent in the medical and agricultural Still definitively demonstrating the symbiotic contexts, must be balanced from evolutionary origin of eukaryotic organelles required the and ecological viewpoints. Immunity does not development of new molecular methods for merely guard the body against other hostile showing evolutionary relationships in the mi- organisms in the environment; it also mediates crobial world. Methods based on comparisons the body’s participation in a community of of ribosomal RNA were developed by Carl “others” that contribute to its welfare (Tauber Woese and colleagues, for exploring the hith- 2000; Agrawal 2001; Hooper et al. 2001; Dale erto unknown evolutionary relationships of mi- and Moran 2006). The immune system has crobes (see Sapp 2009). Those methods, when learned through evolution which organisms applied to mitochondria and chloroplast ori- to exclude and kill, and which organisms gins, revealed them to be relics of formerly to encourage, allow entry, and support. If free-living alphaproteobacteria and cyano- accepted, the symbiont can mutually partic- bacteria, respectively. Today, molecular phylo- ipate in development and physiological pro- geneticists generally agree that the nuclear cesses. Moreover, it can help mediate the genome of the mother cell, the engulfing host, holobiont’s response to other organisms, ef- was itself formed from the symbiotic fusion of fectively becoming “self.” From this vantage, an Archaean and one or perhaps two other there is no circumscribed, autonomous en- lineages. The nature of those non-Archaean tity that is a priori designated “the self.” What symbionts remains a subject of discussion counts as “self” is dynamic and context- among microbial phylogeneticists (Hartman dependent. and Federov 2002; Hall 2011; see also Sapp 2005, 2009). “E PLURIBUS UNUM”: The Negotiated Second, multicellularity may also have been Surveillance of Parts and Wholes initiated by interactions between bacteria and Negotiated surveillance is a general mecha- protists. Certain species of choanoflagellates, nism that has evolved to permit the incorpora- the unicellular clade thought to be the sister tion of potentially self-replicating parts into group of multicellular animals, can be trans- coherent wholes (see Maynard Smith and Sza- formed into multicellular organisms by inter- thma´ry 1995; Michod and Roze 1997; Okasha actions with specific bacteria (Dayel et al. 2003, 2006). We see this, as Lynn Margulis 2011). In the presence of certain bacteria, cells (Sagan 1967) long predicted we would, in the remain together after cell division, and the main transitions in evolution; for in addition to cells form epithelial rosettes sharing a com- providing variation needed for intraspecies mon extracellular matrix and intercellular selection (see above), symbiosis has been criti- bridges. Based on this finding, one mode of cally important in macroevolutionary innova- multicellularity may have arisen as a conse- tion (see, for example, Margulis and Fester quence of a multispecies association of bacteria 1991). and protists altering cellular development. First, and foremost, as mentioned above, Third, the origin of placental mammals may eukaryotic cells are themselves the result of have been predicated on genomic-level inte-

This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions 334 THE QUARTERLY REVIEW OF BIOLOGY Volume 87 gration of exogenous DNA. Every genome is a mous, independent, isolated island of a historical product and, just like the cell, it is Self—is a myth.” the result of ancient symbioses and horizontal gene transfers. We are genomic chimeras: New Perspectives, New Questions nearly 50% of the human genome consists of The understanding that symbionts are criti- transposable DNA sequences acquired exoge- cal for animal development, health, and ho- nously (Lander et al. 2001; Cordaux and meostasis brings with it “new” problems and Batzer 2009), possibly by the horizontal gene opens up novel avenues of investigations. In transfer from microbial symbionts to ani- regard to evolutionary biology, much needs to mal cells (see Dunning Hotopp et al. 2007; be investigated in terms of understanding the Altincicek et al. 2012). Although much of very diversity of microbes, trying to unravel this added DNA is thought to be “parasitic,” their complex relations with each other and some transposable elements may have been with their animal host. The evolution of bacte- critical in creating new patterns of transcrip- rial symbionts and their animal hosts is still an tion (Sasaki et al. 2008; Oliver and Greene untapped research domain of central impor- 2009; Kunarso et al. 2010). The emergence of tance for evolutionary biology, medicine, and the uterus, the defining character of eutherian agriculture. mammals, appears to have been facilitated in- The field of research on Wolbachia endosym- dependently in several mammalian families by bionts that has emerged over the past decade transposons integrating into the regions con- exemplifies the importance of understanding trolling the expression of the prolactin gene. symbiotic associations in each of these fields. These transposons contain transcription factor Wolbachia are transmitted sexually through the binding sites that enable the prolactin gene to cytoplasm of the eggs of many species of insects become expressed in the uterine cells (Lynch and of nematodes. Their effects range from et al. 2011; Emera et al. 2012). Moreover, this mutualism to parasitism. They cause cytoplas- convergent evolution of gene expression via mic incompatibility and parthenogenesis, and the insertion of transposable elements also sug- they can change male offspring to females so as to enhance their own transmission and repro- gests that such transposons can mediate adap- duction (Werren 2005). Molecular phyloge- tive evolution. The selective silencing of such netic analysis has also shown that horizontal transposons by DNA methylation or small in- gene transfer from Wolbachia to host ge- terfering RNAs appears to be another polic- nomes is widespread (Dunning Hotopp et al. ing mechanism that has facilitated evolution 2007). Wolbachia are held to be important in (Chung et al. 2008; Kaneko-Ishino and Ishino understanding rapid speciation and the rich 2010; Castan˜eda et al. 2011). species diversity of insects and nematodes of Thus, animals can no longer be considered symbiosis, and also in controlling insects individuals in any sense of classical biology: an- pests and disease (see, for example, Brels- atomical, developmental, physiological, immu- foard and Dobson 2009). nological, genetic, or evolutionary. Our bodies In regards to medicine, first and foremost must be understood as holobionts whose ana- stands the challenge of elucidating the com- tomical, physiological, immunological, and plex relationship between health, disease, developmental functions evolved in shared re- and changes in the human microbiome. The lationships of different species. Thus, the ho- interactions of host genome, symbionts, and lobiont, with its integrated community of diet become critical. The genomes of certain species, becomes a unit of natural selection mice, for example, have been shown to en- whose evolutionary mechanisms suggest able colonization of specific gut bacteria, complexity hitherto largely unexplored. As which results in an obese or a lean pheno- Lewis Thomas (1974:142) commented when type, depending upon the bacteria’s ability considering self and symbiosis: “This is, when to utilize nutrients (Turnbaugh et al. 2006). you think about it, really amazing. The whole In zebrafish, a particular cohort of gut bac- dear notion of one’s own Self—marvelous, teria is selected when given mouse intestinal old free-willed, free-enterprising, autono- microbes (Rawls et al. 2004, 2006). Although

This content downloaded from 130.58.65.13 on Fri, 14 Aug 2015 15:20:31 PM All use subject to JSTOR Terms and Conditions December 2012SYMBIOTIC VIEW OF LIFE 335 the adage “no man is island” works for hu- a paracrine factor associated with neuronal man interactions, each person is precisely an plasticity) in relevant portions of their brains island to a bacterial cell. The island biogeo- than do conventionally raised mice. Heijtz et graphical perspectives of colonization, suc- al. (2011:3051) have concluded that “during cession, resource allocation, and division of evolution, the colonization of gut microbiota functional modules may be critical in symbi- has become integrated into the programming otic relationships (see Morowitz et al. 2011; of brain development, affecting motor control Muegge et al. 2011; Costello et al. 2012). and anxiety-like behavior.” In another investi- This new symbiotic perspective makes sense gation, a particular Lactobacillus strain has been of certain data and provides a fresh outlook reported to help regulate emotional behavior on human anatomy and physiology. The through a vagus nerve-dependent regulation milk oligosaccharides produced by human of GABA receptors (Bravo et al. 2011). Investi- mothers cannot be utilized by newborn in- gations into the regulation of brain develop- fants; however, they serve as an excellent ment by bacterial products were unthinkable food for strains of Bifidobacillus that enhance before this challenge to the prevailing para- infant nutrition (Zivkovic et al. 2011). The digm. vermiform appendix, long thought of as a ves- Conservation zoology is also greatly affected tigial organ, may actually serve as a reservoir for by acknowledging the diverse effects of symbi- normal gut bacteria such that symbionts can be ont relationships. For instance, knowledge of rapidly replaced after bouts of diarrhea (Smith symbiosis is crucial in preventing the extinction et al. 2009). Diarrhea remains the leading of the spotted salamander in the central states cause of death in children of less-developed of America; and knowledge of the parasitic countries (CDC 2010), and antibiotic-induced symbiosis of Maculinea and the Myrmica ants colitis, caused by the spread of Clostridium after has been critical for the return of Maculinea to the normal symbionts have been killed, can be Great Britain (Thomas 1995). In agriculture, cured by the low-tech procedure of fecal trans- “curing” insects of their vital symbionts may be plants (usually from the spouse; Bakken 2011). an environmental friendly way of controlling If we have evolved the ability to select mi- pests such as aphids. This destroying of the crobial symbionts, perhaps genetically mod- host by killing the symbiont has been shown to ifying these bacteria may enhance health. work in the case of Mansonella, a worm that The curative effect of Lactobacillus on exper- parasitizes humans (Coulibaly et al. 2009). imentally induced intestinal inflammation Last, this new appreciation of symbiosis, can be even more pronounced by genetically where even microevolution might involve in- modifying the Lactobacillus to induce more terspecies interactions, opens up a range of IL-10 (Mohamadzadeh et al. 2011). Also, since new questions for evolutionary biology. The microbes are in part responsible for detoxify- change of a localized, interacting, multispe- ing xenobiotic chemicals, our responses to cies collective over time has been modeled drugs might depend on our microbial popula- by ecological succession, and in one of the tions (Haiser and Turnbaugh 2012). first formulations of ecological succession, What we think is worth studying can be af- Clements (1916) likened succession to devel- fected by our paradigms. One of the most im- opment, viewing the climax community as portant areas of developmental biology has the adult phenotype. Each organism may been the study of mammalian brain formation. have to become modeled in a web of ecosys- Although environmental stimuli were known tem dynamics, where cells come from diverse to affect behaviors and learning, the possibility genotypes. that microbes could regulate neural develop- In the 2009 “Homage to Darwinism” de- ment had not been considered until recently. bate held at Oxford University, Richard Now, however, a microbiota-gut-brain axis Dawkins questioned the bringing of symbi- has recently been proposed (Cryan and osis into evolutionary theory: O’Mahony 2011; McLean et al. 2012). Germ- Take the standard story for ordinary ani- free mice, for example, have lower levels of mals, [where] you’ve got a distribution of NGF-1A and BDNF (a transcription factor and animals [and] you’ve got a promontory, or

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an island or something and so you end up and seeks new relationships among the differ- with two [geographical] distributions. And ent living entities on Earth. We are all lichens. then on either side you get different selection pressures, and so one [group] starts to evolve this way, and [the other] one starts acknowledgments to evolve that way, and what’s wrong with This paper is dedicated to the memory of Lynn that? It’s highly plausible, it’s economical, Margulis, the master architect for rethinking biol- it’s parsimonious. Why on Earth would you want to drag in symbiogenesis when it’s so ogy in terms of interacting consortia. Scott F. unparsimonious and uneconomical? Gilbert is funded by the Academy of Finland and To which Lynn Margulis replied, Because it’s Jan Sapp is supported by the Social Sciences and there (Dawkins and Margulis 2009). Humanities Research Council of Canada. Gilbert would also like to thank H. Deming and D. Fritz for And it is signiﬁcant. For animals, as well as administrative assistance and the NESCent for or- plants, there have never been individuals. This ganizing an outstanding session on animal-microbe new paradigm for biology asks new questions interactions.

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