With multicellularity, as well as possession of multiple nuclei within a single cytoplasm or even microbiomes and endosymbionts, come concerns of maintenance of cooperation among the components of individual organism. Particularly, defection can come from within, via mutation, or from without, from parasites. We've already considered a number of mechanisms that can contribute to cooperation maintenance among individuals. These include, perhaps most importantly, a genetic bottlenecking so that clonality of assembled cells is assured. In fact, genetic bottlenecking in the course of reproduction by multicellular organisms, which typically involves initiation of new individuals from a single cell, can be viewed as representing macroorganisms passing back through what essentially is a unicellular microorganism stage once per generation.

Other mechanisms besides bottlenecking can also limit defection from within, such as reduced mutation rates, employing various within-cell mechanisms that serve to thwart display of greater expediency in cell division (i.e., such that multiple mutations are necessary before substantial defection can occur), and mechanisms of active policing so that defecting lineages may be identified and eliminated. The latter function can overlap that of protection from defectors originating from without. Together these mechanisms are considered to make up an organism's immune functions (Abedon, 2011) . Of course, larger organisms also have to combat predation by species that have evolved to specialize on larger prey organisms.

Conflict-Mediating Adaptations

For multicellularity to be an effective strategy, then those individual cells making up a body must together behave as an individual: cooperating rather than conflicting. Among free-living, unicellular organisms, attaining such cooperation is not trivial, and yet within bodies it is the exception for individual cells to defect against the body as a whole, rather than the rule. Why the difference? The answer is that multicellular organisms possess conflict-mediating adaptations. These conflict-mediating adaptations can be viewed as mechanisms that have been gradually acquired by lineages because those multicellular organisms that came to possess them experienced less disruption from cellular defection (e.g., cancer). The so-protected individuals thereby may have been able to survive longer while in the multicellular state (longer life spans) and thus display, for example, greater size or morphological complexity.

For the sake of the evolution of multicellularity it also is fortunate that smaller, shorter-lived individuals (e.g., diplococci) generally are less dependent on establishing effective conflict-mediating adaptations than are larger, longer-lived individuals (e.g., whales). Thus, the evolution of multicellularity, both logically and more practically in terms of conflict mediation, began with relatively small individuals that only with time evolved into individuals that were both larger and more defection-vulnerable (but also potentially more capable, in certain ways, in their morphological complexity). Part of the story of how this size- and associated complexity-transition occurred consists of the evolution of increasingly sophisticated mechanisms of conflict mediation.

Michod et al. (2003) lists a number of conflict-mediating adaptations that can be useful in engendering cooperation among physically associated cells . These include the existence of a germ line, the tendency for unnecessary or even defecting cells to undergo apoptosis, the potential for self policing, display of relatively low mutation rates, canalization of growth (of which one mechanism is "determinate growth"), etc. Inclusion of "self" policing on this list naturally begs the question of what is self. One answer is that mechanisms exist whereby individual cells, through multiple, redundant controls on the cell cycle, are less able to come to defect via mutation. Another answer is that through immune system functions, body as self is able to eliminate those entities that manage to defect despite the existence other safe guards. Apoptosis, in turn, is a cellular suicide where cells that are unneeded, in the way, or actively defecting my remove themselves for the good of the body, with apoptosis effected either from within a cell or motivated from without by immune system cells. These mechanisms, as pointed out by Michod et al., all evolved to solve near-term problems and therefore in the long term can come to limit the evolution of ever greater complexity. In other words, conflict mediation is simultaneously crucial to the development of greater organismal complexity and potentially limiting to the that evolution.

Table: Different Conflict-Mediating Strategies Used by Multicellular Organisms.

Genetic bottlenecking Initiating of multicellular organisms from a single cell, followed by exclusively asexual cell division in the course of body growth assures high relatedness among interacting cells.
Low mutation rates Reduces rates of generation of defecting genotypes within related or otherwise clonal lineages.
Self or mutual policing If either all or a subset of cells can recognize and then block cheating behavior in other cells (e.g., by inducing apoptosis) then the evolution of cheating will be much less likely.
Barriers to cell movement Barriers inherently exist spatially if cells are incapable of substantial movement (e.g., as seen with plants) but also exist as actually barriers such as basement membranes which can serve to protect animal tissues from invasion by excessively growing or mobilized mutated cells.
Canalized growth Through irreversible differentiation the versatility of body cells can be limited, thereby reducing in at least some instances their potential for cancerous growth.
Pre-emptive discarding of cells Cell lineages that go through numerous rounds of replication are more likely to mutate including to cheater phenotypes. Discarding of such cells, such as those making up the epidermis, can help to prevent future out-of-control replication.
Stringent reproductive requirements Those cells that will give rise to the next organismal generation may be required to go through relatively stringent phases such as complex differentiation, including fruiting body or spore formation, or competition, such as that seen among sperm cells. The result is a potential for antagonistic pleiotropy to limit the longer-term reproductive success of cheater lineages.
Germ lines The greater that the fates of individual cells can be tied together than the lower the potential benefits, over the long term, of cheating behavior. One means of accomplishing such linkage is to limit cell access to organismal reproduction, such as by limiting that reproduction to only germ-line cells.
Germ line sequestration The earlier during development that germ-line cells are separated from normal somatic cells then the earlier that long-term survival of those somatic cells through selfish replication is curtailed.

Germ lines

Germ lines are those cells that give rise to the next generation of multicellular individuals. Those organisms that possess germ lines typically also are sexual, in which members of germ lines will undergo meiosis to creates either gametes or spores. Germ lines may or may not be sequestered early on during development. If they are sequestered, however, then they may be protected within the body from potential mutagens, e.g., by being held at a lower temperatures, or they may be limited to relatively few divisions. The goal of such mechanisms, presumably, is to minimize accumulation of mutations. Gamete production requires differentiation, and resulting gametes are not capable of undergoing further mitotic divisions, thereby limiting the potential of defection, in the form of inappropriate cell division, among the cells destined to initiate the next generation.

The differentiation process itself may serve to limit the participation of cells that already have come to display defection behaviors, since such cells (e.g., cancer cells) typically display less differentiation. A similar mechanism could be at play in organisms that do not sequester their germ lines early on. That is, cells which are destined to give rise to germ lines may be required to display complex differentiation, i.e., phenotypic displays, displays which are less available to cells that otherwise are displaying excessive rates of cell division. These complex phenotypic displays may represent adaptations that better-assure reproductive success. In other words, natural selection during the dissemination step may serve to weed out defectors that arise during the previous growth step. Such a mechanism we have already observed, in outline, in terms of the evolution of virulence, i.e., antagonistic pleiotropy, where alleles that serve to enhance within-body propagation may also reduce the potential for transmission of their carriers to new hosts.

Notable among those multicellular organisms that do not display sequestered germ lines are the plants and fungi. In addition to requirements for sufficient differentiation in tissues before gametes can be formed, a perhaps also important aspect of these organisms is their modularity. That is, mutations in one part of a plant or fungus have less of a potential of bringing down the fitness of the entire organism than do mutations (resulting in cancers) in most animals or their equivalent in smaller, multicellular algae (e.g., volvox). In addition, the relative lack of cellular motility seen with plant and fungal cells may prevent the metastasis that could lead to tumor infestation into multiple parts of these organisms.

By contrast, with animals not only is each anatomical part likely less redundant (and therefore more crucial to organism survival) but tumor cells can become able to move about bodies in a process known as metastasis. In addition, death of a portion of an animal is more likely to kill the entire animal, and thus its germ line, whether the germ line is sequestered or not. The deadliness of cancer in animals thus might be viewed as a cost of mobility, i.e., just as failure of components in a car or a motorcycle are more likely to lead to catastrophic loss of functioning – since these components are all relatively unique and crucial (one engine, one transmission, etc.) – than, say, loss off functioning of portions of large buildings. For example, loss of the air conditioning or heating of one room will not necessarily lead to complete loss of building function (though analogous to vertebrate circulatory systems, the failure of a central air conditioning or central heating unit just might eliminate the functionality of an entire building).

Employing germ lines thus likely plays important roles in reducing the potential for cellular defection. In addition, and importantly, there may exist numerous adaptations that help to enforce this defection-mediating function of relying on germ lines for organismal reproduction. Ultimately, we can view these adaptations as serving to limit which cell lineages within a larger organism can participate in the single-celled dissemination stage that we typically describe as reproduction.

Cancer and Defection

As already implied, there can exist little difference between the concept of cellular defection in multicellular organisms and cancer (or, at least, tumor formation). Cancers represent uncontrolled cellular growth that is also invasive. That is, cancer cells are not only defecting in terms of their rates of population growth but also in terms of invading body locations in which they otherwise do not belong. The result is excessive cell numbers in various body locations. In terms of development of body complexity, we can view cancers as failures of apoptosis, i.e., a lack of self elimination of cells that are not needed and which, through excessive growth, ultimately can become increasingly harmful. We can also view cancers as errors in canalized or deterministic growth, that is, cells which, through mutation, fail to adhere to the developmental patterns required for proper body functioning.

More basically, one can view cancer cells simply as cheaters. How does one prevent cheating? The answers are consistent whether the cheaters are microbes interfering with the functioning of other microbes, cancer cells interfering with the functioning of the collection of individual cells we call bodies, or, indeed, microbes (or other organisms, i.e., parasites) interfering with the bodies of others. That is, bottlenecking, clonality, and antagonistic pleiotropy: Cancer cells are a break from clonality which initially is established via bottlenecking. Control of mutation rates along with various forms of policing help to maintain clonality once established. But, ultimately, the cancer phenotype interferes with the formation of new individuals derived from the genotype of the cancer-cell lineage. That is, cancer cells, as poorly differentiated individuals, are less capable of either displaying the adaptations necessary for progeny production (i.e., organismal reproduction) or are less able to support progeny production by a dedicated germ line. The more stringent the requirements for such reproduction – imposed either by environments or by the intrinsic properties of organisms – then the lower the potential for cancer cell contribution to the next generation. The consequence is stronger selection, over the longer term, against cancer formation.

This in a sense is form of policing, and indeed self policing, where the properties of a cheater are such that their ability to cheat is limited. Cancer cells can destroy bodies, but (mostly) they cannot go any further than that in their cheating. This in fact creates a positive feedback towards cancer prevention. By making cancers dead end lineages, then individual selection can proceed in only one direction, and that is towards protection of bodies, and therefor of germ lines, that is, by interfering with cancer progression. Genomes guard against defection from within by reducing mutation rates, propagating through stages that result in severe bottlenecking, and via various forms of policing against defectors as they nonetheless can arise. The latter, in combination with body cohesiveness along with numerous anatomical and chemical barriers together protect bodies from defectors from without. But ultimately this protection is assured by greatly limiting the potential for defectors from within to display any more than within-body competitiveness. Just as requirements for transmission can limit the potential for parasites to evolve ever greater expediency and resulting virulence, so too requirements for a body's own "transmission" to the next generation selects against the exact same phenomena among bodies as can potentially be displayed by their own cells, that is, the anti-body "virulence" of cancers. Just as limiting opportunities for transmission may result in selection among parasites towards greater commensalism, so-too can limitations on successful reproduction for bodies as a whole select against non-"commensalistic" behavior among body cells. And by further limiting the potential for even non-mutated body cells to contribute to the next generation, the development and then maintenance of what are effectively "mutualisms" between somatic cells and germ line cells is assured. You get what you select for, and multicellular bodies are set up literally to give rise to properly functioning, mutually cooperative, and mostly cancer free, multicellular bodies.


In the end, perhaps not surprisingly, we can view the collection of cells making up bodies not so much as inherently distinct from clonal microbial populations as instead the fruition of propensities otherwise very apparent among microbes. These include tendencies to cooperate, especially intra-clonally and colonially, along with mechanisms of progeny reproduction and dissemination that serve to enhance the likelihood that cooperation will occur in the next generation. Those species for which this feedback does not occur either will tend toward less cooperative behaviors, or will never establish cooperative/colonial habits in the first place. With those species for which this feedback does occur, however, cooperation along with conflict-mediating adaptations can conspire to create individuals that are more competitive within specific niches as groups of cooperating cells. The result is much of the life that we see all around us including, for example, ourselves.