I revisit two theories of cell differentiation in multicellular organisms published a half-century ago, Stuart Kauffman's global gene regulatory dynamics (GGRD) model and Roy Britten's and Eric Davidson's modular gene regulatory network (MGRN) model, in light of newer knowledge of mechanisms of gene regulation in the metazoans (animals). The two models continue to inform hypotheses and computational studies of differentiation of lineage-adjacent cell types. However, their shared notion (based on bacterial regulatory systems) of gene switches and networks built from them, have constrained progress in understanding the dynamics and evolution of differentiation. Recent work has described unique write-read-rewrite chromatinbased expression encoding in eukaryotes, as well metazoan-specific processes of gene activation and silencing in condensed-phase, enhancer-recruiting regulatory hubs, employing disordered proteins, including transcription factors, with context-dependent identities. These findings suggest an evolutionary scenario in which the origination of differentiation in animals, rather than depending exclusively on adaptive natural selection, emerged as a consequence of a type of multicellularity in which the novel metazoan gene regulatory apparatus was readily mobilized to amplify and exaggerate inherent cell functions of unicellular ancestors. The plausibility of this hypothesis is illustrated by the evolution of the developmental role of Grainyhead-like in the formation of epithelium.

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The annual incidence of Lyme disease, caused by tick-transmitted Borreliella burgdorferi , is estimated to be at least 476,000 cases in the United States and many more worldwide. Ten to 20% of antimicrobial-treated Lyme disease patients display posttreatment Lyme disease syndrome (PTLDS), a clinical complication whose etiology and pathogenesis remain uncertain.

Although discussed by 20th century philosophers in terms drawn from the sciences of non-living systems, in recent decades biological function has been considered in relationship to organismal capability and purpose. Bringing two phenomena generally neglected in evolutionary theory (i.e. inherency and agency) to bear on questions of function leads to a rejection of the adaptationist ‘selected effects’ notion of biological function. I review work showing that organisms such as the placozoans can thrive with almost no functional embellishments beyond those of their constituent cells and physical properties of their simple tissues. I also discuss work showing that individual tissue cells and their artificial aggregates exhibit agential behaviours that are unprecedented in the histories of their respective lineages. I review findings on the unique metazoan mechanism of developmental gene expression that has recruited, during evolution, inherent ancestral cellular functionalities into specialized cell types and organs of the different animal groups. I conclude that most essential functions in animal species are inherent to the cells from which they evolved, not selected effects, and that many of the others are optional ‘add-ons’, a status inimical to fitness-based models of evolution positing that traits emerge from stringent cycles of selection to meet external challenges.

Genetic heterogeneity and homogeneity are associated with distinct sets of adaptive advantages and bottlenecks, both in developmental biology and population genetics. Whereas populations of individuals are usually genetically heterogeneous, most multicellular metazoans are genetically homogeneous. Observing that resource scarcity fuels genetic heterogeneity in populations, we propose that monoclonal development is compatible with the resource‐rich and stable internal environments that complex multicellular bodies offer. In turn, polyclonal development persists in tumors and in certain metazoans, both exhibiting a closer dependence on external resources. This eco‐evo‐devo approach also suggests that multicellularity may originally have emerged through polyclonal development in early metazoans, because of their reduced shielding from environmental fluctuations.