  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 chromatin-based 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.
