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== Mechano-chemistry, mesenchyme, and epithelia – CAMs & SAMs in morphoregulatory spacetime ==
[[File:3311.fig.1.jpg|thumb|Mesenchymal-epithelial transitions – epithelia to mesenchyme (EMT) and mesenchyme to epithelia (MET) transitions utilizing CAMs and SAMs to form epethelia; and, growth factors and inducers to mediate the transition to mesenchyme as the CAMs and SAMs are withdrawn or localized on the cell membrane.]]
Edelman's isolation of NCAM lead him to theorize on the role of cell adhesion molecules (CAMs) and substrate adhesion molecules (SAMs) in the formation of the animal bodyplan in both realtime and over evolutionary time. Topobiology is primarily dedicated to this issue that is foundational to the understanding of neural Darwinism and the formation of the primary repertoire of TNGS.

In his ''regulator hypothesis'', Edelman hypothesizes about the role of cell surface molecules in embryogenesis and how shifting expression of these molecules in time and place within the embryo can guide the development of pattern.{{sfn|Edelman|1987b|p=93-100|loc=The Regulatory Hypothesis}} Later, he will expand the hypothesis into the ''morpho-regulatory hypothesis.''{{sfn|Edelman|1988|p=127–172|loc=The Morphoregulator Hypothesis:  Mechanochemistry linked to developmental genetics}} He describes the embryonic cell populations as either organized as mesenchyme or epetheilia.

Edelman characterizes the two population types as follows:

* Epithelia – a population of cells that are organized into coherent tissues, that have well established CAM patterns; as well as a stable pattern of substrate adhesion between the cells and the extracellular matrix.
* Mesenchyme – a population of cells that are loosely associated and migratory, that have retracted (or localized) their CAM and SAM molecules such that they can follow homophilic and heterophilic gradients within other cell populations of the embryo.

He envisages a CAM, and SAM, driven cycle where cell populations transform back and forth between mesenchyme and epithelia via epithelial-mesenchymal transformations,{{sfn|Edelman|1988|p=67-71,219}} as the development of the embryo proceeds through to the fetal stage. The expression of the CAMs and SAMs is under genetic control, but the distribution of these molecules on the cell membrane and extracellular matrix is historically contingent upon epigenetic events, serving as one of the primary bases for generating pre-existing diversity within the nervous system and other tissues.

=== The developmental genetic question ===

There are many developmental questions to be considered, but Edelman is able to succinctly summarize the problem in a way that will show a clear explanatory path forward for him. The ''developmental genetic question'' defines the problem – and, the theoretical approach for him.

<blockquote>"How does a one-dimensional genetic code specify a three-dimensional animal?"{{sfn|Edelman|1988|p=217}} – Gerald M. Edelman, from the glossary of ''Topobiology''</blockquote>

By 1984, Edelman would be ready to answer this question and combine it with his earlier ideas on degeneracy and somatic selection in the nervous system. Edelman would revisit this issue in ''Topobiology'' and combine it with an evolutionary approach, seeking a comprehensive theory of body plan formation and evolution.

=== The regulator hypothesis ===

In 1984, Edelman published his ''regulator hypothesis'' of CAM and SAM action in the development and evolution of the animal body plan.

Edelman would reiterate this hypothesis in his ''Neural Darwinism'' book in support of the mechanisms for degenerate neuronal group formation in the primary repertoire. The regulator hypothesis was primarily concerned with the action of CAMs. He would later expand the hypothesis in ''Topobiology'' to include a much more diverse and inclusive set of morphoregulatory molecules.

=== The evolutionary question ===

Edelman realized that in order to truly complete Darwin's program, he would need to link the developmental question to the larger issues of evolutionary biology.

<blockquote>"How is an answer to the developmental genetic question (q.v.) reconciled with the relatively rapid changes in form occurring in relatively short evolutionary times?"{{sfn|Edelman|1988|p=219}} – Gerald M. Edelman, from the glossary of ''Topobiology''</blockquote>

=== The morphoregulator hypothesis ===

Shortly after publishing his ''regulator hypothesis'', Edelman expanded his vision of pattern formation during embryogenesis - and, sought to link it to a broader evolutionary framework.  His first and foremost goal is to answer the ''developmental genetic question'' followed by the ''evolutionary question'' in a clear, consistent, and coherent manner.