In what sense is the "Differential Adhesion Hypothesis" "Thermodynamic"? and related questions about clusters of cells that behave as if they have "Surface Tension"

Liquid drops, and also bubbles, round up as if they have a contractile layerat their surface.

For many years, scientists believed this behavior was really caused by contractility.
The real cause is pulling forces of attraction between individual molecules.

Clusters of cells, especially embryonic cells, behave like liquids with surface tension.
This liquid-like behavior might be a measure either of cell-cell adhesion, or because they really do form actively contractile surface layers.

The Differential Adhesion Hypothesis concludes that (a) adhesion is attraction, (b) that cells are pulled by adhesion forces, [c) that sorting out is caused by quantitative differences (in amount) of cell-cell adhesion, that (d) adhesion can be measured by the amount of force needed to flatten aggregates of cells (for example, by centrifugation).

An important aspect of cell sorting is that the same end result is reached by two or more different sequences of events. A good example is that heart cells sort out to interior positions relative to livercells; and clusters of liver cells engulf clusters of heart cells.
Another example is that neural ectoderm cells move to the interior either by invagination or by being engulfed, and also if dissociated and randomly mixed with mesoderm cells.

Concepts and vocabulary of thermodynamics can often be used to describe and explain phenomena in which the same end result can be reached by means of two or more (or many) sequences of intermediate states. Josiah Gibbs (who incidentally was the second person in the USA to receive a PhD) invented the concept of thermodynamic free energy. "Free" is used in the sense of "available for doing work". The more modern synonym is "The Gibbs Function" G = H - TS expresses the counter-balance between heat release versus increases in entropy. Gibbs called entropy "mixedupness". Gibbs also introduced the modern form of the concept of vectors, but wasn't appreciated in his day.

Many scientists believe that thermodynamics explains anycase in which something gravitates to the same end result by means of more than one pathway (= sequence of intermediates).
This is why cell sorting and engulfment are claimed to be best explained by thermodynamics.

Actually, counter-balance between opposing forces is a broader and more general concept than minimization of free energy. (which also is related to the minimization of potential energy) Sometimes scientists use these mysterious concepts to intimidate one another.

If all forces in a closed system happen to be "reversible" (= "conservative"), in the sense of not expending energy when in static balance, in such cases thermodynamics really does apply.

From this, some conclude that only reversible forces can cause the same end results to be reached by different intermediate pathways. That led to belief that active contraction of actin & myosin couldn't produce cell sorting and engulfment. I published a paper arguing that the surface tension-like behavior of cell sorting, invagination & engulfment are caused by active contractions, and that although they couldn't occur without adhesion, they are not measures of adhesion.

This debate continued for many years. The DAH mostly won, and textbooks treat it as proven truth.

Nardi & Stocum consider that engulfment of cell aggregates is a measure of cell-cell adhesion, instead of resulting from active contraction of cells. From that they conclude that limb buds have a proximo-distal gradient of adhesiveness. (But maybe it's really a gradient of surface contractility).

Malcolm Steinberg's last paper before he died a few years ago (M Lisa Manning, et al. PNAS 2010) reinterprets cell sorting as resulting from "coaction", = partly adhesion and partly contraction.
"Two opposing theories about the mesoscopic origin of tissue surface tension have coexisted over the last 30 years"

Carl-Phillip Heisenberg and his group (Krieg et al., Nature 2008) had used atomic force microscopy to measure cell adhesions and contractility. Also good is "Sophistications of Cell Sorting" by J B A Green, in Nature Cell Biology 10 pp 375-377 (2008). & remember the black knight in Monty Python!

Scientists interpret data in whatever way most closely fits whatever they already believe. Getting to the same end result by 2 or more pathways should be reconsidered in terms of homeostasis.

Returning to a state can have the same cause as getting to that state in the first place. But should we assume that leg regeneration has the same causes as leg development in embryos? And how can either a contractility gradient or an adhesion gradient contribute to leg regeneration?

We need more theories, especially theories that make predictions.

Although Mendeleev's "Periodic Table of the Elements" was preceded by analogous systems, his made predictions about missing elements. That stimulated research by others. Earlier systems had made excuses for gaps, rather than predictions to be searched for.


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