Wednesday Feb. First: Many facts remain to be discovered and proven.

A little more about cell sorting & Differential Adhesion Hypothesis: Why be interested in such things?


One reason is that many birth defects result from failed or incomplete cell rearrangements.

A condition called spina bifida occurs when neurulation is incomplete, leaving the neural tube incomplete or open at the rear.

Another birth defect occurs when the archenteron doesn't fuse with the stomodeum = mouth not connected to throat.

Many birth defects of the heart are failures of fusion, or fusions at abnormal places.

To avoid and cure such birth defects: we need better understanding of physics of embryos.

There will be a more extensive lecture on birth defects later in the course.


What does it mean when the same end result can be reached by 2 or more alternative pathways:

For example, neural tube formation by (1) folding (2) sorting (3) engulfment as discussed in the lecture on January 30:

[A] Minimization of thermodynamic free energy?
That is the central idea of the Differential Adhesion Hypothesis

[B] Shape Homeostasis? Advocated by me & a few others. Emphasis on rules obeyed

[C] Counter-balanced forces? "Biotensegrity" An international meeting in DC last year

Two or more different mechanisms serve the same function.
Each pathway a different causal mechanism?

Please suggest other possibilities, and experimental tests


In fact, tissue culture cells accumulate on the most adhesive surfaces available.

Does that mean cells are pulled by adhesion forces? (as in the "thermodynamic" theory)

Or do cells pull themselves by acto-myosin contraction? "tug of war" balance of forces

Distinction between "force of adhesion" versus "strength of adhesion"

Does it really matter which of these is true? Do medical cures depend on knowing?

"Haptotaxis"is the name given for selective adhesiveness, i.e. preferential accumulation of cells on a more adhesive surface. Sometimes this is interpreted to mean chemotaxis toward immobilized chemicals, but that was not the original definition.

    video of cells accumulating on a palladium-coated surface (darker grey sides) rather than on the uncoated polystyrene in the center

    video of cells adhering to islands of palladium that have been shadowed onto a polystyrene surface


What are the forces that cause gastrulation? Neurulation? Wound closure? Migration of pigment cells? Creation of color patterns in skin?

A classic work on this topic is D'Arcy Thompson's influential big book "On Growth and Form."

The entire text is available on line:

D'Arcy Thompson's ideas will be discussed in more detail in a future lecture.

Why are Aurelia jelly-fish shaped like air bubbles rising through water?


i) Do you think gastrulation or neurulation have the same causes as cell sorting?

ii) Does Steinberg's evidence of transitivity of inside-outside sorting support his belief that quantitative differences (in amounts of adhesiveness) cause cell sorting, and therefore cause gastrulation?

iii) Neurulation is believed to be caused by differences in contractile differences in cell surfaces. Can you fit that in with observations that random mixtures of neural tube cells sort out to internal positions and form hollow tubes?

iv) When the same end results can be reached by two or three or more different pathways (sequences of intermediate arrangements) does that mean that thermodynamics should be used to explain the causes?

v) Do hypotheses help biologists understand causes?

vi) Are hypotheses the best way to invent experiments?

vii) Most vertebrates form their central nervous system from sheets of cells that fold and seal their edges together. In dramatic contrast, teleosts form their nervous systems by hollowing out solid rod of cells.

What do you conclude (or guess) from this?
That the mechanisms are fundamentally different?
That the mechanism of sheet folding can also cause hollowing?
Something else?

viii) Birds form their neural tubes by folding a sheet of cells, except the posterior 15 or 20% parts of birds form their neural tubes by hollowing out ("cavitation") of a solid rod of cells.
Does this affect your opinion about whether the same mechanism can cause folding, and also cause cavitation?
and also cause sorting out of randomly mixed cells?

ix) Neural tubes expand by pumping water into their interior. If the posterior ends of neural tubes were open, then inflation by water pressure couldn't work?
Recently, it occurred to me this may be why the posterior ends of bird neural tubes form by cavitation, and also why the entire neural tubes of teleosts cavitate instead of folding.
Can you figure out a reason?
Hint: it has to do with progressive formation of the body from head to tail.

x) Tissues grafted from one part of an embryo to another sometimes move back to their normal original locations.

& Rotated tissues sometimes rotate back to their original orientation?
What can this mean? Is it related to sorting out of randomly dissociated cells?

Can we ever find out if we mistake effects of contraction for results of contractility?


Some comments on a paper by Steinberg and his collaborators:

Coaction of intercellular adhesion and cortical tension specifies tissue surface tension

M. Lisa Manning, Ramsey A. Foty, Malcolm S. Steinberg, and Eva-Maria Schoetz
Edited* by Barry H. Honig, Columbia University/Howard Hughes Medical Institute, New York, NY, and approved June 7, 2010 (received for review March 20, 2010)

Text quoted from this paper:

"...But how are tissue surface tensions generated? Different theories have been proposed to explain how mesoscopic cell properties such as cell-cell adhesion and contractility of cell interfaces may underlie tissue surface tensions. Although recent work suggests that both may be contributors, an explicit model for the dependence of tissue surface tension on these mesoscopic parameters has been missing. Here we show explicitly that the ratio of adhesion to cortical tension determines tissue surface tension. Our minimal model successfully explains the available experimental data and makes predictions, based on the feedback between mechanical energy and geometry, about the shapes of aggregate surface cells, which we verify experimentally. This model indicates that there is a crossover from adhesion dominated to cortical-tension dominated behavior as a function of the ratio between these two quantities.

"Two opposing theories about the mesoscopic origin of tissue surface tension have coexisted over the last 30years. One, the differential adhesion hypothesis (DAH), postulates that in analogy to ordinary fluids, tissue surface tension is proportional to the intensity of the adhesive energy between the constituent cells, which are treated as point objects. The DAH has proven successful in a variety of studies with cell lines (2-5, 15) , malignant (13, 14) and embryonic tissues (1, 5, 8, 16) and is widely accepted (12, 17)

"However, recent experiments using atomic force microscopy (AFM) (19) and TST (see data in this study) indicate a dependence of the surface tension on actin-myosin activity in the cell, interpreted as supporting an alternative theory in which cortical tension in individual cells is thought to be the determining factor. The differential interfacial tension hypothesis (DITH) developed by Harris (20), Brodland (21), and Graner (22) relates tissue surface tension to the tension along individual cell interfaces. The DITH theories are appealing because they recognize that individual cells are not point objects; a cell's mechanical energy changes with cell shape and the cortical tension clearly plays a role in this energy balance.

"Recent work has emphasized that interfacial tensions arise from a balance of adhesion, cortical tension, and cortical elasticity (17, 19, 23, 24). However, the exact nature of this interplay remains to be elucidated..." "The remaining analysis does not depend on the mechanistic origin of these forces, but simply requires that the first higher-order term is of the form

"The lowest energy states corresponding to this energy functional are complicated because the term introduces a length scale that is not necessarily the same as the length scale introduced by the incompressibility constraint."

Their revised ideas are based on misinterpreting enveloping layer cells as being deep cells in zebra fish blastulas, and their pretentious BS equations are meant to impress people, not to be understood.


At the end of the lecture, Hox genes in five minutes:

Many genes that alter embryos code for transcription factors
Families of transcription factors include: Hox, zinc finger, leucine zipper, and others

These gene sequences are astonishingly conservative through evolution (for example have homologous sequences in flies and in vertebrates) although they don't necessarily have the same function.

Hox (homeotic) genes - found in "all" animals

From the Wikipedia article on Hox genes:

"A fly can function perfectly well with a chicken Hox protein in place of its own. So, despite having a last common ancestor that lived over 670 million years ago, the chicken and fly version of the same Hox gene can actually take each other's places when swapped." .

"Colinearity of Hox genes In some organisms, especially vertebrates, the various Hox genes are situated very close to one another on the chromosome in groups or clusters. Interestingly, the order of the genes on the chromosome is the same as the expression of the genes in the developing embryo, with the first gene being expressed in the anterior end of the developing organism. The reason for this colinearity is not yet completely understood ".



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