Biology 446    Unsolved Problems Fall 2011



Spontaneous rearrangement

How are complex geometric structures created by properties of their component parts? By what means can structures re-build themselves?

Wilson's Phenomenon of sorting out of dissociated sponge cells.

Holtfreter's Phenomenon of sorting out of randomly mixed embryo cells.
(And are the mechanisms of gastrulation & neurulation the same as sorting?)
By what experiments and results could we answer this question, for sure?

What concepts and analogies help us to think about these phenomena?

I) Minimization of thermodynamic free energy? Gibbs, Clerk-Maxwell, etc.
    A) Parts spontaneously gravitate back toward original geometric arrangement.
    B) Idealization that only conservative forces are acting (all springs & no motors)?
    C) Therefore the system minimizes thermodynamic free energy?

Malcolm Steinberg believes that if A is true, then B and C have to be true.
(as if only reversible forces can be stably counterbalanced) He thinks this is an insight.

Actually, B doesn't have to be true. And if B isn't true, then neither will C be true.
But S. believes that Gibbs or somebody proved that gravitation to some particular geometry can only be produced by forces that are reversible = "conservative" (don't expend energy when balanced). This is a fallacy, but only one researcher ever called his bluff in print.

II) Fuller & Ingber's popularization of "Tensegrity". (The "Oh-Wow" method of reasoning)
(Suspension bridges and tents were already invented long before.) What's special about tensegrity is not that pulls & pushes are counterbalanced, but avoidance of bending and shear, plus a related tendency of loading forces to spread out, not bunch up.

Dome houses' strength & efficient use materials is the same reason they leak.
Imposed forces spread out by distortions of shape (thereby making gaps & holes)
Strengths of building materials are always limited, to a small fraction of bond strengths, by stress concentrations.

III) Shape Homeostasis (First proposed under the name "anatomical homeostasis")
Harris, David Stopak, Timothy Otter, and a few others. (& we get about a hundredth the respect Steinberg does.)

Analogous to Claude Bernard and Walter Cannon's idea (fact) of homeostatic control of quantities such as body temperature, Blood pH, glucose concentration, blood pressure, + just about all physiological properties.

Hypothesize that some cell forces change strengths in response to abnormalities of cell arrangements.
Changes in strengths of forces pull or push cells and collagen (& cartilage?) back toward correct shapes.
Negative feedback can control shapes just as well as it can control amounts.

Ecologists have made good use of the homeostasis concept. Plus the Gaia idea + all that.

They have the advantage of nobody claiming that convergence to a stable state means free energy minima.

#1) Related questions and paradoxes about 3-D conformations of amino acid chains (i.e. proteins)

The true folded shapes of proteins can always be discovered and proven by X-ray diffraction. If they crystallize.
(And also by Nuclear Magnetic Resonant interactions between hydrogens, at least if protein not too big.)

But what about computer predictions of protein folding based on knowing the amino acid sequence?
The best/most accurate programs predict the correct folding pattern for 80% of proteins. 1/5 are wrong.
Progress has been stuck at 80% for decades. They aren't getting better & nobody understands why not.

#2) Levinthal's Paradox. Small proteins can fold (and also RE-fold, after denaturation = random folding) in only a thousandth of a second, or less. Everyone assumed they find whatever folding pattern minimizes free energy, until Cyrus Levinthal "did the math" on how many different combinations of folding would need to be tried. Billions of years would be needed to try all possible combinations of folding. So they can't try them all.

This leads to the concept of "Folding Funnels" that lead to protein conformations that are only local minima. In contrast to Differential Adhesion, this thermodynamic reasoning is correct; it just doesn't give right answers.

#3) Diseases caused by self-catalysing of misfolding of certain brain proteins. Alzheimer's disease? + others.

#4) Prion-caused diseases like "Mad Cow Disease", Kuru and Scrapie. (misfolding started by food proteins)
Should we think of these as creating abnormal folding funnels? If so, how could that be avoided or cured?


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