Adventures With Theories And Computer Simulations:

Theories can be helpful without being correct. Mistaken paradigms often lead to major discoveries. What else have we got to work with, after all, than whatever paradigms are temporarily dominating whichever subject we are trying to make sense of?

This inevitable fact is well-illustrated by the relation of Malcolm Steinberg's theory of cell rearrangement (which I continue to regard as a mistaken paradigm) and the important discoveries by Nardi and Stocum about regenerating limb buds of salamanders. Whether or not Steinberg's theory turns out to be correct, in the long run, we can still learn from its effects on the design and interpretation of Nardi and Stocum's experiments.

Most of my friends in research, including my thesis advisor, despised theories and thought I should ignore them, and stick to solid facts. Many or most of my students had (& have?) this same opinion.

My counter-argument is that one person's fact is another person's theory. Except for the simplest details of what we observe, almost all of what we think we observe are theoretical interpretations. What facts we see depend on which paradigms we believe. Professor Steinberg and his student Herbert Phillips are two of the best illustrations of scientists whose "facts" were interpretations. When they saw masses of one kind of cell being engulfed by masses of some other kind of cell, their interpretations became certainties. In particular, they were certain that whichever kind of cell got engulfed had a larger "thermodynamic reversible work of adhesion".

My "fact", in contrast, was that the cells getting engulfed were contracting more strongly along interfaces between cells and culture medium (and between cells of one type and another). Most embryologists accept that the infolding of the neural tube is caused by strengthened contractility of the apical, concave surface of the neural plate. Two of Holtfreter's most important discoveries were (first) that clumps of neural tube cells get engulfed by epidermal cells, and (second) that randomly mixing up individual epidermal cells and neural tube will result in the latter sorting out to internal positions relative to the latter. The key point is that you get the same end result (neural inside epidermal) whenever you mix those two kinds cells. If they are in clumps, then the epidermal clumps engulf the neural clumps; if neural and epidermal cells are randomly intermingled, the result is that the neural cells sort out to internal positions, and (thirdly) normal neurulation results from infolding of the neural tube.

What can it mean that you get the same end result by any of three different pathways? Quite a few people immediately think "thermodynamics!". They recall, from somewhere, that minimization of thermodynamic free energy, and/or maximization of entropy, will cause systems to gravitate to the same end result by any of two or three or more pathways. They got the idea that minimization of free energy was the only possible reason (or at least the most likely reason) that you can get the same end results via different pathways. Who is to tell them otherwise. Thermodynamics frightens most critics away. We are lucky that this fallacy didn't prevent development of the whole concept of homeostasis.

A lesson for us all to realize is that almost all our facts are interpretations, in the sense that they are based on one theory or another. I try to let part of my mind "believe" one theory, and another part of my mind "believe" another theory, and so on for as many theories as have some basis in reality or logic. That "lucid" paper I published, way back in 1976, was intended to sort out possible explanations, and compare the evidence for each.

That paper got interpreted as an attack on Steinberg. His feelings were hurt. His many enemies wrote me fan letters. Jack the Giant Killer never got half as much praise. My paper had not even been meant to propose any specific alternative theories. They were requested by the editor (who was the membrane researcher, Danielli) and both the referees, neither of whom liked the paper. One of them wrote "We already have a theory of cell sorting! Why do we need another one?" That objection flummoxed me, at the time, but is food for thought.

My conclusion is the exact reverse. We should always have at least two theories, or as many as we can get. Furthermore, textbooks should tell us about the previous theories, that got disproven or otherwise discarded, and what the key evidence was. Usually, they don't. One historical progression that is often recounted happens to be the abandonment of the Davson-Danielli theory of membrane structure, in favor of the John Singer - Garth Nicholson "Fluid-Mosaic" theory. A critic could have said: "We already have a theory; Why do we need another one?"

Theoretical papers, at least in biology, almost always advocate one particular theory, and make some kind of incomprehensible calculations based on it, leading to a conclusion that it is correct. This is especially true of computer simulation papers.

Seldom do papers even-handedly compare the strengths and weaknesses of opposing theories. Even more rare is proposal of experiments, although that seems to me the single most useful thing that any theoretical paper could do.

Please read the following published papers: Skimming through them, and getting the general idea, is sufficient.
Be ready to discuss them in class by Monday Nov. 3.

Harris, A.K., and S.L. Gewalt (1989). Formation of the contractile ring in cytokinesis. Journal of Cell Biology 109, 2215-2223.

Rappaport, R., and B.N. Rappaport (1994). Cleavage in conical sand dollar eggs. Developmental Biology 164, 258-266.
This one should be available for free if you are connected to the UNC system. Please let us know if you have trouble getting it. The rest of the papers are freely available anywhere.

Poirier, C.C., W. P. Ng, D.N Robinson, and P.A. Iglesias (2012). Deconvolution of the cellular force-generating subsystems that govern cytokinesis furrow ingression. PLoS Computational Biology 8, e1002467

Manning, M.L., R.A. Foty, M.S. Steinberg, and E.-M. Schoetz (2010). Coaction of intercellular adhesion and cortical tension specifies tissue surface tension. Proc. Natl. Acad. Sci. USA 107, 12517-12522.


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