Questions for class discussion Unsolved Problems Nov. 8, 2017

1) A possible cure for muscular dystrophy: Some treatment that allows plasma membranes to stretch without tearing. (Remember that scanning electron micrograph of that cell which had many retraction fibers?)

2) Because dosage compensation (in mammals) works by "turning off" all the genes on one X chromosome or the other, at random, at different locations, and also given that the dystrophin gene is on X chromosomes, then in women who have one defective copy of that gene, shouldn't half their cardiac muscle cells die? HINT: Why shouldn't this problem also occur in skeletal muscle cells?

3) Studies using flexible substrata indicate that mesenchymal cells and some glial cells contract just as strongly as muscle cells: Therefore, in people with muscular dystrophy, why don't these other cell types damage themselves just as much as muscle cells do?

4) Why don't smooth muscle cells of people with muscular dystrophy get damaged as much as cardiac and skeletal muscle cells?

5) Discuss whether formation of retraction fibers results from weakening physical connections between the cytoskeleton and the inside surface of the plasma membrane? Pro or con. What else could cause it?

6) How could you test that idea? If true, should abnormal retraction fibers occur in people who have muscular dystrophy?

7) Are retraction fibers as important, or as interesting, as filopodia? Why or why not?

8) Does Anfinsen's concept also apply to antibody proteins and T-cell receptors? In other words, are the tertiary structures of all proteins caused by amino-acid sequences?

9) Suggest how autoimmune diseases might result from situations in which more than one folding pattern have the same free energy and are therefore equally stable.

10) Is the phrase "more than one" singular or plural? What about 2 or more? What about 1.99 ?

11) What different diseases are believed to be caused by mis-folding of proteins in nerve cells?

12) Shouldn't the amyloid plaques also develop, not just in nerve cells, but also in other differentiated cell types?

13) Invent some possible reasons? (Including "Maybe they do develop in other cell types, but researchers haven't noticed yet.")

14) Discuss whether the mechanism by which memory and or skills might be stored in the brain in the form of changing conformational folding patterns of some protein found in nerve cells? (That would serve the functions that transistors, and before them magnets, serve in computers.)

15) Suggest medical significance of such a memory mechanism. Suggest experiments or other observations to test (prove or disprove) whether such a mechanism exists.

16) Why else should nerve cells be the main locations where amyloid plaque accumulates?

17) Mutations in certain genes are known to cause Alzheimer's disease to begin at an earlier age and to get worse faster. Suggest what might be the normal function of the normal version of the genes in which mutations produce Alzheimer's disease.

18) Discuss the following claim: For every different theory of how memory works, there must be at least one corresponding theory of the mechanism of Alzheimer's disease.

19) Stimulating increased unfolding of proteins (perhaps by increased effectiveness of chaperone proteins, or even by high concentrations of urea in body fluids or cytoplasm, or very high hydrostatic pressure) might lead to cures for Parkinson's disease.

20) Levinthal's paradox is based on what over-simplification(s)?

21) Levinthal's paradox suggests the possibility that most proteins never test the stability of many folding patterns that would have very low free energy if they were ever formed.

22) To what extent would you regard Alzheimer's disease as resulting from proteins finding their way to stable folding patterns that do not normally exist? (and are harmful if reached).

23) Have you read Kurt Vonnegut's science fiction novel "Cat's Cradle" and remember the meaning of the fictional alternative crystalline form of water named Ice-Nine? If so, please explain it to the class. How is the concept relevant to prions, etc.? In your opinion, which is Vonnegut's best novel?

24) What about "Blood Music" by Greg Bear? How is it related to actual biological phenomena?

25) X-ray diffraction studies indicate that antibody binding sites are always (? Almost always?) lined by four beta pleated sheets (protein folding pattern). Discuss why this is surprising in relation to the VDJ random recombination mechanism which creates the amino acid sequence of antibody binding sites. What about the hyper-mutation that also contributes to variability of shapes of antibody binding sites?

26) Please invent some experiments to test Stopak & Harris so-called "dogma" about the mechanism of formation of ligaments, tendons and skeletal muscles (= Testable predictions, especially predictions of what shouldn't happen, and would disprove the theory if actually shown to occur).

27) For example, what ought to happen if the radius and/or the ulna were surgically moved to different locations in the early limb bud of an embryo? What sorts of abnormality would / should be caused to develop?

28) Please suggest hypothetical birth defects that, if they really occurred, would be strong evidence either in favor of this theory, or against it.

29) What if somebody grafted a piece of embryonic heart into the hind limb of an embryo, and the result were formation of a normal-looking gastrocnemius made largely out of mono-nucleated muscle cells that contract spontaneously about once a second?

30) What if you surgically removed all the cartilages from an early limb bud, and the results were formation of normal-looking muscles that had no attachments to skeleton? Conversely, what if the result was non-alignment of skeletal muscle cells? Which result would the theory predict, and which could disprove it?

31) How do you think collagen fibers get tightly wrapped around early developing blood vessels? Can you invent any other possibilities?

32) Vertebrates in which the genes for type I collagen have been deleted or prevented from transcription have been observed to die from burst capillaries soon after the heart begins to pump: What do you conclude?

33) Do you expect that totipotent stem cells will be needed for arms and legs to be regenerated? Why might grafted muscle and cartilage cells be just as effective as cells that can be induced to differentiate into any differentiated cell type?