Unsolved Problems: Biology 446, Albert Harris

Topics to be covered during fall semester 2010

  I) Ossification: mechanism of causing calcium and phosphate precipitation amongst collagen fibers (1/3 of weight).
How is bone increased and concentrated, and strengthened at locations of strongest stress?
(so that bones in the serving arm of a professional tennis player are about 30% stronger and more dense than normal!)
Conversely, is this the same mechanism that weakens bones of astronauts during weightlessness! (They will never get to Mars?)
What controls counterbalance of osteocytes versus osteoclasts? (which, or both, are changed by mechanical stress?)
Is there really a role for electric voltages in controlling bone formation?; If so is it DC voltage or AC changes in voltage?
If so, is this control voltage generated by piezoelectricity, electroosmosis, or poroelectricity?
What controls amounts and locations of bone destruction by osteoclasts?
How can this destruction be reduced in older people, so as to avoid, reverse and cure osteoporosis? By inhibiting (or inducing death of) osteoclasts? Or by stimulating osteoblasts?
  II) Protein folding configuration: Levinthal's Paradox (that there is not enough time to find correct folding pattern.)
versus Anfinsen's experiments that proved proteins actually do find consistent folding patterns, even from many initial patterns!
Logical relation of predictability to determinism: The best computer programs on the fastest computers predict the correct folding pattern about 80% of the time, and get the rest wrong. They can't even predict when they are most likely to be wrong.
A related question is whether less-predictable amino acid sequences should be especially unstable? And produce Mad Cow Disease, Kuru, Alzheimer's Disease, and related phenomena caused by proteins re-folding to pathological, & self-stimulating, tertiary structures.
A set of paradoxes pointing toward some breakthrough: Something BIG nobody has thought of.
  III) Self-perpetuation and mutual exclusiveness of animal cell cytodifferentiation.
Do the luxury genes transcribed by (all?) cells of a given differentiated cell type have the same base sequences in their promoter regions? Is there/are there the same transcription factors for each particular kind of differentiated cell?
What is/are the mechanism of self-perpetuation of each differentiated state? How is this related to "Mutual exclusiveness?"   Why are cancer cells an exception, and tend to make proteins that should only be made by different cell types?
Is mutual exclusiveness related to the mechanism that prevents lymphocytes from making more than one shape of binding site?
Reversibility of cell differentiation could/would be as useful as embryonic stem cells!!
  IV) Immune self-tolerance. What is the mechanism by which anti-self B and T lymphocytes are weeded out?
Answer that question and find cure for Multiple Sclerosis, Lupus, Rheumatoid Arthritis & other autoimmune diseases

Also, the paradoxical increasing rates of Asthma. (Does this result from clean, or dog-deficient households?)
  V) The Driesch Phenomenon: "Regulation", as this word is used in embryology?
The ability of embryos to correct for damage, including ½ or ¼ embryo fragments developing normal bodies.
Can regulation only be explained by diffusion gradients of positional information? What are other possibilities?
Does regulation always have the same basic mechanism? E.g. in urchin eggs as in slime mold fruiting? How to test theories?
What explains the failure of regulation of the "killed" cells in Spemann's earlier "hot needle experiment"?
Is there a fundamental difference that makes nematode and fly embryos so "mosaic" = non-regulative? What could it be?

  VI) The Clock & Wavefront hypothesis: "regular periodicity of somite formation…and of dermal papillae
This is an interesting intermediate between positional information and reaction-diffusion. Has it now been proven?
  VII) The Danowski Phenomenon: Discovered in this department, by a woman who is now a Professor at Union College.
Microtubule poisons somehow stimulate increased contraction of cytoplasmic actin, and reverse effects of actin disruption.
What explanations have been proposed/published, and what confirming or contradictory evidence? (do a web search).
Does this phenomenon mean that microtubule dynamics is part of the normal system for controlling actin?
(For example, in the induction of the contractile ring in cytokinesis of animal cells, after mitosis?
  VIII) Athrerosclerosis What really happens? Is it really just due to deposition of cholesterol on, or in, the walls of arteries?
Or is it a reorganization of smooth muscle cells? Or digestion of collagen fibers in artery walls?
How can atherosclerosis be minimized, or reversed? What accounts for different levels of severity in different people?
  IX) How is it possible to have learned so much about the molecular causes of cancer yet not have found really effective cures?
Do all the treatments actually work the way they were designed to? Or by some un-intended methods?
Is the specificity of DNA-damaging drugs and anti-mitotic drugs because non-cancerous cells halt at check points, but cancer cells continue through (defective) check points, thereby suffering more damage? Note this differs from tradition!
"The median is not the message!" Why did Stephen Gould survive 30 years longer than predicted by averages?
Should researchers focus on rare individuals who survive cancer much longer than predicted? (to find ways for others to survive)
How did Coley's toxins cure >1000 terminal cancer patients? But then research on the subject hasn't been continued?
  X) How to prove or disprove Stopak & Harris' theory of traction for aligning collagen fibers in muscles, blood vessel walls?
Slipped Discs:
can some new kinds of treatments might be invented, besides screwing together adjacent vertebral centra?
  Students in this course are encouraged to suggest more unsolved questions to be added to this list.  



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