A) In your opinion, what specific advances in knowledge would be most helpful in finding cures for autoimmune diseases? Please explain your main reasons for this opinion.

B) Remember those MRI images of the brain of the Multiple Sclerosis patient in the Wikipedia article about MS. Did these images give you any new ideas, or tend to support or disprove any particular theories about MS? What specific features would you look for, if you had access to several hundred more sets of images like them, from other people? (Features that could lead to a better understanding of this disease).

C) What evidence shows that Multiple Sclerosis is partly, but not entirely, caused by genetic differences? Does the evidence support, or disprove, the possibility of MS susceptibility being the result of mutations in one particular gene? Or would there need to be many genes?

D) Hypothesize the normal functions of whatever genes contribute to increased susceptibility to multiple sclerosis. (Hint: genes coding for myelin proteins? genes coding for enzymes that catalyze recombination of VDJ DNA sequences. What else? As many as you can think of.)

E) If you knew what proteins were coded for by the genes whose mutations increase the probability of MS, could that knowledge guide you toward more effective treatments, or even a cure? Please invent plausible possibilities or examples.

F) Please argue pro or con: If glatiramer really does much good for MS patients, then new and much more effective treatments might soon be found.

G) What is most misleading about the idea that the immune system can detect special properties of cells that are possessed only by "self". Do bullets work by detecting special properties of "targets"? When a bullet hits something you didn't aim at, is that because the bullet mistakenly detected "target-ness"at the wrong locations? Does the accuracy of a rifle depend how correctly it detects target-ness? Please think of a better analogy than my joke about detecting target-ness.

H) Discuss the advantages and disadvantages of depending on economic motivation to guide searches for new and better cures for diseases? What about for the purpose of concerting rapidly fatal diseases into chronic diseases, instead of into rapidly curable diseases? What ideas can you propose for improving the current system?

Why might it help to make patents last longer, and apply to a wider range of treatments? (Which is exactly the opposite to what most reformers advocate.)

I) Based on what expectation about the biochemical effects of bisphosphonates were they tried as treatments for osteoporosis? How do they really work?

J) If a drug turns out to work for some completely different reason than what gave people the idea of trying it, should that affect the validity of whatever patents apply to its sale? Please suggest arguments on BOTH sides of this question.

K) What approach has the best chance of discovering an actual cure for osteoporosis? And explain your reasoning.
Ditto for Lupus; Ditto for MS. Ditto for Muscular Dystrophy? For some other disease?

L) How could electro-osmosis of skeletal tissues be misinterpreted as piezoelecricity? (Would it be sufficient if much higher percentages of biologists and physicians had heard of piezoelectricity than had heard of electro-osmosis?)

M) Briefly compare the textbook description of water flow pathways inside sponges, in contrast to what I advocate. What is the relevant evidence? What further experiments are needed to settle the argument conclusively?

N) Ditto for Malcolm Steinberg's "thermodynamic" theory of cell sorting, in contrast with the theory of differential interfacial contraction.

O) Why are macrophages so interesting? How could improved understanding and ability to control macrophages lead to treatments and cures for atherosclerosis?
Ditto for osteoporosis?
What other diseases might result from misbehavior of macrophages?

P) Invent possible reasons why macrophages respond in the opposite way than other cells to electric fields, hydrophilic surfaces, roughened surfaces, proteolytic enzymes and calcium ion concentrations. Suggests experimental tests for your hypothesis.

Q) Is Physics really more advanced than Biology? Please argue pro or con; or give some "pro" arguments and some "con" arguments. What do you believe are the main factors that tend to slow down the progress of Biology, relative to physics?

R) On what subject has your opinion changed the most as a result of the content of this course? (and explain why)

S) If Watson and Crick hadn't published their DNA structure (if they hadn't been born) then who else would have come up with the correct idea about how amino acid sequences are coded by nucleotide base sequences? (And please explain why)

T) What if Watson had never received a post-doctoral fellowship for study in Europe? Do you think that he or Crick would have made such a discovery?

U) Was it justified to spend money meant for polio research for this purpose, in your opinion, pro and or con.

V) Can you briefly summarize, in your own words, the conclusions and reasoning of the web page about "Why Math Isn't Just About Numbers"?

W) Which part of this web page is most relevant to the dispute about whether Steinberg's Differential Adhesion Hypothesis is really based on thermodynamics?

X) Do homeostatic mechanisms minimize thermodynamic free energy?

Y) Explain how to use variations in the slope of a line to produce a graphic representation of difference in the strength of a homeostatic feed-back mechanism (like that that resists changes in body temperature) as a function of the current values of whatever variable the homeostatic mechanism regulates.

Notice that variations in direction and strengths of the negative feedback (and also positive feedback) can be represented graphically either by differences in the slope of a line, or by differences in the height of a line. Also consider that the concept of Gibbs' Free Energy is based on using slopes of lines and planes to represent directions and strengths of forces. Why does this gimmick work even for non-conservative forces, IF you are only graphing effects on only one variable. Don't worry if you don't see what I am getting at here.
Energies can be regarded as integrals of forces; Forces can be regarded as slopes of energies.

Z) If you were to begin a research career, and were limited to one of the topics discussed this semester (including in student reports), which one would you study, and why? Reasons can include likelihood of actually solving a problem conclusively.

aa) What are some specific examples in which Kuhn's ideas were most accurate? That can include progress being blocked by the dominance of a given paradigm.

bb) Alternatively, please describe examples where scientific progress was most different from Kuhn's ideas.

cc) Are there good example of the classical idea of "invent a hypothesis, do an experiment to test it" etc.?

dd) In what sense did Watson and Crick invent hypotheses, compare predictions of their theories with observations, modify their theories to make the fit the data better, etc. with the difference that their "experiments" consisted of looking in books, talking to other scientists, and borrowing other people's research?

ee) Can "Genomic" types of information possibly help find a cure for autoimmune diseases?
If the answer is yes, then explain how base sequences can reveal how the self-tolerance mechanism works, or what goes wrong with the tolerance mechanism in people with an autoimmune disease.
Hint: What about differences between base sequences of one B Lymphocyte and another? Base sequence abnormalities of people who have MS? ...Of close relatives of MS patients? Differences in base sequences between identical twins, one of whom has MS and the other of whom does not have MS.

ff) If you could get the exact base sequences of any cells you wanted, which would you predict should be the most helpful in finding a cure for autoimmune diseases? finding more effective treatments for cancer? For delaying or reversing effects of aging? Or any other disease discussed in this course, including in student reports.

gg) Please explain the false assumption in the underlined part:
(From an Encyclopedia Brittanica Article about "monoclonal antibodies")

"Although the preparation of monoclonal antibodies from rat or mouse cells has become routine practice, the construction of human hybridomas has not been as easy. This is partly because most human myeloma cells do not grow well in culture, and those that do have not produced stable hybridomas."
Hint: Why not fuse human B-lymphocytes with mouse myeloma cells, instead of with human myeloma cells? What would be a reason for making human hybridomas?


hh) Please explain the false assumption in the underlined part from the same encyclopedia:

"Antibody, also called immunoglobulin, a protective protein produced by the immune system in response to the presence of a foreign substance, called an antigen. Antibodies recognize and latch onto antigens in order to remove them from the body. A wide range of substances are regarded by the body as antigens, including disease-causing organisms and toxic materials such as insect venom."
When an alien substance enters the body, the immune system is able to recognize it as foreign because molecules on the surface of the antigen differ from those found in the body.


ii) Do antibodies "latch onto" antigens ...
Because the shape of the binding site fits (is complementary in shape an charge distribution) to the shape of the antigen?
Because they have previously contacted those same antigins, and been imprinted with the antigen's shape?
Because B-lymphocyte self-destruct if they contact recognizes the shape of the antigen?


jj) Argue pro or con: Frequent use of the words "recognize", "self" and "non-self" traps people's thinking in an outdated paradigm about the mechanisms of immunity and the causes of autoimmune diseases. Explain the paradigm, and why it is out of date.

kk) Osteoclasts and skeletal muscles have hundreds of nuclei per cell, and they get that way by fusion of uninucleate cells, and never by mitosis of cells that have already fused. Guess (hypothesize) possible reasons why they become nucleate by fusing, instead of by inhibition of cleavage.

ll) If you have some uninucleate muscle cells in tissue culture, and treat them with a poison that prevents cells from dividing during mitosis, then even if you wash away the poison, some mechanism prevents any more than one mitosis from occurring. Hypothesize why? Invent experiments to test your theories?

mm) In regenerating salamander legs, muscles near the cut edge divide into diploid cells that have one nucleus per cell. If mammal skeletal muscles can't divide into uninucleate cells, might that be why we can't regenerate legs? When a tetraploid salamander regenerates a leg, what would it mean if its muscles separated into some diploid cells, as well as some tetraploid cells?

nn) To achieve replacement of missing body cells, which of the following do you need?
(a) cells that have never differentiated,
(b) cells that have reverted back to being undifferentiated,
or (c) a method that can cause cells to switch from one differentiated cell type to another?

Which of these three (a, b or c) would you call "stem cells"?

oo) Although regeneration of salamander legs includes some conversion of dermal (skin mesoderm) cells into cartilage cells, most of the new skeleton is made of cells that were already cartilage cells before the amputation, and ALL of the newly-formed muscle is made of cells that were already parts of other muscles before the amputation. Why are stem cells so important for regeneration?

Alternatively, argue why stem cells may NOT be either necessary or sufficient to provide leg regeneration.

pp) Osteoclasts need to have a large area in order to seal off broad enough areas of bone surfaces to accumulate acid and enzymes between bone and osteoclast (Analogous to fumigating a house or a tree with insecticide). Based on this need of osteoclasts, please invent one or more new strategies for curing or preventing osteoporosis in people.

qq) Several introductory textbooks claim that animal cells are the sizes they are because if they were any bigger then they would be harmed by not enough oxygen or glucose getting to the cells. As far as I know, there is no evidence in favor of this idea, and quite a bit of evidence against it. Please suggest either experiments or other observations that support or disprove this theory.

Can you figure out what believers in this idea probably assume about the relative rates of movements of molecules inside cells as compared with speeds of transport in blood and lymph.

rr) If you could stimulate human dermal cells to dedifferentiate, and then fuse together and differentiate into new muscle cells, then how would this help you treat or cure muscular dystrophy?

ss) If you invented a drug or other treatment that would cause macrophages to fuse with myotubes (=multinucleate skeletal muscle cells) instead of fusing with osteoclasts (as they normally do), then how would this enable you to treat or cure muscular dystrophy with bone marrow transplants?

tt) A graduate student once tried to make giant (~ 50-100 times normal size) tissue culture cells. He tried culturing cells in medium containing drugs that prevented mitosis, and other drugs that inhibited cytokinesis (cleavage into daughter cells).
Cells from cancerous cells continued to grow larger without apparent limit.
Cells from non-cancerous cells grew to around 4 or 5 normal size, and then stopped. No more increase in size; no more DNA synthesis; no more attempts at mitosis or cleavage.

Hypothesize possible causes of such a set of phenomena. How could you test different possibilities? What would you expect happened when the culture medium was replaced with medium lacking drugs?

uu) Multiple Sclerosis is unlike other autoimmune diseases in that both B and T lymphocytes are formed that have the same specificity for a certain "self" molecule ("antigen"). Why should you expect attack either by B lymphocytes or t-lymphocytes, but not both B and T. Invent possible explanations. Design experimental tests? Why does being attacked by both kinds of lymphocytes make MS more difficult to treat? Or maybe you can turn this odd fact to your advantage.

vv) Lupus is unusual among autoimmune diseases in that lots of different "self" molecules get attacked. Not only does each Lupus patient have three or four or a dozen different clones of anti-self B lymphocytes, each specific for a different, unrelated antigen. (These might include histones, RNA and/or collagen, In addition, these B lymphocyte specificities are different for one patient than for another (Histones and RNA in one patient, Histones in another). This make Lupus difficult to diagnose; it also causes some to think that Lupus is several unrelated diseases, that should not be called by the same name: what do you think, and why?

Which do you tend to conclude? That the tolerance mechanism has failed? Or that the Generator of Diversity has either not been turned off or has become reactivated. If the molecular cause is special, is that a reason for continuing to use one name, rather than splitting among many.

ww) Antibody synthesizing "memory cells" are said to "recognize" whether other molecules are "self" or "non-self".

What specific property of memory cells differs in what way depending on whether its binding sites fit a "self" molecule?

(Hint: this is a trick question! Second hint: Is the reason a given anti-self memory cell doesn't attack self molecules because it recognizes them? Or because they were already eliminated? Or because that Memory Cell died long ago?)

xx) Multiple Sclerosis and other autoimmune diseases are sometimes treated with monoclonal antibodies that selectively bind and harm all B lymphocytes. These suppress the entire nervous system, and leave the patient extremely vulnerable to infections. What is needed instead?

yy) Discuss whether and why it is more profitable to invent a treatment that temporarily fixes one or more of the abnormalities of cancer cells, or (alternatively) to invent a drug that selectively kills cells that have one ore more of the special properties of cancer cells. In short, do economic motivations encourage converting fatal diseases to chronic diseases? Does this tendency also apply to multiple sclerosis? Can you suggest who to avoid this tendency?


The following questions are taken from last year's list of review questions, which has been linked to the bottom this year's syllabus page for much of the semester. Some of them are somewhat redundant with ones in the list above.

1) Regarding leg regeneration of salamander legs, cell marking studies show that regenerated muscles and cartilages develop from cells that had previously been parts of muscles and cartilages in the stump. Assuming that all differentiated cell types of regenerated legs likewise regenerate from cells their same cell type, argue pro or con that regeneration works by rearrangement of differentiated cells.

2) Embryonic development of legs and other organs has long been assumed to work by controlling cell differentiation according to location. Argue pro or con whether this generalization is true or false (about the beliefs of biologists and textbooks.) Argue pro or con whether this assumption is accurate or not, as regards how development really works.

3) H. V. Wilson believed that dissociated sponge cells either redifferentiate according to their random locations, or possibly that undifferentiated archeocytes (= stem cells) differentiate into whichever cell type is needed at their random location. What is a third possibility? How might Wilson's assumptions about cell sorting be related to the first sentence of question number two?

4) How would sponge cell reaggregation be explained by the differential adhesion hypothesis?

6) In the game "20 Questions", you try to identify an unknown something based on asking 20 yes or no questions about it. Please invent 10 "yes or no" questions the answers to which would be most useful in finding a cure for cancer. The questions must be "yes or no", and not something like "what causes spontaneous remissions" For each of your questions, explain why you expect the answer would be, or might be, so useful. What would you conclude if the answer to that question were "yes"? What would you conclude if the answer to that question were "no"?

10) Argue pro or con: so far, knowledge of the molecular cause of cancer (or Multiple Sclerosis; or Muscular Dystrophy; or ALS) has been little or no help in treating or curing these diseases.

11) How might treatment of any of these 4 diseases be helped by finding differences in the DNA base sequences (i.e. differences between people with one of these diseases, as compared with normal people)?

12) Please discuss what relevance the following has for cancer and autoimmune diseases: The first billion dollar drug was a stomach ulcer treatment, with temporary effects, which patients had to keep taking permanently. Meanwhile, the medical main-stream strongly resisted use of an easily-testable, long lasting and cheap cure for ulcers (consisting of a combination of antibiotics and bismuth). Meanwhile, stomach ulcers killed six thousand Americans per year.

22) Without at least one hypothesis, you can't design an experiment. Nobody can interpret the meaning of the results of an experiment, except in terms of some theory. Explain why or why not, using examples from research topics studied in this course.

25) Argue pro or con whether cancer research needs a big paradigm shift more that it needs more data. (Include discussion of what the dominant paradigms currently are, as regards cancer and cancer treatments). Hint: Rate of growth. Treatment by what kinds of poisons? Whether treatments should suppress abnormalities, and as opposed to what?

28) What about Karl Popper's key concept of disprovability? Please either criticize or praise several biological theories, as regards their potential susceptibility to disproof. For example, to what degree did they "stick their necks out? You could start with Manning et al.'s paper about "co-action".

30) Popper has been criticized on the basis that what seems like a disproof in terms of one paradigm will usually make perfect sense in terms of some other paradigm. Discuss whether a phenomenon that disproves a theory depends on some other theory. Discuss examples in biology? Or argue that there aren't any examples.

31) In what sense did Watson and Crick use the classic elementary "Scientific Method" (about formulating theories, etc.), except that instead of testing their hypotheses by doing experiments on DNA, their experimental tests were based on other people's data, facts in books, geometrical models, and what else?

32) Does it (should it?) help research scientists to learn about the Philosophy of Science? It what ways might it help? In what ways might it hinder? (maybe by distraction?)

35) Guess some particular scientific phenomenon, that is currently taught as fact, that you think is most likely to be disproven. Discuss your reasons, such as evidence against the current paradigm, lack of sufficient evidence in its favor, logical flaws, etc.

36) Predict (and explain your reasoning) two or three major breakthroughs that seem to you very likely to occur soon? Will these (probably?) be new facts, new interpretations of old facts, or new connections between "old" facts (that had already been discovered)?

39) List examples of paradigm shifts from your own education, where you once accepted one set of related assumptions, but then switched to another set, and perhaps a third or a fourth. For example, what different sets of assumptions have you held regarding how people with type A blood manage not to attack it with antibodies. (In high school, I assumed this was somehow because of genetic linkage; what about you?)

41) For several years, Popper claimed that Darwinian Evolution wasn't truly "scientific" (because he believed that there were no experiments that could possibly disprove it, in the sense that its supporters could always invent a plausible explanation). Do you agree? What arguments can you make against such an opinion?
Suppose you had a time machine, or any way of directly observing evolution, would invention of new methods shift a theory from being non-scientific to being disprovable? In other words, should we base philosophical conclusions on the availability of methods needed to disprove phenomena?

43) It is still not known whether or not leg regeneration in salamanders has the same basic mechanism as their original embryonic development. Please argue pro or con (or both?), displaying as much knowledge as you can, including knowledge indirectly related to regeneration.

49) What have you been taught and/or learned in this course that is most directly contrary to something that you were taught in some other course? Please make lists of arguments and evidence on both sides of this difference of belief.

50) Please invent and answer some question about a topic covered in the course, but which especially interests you and about which none of the questions asked above gave you a chance to demonstrate the excellence of your understanding or the depth of your insight (= that you wish I had asked)


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