St Crispin's speech: To inspire you to invent better cures for cancer and autoimmune diseases, please watch this excerpt from Shakespeare's play Henry the Fifth:

or another version:

The origin of the (20th most common) surname "Harris" is from supporters of the several late medieval English kings named Henry, which was then pronounced "Harry".



Sample Final Examination Questions for Unsolved Problems, 2011

The final exam will be "Open Book", which includes free use of your own class notes,

And you can choose which questions to answer from among a choice of at least one and a half as many alternative questions. For example: 6 out of 9 or 10 questions.


Please note: there are now a total of 30 questions. If you don't see all the questions, please let the webmaster know.

Some of the questions refer specifically to multiple sclerosis or arteriosclerosis, because these conditions were covered in detail in last year's class. Similar questions might be asked about medical topics that we discussed more fully this year.

A typo was fixed in question 5, and a link was added to question 27, on Tuesday afternoon at 3:50 pm.


{I solemnly promise to be fair in grading conclusions that I disagree with at least as favorably as I grade answers that happen to match my current opinions. In other words, please don't try to guess what I believe, and argue in favor of it. Strategically, you could be better off to present well-argued opinions that are different from mine. Please believe me about this. A. H.}

As these sample questions suggest, you will be very wise to review the summaries about Popper and Kuhn; But I do not suggest rushing to read the original books by either of these philosophers of science.

IT IS OK TO DISCUSS THESE SAMPLE EXAM QUESTIONS WITH ANY OTHER MEMBERS OF THE CLASS. (But please don't ask faculty members, graduate students or others, until after the exam.)

And please don't ask me to tell you the answers. I am willing to make hints or suggestions, or to clarify the questions, but not simply to answer them.


Please read the Wikipedia articles on "War On Cancer" and on the meaning of the word "Druggable"; also see "Undruggable".

A quote from the "War..." article:

"Though there has been significant progress in the understanding of cancer biology, risk factors, treatments, and prognosis of some types of cancer (such as childhood leukemia) since the inception of the National Cancer Act of 1971, progress in reducing the overall cancer mortality rate has been disappointing. Many types of cancer remain incurable (such as pancreatic cancer) and the overall death rate from cancer has not decreased appreciably since the 1970s."

#1) Would I be unfair to claim that that the "war" was a political campaign to accomplish two related goals?
   a) To convince the subject that cancer research was going to be increased and/or improved (somehow).
   b) To re-channel NIH research money more narrowly toward virology, and genetic abnormalities of cancer cells.

   c) Were both goals successful?
   d) Unfortunately without producing appreciable improvement in cancer treatment?


PLEASE ARGUE EITHER PRO OR CON about the following rather extremist paragraphs.
[Good arguments will earn the best grades. It won't work to try to figure out what the grader believes & support that. Anyway, a good answer will need specific examples and logical arguments that go beyond what the questions assert]

#2a) Despite great success in discovering that nearly all human cancers are caused by somatic mutations in a rather small number of specific genes (named oncogenes, like ras etc.) nobody can figure out how to convert knowledge of this kind into treatments that kill just those cells with mutant oncogenes. (for example by causing poisons or antigens to be produced by the proteins coded for by mutant oncogenes)

#2b) That strategy is seldom or never discussed; very little research is oriented toward that goal; and NO available chemotherapy drug works in any such way. One drug, that starts with a G, works by inactivating the protein coded for by one particular oncogene (a translocation that produces a fusion protein, that is an over-active kinase). Imagine a drug that gets converted by such an over-active enzyme into a poison, or that is caused to release a polio or measles antigen. (i.e. that would kill cells, or cause them to be attacked by t-lymphocytes)

#3) Can we design economic motivations that would favor development of drugs that actually cure cancer (so that patients wouldn't need to keep taking the drugs, because cancers wouldn't keep coming back)?
Could such drugs ever be anywhere near as profitable as drugs that produce temporary remissions?
Do companies decide between research strategies based on which one will be more profitable?
Do economic motivations affect business choices, consciously or subconsciously?

#4) Does the existence and meaning of the word "druggable" prove that main-line cancer research is locked into the assumption that the one and only practical strategy is to find chemical drugs that work by selectively binding to oncogene proteins, so as to make them less abnormal?
Please notice that the definition refers specifically to pancreatic cancer! Although it doesn't mention the fact that most cases of pancreatic cancer are caused by mutation of ras genes, I would assume they know that. Mutant ras genes code for ras proteins that still bind to GTP, but can't catalyze conversion of GTP to GDP. Therefore, the mutant ras protein gets stuck in the shape that stimulates cell growth.

"The signing of the National Cancer Act of 1971 by then U.S. President Richard Nixon is generally viewed as the beginning of the war on cancer..." [although it was a narrowing of direction, not an increase in total amounts of cancer research.] "Despite significant progress in the treatment of certain forms of cancer (such as childhood leukemia " [which resulted from research that had already been finished at that time, incidentally] ", cancer in general remains a major cause of death nearly 40 years after this war on cancer began, leading to a perceived lack of progress..." ["Nearly" means exactly]

"New research directions, in part based on the results of the Human Genome Project, hold promise for a better understanding of the genetic factors underlying cancer, and the development of new diagnostics, therapies, preventive measures, and early detection ability." [FIND THE PROPAGANDA]

"However, targeting cancer proteins can be difficult, as a protein can be undruggable."
Undruggable proteins are proteins that are difficult to target in drug development. Undruggable proteins are hard for pharmaceutical researchers to target, as they do not have suitable loci that bind to small organic molecules. For instance, proteins responsible for pancreatic cancer are undruggable.

More Questions for Unsolved final exam 2011. Posted December 2, 3:30 pm

#5) Regarding the Warburg phenomenon, in the sense of the abnormality of cancer cells that somehow causes excess secretion of lactic acid, and reduced use of mitochondria to oxidize lactic acid to provide energy for conversion of ADP to ATP. It was discovered in the 1920s by one of the most famous biochemists in the world, Otto Warburg, who had already won the Nobel prize for other research. Warburg was an egomaniac, and alienated most cancer researchers by claiming that neither genes nor viruses cause cancer. Instead Warburg thought cancer was caused by defective mitochondria. Very little further research has been done on this subject, and the phenomenon is not mentioned anywhere in the (very good!) textbook used in this department's (also very good) course on Cancer Biology.

a) Does Warburg's effect predict that cancer cells absorb much more glucose than normal cells? In fact, they do. Radioactively labeled glucose is how PET scans distinguish cancer cells from normal cells. Cancer researchers apparently didn't think of this until much later. Should it have been obvious? Why or why not?

b) Glucose is a normal component in tissue culture medium. Would you predict that cancer cells would be selectively harmed (relative to equivalent normal cells) by reducing the concentration of glucose available to them? [And what would it tell you about causal mechanisms if it did?]

c) If you added a much higher concentration of glucose to tissue culture medium, what would you predict would happen: * That cancer cells would grow and divide more than normal cells, to an increased degree? ** That normal cells would speed up their rates of growth or upper limits on growth, and become more like cancer cells in their growth and behavior. [And what would it tell you about causal mechanisms if they did?]

d) Specifically, would you predict that normal cells would secrete more lactic acid when cultured in medium containing increased concentrations of glucose? [And what would it tell you about causal mechanisms if they did?]

e) Warburg believed that cancer is caused by defective mitochondria, specifically by decreases in their oxidative phosphorylation. How could that defect cause cells to grow without control? [And what would it tell you about causal mechanisms if they did?]

f) If that were true (i.e. that defective mitochondria cause uncontrolled growth), then chemotherapy drugs would need to do either of what TWO things? (Hint: the less obvious of these two might be more effective; and you might invent three or more).

g) Suppose you have a way to transfer nuclei from one cell to another, leaving cytoplasm behind, and suppose that you also can do the reverse. Please design a series of experiments by which you could use nuclear and/or cytoplasmic transplantation to test as many different theories about the Warburg phenomenon as you can.

h) Invent some other experiments, using other techniques, to test alternative explanations for the Warburg phenomenon, and its relation to cancer.

i) PET scans are used to detect lymphoma and leukemia cells (that live right in the blood). What does this suggest about the widely advocated theory that cancer cells use anaerobic ATP synthesis because they can't get enough oxygen?

j) Remember the paper we discussed early this semester about abnormalities in mitochondrial reproduction in relation to cancer? Did that paper mention the Warburg phenomenon? Could they have strengthened their argument by including the Warburg phenomenon?

k) How is the following abstract a good example of NOT thinking?

J Bioenerg Biomembr. 2007 Jun;39(3):267-74.

The Warburg effect and its cancer therapeutic implications.

Chen Z, Lu W, Garcia-Prieto C, Huang P.

Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, 7435 Fannin Street, Houston, TX 77030, USA.

Increased aerobic glycolysis in cancer, a phenomenon known as the Warburg effect, has been observed in various tumor cells and represents a major biochemical alteration associated with malignant transformation. Although the exact molecular mechanisms underlying this metabolic change remain to be elucidated, the profound biochemical alteration in cancer cell energy metabolism provides exciting opportunities for the development of therapeutic strategies to preferentially kill cancer cells by targeting the glycolytic pathway. Several small molecules capable of inhibiting glycolysis in experimental systems have been shown to have promising anticancer activity in vitro and in vivo. This review article provides a brief summary of our current understanding of the Warburg effect, the underlying mechanisms, and its influence on the development of therapeutic strategies for cancer treatment.

Questions added December 3rd, 1:30 pm

#6) Based on what you have learned about pushing forces exerted by electroosmotic swelling of cartilage, and about the exertion of puling forces by cell traction, figure out and explain as much as you can about each of the photographs and drawings posted on the web page under the title "Collagen and cartilage".

Some photographs show histological sections through normal animal cartilages; four of these are seen by polarized light, so that alignment of collagen fibers in different colors produces blue and yellow colors; others show living cells in tissue culture, and the effects of these cells on collagen that was chemically purified from other animals, and then mixed with living tissue culture cells.

Two of the illustrations are drawings; one shows effects of compression on differentiation of mesodermal cells; the other ilustrates swelling of cartilage counterbalanced by stretching of collagen fibers, some of which are wrapped around the outer surfaces of cartilage, and others of which run through the interior of cartilage. (and all of which produce colored effects, when seen by polarized light).


#7) Many people are infected by Helicobacter, but for some reason don't get ulcers. Suppose that almost everybody was infected by these bacteria, but that they only produced ulcers in people who worried a lot (which is actually NOT true, but suppose it were), then would you say, or would most people say, that worry is the cause of ulcers?

Would you still say that, if killing these bacteria by means of antibiotics produces an actual cure of ulcers?)


#8) Discuss the fact that no pharmaceutical company played any role in discovering the cure for ulcers, but did invent a series of chemicals that inhibit acid secretion in the stomach (which included the first billion dollar a year drug), and that hospital testing of these drugs on volunteer patients never included antibiotic treatment as an option or as a control experiment. (These tests were done years after Helicobacter and its effects had been discovered.

Is this history relevant to the search for drugs to treat cancer? In what way, if any? (Do not hesitate to argue either side of this question.)


#9) How is cell sorting suspected of being related to normal cell rearrangements that occur during embryonic development? Do cancerous cells sort out from non-cancerous cells? Suggest what this might imply about the cause of spreading of malignant cancer cells to abnormal parts of the body, in relation to the causes of normal cell rearrangements that occur in developing embryos.


#10) Invent a research program for Idiopathic Pulmonary Fibrosis (see web page: What experiments you would propose to do? How you would interpret results of these experiments? What main questions you would try to answer? What new treatments and cures could possibly be found, based on the results of your questions, experiments, and answers?


#11) Compare and/or contrast Thomas Kuhn's opinions with what you have learned in this course about specific scientific questions, phenomena or experiments. For example, do beliefs about the causes of atherosclerosis correspond to Kuhn's ideas; Or do they fit elementary ideas of "The Scientific Method"? (From High School, or Intro. Biology)

#12) What about Karl Popper's opinions, as compared with actual subjects (about atherosclerosis, multiple sclerosis, the mechanism of gene control, or any other combination of research subjects)?

#13) What is the smallest number of alternative hypotheses that you would need to have, in order to design good experiments? Two? One? None? Can you design an experiment without at least one theory? ...That the experiment is designed to DIS-prove? ...That the experiment is designed to confirm? Your answer should include as many specific examples as you can think of.

#14) Suggest examples from the past or current history (of one or more specific research subjects) in which a newly discovered phenomenon did NOT replace and disprove an earlier theory that had until then been confidently believed to have been proven true.

#15) Make a list of as many examples as you can (perhaps starting with ulcers) in which there has been a major scientific breakthrough ("paradigm shift"), including for each example:

    a) What is now believed.
    b) What was previously believed.
    b) The major change that has occurred (in how scientists explain each particular phenomenon)
    c) The main evidence or experiment that caused the breakthrough.

#16) If you had to make a bet about what major current biological belief will turn out to have been wrong, misleading or deeply misguided (including medical beliefs and treatments) which would you predict is wrong? The following are some possible examples: Gene therapy? "Adult stem cells"? Anti-cholesterol drugs? Self-tolerance by clonal selection? Hox genes as fundamental control phenomena in embryos? But you can choose any example that you want.

#17) In your opinion, are Physics and/or Chemistry more advanced than Biology? In what respects? For what reasons? What changes would cause Biology to catch up?

#18) Make a list of specific "Yes or No?" questions, the answers to which would advance medical science the most. (List these in descending order of importance, starting with those that would help cure the most people.)

#19) Contrast what Kuhn says actual scientists spend most of their time doing, versus what Popper says good scientists should try hardest to do. (Include as many specific examples as you can from current and past scientific research.

#20) What surprised you most, among the facts and principles that you learned about in this course?

#21) Imagine that you now had to choose a topic, and plan experiments, to earn a Masters Degree or a PhD. What topic would you pick? Describe the experiments that you would plan to carry out, and what conclusions you would expect them to lead to.

#22) Consider the following aphorism: "The more surprised you are by an observation, the more information it is trying to tell you! But the more difficult it will to interpret." Think of examples in which this is NOT true. As many as possible.

#23) What various different advantages did Watson and Crick have over Rosalind Franklin? Were there any of these advantages of which they did not take selfish advantage?

#24) Imagine that Watson had been an ordinarily generous person: Write a page-length autobiographical description of how he synthesized facts and ideas that he learned from Franklin, Crick, Pauling, Delbruck, Bragg and others, leading to a Nobel Prize, shared between himself, Franklin and...who? Chargaff?

#25) Why would Chargaff have been wise to invent hypotheses about how genes encode information?

#26) Imagine another planet, on which life evolved so as to use proteins as the genetic material - with no DNA or RNA, just protein. Invent details as to how this could work. Would it be more practical to have life with just nucleic acids (and no proteins? Or the reverse? Why?).

#27) Two bright-colored diagrams are on the web site, illustrating how Eratosthenes actually did "measure" the diameter of the earth based on the lengths of shadows on a certain day at a certain place. Please explain the logical basis of Eratosthenes' measurements and calculations; and also explain how he could have misinterpreted these same observations as a measure of how far the sun is from the earth. Please relate this difference to Kuhn's ideas about paradigms, and how they channel our interpretation of data. (Feel completely free to discuss this question with other students before the exam. It's OK just to flat out ask another student to explain it to you; and likewise OK for you to explain it to them. Assuming you get the point, yourself! No fair giving them deliberately misleading explanations.)

#28) a) To what extent were embryonic stem cells a discovery? (That something existed that had not previously been realized to exist.)

b) Or to what extent was stem cells' "discovery" more of an invention? (That damaged or lost cells of the body could be replaced from undifferentiated cells - equivalent to how blood cells are continually replaced by stem cells in the bone marrow?)

#29) Invent different ways to produce antibody molecules that specifically fit the shapes of germs, while avoiding autoimmune diseases? (In addition to clonal deletion of lymphocytes that randomly created genes for binding sites that fit some "self" molecule.) For example, before you learned about clonal selection and the generator of diversity, how did you think people with type A blood avoided making anti-A antibodies?

#30) Suppose that somebody took DNA from mouse B-lymphocytes that were being used to synthesize monoclonal antibodies, and "transformed" this DNA into mouse embryos at the one-cell stage, explain why it would be expected that some mice developed from these transformed embryos would only be able to make antibodies specific for the same antigen as the monoclonal antibodies were specific for. (In other words, make antibodies against that one antigen, but no others.)

a) What combination of phenomena would explain this result? (Explain your reasoning.)

b) If you mated such a mouse with a normal mouse, what would be the pattern of inheritance of this strange property of making antibodies against that same, specific antigen, but not making antibodies against any other antigen? (Explain your reasoning.)

c) Suppose the monoclonal antibodies had been specific for binding to some "self" antigen of the strain of mice into which the DNA was "transformed". Why might some of the mice not be able to produce any antibodies at all.




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