Review Questions, that you should be able to discuss

Your essay ought to include consideration of the ideas of Kuhn, Popper and/or any other philosophers of science you know about, and whose ideas are relevant. You can also argue, for example, that Kuhn's ideas are NOT relevant to whatever scientific question you are writing about, or even that the history of research, and interpretation of research, tends to DIS-prove the generalizations that Kuhn advocated - ditto for the ideas of Karl Popper. i.e. you can argue that scientific progress is, isn't, should be, shouldn't be an example of how Karl Popper believed how science ought to work.

That could include whether or not the scientific question is provable or disprovable in principle, or in fact. (Remembering Popper's criterion of disprovability, in principle)

#1) There is an idea the cause of cancer is abnormally fast rates of growth and/or more frequent or faster mitotic divisions.

a* Why do you suppose people got this idea? Originally?

b* What observations tend to support explanation of cancer?

c* What other observations should be made to test whether the idea is true?
What results would support it? What results would tend to disapprove it?

d* What data would you look for, like counting cells (either directly or by measuring amounts of incorporation of thymidine into DNA, or something else), for example if you were writing a grant proposal to fund research that could prove or disprove the idea.

e* The first chemotheraputic drugs were inhibitors of DNA synthesis, and succeeded in curing thousands of children of leukemia, that otherwise killed victims very rapidly.

To what degree is the effectiveness of these drugs a confirmation of the theory about faster growth (which was what motivated the invention and use of those drugs?

f* Can you argue pro or con, whether the major side effects (anemia, hair loss, nausea) of these drugs are evidence that the drugs kill fast growing cells?

You might consider the logic of the following "syllogism":

If a drug causes these side effects, that fact proves the drug works by killing cells in proportion to their growth rates!?

g* Anti-growth drugs have turned out to be able to cure many kinds of cancer: (For example, childhood leukemia)

So, please consider (either PRO, or CON. Or pro AND con) the logic of the following reasoning:

If these same drugs also kill cancer cells, that proves cancer is caused by faster than normal rates of growth?!

h) Then it was discovered that some of these same chemotherapy drugs are also effective treatments for slow-growing cancers.

What does that prove, disprove, or tend to suggest?

i) At least 95% of cases of Follicular Lymphoma (one of almost dozen sub-kinds of non-Hodgkins Lymphoma) are known to be caused by increased concentrations of the "bcl-2" protein, the only effect of which is inhibition of "apoptosis" (=programmed cell death). Nevertheless, the DNA cross-linking poison "cyclophosphamide" is very effective against this form of cancer, despite its cells not growing any faster than normal cells.

What does this prove, disprove, or tend to suggest?

j) Any chemical that interferes with DNA synthesis will be tried out as a possible treatment of cancer. What does this prove, disprove, or tend to suggest?

k) Any chemical that damages microtubules, or otherwise interferes with mitotic spindles, will also be tried out as an anti-cancer drug: same question? (chemicals that don't have these effects are unlikely to be tested, at all.)

l) Vinblastine and vincristine are anti-microtubule drugs, and also effective anti-cancer chemotherapy drugs.

In contrast, although colchicine is just as effective as a drug for preventing mitosis, it failed all tests for treating cancer.

What does this combination of facts prove, disprove, or tend to suggest? i.e. the fact that some anti-microtubule drugs are very effective against cancer but other drugs that are just as effective at blocking mitosis are not effective against cancer.

m) Can the reasons be differences in permeability of cells to the drug?
(hint: Considering they are equally effective in blocking mitosis.)
Can you explain why or why not?

n) What intuitive reason is there for thinking that if a cell divides rapidly, then it is likely to be killed by a drug that inhibits division? And likewise for copying of DNA?

If they crawled faster than normal, would that mean you could kill them by inhibiting locomotion?

o) "Kinases" are enzymes that lower the activation energy for forming covalent bonds between phosphate groups and serine, or threonine, and/or tyrosine groups in proteins, which results in those proteins changing their conformation

The drug known as Gleevec (and other names) selectively inhibits an abnormally active mutant form of a protein kinase that causes a certain kind of leukemia (chronic myologenous leukemia), and is somehow able to kill those cancer cells that have this abnormally active enzyme. As expected, Gleevec selectively kills this kind of cancer cells, and has induced remissions, and delayed deaths for many years.

PLEASE BE PREPARED TO ARGUE BOTH SIDES OF THE FOLLOWING:

* It makes sense that this drug should tend to cure this kind of cancer?

** It makes no logical sense for cells to be killed by means of inactivation of an enzyme that they are not supposed to have normally, anyway.

* In order to cure cancer cells, you need to fix their abnormalities (?)

** In order to cure cancer, you need to kill (selectively) just those cells that have those abnormalities.

*** Suggest some other idea...

#2) I hope nobody will consider me disrespectful if I propose a "PATRON SAINT" of Unsolved Problems:

A certain surgeon in the midwest who operated on over a thousand ulcer patients, and broke two records:

* The highest rate of permanent cures of ulcers.

* The highest frequency of bacterial infections of the wound sites of his patients (i.e. the worst sterile technique)

"...ulcers are associated with Helicobacter pylori..."

" A major causative factor (60% of gastric and up to 90% of duodenal ulcers) is chronic inflammation due to Helicobacter pylori..."

" Some suggested risk factors such as diet, and spice consumption, were hypothesized as ulcerogens (helping cause ulcers) until late in the 20th century, but have been shown to be of relatively minor importance..."

" Bismuth compounds may actually reduce or even clear organisms, though the warning labels of some bismuth subsalicylate products indicate that the product should not be used by someone with an ulcer."

"Treatment of H. pylori usually leads to clearing of infection, relief of symptoms and eventual healing of ulcers."

"Helicobacter pylori was rediscovered in 1982 by two Australian scientists, Robin Warren and Barry J. Marshall as a causative factor for ulcers. In their original paper, Warren and Marshall contended that most gastric ulcers and gastritis were caused by colonization with this bacterium, not by stress or spicy food as had been assumed before."

"The H. pylori hypothesis was poorly received.""

"...in an act of self-experimentation Marshall drank a Petri dish containing a culture of organisms extracted from a patient and five days later developed gastritis. His symptoms disappeared after two weeks, but he took antibiotics to kill the remaining bacteria at the urging of his wife, since halitosis is one of the symptoms of infection. This experiment was published in 1984 in the Australian Medical Journal and is among the most cited articles from the journal."

"In the United States about 4 million people have active peptic ulcers and about 350,000 new cases are diagnosed each year. Four times as many duodenal ulcers as gastric ulcers are diagnosed. Approximately 3,000 deaths per year in the United States are due to duodenal ulcer and 3,000 to gastric ulcer."

"edit: Old introduction said:

By far most instances are now known to be due to Helicobacter pylori, a spiral-shaped bacterium that lives in the acid environment of the stomach.
This wording was not really true , as the linked article states, ~70% of H. pylori infections are asymptomatic, and ~2/3 of world population is infected. So while H. pylori is only one causative factor..." (OH YES; IT REALLY IS TRUE!)

Can you find examples of what Kuhn advocated? Explain why it was foolish to remove the 'old introduction?

#4) Thousands of experiments are done on hospital patients every year, but Marshall had to experiment on himself.

(1994 minus 1984 equals ten years. multiplied by 3,000 deaths plus 3,000 more deaths = 60,000 avoidable deaths)

Discuss possible reasons. You might consider the following quotes from Wikipedia's excellent " Timeline of peptic ulcer disease and Helicobacter pylori" (Which you might consider reading all of)

"A single study, conducted in 1954, did not find evidence of bacteria on biopsies of the stomach stained traditionally; this effectively established the acid theory as dogma. This paradigm was altered when Warren and Marshall effectively proved Koch's postulates for causation of PUD by H. pylori through a series of experiments in the 1980s; however, an extensive effort was required to convince the medical community .

1910 Schwartz publishes the excess acid theory of the ulcer, coining the famous phrase "no acid, no ulcer."

1951 J. Allende publishes a book describing the treatment of gastric ulcers with penicillin.

1960 Lykoudis is awarded a Greek patent (#22,453) for his antibiotic treatment of PUD (ulcers)

1966 Lykoudis' manuscript is rejected by the Journal of the American Medical Association.

1968 Lykoudis is fined 4,000 drachmas for treating PUD patients with his treatment, which includes antibiotics.

1984 July 31: The New York Times publishes an article by its medical correspondent Dr. Lawrence K. Altman on the possible link between H. pylori and PUD. He states in 2002, "I've never seen the medical community more defensive or more critical of a story" since he joined the newspaper in 1969.

1994 Patents for acid reducing drugs expire, removing financial incentive to resist antibiotics as treatment of PUD (i.e. ulcers) A conference held by National Institute of Health (USA) demonstrates the general acceptance of H. pylori as cause of PUD in the US." (i.e. That same year)

2005 Warren and Marshall are awarded the Nobel Prize in Physiology or Medicine for their work on H. pylori..."

Discuss, pro and or con, the effects of patents on improvement of medical treatments.
1960 Lykoudis... 1994 Patents for acid reducing drugs expire

For example , imagine that someone in the late 1800s (yes, eighteen-hundreds) discovered that otherwise fatal forms of cancer can be permanently cured by injecting patients with certain fever-causing extracts of infectious bacteria. Would that discovery have been further improved, or would it have been abandoned and no longer used to treat patients?

" Coley's Toxins: 1893 to 1963 http://en.wikipedia.org/wiki/Coley's_toxins - take a look!

Propose what improvements in patent law, and/or other government policies or programs (e.g. the NIH, the NSF) could be changed in ways that would favor discovery of cures for cancer and other major diseases.

#6) Remember the Duke scandal about falsified Genomics data? What happened, more or less? How much blame should go to the Intern? (whose name starts with a P) How much blame is deserved by the Principal Investigator? (whose name starts with an N) How much blame is deserved by the TV program that hyped it, then blamed it? (Whose name starts with a 6)

#7) Remember what Popper said is (or should be) the dividing line separating Science from non-Science?
(Hint: Potential disprovability)

By that criterion, is Genomics scientific ? Or is it a fad, that has never led to improved treatment for any disease.(?) And never will? Or is sure to, someday. In order to be regard it as scientific, wouldn't people have to agree what criteria could conclusively disprove it?

Also consider that one of the main arguments in favor of genomics is that it is sure to produce results. (Notice the similarity to Popper's objection to the "sure to produce answers" aspect of Marx, Freud & Adler.) [Adler invented the"Inferiority Complex" concept, which is the opposite of what you would guess.] { Minderwertigkeitsgefühle! Gesundheit!! }

You can organize your answer around any go the diseases or other phenomena discussed in this course. The Duke cancer genomics scandal, in my opinion, lends itself to consideration from Popper's point of view. For example, what experimental results would conclusively DIS-prove the theory that cancer chemotherapy could be made much more effective than it now is (using the same drugs) by finding correlations between the unique DNA sequences of individual patients and the survival times of previous patients who had the same DNA sequences and were treated with a given drug.

Frankly, I myself became tentatively convinced that the "need" (motivation) to fake their data amounts to as much of a conclusive disproof of their whole approach as will ever be possible for any medical school to produce.

Please argue against this point of view. (i.e. that they could only confirm their hypothesis by fraud, despite having accumulated a huge amount of data, involving very many human patients, PROVES the theory isn't true.

#8) Figure out, or speculate pro and con, about why so many people are intuitively attracted by the idea that the immune system works by distinguishing whether molecules are self or non-self, and selectively attacking any molecules that are non-self. For some reason, a huge percentage of the public believes this. Even the majority of biologists believe it, although it has never been one of the "Kuhnian" paradigms that were at any time believed by immunologists. In other words, it is not even out of date; it is a product of the "parallel universe" of introductory biology textbooks, with their many junior college fallacies, that textbook authors faithfully copy from each other. One explanation somebody suggested to me is that "It's easier to understand that way."

Reflect upon how the clonal selection hypothesis accounts for the fact that we hardly ever continue to have B-lymphocytes whose antibody binding sites fit any molecule that is a normal part of your body: because they either self-destruct or are permanently inactivated.
Next, please combine that explanation with the fantasy about cells distinguishing self from non-self...

Visualize each molecule being tested by lymphocytes! How can they detect "self" molecules? Simple! When a lymphocyte binds specifically to a molecule, the lymphocyte knows that a molecule is self by the criterion that the lymphocyte self-destructed several years previously.

"Hmm? Is this self? Do I exist." Please invent a joke based on what Descartes said about "... therefore I am"

Two lymphocytes go into a bar; one lymphocyte quotes Descartes; the other lymphocyte says "I exist, therefore anything my binding sites bind to must be non-self."

#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) 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.

#11) 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.

#12) 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.

#13) 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.

#14) 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?

#15) 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.)

#16) 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.

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

#18) 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.

#19) 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.

#20) 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?

#21) 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?

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

#23) 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?).

#24) 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?)

#25) 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?

#26) 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.

#27) What property do a few hundred genes need to have in order to be transcribed (only?) in cells of each particular differentiated cell type? What molecular mechanism "turns off" all the luxury genes transcribed by all other differentiated cell types?

#28) The evolutionary origin of a new differentiated cell type occurs how? Does a new cell type split off from a previous cell type? Or do two new differentiated cell types split apart, each taking part of the functions, and transcribing a subset of the same genes as a previously-formed cell type? (Several writers have hypothesized this as the only possibility; and indeed, I can't invent any other).

#29) (How) can these mechanisms be deduced / tested using an organism's complete DNA base sequence?

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