Issues For Class Discussion Nov. 28, 2012

Cell Differentiation: (an even more important phenomenon than "operons", & notice the rewards earned by explaining THOSE things!)

I) Turn on unlinked sub-sets of genes   II) Permanence of each differentiated cell type   III) What blocks cells from becoming two cell types?

TO BE EXPLAINED IN TERMS OF BASE SEQUENCES: I) How do differentiated cells "turn on" their own sub-set of genes (only B-cells make antibodies! Hemoglobin only by RBCs)

    (Is the explanation simply promoter regions, mostly "upstream" of the "structural genes" i.e. DNA that codes for the protein?)

    (Many or most lymphomas are known (?) to be caused by chromosome breaks, and rejoining at some wrong place (translocation))
    (moving an oncogene to a place just downstream of a/the promoter region of either the antibody heavy chain, or one of the light chains will result in that cell synthesizing far too much of the oncogene protein, and therefore being cancerous, IF it differentiates as a B-lymphocyte!)

[A specific example is follicular lymphoma, in which the structural gene for the protein named "BCL-2" (which inhibits apoptosis) gets translocated to the part of another chromosome next to the promoter of the antibody heavy chain.]

This is treated with drugs that cross-link DNA (non-specifically), and monoclonal antibodies that specifically bind a certain protein only on B-cells. No apparent thought is given to methods that might cause these cancer cells to de-differentiate: If they weren't B-cells, then wouldn't they not be cancerous?

II) By what means do differentiated cells prevent themselves from either becoming undifferentiated or switching to being another cell type? Method of self-perpetuation? For example, genes that code for transcription factors might be downstream of promotor regions "that turn themselves on"

III) No law prevents an MD from also getting a law degree. But some very strong mechanism blocks differentiation into two cell types. If you fuse a liver cell with a heart cell, you produce cells that suppress the "luxury genes" of liver and of heart (both). What biological goal/function does this accomplish?
What is the molecular mechanism of the suppression of both sets of luxury genes?
Is the mechanism the same as or closely related to that which "turns on" gene transcription in normal differentiated cells?
How permanent would the effect be if you transplanted one of the blocked nuclei back into a cytoplasm of its own; or liver with liver?
Does such fusion and inactivation occur in the body? What would be the symptoms? Cell fusion is caused by several disease-causing viruses.
Could you cure liver cancer by fusing the cancer cells with B-lymphocytes, or some other cell type?


Originally, THE big selling point of the genome project is that the answers to these questions would be obvious from complete base sequences. In fact, not one has been answered (=confirmation of past hypotheses; or revalation of new/true mechanisms).

Even as an intellectual puzzle, it is tantalizing why genomics has managed to be such a total flop, discovering no mechanisms, not helping cancer, etc.
Possible reasons?:
They keep busy with semantic hype about what % of genomes are junk? People are so committed to the Operon analogy, they are blind to how differentiation really works?
They haven't quite spent enough hundreds of millions of dollars, yet! (but with just a tiny few millions more...what will happen?)
The user-unfriendlyness of the ENCODE computer interface is a fiendishly clever parody of the difficulties of explaining phenomena with DNA sequences.

Just as great artists, sculptors and novelists express the deepest emotions and ideas, indirectly in the form of paint on surfaces, chipping of rock, words on paper, perhaps deeply philosophical and artistically sophisticated DNA sequencers have realized that the one best artistic medium for transmitting to other minds how the genome works is by means of ingeniously engineered frustrations in their computer interface for ENCODE? Leonardo Da Vinci, Call your office.
Alas, we philistines are proving to be as blind to this new art form as the traditionalist art academicians were blind to the greatness of expressionists painters!
OK; that's enough of that joke! But do you see any valid point being made? (That's what comes of mixing Lewis Carroll with Eddy Izzard.)


The philosophical bias called "reductionism". If you learn enough detailed facts, the general principles will automatically self-assemble? Not to wait patiently for this self-assembly to happen is bias!
You can't break eggs without making omelets.
About which Wikipedia has an excellent article (which I recommend, but do not assign):

Please ask yourself whether funding policies of the genome project are evidence (symptoms!) of extreme reductionism.

Viewed from inside the mind, philosophical beliefs seem like common sense; and sometimes they become invisible. Belief? What belief? I see what I paint!
Here is another backwards quote, from President Eisenhower: "I don't know much about art: but I like what I know.") [He said the reverse, but really meant this]

"Emergent properties" is the other main concept you need to know about in order to participate in discussions of reductionism (also "emergence") The key idea is that unexpected results may be (=often are) caused by properties or situations from which you would (could?) never have predicted. is very much worth reading.

People who don't think that their ideas result from abstract philosophical ideas are totally locked in to some very strong beliefs, which they don't even know what these beliefs are? "Common Sense" really means biases that imprison us.

In the entire history of science, can anyone tell me one example of a significant advance that didn't start out as a hypothesis?

Maybe there are some?

But I challenge you to tell me one. (And I will be very favorably impressed if you can)

What about trying to think of examples of fundamental concepts that are not replacements for very different explanations of the very same phenomena?

What breakthrough wasn't either the invention or the confirmation of a new hypothesis?

For how many scientific facts can you tell me what erroneous beliefs the facts are replacements for? And were those earlier beliefs also replacements? For what?

SOME EXAMPLES: The reason you can only get smallpox (polio, measles, german measles, etc. once is because...?

a) Germs use up some unique chemical in your body, without which they cannot live.
[In which case, how would vaccines work?]

b) Antibodies are inherited and evolved like any other property, by natural selection. But how does that allow us to explain acquired immunity? (And how could antigens stimulate antibody production? Why aren't people more curious about that?)

c) Antibodies against new artificial chemicals prove that binding site shapes are created by moulding each antibody molecule around an antigen, analogous to stamping a signet ring into hot wax. Wasn't that pretty convincing? Linus Pauling believed he had proved it!

d) A generator of diversity produces billions of clones of lymphocytes, each of which makes binding sites of its own random shape.

Which of these categories of theory includes any possible reason why we don't make antibodies against our own molecules?

Elementary textbooks and faculty who don't know any better parrot the myth that germs are recognized because they are not self. Can we figure out where they got this totally wrong idea? What intuitive attractions cause people to like it so much? Is there any truth at all in this pseudo-explanation? Please suggest what it is, or what it might be.

About what percentage of students? of faculty? of textbooks? of practicing MDs!! of news stories about MS, asthma, etc. believe this is how immunity works.

If immunity really did work that way, then how would we expect to explain allergies? What would cause MS? How would you try to cure it? What new information would search for?

What would "recognize" mean? What would "self" mean?

This is a well-intentioned attempt to explain McFarland Burnet's great breakthrough, and bungles it by not mentioning the origin of those billions of lymphocytes.

     This is as good as a lecture can be, by a person who misses a key point.




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