Unsolved Problems: Discussion topics for Sept. 4, 2013Remember Dolly the Sheep? Researchers have transplanted mouse B-lymphocyte nuclei into mouse oocytes, and produced clones of mice ALL of whose B-lymphocytes make identical binding sites (with the same shapes and amino acid sequences as the antibodies made by that lymphocyte from which they had gotten the nucleus that they transplanted.a) Is this the result that you would have expected? Why or why not? b) Some mechanism must be preventing the B-lymphocytes of the cloned mice from splicing VDJ regions: right? What function would be served (in normal animals) by such a preventative mechanism? (Hint#1: If a nucleus has already undergone VDJ recombination, can it be allowed to do that a second time?) (Hint#2: Remember that diploid animals have two of the VDJ "do it yourself kits"? (So why don't mammals made two kinds of antibodies? But notice that if they made two different kinds of heavy chains and two different kinds of light chains, and if these combined randomly, then there would be four different shapes of binding sites.
c) If VDJ recombination continued through our lives (instead of just at some stage of early embryonic development), then what evidence would/could either prove or disprove this? d) Is continuation of VDJ recombination consistent with the inability of the cloned mice (in question a) to make any more than one identical shaped binding site? e) Consider a person or animal who receives a bone marrow transplant. Are they going to have the same immunities and allergies as the person who donated the bone marrow? Or will they need new vaccination? f) Please take a look at the Wikipedia article about autoimmune diseases. I quote the first sentence: "Autoimmunity is the failure of an organism in recognizing its own constituent parts as self, thus leading to an immune response against its own cells and tissues." Can we make a list of all the mistaken ideas revealed by this one sentence? Can a person who believes this make any positive contribution toward curing autoimmune diseases? Where did they get such an idea? Try to put yourself in their minds? Do they show any evidence of self-doubt? How could you talk them out of it? Do organisms recognize anything as self? If we banned the words "recognize" and "self", could that be a big step toward cured for autoimmune diseases? g) Can you find anywhere in this article, or in its "Talk" section, that even suggests anything like V(D)J recombination? (Or any form of generation of diversity, like hyper-mutation) h) Wikipedia does have an article titled "V(D)J recombination" Here are two quotes from that article "...because of its randomness in choosing different genes, is able to diversely encode proteins to match antigens from bacteria, viruses, parasites, dysfunctional cells such as tumor cells, and pollen." "Failure of the cell to create a successful product that does not self-react leads to cell apoptosis." And a quote from the "Talk" page. "In the intro: V(D)J recombination nearly randomly combines Variable, Diverse, and Joining gene segments...Sounds strange. Is this process really random?" What mistaken assumptions are these well-meaning people making? How do you suppose such major discoveries escaped the knowledge of 99% of the educated public? ("sounds strange", indeed.)
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