A big opportunity for future medical breakthroughs#1) Besides non-specific barriers, we have special cells that can make proteins that specifically bind to germs, by having complementary shapes (like a glove fits a hand).The binding protein fits molecules of the germ like a shoe fits a foot
#2) These binding proteins are called antibodies. Other molecules, analogous to antibodies but on cell surfaces, are called T-cell receptors, also have shapes complementary to viral proteins, and induce death of those host cells that make these proteins (which therefore must be infected) . #3) Any molecule to which an antibody binds (selectively) is called an antigen. For example, the blood group substances A and B are antigens for the antibodies"against" them. An antibody protein whose binding site fits (is complementary to) molecules of blood antigen A, is called an antibody against A. Cinderella's shoe is analogous to an anti-foot antibody, that happens to be specific for Cinderella's foot. The word antigen reflects an old (but misguided) theory, that the shape of the binding site was somehow stimulated by contact with the antibody. Really, the DNA that codes for antibody binding sites is generated by a random process that occurs in your body, BEFORE you were ever exposed the antigen of those antibodies. (Cinderella's shoes were NOT made to order; but bought off the shelf) #4) Our gradual recovery from an infection results largely from our synthesis of more and more antibodies and T-cell receptors; which allow us to fight off germs of that particular kind. For many diseases, we become permanently able to fight off that kind of germ, after being sickened only once, because those germs are so sensitive to small amounts of antibodies against them.(or small numbers of T-lymphocytes whose T-cell receptor proteins have the exact complementary shape to that germ's proteins) Polio, Measles, German Measles, Smallpox, Influenza strains etc. for viruses as well as bacterial diseases. Being bitten by a given kind of poisonous snake also makes you somewhat more immune also - so this mechanism doesn't just apply to germs. #5) The shapes of antibody binding sites are caused by the amino acid sequence of that part of the antibody molecule. Different antibodies (antibodies against different antigens) have different amino acid sequences in the binding site part of the antibody molecule. #6) Deliberate injection with molecules from a given germ (or with killed or weakened forms of the germ) can sometimes stimulate the immune system almost as well as having had the disease. This is how vaccination works. Vaccination began with deliberate infection with weaker genetic variants of smallpox virus; This method was introduced from Turkey into England around 1700. The Queen immunized 2 of her daughters, after experimenting on "death-row" criminals, and then on orphans. The method was then advocated by Voltaire and Cotton Mather! Almost 100 years later, Jenner showed that infection with cowpox makes people immune to smallpox. This then became the standard method, and continued until the 1970s, when the WHO eliminated the last cases of smallpox. It was then intended to destroy all stocks of Smallpox virus, so that the disease would be permanently extinct. But then Russia was found to have cheated on the germ warfare treaty by manufacturing tons of Anthrax germs, not to mention Iraq, North Korea & such rabid countries. So now thousands of physicians and nurses are being vaccinated with smallpox, with a fraction of a % being killed or badly injured. A germ warfare attack using actual Smallpox could kill 10-50% of persons exposed! Or possibly more! And who would treat the sick? #7) From 1700 to the mid 1800s, Smallpox was the only disease against which you could be vaccinated(and there were many theories [all wrong] about the mechanism by which diseases produced immunity) Pasteur then invented the idea of chemically weakening germs of many different kinds, thereby creating vaccines for diseases other than Smallpox. He made vaccines against Rabies, Anthrax, etc. New vaccines are still being developed for more diseases.
Some vaccines consist of killed germs; #8) Historically, it took a long time, and many blind alleys, to figure out the mechanism of this acquired immunity. The answer was very different from what people guessed; and the correct guess (by Burnet, Jerne and others) was a supremely great act of creative imagination; as great as Relativity, but easier to understand. (And I'll bet it is different from what you think!) The genes for antibodies did NOT evolve in the usual way, and do NOT depend on your ancestors having been exposed to particular species of germs. The DNA coding for antibody binding sites turns out to be produced by random events in your own embryonic development, followed by selection between billions of lymphocytes, each making antibodies with its own shaped binding site. #9) One BIG part of the mystery remains unsolved: How does this system eliminate its anti-self antibodies, that (would) have shapes complementary to all the body's own normal molecules. This is the mechanism of self-tolerance Even partial failure of the tolerance mechanism causes autoimmune diseases, which include Multiple Sclerosis, Lupus, many kinds of arthritis, and many other very cruel diseases. These diseases differ in which normal molecules get attacked. But if you could control the tolerance mechanism, then you could cure all these diseases. #10) Allergy When your immune system attacks something like pollen or poison ivy, that would not otherwise hurt you. The body's attack mechanisms are the same as those that attack germs; which is why allergy to pollen feels so much like a cold. The poison ivy toxin somehow causes cells to be attacked by the same mechanisms that reject grafted skin (but I don't know whether having a skin graft be rejected feels like poison ivy!) #11) The DNA that codes for the binding sites of antibodies is NOT inherited or evolved in the usual way. What you inherit is a do-it-yourself-kit for constructing the DNA base sequences for any of billions of different shaped binding sites. Antibodies are peculiar to vertebrates, something that our phylum has evolved that others don't have. The do-it-yourself-kit works significantly different in mammals than in birds, surprisingly. And there is much to be learned. #12) The Clonal Selection Theory is based on Darwinian evolution, and directly analogous to it! (and was originally called the Natural Selection Theory) V(D)J recombination, and all that... Possible alternative mechanisms for eliminating B lymphocytes that would make antibodies that would bind to some "self" molecule of your own body (for example, if a person with type A blood were to make antibodies than bind to the type A antigen.)
I) Anti-self B lymphocytes die (induced programmed cell death?)
2b) or unable to copy their DNA, 2c) or unable to synthesize their antibody 2d) or unable to secrete their antibody, or 2e) not sensitive to being stimulated to grow by their antigen 2f) or something else nobody has thought of
(and thereby choose some different specificity) IV) Something else that no one has thought of yet...
The same alternative theories could apply to T-cells as to B-cells.
What evidence might tell which answer is correct? Alpha) Sometimes people who abnormally weak in making antibodies against germs are more prone to have autoimmune diseases! Which is cause and which effect? Possibly the weakness of their immune system causes failure to eliminate anti-self clones!? Beta) Experimental "knock out" removal of an essential gene for programmed cell death (in mice) results in symptoms very much like the disease called lupus (abnormal production of many different anti-self antibodies) Gamma) Repeating of the DNA V(D)J recombination is induced when stop codons are produced in the variable sequence region. [Hint: if this can induce "trying again", then maybe repetition of the DNA recombination process can also be induced by what?]
Questions that you might be asked on the exam:a) What is the name of the special proteins secreted by the immune system that have complementary shapes to fit germs?b) What are three different ways that binding of these proteins can harm bacteria? c) What are "T-cell receptors", and what are the somewhat like (except that they are not secreted to the space outside cells) d) During the time when you have a cold or other disease, but then begin to be able to kill off the germs, what property of your body is being changed or improved? e) Why does this change prevent you from catching that same disease over again right away, and sometimes protects you from ever catching that particular disease again? f) If a person or animal has previously been bitten by a certain kind of poisonous snake, then why do they become somewhat immune to the venom of that species, but NOT to venom of other species? (Unless they use the same venom) g) What was the first disease that anyone was vaccinated against? h) In about what year (+/-15)was the vaccination method introduced into Europe, almost a hundred years before Edward Jenner's "Cowpox" method? i) What scientist first developed methods for vaccinating people and animals against other kinds of different bacterial and viral diseases? j) Basically, how does this method work? k) What are three different materials that vaccines sometimes contain? *l) The binding sites for antibodies and T-cell receptors are generated by random creation of different DNA base sequences that occurs when? Was it thousands of years ago, in the genes of your ancestors? [Hint: NO: somewhere else!] *m) How is natural selection related to the production of lymphocytes that secrete antibodies against particular germs? n) Vaccination against a certain kind of germ causes which lymphocytes to do what? [Hint: those lymphocytes whose antibodies bind to that kind of germ...do what?] o) What about lymphocytes that make antibodies whose binding sites fit any kind of normal molecule in your body? What should happen to them? *p) Relate Darwinian evolution to the answers to the three preceding questions? q) What is meant by the Variable regions, the Diversity regions, and the Joining regions of DNA, and the recombination between them? "V(D)J recombination" r) If there were 100 alternative V regions, recombining with 10 alternative D regions and 10 alternative J regions, then how many different kinds of antibodies could result? (How many different alternative amino acid sequences in the binding sites?) *s) How could even more alternative shapes of binding sites could be generated by this recombination if the locations of cutting and splicing between the DNA sections were "sloppy" and varied from one lymphocyte to another? *t) Regarding this cutting and splicing of DNA, suppose that each recombination events has a 2/3rd chance of shifting the reading frame (remember reading frames, from what we learned about proteins synthesis?) then if there were 5 separate recombinations in the generation of the DNA for each antibody binding site (3 for the heavy chain gene; and 2 more for the light chain gene), then what is the fifth power of 1/3rd? [Hint 1/81st] Therefore, would you expect the equivalent of frame-shift mutations to occur most of the time in this process? [Hint: yes, you should expect that, although most scientists don't notice this] *u) Based on what you know about folding of amino acid chains, why should addition or removal of a proline cause especially large differences in antibody specificity? (that is: very big differences in the shapes of the binding sites?) v) Could you become "allergic" to a certain kind of germ? Would this be called an allergy, or would it be called something else? w) Would you ever deliberately try to make a person become allergic to germs of a certain species? If you did have a method for stimulating allergy to a certain germ, then this method would be called what? x) If a given antigen were shaped like Cinderella's foot, then what would be the shape of the binding site of antibodies against her feet? y) Would antibodies against different antigens have the same or different amino acid sequences? What about in some parts of their antibody sequences? z) What would happen if a certain drug somehow reactivated the process of VDJ recombination in cells of your body? **!) Suppose that all samples of Smallpox virus everywhere in the world were destroyed: then would that amount to the deliberate extinction of a species? **@) Suppose that the DNA base sequence of Smallpox virus was known; could this be used to re-create the species after its extinction? If so, then should the sequence be kept top secret? *#) If the genes for antibodies against particular antigens (the A blood group antigen, for example) had been evolved in the usual way, by mutations in your ancestors, followed by natural selection, then what would produce self-tolerance of people with type A blood? (That is: invent a mechanism for preventing them from making anti-A antibodies.) In that case, what could be the mechanism causing autoimmune diseases? *$) Suppose that the binding sites for antibodies were made by molding around antigens, and then kept their shape, as everyone believed from about 1920 to after 1960, then figure out a mechanism for self-tolerance. THEN, what could be the mechanism causing autoimmune diseases? **%) If you knew the entire DNA base sequence for humans, figure out how you might use this information to discover the mechanism of self-tolerance, and thereby invent cures for all autoimmune diseases? [Hint: Would you guess that the poster-designers at the American Museum of Natural History have a clue how to answer this question/]
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