Biology 466    Unsolved Problems Fall 2013 Pre-Crick-Watson Knowledge About Genes Genes are located along chromosomes. (Genetic mapping, since 1912) Genes somehow determine the ability of enzymes to catalyze chemical reactions. (Beadle &Tatum, 1940) Changes in genes (mutations) tend to produce sudden jumps in phenotype. Mutations can be produced by X-rays, UV-light, and some chemicals. (Muller, 1920s) Chromosomes are made out of about half (or more) protein and half DNA. The proteins of chromosomes tend to be very basic. Cytoplasm contains a slightly different kind of nucleic acid. ("yeast nucleic acid") As late as when I was in college (early 1960s), many of my professors and textbooks taught that DNA was in animals ["thymus nucleic acid"] but RNA was in plants ["yeast nucleic acid"]. ! Enzymes are proteins. ! Denatured enzymes can sometimes refold to their original shape. (Therefore this shape can't have been imposed by the shape of genes!) No functions were known for nucleic acids, except to compensate for the negative charge on chromosome proteins. Nucleic acids had been discovered around 1870. Nucleic acids were known to consist of either rings or chains of alternating ribose sugar and phosphate, with the four bases adenine, guanine, cytosine and uridine (thymidine =methyl uridine) as side chains attached to ribose. (But people thought of them as analogous to complex polysaccharides, as found in cartilage, wood, on cells' outer surfaces, etc.) And the ribose-phosphate chains were [usually] thought to run in small circles. With only 4 bases, it's impossible to code for 20 amino acids' said people who used dots and dashes to code for 26 letters and 10 numbers, etc. Avery had proven that DNA, and not protein, is the part of bacterial chromosomes that carries the genetic information for the particular property of causing fatal pneumonia. * Pauling and Delbrück had published a paper pointing out that photography requires positives and negatives, molding phonograph records depended on positive and negative molds, etc. and concluding that something analogous to this ought to be needed for chromosome and gene duplication. (~1940) ** Nobody had written that if a self-copying molecule contains subunits with complementary geometry, then something like Chargaff's rules are to be expected. If A fits B, and X fits Y, etc. then the total amounts of A and X can vary, but amounts of A will equal amounts of B, etc. * Delbrück had persuaded Schrödinger to write (in "What is Life") that low mutation rates imply high activation energies for whatever chemical or physical properties encode genes. (Based on reasoning about Brownian motion and activation energies for chemical reactions) Re-folding of proteins doesn't have high enough activation energies to produce low mutation rates. Also, heat would be a very strong mutagen. * As to helical structures, any very elongate structure is either a helix, a straight line, or too irregular to produce a distinct diffraction pattern. ** Conversely, it is a BIG problem to duplicate both chains of a double helix, because they entangle. Topoisomerase enzymes solve this problem, but independent referees could (or should) have recommended that Nature reject Watson & Crick's Nature manuscript on this basis. ~99% of manuscripts now submitted to Nature get rejected, based on even tiny weaknesses. So what lesson do we learn from Watson's life? About being a selfish jerk? About abstract reasoning? About carefully considering abstract predictions? If Chargaff had read the positive <-> negative paper by Pauling and Delbrück? (Or vice versa) Then would X-ray diffraction have been needed to figure out how DNA encodes genes? Would Avery's work have been needed to figure this out? An alternative title suggested for "The Double Helix" was "Base Pairs" Do you understand why this alternative would have been doubly good. Are insecure egomaniacs the only people who can make big jumps in conceptual reasoning?

 

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