The history of the identification of DNA as the genetic material consists of decades of parallel work in chemistry and genetics, with a little bit of physics mixed in just before convergence. To believe DNA is the genetic material you have know a little about both DNA and genetics. Chemists were working from the bottom up while geneticists were working from the top down, which made communication between the two cultures difficult. Biochemists needed to overcome the assumption that proteins, which they had shown were the catalysts that defined all the other specific metabolic pathways in the cell, were not also the ultimate chemical templates. Geneticists needed to understand that a complete model for gene replication and expression requires specific biochemical pathways, and a demonstration that they actually exist.
	CHEMISTRY 1869Johann Miescher describes an acidic material containing phosphorus, apparently of high molecular weight, associated with the nuclei of cells. Salmon sperm, where the nucleus is a large proportion of the cell, was discovered to be a rich source of this material. 1889Richard Altmann first uses the term "nucleic acid". 1940George Beadle and Edward Tatum associate the presence of an altered gene with a defective enzyme. They coin the rule: "One gene, one enzyme". 1944Avery, MacLeod and McCarty report that traits of one strain of bacteria can be transmitted to another strain by adding the DNA extracted from the first strain to a culture of the second; and the transmitted traits are maintained in the progeny and inherited as any other trait. 1949Pauling's group shows that the hemoglobin protein from a person having the sickle cell anemia mutation has an altered charge; thus the protein must have a different chemical structure. 1952Hershey and Chase show that only the DNA of a bacterial virus enters the bacterial host. If the protein coat of the virus is removed, the infected bacterium still produces normal progeny . 1953James Watson and Francis Crick publish the structure of double stranded DNA with complimentary base pairs. 1955Vernon Ingram shows that the sickle cell hemoglobin protein has one altered amino acid. 1956Fraenkel-Conrat learns how disassemble tobacco mosaic virus into RNA and protein and reassemble these components into infectious virus. He makes hybrids between viral mutants, and finds that the genetic traits of the progeny come from the nucleic acid, not the protein. 1958Messelson and Stahl show that a new DNA molecule contains one strand from the parent and one strand that is newly synthesized; just what the Watson-Crick model predicts. 1961Nirenberg shows that UUU codes for the amino acid phenylalanine			GENETICS 1865Gregor Mendel presents a paper on plant hybridization. Some genetic traits behave as discrete entities and are transmitted and distributed among progeny in predictable ratios. These entities are called "elements" by Mendel, they later become known as "genes". His work is then forgotten. 1900Mendel's ideas and paper are rediscovered; the field of genetics is restarted.   Genes are found to be transmitted in linkage groups, with the number of groups equal to the number of chromosomes seen in the cell nucleus. Thus the abstract concept of a gene is associated with a specific structure in the cell, the chromosome.   Just before cell division the chromosomes double, and one copy of each moves into each of the new daughter cells. This is just what you would expect for genetic material.   Within a linkage group, the frequency of gene exchange defines a linear map for the genes. This generates an image: genes are beads on a string. With specific stains it is possible to see characteristic dark and light band patterns on chromosomes. Some of the bands can be associated with specific genes. Now you can see the beads on a string. 1955Seymour Benzer shows how to extend the process of genetic mapping to a group of mutations in a single gene of a bacteriophage. Again he can construct a linear map, and finds a minimal separation between mutants which is almost exactly what one would expect if the closest mutants were one nucleotide apart. Thus he has pushed genetic mapping to the ultimate resolution, and the genetic quantum is the base pair.

	Why didn't the 1944 paper by Avery, MacLeod, and McCarty convince everyone that DNA was the genetic material? There was no molecular mechanism proposed or imaginable. While the chemical structure of nucleotides was known, neither the structure or function of DNA was established. One popular theory was that DNA was a random polymer of the four nucleotides and it functioned as store of energy, much like starch, a polymer of sugar. The ribonucleotide ATP was known to be a major intermediate for energy transfer, so it might seem plausible that a polymer of nucleotides was an energy reserve. In contrast, proteins were known to have specific structures. Enzymes, which are proteins, catalyze specific chemical reactions. While chromosomes contain DNA, they are also rich in proteins. Why give up on the one class of molecules that were known to control many of the chemical reactions in the cell, for DNA, for which both structure and function were unknown? Biochemists think from the ground up. They start from molecules whose structure and usually function are known, and work up to larger and more complicated molecules. The 1961 work by Nirenberg was the first identification of a specific chemical reaction catalyzed by a specific nucleic acid: the formation of a peptide bond to phenylalanine by the tri-nucleotide UUU. The Avery et al. results were just too far ahead of their time. New observations and theories must only extend the known world a certain amount. If there is no infrastructure that makes you say "of course, that's how it works" then it doesn't resonate, it doesn't mean anything, it doesn't stick.		What was unusual and dramatic about the Watson-Crick structure for DNA? X-ray diffraction data was only part of the argument for the structure. Native DNA does not crystallize, but rather forms strands of parallel helices, with different nucleotide sequences. Thus, unlike a crystal of a pure protein, an x-ray diffraction pattern of native DNA contains orders of magnitude less information. There were about a dozen blurred smudges, related by 4 fold symmetry. The usable information was: a helix: the characteristic "X" pattern of spots a repeat distance of 34 A in the fiber direction a very strong reflection of spacing 3.4 A The bases were known to be planar, strongly suspected to stacked parallel to each other. Watson and Crick knew enough chemistry to put the charged phosphates as far apart as possible, at the outer surface of the helix. The breakthrough was Watson's model for base pairing: A with T and G with C. This explained the A=T and G=C pattern seen in all DNA, chronicled in monographs by Chargaff. More significantly, it provided a model for DNA replication. The Watson-Crick model was as much top-down as bottom up. They were sure DNA was the genetic material, and that its structure would reveal the mechanism. The last sentence of their paper could have written before they guessed the structure. It was many years before a small DNA helix with a specific nucleotide sequence could be crystallized and its structure directly determined. Watson and Crick were correct.