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History of Genetics - Molecular Genetics

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Molecular Genetics

The period covering the first half of the twentieth century is often referred to as "classical genetics." Morgan had set the tone, treating the gene as an abstraction and the Mendelian analysis of experimental data as an algorithm. But as early as 1922 Muller had drawn the analogy between bacterial viruses and genes and glimpsed the possibility of grinding "genes in a mortar" and cooking them "in a beaker." There existed too a continuing concern during this period to identify gene products chemically, working with flower pigments in plants and eye pigments in insects. Nonetheless, the chemical constitution of the gene remained vague, and geneticists were content to assume it was a protein of a special kind: one that can both catalyze its own reproduction (autocatalysis) and provide an enzyme that catalyzes a quite different reaction in the general metabolism of the cell (heterocatalysis.)

The protein nature of the gene was called into question in 1944 when three Rockefeller scientists, Ostwald Avery, Colin MacLeod, and Maclyn McCarty, published their identification of the so-called transforming principle as deoxyribonucleic acid (DNA). This principle, obtained from dead bacterial cells of one strain, was shown to transfer a characteristic from that strain to another strain. This extract contained only the minutest traces of protein; the rest was DNA. Geneticists knew about this work, but the majority assumed that the DNA was acting as a mutagen, altering the genetic constitution of the recipient cell, not transferring a gene. Evidence from other quarters was needed to shift the status quo. It came from the cytochemists and the phage biologists. The former discovered the correlation between the quantity of DNA in the nucleus and the number of chromosomes. Germ cells had half the content of body cells. Cells containing multiple sets of chromosomes (polyploids) had correspondingly raised DNA content. The same was not true of protein.

Phage biologists did not achieve as clean a transfer of DNA in their work as had Avery in his, but they were able to separate the functions of the protein and the nucleic acid of the phage particle, assigning the protein to the task of attaching to the host and causing it to burst (lyse), whereas the nucleic acid finds its way into the host and is used to constitute the progeny phage particles. By 1952 Alfred Hershey and Martha Chase at Cold Spring Harbor Laboratory could show that 85 percent of the parental DNA is present in the progeny particles. This result had an impact because of the visual evidence previously provided by the electron microscope of the sperm-like particles and their "ghosts" empty, their DNA contents removed.

Making the case for DNA acting as the repository of the genetic specificities of the organism called for establishing the kind of structure DNA possesses that would permit it to function thus. Known to be a long-chain molecule, its backbone composed of sugar rings attached to one another by phosphate arms, it has only four kinds of side-groups attached to the sugars—the bases adenine, guanine, thymine, and cytosine. This contrasts unfavorably with the proteins, for they have twenty different amino acids that can be arranged in countless different sequences.

The proposal of the double-helical model of DNA by James Watson and Francis Crick in 1953 overcame this difficulty because their structure, a cylindrical one with the four kinds of bases packed inside the two helically entwined sugar-phosphate backbones, permits any kind of sequence of the bases. Moreover, these bases are paired by weak bonds across from one base to its opposite number, adenine with thymine, guanine with cytosine. Watson and Crick therefore visualized the duplication of the gene as the result of separating the two chains of the parent double helix and attaching free bases to those now unpaired in accordance with the above complementary relations.

The work of Rosalind Franklin and Maurice Wilkins in London had not only aided Watson and Crick in devising their proposed structure, but when published alongside it offered crucial support. Yet it was not until 1958 that evidence from quite different approaches was published confirming predictions made from the model. Only then did interest in the structure become widespread. In genetics the work of Sydney Brenner, Francis Crick, Leslie Barnett, and R. J. Watts-Tobin, using mutagenesis in bacteriophage to establish the general nature of the genetic code, was published in 1961. It marked a success in applying the genetic approach to questions at the molecular level, for they showed that the genetic message is composed of triplets of bases, read from a fixed starting point, in only one direction, and without commas between the triplets. Meanwhile biochemists had been establishing the identity of the amino acids coded by given triplet sequences of bases.

It was the physicist George Gamow who had first suggested a DNA code for the amino acids in proteins. He had hoped the right code could be established by mathematical reasoning but had to accept that nature does not use the most mathematically elegant solution. The amino acid sequences being discovered in proteins showed no limitations on the permutations of nearest neighbors of the kinds required by these mathematical codes. Hence the need to turn to the biochemists and the geneticists to solve the problem. They attacked it with vigor, and by 1966 the full details of the code were established. But the major transformation of genetics came with the introduction in the 1970s of the techniques of recombinant DNA technology that made directed manipulation of the genetic material possible.

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