Dna's Molecular Structure

Erwin Chargaff, a biochemist at Columbia University, confirmed and refined Avery's conclusion that DNA was complex enough to carry genetic information. In 1950, Chargaff reported that DNA exhibited a phenomenon he dubbed a complementary relationship. The four DNA bases—adenine, cytosine, guanine, and thymine (A, C, G, T, identified earlier by Levene)—appeared to be paired. That is, any given sample of DNA contained equal amounts of G and C, and equal amounts of A and T; guanine was the complement to cytosine, as adenine was to thymine. Chargaff also discovered that the ratio of GC to AT differed widely among different organisms. Rather than Levene's short molecules, DNA could now be reconceived as a gigantic macromolecule, composed of varying ratios of the base complements strung together. Thus, the length of DNA differed between organisms.

 

Even as biochemists described DNA's chemistry, molecular physicists attempted to determine DNA's shape. Using a process called X-ray crystallography, chemist Rosalind Franklin and physicist Maurice Wilkins, working together at King's College London in the early 1950s, debated whether DNA had a helical shape. Initial measurements indicated a single helix, but later experiments left Franklin and Wilkins undecided between a double and a triple helix. Both Chargaff and Franklin were one step away from solving the riddle of DNA's structure. Chargaff understood base complementarity but not its relation to molecular structure; Franklin understood general structure but not how complementarity necessitated adouble helix.

 

In 1952, an iconoclastic research team composed of an American geneticist, James Watson, and a British physicist, Francis Crick, resolved the debate and unlocked DNA's secret. The men used scale-model atoms to construct a model of the DNA molecule. Watson and Crick initially posited a helical structure, but with the bases radiating outward from a dense central helix. After meeting with Chargaff, Watson and Crick learned that the GC and AT ratios could indicate chemical bonds; hydrogen atoms could bond the guanine and cytosine, but could not bond either base to adenine or thymine. The inverse also proved true, since hydrogen could bond adenine to thymine. Watson and Crick assumed these weak chemical links and made models of the nucleotide base pairs GC and AT. They then stacked the base-pair models one atop the other, and saw that the phosphate and sugar components of each nucleotide bonded to form two chains with one chain spinning "up" the molecule, the other spinning "down" the opposite side. The resulting DNA model resembled a spiral staircase—the famous double helix.

 

Watson and Crick described their findings in an epochal 1953 paper published in the journal Nature. Watson and Crick had actually solved two knotty problems simultaneously: the structure of DNA and how DNA replicated itself in cell division—an idea they elaborated in a second path breaking paper in Nature. If one split the long DNA molecule at the hydrogen bonds between the bases, then each half provided a framework for assembling its counterpart, creating two complete molecules—the doubling of chromosomes during cell division. Although it would take another thirty years for crystallographic confirmation of the double helix, Crick, Watson, and Rosalind Franklin's collaborator Maurice Wilkins shared the 1962 Nobel Prize in physiology or medicine (Franklin had died in 1958). The study of molecular genetics exploded in the wake of Watson and Crick's discovery.

 

Once scientists understood the structure of DNA molecules, they focused on decoding the DNA in chromosomes—determining which base combinations created structural genes (those genes responsible for manufacturing amino acids, the building blocks of life) and which combinations created regulator genes (those that trigger the operation of structural genes). Between 1961 and 1966, Marshall Nirenberg and Heinrich Matthaei, working at the National Institutes of Health, cracked the genetic code. By 1967, scientists had a complete listing of the sixty-four three-base variations that controlled the production of life's essential twenty amino acids. Researchers, however, still lacked a genetic map precisely locating specific genes on individual chromosomes. Using enzymes to break apart or splice together nucleic acids, American scientists, like David Baltimore, helped develop recombinant DNA or genetic engineering technology in the 1970s and 1980s.

 

Genetic engineering paved the way for genetic map-ping and increased genetic control, raising a host of political and ethical concerns. The contours of this debate have shifted with the expansion of genetic knowledge. In the 1970s, activists protested genetic engineering and scientists decried for-profit science; thirty years later, protesters organized to fight the marketing of genetically modified foods as scientists bickered over the ethics of cloning humans. Further knowledge about DNA offers both promises and problems that will only be resolved by the cooperative effort of people in many fields—medicine, law, ethics, social policy, and the humanities—not just molecular biology.