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Genetics and Genomics Timeline
Marshall Nirenberg (1927-) cracks the genetic code

The basic chemical pathways by which DNA directs synthesis of proteins were clarified by about 1960. But the genetic code—the little language encrypted in molecules of DNA—remained a mystery. Speculation about it was fruitful during the 1950s, but the code was cracked by experiment.

Marshall Nirenberg
In 1961 Marshall Nirenberg, a young biochemist at the National Institute of Arthritic and Metabolic Diseases, discovered the first "triplet"—a sequence of three bases of DNA that codes for one of the twenty amino acids that serve as the building blocks of proteins. Subsequently, within five years, the entire genetic code was deciphered.

RNA, the close kin and working partner to DNA, provided the key to the code. While DNA resides almost entirely in the cell nucleus, protein synthesis takes place in the cytoplasm, where RNA is found. On molecular workbenches known as ribosomes, sequences of RNA, transcribed from stretches of DNA, serve as instructions for manufacturing proteins. Protein synthesis represents the fundamental work of the genes.

Nirenberg's series of key experiments, carried out initially with German scientist Johann Matthaei, employed test-tube techniques. Nirenberg and Matthaei set up a "cell free system" with "sap" from ruptured E. coli cells containing enzymes and an energy system. To this they added simple chains of RNA, comprised of just one of the four RNA bases (uracil, cytosine, adenine, and guanine). They also added amino acids, one of which was radioactively tagged.

The breakthrough came when Matthaei added "poly-U"—RNA comprised entirely of uracil bases—to the mix. After brief incubation at normal body-heat temperature, radioactive measurements indicated synthesis of long protein-like molecules. These molecules were made entirely of the amino acid phenylalanine. Nirenberg and Matthaei concluded that the RNA sequence "UUU" directs the addition of phenylalanine to any growing protein chain.

Nirenberg went on to decipher other triplets in the genetic code—a total of thirty-five by 1963, and over sixty by 1966. As suspected, each "codon" was found to consist of three bases in a specific order. With four bases, there were 64 possible triplets. The code was thus redundant: more than one codon could stand for a specific amino acid. Both AAG and AAA, for example, code for the amino acid lysine. Three of the codons, it was eventually discovered, signal the end of any particular amino acid chain.

Har Gobind Khorana, at the University of Wisconsin, adapted Nirenberg's experimental system, and confirmed and extended his work. Nirenberg and Khorana were awarded the 1968 Nobel Prize in Physiology or Medicine, shared with Robert W. Holley, "for their interpretation of the genetic code and its function in protein synthesis."

Marshall Nirenberg winner of the
1968 Albert Lasker Award for Basic Medical Research

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