Cracking the Genetic Code for Protein Biosynthesis

The structure of DNA was determined in 1953 by Watson, Crick, and Franklin, with strands of the double helix consisting of four nucleotides: adenine (A), thymine (T), cytosine (C), and guanine (G); in RNA, uracil (U) replaces T. But how was the genetic information contained in the DNA molecule translated to the biosynthesis of a protein?

The Russian physicist George Gamow postulated that a three-letter nucleotide (codon) could define up to sixty-four amino acids, more than sufficient to code for all twenty amino acids used to build proteins. In 1961, Marshall Nirenberg, with J. Heinrich Matthaei at the National Institutes of Health, sought to determine what amino acid would be formed after a single nucleotide was added to a reaction mixture. UUU produced the amino acid phenylalanine, cracking the first letter in the genetic code. Shortly thereafter, the addition CCC was found to yield proline. Har Gobind Khorana at the University of Wisconsin-Madison produced more complex sequences composed of repeated twonucleotide sequences, the first of which was UCUCUC, read as serine-leucine-serine-leucine . . .; subsequently, the remainder of the codons were determined.

This image depicts the relationship between the codon (the three-letter nucleotide consisting of adenine, thymine, cytosine, and guanine or uracil) and the encoding of amino acids.

In 1964, Robert Holley, at Cornell University, discovered and established the chemical structure of transfer RNA (tRNA), thus providing the link between the role of messenger RNA (mRNA) and ribosomes. The information needed to make a protein is first attached to tRNA and then translated to messenger mRNA in a ribosome. Each tRNA only recognizes one set of three nucleotides in mRNA, and tRNA binds to only one of the twenty amino acids. A protein is formed by the addition of one amino acid at a time. Nirenberg, Khorana, and Holley were jointly awarded the 1968 Nobel Prize. Apart from variations, the genetic codes used by all forms of life are very similar. Based on the theory of evolution, the genetic code was established very early in the history of life.