Deciphering the genetic code

Searching for the Rosetta Stone of life

Now, with the proposed structure of DNA at hand, it was intriguing to understand the language of DNA - to crack the genetic code. The problem was how to translate a four-letter vocabulary to a 20-letter vocabulary. The race was on. The problem was hard to solve in theory because only protein sequences were available and the 1950s the term 'gene' represented the smallest unit of genetic information, but no DNA sequence was available until mid-1960s. Had DNA sequences been available, the puzzle would probably have been straightforward to solve. At that time the only way for scientists was to collect and analyze protein sequences.

Being one of the fascinating scientists of the twentieth century, George Gamow, proposed the famous Big Bang Theory and also a relationship between DNA and proteins in his 1954 letter to Nature. When he was studying the Watson's and Crick's helix structure, he observed, as he wrote "holes," comprising sequences of three base pairs; consequently, Gamow proposed that a triplet of base pairs code for each amino acid or codons as scientists call the triplets today. Gamow, the founder of the RNA Tie Club, suggested that these words are overlapping and could produce words in any order, however, later research unveiled the words to be non-overlapping. Early 1955, in a note to the RNA Tie Club, Francis Crick first criticised Gamow's scheme for overlapping codons and the list of amino acids, later unveiling his thoughts about the adaptor hypothesis (*).

The 1968 Nobel Prize in Physiology or Medicine went to Robert W. Holley, Har Gobind Khorana and Marshall W. Nirenberg for "for their interpretation of the genetic code and its function in protein synthesis."

Nirenberg and a post-doctoral visitor, Heinrich J. Matthaei, revealed the first word in the dictionary of life in their October 1961 PNAS paper, entitled "THE DEPENDENCE OF CELL-FREE PROTEIN SYNTHESIS IN E. COLI UPON NATURALLY OCCURRING OR SYNTHETIC POLYRIBONUCLEOTIDES." This first word or codon was UUU, which produced amino acid phenylalanine. Importantly their experiments proved messenger RNA is required to convey the instructions on DNA to protein assembly.

Although proteins consist of only 20 different amino acids, the three letter code yields 64 combinations. Nirenberg and his co-workers solved the total of 54 of these. They published 27 of these in the 1965 article "RNA CODEWORDS AND PROTEIN SYNTHESIS, VII. ON THE GENERAL NATURE OF THE RNA CODE," in PNAS.

The codons marking the end of the codon sequence, stop codons, were discovered by Richard Epstein and Charles Steinberg. In RNA these three codons are UAG (amber), UAA (ochre) and UGA (opal). In DNA they are encoded with T instead of U: TAG (amber), TAA (ochre) and TGA (opal or umber). When you discover something new, you get to name it; thus, the discoverers named the first codon after their friends Harris Bernstein's last name, which means "amber" in German. To keep the names within the theme of colors, Epstein and Steinberg gave color names to the two last codons also(*).

When in 1957 ribosomes, cell's protein factories, were known as microsomes and their function unknown, Crick gave a public lecture at University College London, introducing his "Central Dogma," the information flow between DNA, RNA, and protein. He explained that "Once information has got into a protein it can’t get out again. Information here means the sequence of the amino acid residues, or other sequences related to it.” He also made a daring prediction that an 'adaptor' molecule on which amino acids attach must exist and this molecule would carry them to sites where proteins are synthesized(*). Today this molecule is known as transfer RNA, tRNA. See also Crick's unpublished notes, "Ideas on protein synthesis (October 1956)." Crick published a more complete version of the Central Dogma in 1970 in Nature.

Holley's succeeding work, published in 1965(*), proved Francis Cricks 1957 theory of the existence of a specific adaptor molecule to be correct. Holley determined the structure of transfer RNA, tRNA. This discovery explained the mechanism of protein synthesis from messenger RNA, mRNA.