This sample of tobacco mosaic virus RNA was part of the National Institute of Health lab of Dr. Marshall Nirenberg, a scientist who won the 1968 Nobel Prize in Physiology or Medicine for his work in helping to “crack the genetic code,” or to understand the way DNA codes for the amino acids that are linked to build proteins. Prior to the availability of synthetic oligonucleotides (see object 2001.0023.02), Nirenberg used this sample of tobacco mosaic virus RNA as a source of mRNA for his experiments in optimizing the function of cell-free protein synthesis systems, an important precursor to his work of cracking the genetic code.
By the late 1950s, scientists understood that DNA was the molecule containing the instructions for life. The structure of DNA was also known-- a sort of twisted ladder shape known as double helix where the “side rails” consisted of a sugar phosphate backbone and the “rungs” were made of paired nucleic acid bases (represented by A, T, G, C). The structure suggested that the order of the bases formed a code representing the order in which amino acids should be joined to produce different kinds of proteins.
But what was the code? What order of bases made up the “code words” or "codons” DNA used to represent each of the 20 amino acids? Researchers hypothesized that each codon for amino acid would be three bases long. If it was only two bases long, that would allow for only 16 different combinations of the four bases (4^2 = 16). If each codon was three bases however, that would result in 64 possible codons (4^3 =64), plenty of codons to represent each of the 20 amino acids separately.
With this knowledge, Dr. Nirenberg and his colleagues set about trying to figure out which three-base combinations represented each amino acid. It was known at the time that DNA is “transcribed” into a template RNA that interacts with ribosomes in the cell to produce proteins. Because RNA, not DNA, is what the cell reads directly to make proteins, Dr. Nirenberg reasoned that he could use a man-made stand-in for RNA that had a repeating known sequence (the same codon over and over) to produce proteins consisting of only one amino acid.
These stand-ins were known as “oligonucleotides” (see object 2001.0023.02). Using a cell-free system (one that has all the necessary parts for protein synthesis in a test tube rather than in a cell) Dr. Nirenberg introduced the oligonucleotides, consisting only of a single base, uracil, represented by U, over and over. This meant the only codon that could be read by the system was UUU or “poly-U.”
He then fed the system a supply of all 20 amino acids, one of which was radioactively labeled. Twenty different experiments were done, with only a single kind of amino acid radioactively labeled per experiment. Only when the cell was supplied with the radioactively labeled amino acid, phenylalanine, did the specially made poly-U oligonucleotide produce a radioactive protein. Nirenberg had demonstrated that the codon “UUU” is the code word for phenylalanine, and in doing so, he had cracked the first word in the genetic code.
Within five years, between the work of Nirenberg and that of several scientists using similar methods, the code for the remaining 63 codons would be understood.
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