By 1958, experiments and analysis such as the Avery–MacLeod–McCarty experiment, the Hershey–Chase experiment, the Watson–Crick structure and the Meselson–Stahl experiment had shown DNA to be the molecule of genetic information. It was not known, however, how DNA directed the expression of proteins, or what role RNA had in these processes. Nirenberg teamed up with Heinrich J. Matthaei at the National Institutes of Health to answer these questions. They produced RNA composed solely of uracil, a nucleotide that only occurs in RNA. They then added this synthetic poly-uracil RNA into a cell-free extract of Escherichia coli which contained the DNA, RNA, ribosomes and other cellular machinery for protein synthesis. They added DNase, which breaks apart the DNA, so that no additional proteins would be produced other than that from their synthetic RNA. They then added 1 radioactively labeled amino acid, the building blocks of proteins, and 19 unlabeled amino acids to the extract, varying the labeled amino acid in each sample. Only in the extract containing the radioactively labeled phenylalanine, was the resulting protein also radioactive. This implied that the genetic code for phenylalanine on RNA consisted of a repetition of uracil bases. Indeed, as we know now, it is UUU (three uracil bases in a row). This was the first step in deciphering the codons of the genetic code and the first demonstration of messenger RNA (see Nirenberg and Matthaei experiment).[10][11][12][13][14][15][16]
In August 1961, at the International Congress of Biochemistry in Moscow, Nirenberg presented a paper to a small group of scientists, reporting the decoding of the first codon of the genetic code. Matthew Meselson, who was in the audience, spontaneously hugged Nirenberg at the end of the talk and then told Francis Crick about Nirenberg's result.[17] Crick invited Nirenberg to repeat his performance the next day in a talk to a much larger audience.[18][19] Speaking before the assembled congress of more than a thousand people, Nirenberg electrified the scientific community.[17] He quickly received great scientific attention for these experiments. Within a few years, his research team had performed similar experiments and found that three-base repeats of adenosine (AAA) produced the amino acid lysine, and cytosine repeats (CCC) produced proline. The next breakthrough came when Philip Leder, a postdoctoral researcher in Nirenberg's lab, developed a method for determining the genetic code on pieces of tRNA (see Nirenberg and Leder experiment). This greatly sped up the assignment of three-base codons to amino acids so that 50 codons were identified in this way. Khorana's experiments confirmed these results and completed the genetic code translation.
The period between 1961 and 1962 is often referred to as the "coding race" because of the competition between the labs of Nirenberg at NIH and Nobel laureate Severo Ochoa at New York University Medical School, who had a massive staff. Faced with the possibility of helping the first NIH scientist win a Nobel prize, many NIH scientists put aside their own work to help Nirenberg in deciphering the mRNA codons for amino acids. Dr. DeWitt Stetten, Jr., director of the National Institute of Arthritis and Metabolic Diseases, called this period of collaboration "NIH's finest hour".[20]
Nirenberg's later research focused on neuroscience, neural development, and the homeobox genes.
^Eiserling, F; Levin, JG; Byrne, R; Karlsson, U; Nirenberg, MW; Sjoestrand, FS (1964), "Polyribosomes and DNA-dependent Amino Acid Incorporation in Escherichia coli Extracts", Journal of Molecular Biology, vol. 10, no. 3 (published December 1964), pp. 536–40, doi:10.1016/S0022-2836(64)80073-5, PMID14257696
^BLADEN, HA; BYRNE, R; LEVIN, JG; NIRENBERG, MW (1965), "An electron microscopic study of a DNA-ribosome complex formed in vitro", J. Mol. Biol., vol. 11 (published Jan 1965), pp. 78–83, doi:10.1016/S0022-2836(65)80172-3, PMID14255762
^BERNFIELD, MR; NIRENBERG, MW (1965), "RNA Codewords and Protein Synthesis: The Nucleotide Sequences of Multiple Codewords for Phenylalanine, Serine, Leucine, and Proline", Science, vol. 147, no. 3657 (published Jan 29, 1965), pp. 479–84, Bibcode:1965Sci...147..479B, doi:10.1126/science.147.3657.479, PMID14237203
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