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Poly(U) cracked the code: a Marshall Nirenberg memoir

The recent death of Marshall Nirenberg reminds us of his remarkable contribution to molecular biology in 1961. Marshall’s place in all the textbooks on biology, biochemistry, and microbiology is secure and deserved: he opened the door to elucidation of the genetic code in an elegant and straightforward way. Marshall came to my attention with a note in a biochemistry journal that worried me a great deal. The note stated that first, E. coli ribosomes, prepared very crudely, could incorporate radioactive amino acids into protein. Second, washing the ribosomes with salt reduced the level of incorporation. Third, adding back some RNA that had been removed by the salt wash restored the level of amino acid incorporation. Based on these results, Marshall concluded that the RNA washed off had something to do with programming protein synthesis on the ribosomes (1). This note worried me because at exactly that time I was working with Jim Ofengand in Cambridge, furiously trying to show that E. coli ribosomes we had programmed with RNA from a plant virus were actually synthesizing the plant virus coat protein (2). There was no question that we were making new protein, but the identity of the product was troubling; its tryptic fingerprint did not match that of the coat protein. My experiments with Jim had been prompted by the results from Cal Tech in the summer of 1960, when Sydney Brenner, Francois Jacob, and Matt Meselson found that an unstable RNA carried the genetic information of phage T2 from the DNA to the ribosome in infected E. coli. Many people knew that plant viruses were a good source of RNA having a specific nucleotide sequence, so we thought that it would be only a short time before Marshall did the same experiments we were doing. That happened. Marshall arranged to go to Berkeley to the laboratory of Heinz Fraenkel-Conrat, one of the world experts on tobacco mosaic virus (TMV). There, he repeated the experiment exactly as we had done it in Cambridge, with the same result— namely, that the added plant virus RNA stimulated the synthesis of new protein tremendously. At this point our results diverged. While we were never able to show what protein we were making, the group in California published a result that was interpreted to mean that they were making the virus coat protein. Later this result was shown to be wrong, but at the time it was quite exciting (although it was overshadowed by the control experiment that Marshall did back in Bethesda). What sorts of controls might one do to show that the system was faithfully translating the nucleotide sequence of the RNA into the amino acid sequence of a protein? Suppose one had RNA with a nonsensical sequence and used that to attempt to program synthesis of a protein. It should not work. And so Marshall used a simple synthetic RNA containing a string of the nucleotide uridine (polyU for short). And indeed, when added to E. coli ribosomes it did not stimulate the synthesis of a protein but instead directed the synthesis of a simple polypeptide, polyphenylalanine (3). At one stroke, he showed that the code could be broken—that by using synthetic RNAs of defined sequence it should be possible to determine all the elements of the genetic code. And this