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activity also affected Mirsky’s DNA samples, and enzymes that had no effect on DNA did not affect the activity of the extract. This should have led to great excitement, but Mirsky was unimpressed. As he explained to the Avery group, the transforming principle could not be made of DNA because nucleic acids were all alike. As their late Rockefeller Institute colleague Phoebus Levene had argued more than three decades earlier in his tetranucleotide hypothesis, the components of nucleic acids – the two kinds of base, the purines (adenine and guanine) and the pyrimidines (cytosine and thymine; thymine is replaced by uracil in RNA) – were present at similar levels. Although DNA was known to be a component of cell nuclei, its apparently boring nature meant that it was not thought to have biological ‘specificity’ – the term used at the time to describe the unique effects of a particular molecule. Proteins, in contrast, were extremely varied, and could be active even at very low levels. It was quite possible that despite all the treatments to remove proteins from their extracts, minute amounts of very powerful protein molecules remained, Mirsky explained.
    Although most scientists agreed that DNA did not have the necessary variability to have specificity, some were not so sure. In July 1941, at the annual Symposium on Quantitative Biology held at Cold Spring Harbor Laboratory out on Long Island, Jack Schultz pointed out that the supposed uniformity of nucleic acids was based on a single data point – all the DNA that had been studied had been taken from the thymus gland of cows. The suggestion that DNA structure was uniform could be accepted ‘only as a first order approximation’, he argued: ‘much new data is necessary before we can exclude the possibility of specificities in the nucleic acids themselves’. 13 However, Schultz was firmly convinced that genes were made of what he called nucleoproteins – proteins that were known to be tightly associated with nucleic acids in the chromosomes.
    In 1943, Mirsky underlined the growing sense of mystery surrounding nucleic acids when he wrote an article that was supposed to sum up current knowledge about nucleoproteins. Strikingly, he had little to say about proteins and instead concentrated on nucleic acids, and above all on DNA. Mirsky described how the nucleic acid component of a solution could be identified by its reaction to ultraviolet radiation; this was due to the responses of the pyrimidine and purine bases, which apparently lay in rings, perpendicular to the central axis of the molecule. Using this procedure, it was possible to show that, in animals and plants, chromosomes were largely made of DNA, and that DNA was also present in bacteria and in viruses. Finally, it seemed that nucleic acids were involved in both metabolic processes and the replication of chromosomes. Although there was no direct evidence for any link between proteins and genetic functions, Mirsky nevertheless concluded that the proteins found with DNA were at the heart of heredity:
    The great accumulation of desoxyribose nucleoproteins in the chromosome strongly suggests that these substances either are the genes themselves or are intimately related to the genes.
    In retrospect, virtually all the evidence that Mirsky summarised indicated that DNA was basis of heredity, and yet – like everyone else outside the Avery lab – he argued that genes were made of proteins that were bound up with DNA. He could not see what now appears obvious because there seemed to be no way in which DNA could contain the kind of variability that was necessary to produce the wide range of genetic effects. For Mirsky, Levene’s suggestion that DNA was composed of a monotonous repetition of the four bases was ‘a definite restriction in possible variation among the desoxyribose nucleic acids’. 14
    Despite these arguments, Avery and McCarty were increasingly convinced that DNA was the transforming principle and