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On the day of the lecture, Francis was unable to go down to London, and I went alone, still oblivious to the difference between the crystallographic terms “asymmetric unit” and “unit cell.” As a result, the next morning I mistakenly reported to Francis that Rosalind’s DNA fibers contained very little water. My error only came to light a week later, when Rosalind and Maurice came up from London to look at a three-chain model that we had hastily constructed. It had DNA’s sugar-phosphate backbone in the center with the bases facing outward. Upon seeing it, Rosalind immediately faulted its conception, saying the phosphate groups were located on the outside, not the inside, of the molecule. Moreover, we had proposed DNA to be virtually dry, whereas, in fact, it was highly hydrated. And we got the unmistakable impression that the King’s group considered the pursuit of the DNA structure to be their property, not one to be shared with their fellow MRC unit in Cambridge. All too soon we learned that Sir Lawrence Bragg was of the same mind, when he told us to refrain from all subsequent DNA model-building activities. In stopping us Bragg was not motivated solely by a need to remain on good terms with another MRC-­supported group. He wanted Francis to focus exclusively on research for his PhD and be done with it.

This debacle, however, would not have occurred if Francis and I had started to think as if we were chemists. Even without the King’s x-ray patterns, there were clues in the chemical literature that should have led us to propose a double helix as the basic structure of DNA. From the start we should have restricted ourselves to models in which externally located sugar-phosphate backbones were held together by hydrogen bonds between centrally located bases. Strong ­physical-chemical evidence for bases so held together had come from the postwar experiments of John Gulland. In 1946, his Nottingham lab showed that within native DNA molecules the bases are so arranged as to hinder them from exchanging hydrogen atoms. These data suggested widespread hydrogen bonding between DNA bases. This insight was widely available, published by the Cambridge University Press in the 1947 SEB Symposium volume on nucleic acids.

Furthermore, given Linus Pauling and Max ­Delbrück’s prewar proposal that the copying of genetic molecules would involve structures of complementary shape, Francis and I should have reasonably focused on two-chain rather than three-chain models. In a two-chain model, each DNA base would hydrogen-bond exclusively to one with a molecule of complementary shape. In fact, experimental data pointing to this conclusion, too, already had been published, most coming from the lab of the Austrian-born chemist Erwin Chargaff in New York. Without understanding the significance of his discovery, Chargaff reported that in DNA, the amounts of the purine adenine were roughly equal to the amounts of the pyrimidine ­thymine. Likewise, the amount of the second purine, guanine, was similar to the amount of the second pyrimidine, cytosine.

The exact shape of such base pairs would depend upon where the atoms available for hydrogen bonding were located on each base. In 1951, few chemists knew enough quantum mechanics to make such inferences. So that fall we should have sought advice from the several British chemists trained in this esoteric field. In retrospect, Alex Todd’s lab, after determining the covalent linkages in DNA, should have moved on to determining what the molecule looks like in three dimensions. But in those days, even the best organic chemists thought such problems were better left to x-ray crystallographers. In turn, most x-ray diffraction experts felt the time had not yet arrived to tackle biological macromole­cules. In a sense, then, the field was wide open.

Even after he found the alpha helix, Linus ­Pauling remained only moderately attentive to DNA, never seriously believing that it had a genetic role. Even so, when hearing of Maurice Wilkins’s crystalline photo, he asked to have a look, being misinformed that ­Maurice himself was not seriously trying to determine the structure. As that was precisely what ­Maurice was up to, he quickly replied that he wanted more time to look over the photo before releasing it to others. Undeterred, Linus wrote directly to the King’s boss, John Randall, but this approach was likewise unsuccessful. Linus lost the scent until a year later at a summer phage meeting outside of Paris, where he first learned of the work recently completed at Cold Spring Harbor by Alfred Hershey and Martha Chase, showing that phages were also made from DNA. The news convinced Linus he must go after the DNA structure despite his lack of high-quality DNA x-ray photos. His voyage back to the States could have been a great fortuitous opportunity. Also on board the transatlantic boat was Erwin Chargaff, who like Pauling had come to Europe to attend that summer’s International Biochemical Congress in Paris. But instead of learning about the equivalence of A with T and G with C, Linus took an instantaneous dislike to his shipmate and avoided him all across the Atlantic.

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Tagged: Biomedicine

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