The Double Helix

From my first day in the lab I knew I would not leave Cambridge for a long time. Departing would be idiocy, for I had immediately discovered the fun of talking to Francis Crick. Finding someone in Max’s lab who knew that DNA was more important than proteins was real luck. Moreover, it was a great relief for me not to spend full time learning X-ray analysis of proteins. Our lunch conversations quickly centered on how genes were put together. Within a few days after my arrival, we knew what to do: imitate Linus Pauling and beat him at his own game.

In place of pencil and paper, the main working tools were a set of molecular models superficially resembling the toys of preschool children.
We could thus see no reason why we should not solve DNA in the same way. All we had to do was to construct a set of molecular models and begin to play—with luck, the structure would be a helix.

It was from his father. In addition to routine family-gossip was the long-feared news that Linus now had a structure for DNA. No details were given of what he was up to, and so each time the letter passed between Francis and me the greater was our frustration. Francis then began pacing up and down the room thinking aloud, hoping that in a great intellectual fervor he could reconstruct what Linus might have done. As long as Linus had not told us the answer, we should get equal credit if we announced it at the same time.

I realized that the phosphate groups in Linus’ model were not ionized, but that each group contained a bound hydrogen atom and so had no net charge. Pauling’s nucleic acid in a sense was not an acid at all. Moreover, the uncharged phosphate groups were not incidental features. The hydrogens were part of the hydrogen bonds that held together the three intertwined chains.

Without the hydrogen atoms, the chains would immediately fly apart and the structure vanish.

Everything I knew about nucleic-acid chemistry indicated that phosphate groups never contained bound hydrogen atoms. No one had ever questioned that DNA was a moderately strong acid. Thus, under physiological conditions, there would always be positively charged ions like sodium or magnesium lying nearby to neutralize the negatively charged phosphate groups. All our speculations about whether divalent ions held the chains together would have made no sense if there were hydrogen atoms firmly bound to the phosphates. Yet somehow Linus, unquestionably the world’s most astute chemist, had come to the opposite conclusion.

Francis was explaining to John and Max that no further time must be lost on this side of the Atlantic. When his mistake became known, Linus would not stop until he had captured the right structure. Now our immediate hope was that his chemical colleagues would be more than ever awed by his intellect and not probe the details of his model. But since the manuscript had already been dispatched to the Proceedings of the National Academy, by mid-March at the latest Linus’ paper would be spread around the world. Then it would be only a matter of days before the error would be discovered. We had anywhere up to six weeks before Linus again was in full-time pursuit of DNA.

Interrupting her harangue, I asserted that the simplest form for any regular polymeric molecule was a helix. Knowing that she might counter with the fact that the sequence of bases was unlikely to be regular, I went on with the argument that, since DNA molecules form crystals, the nucleotide order must not affect the general structure. Rosy by then was hardly able to control her temper, and her voice rose as she told me that the stupidity of my remarks would be obvious if I would stop blubbering and look at her X-ray evidence.

[…]

Without further hesitation I implied that she was incompetent in interpreting X-ray pictures. If only she would learn some theory, she would understand how her supposed antihelical features arose from the minor distortions needed to pack regular helices into a crystalline lattice.

Though I kept insisting that we should keep the backbone in the center, I knew none of my reasons held water. Finally over coffee I admitted that my reluctance to place the bases inside partially arose from the suspicion that it would be possible to build an almost infinite number of models of this type. Then we would have the impossible task of deciding whether one was right. But the real stumbling block was the bases. As long as they were outside, we did not have to consider them. If they were pushed inside, the frightful problem existed of how to pack together two or more chains with irregular sequences of bases. Here Francis had to admit that he saw not the slightest ray of light.

Fortunately, by the time my letter reached Cal Tech the base pairs had fallen out. If they had not, I would have been in the dreadful position of having to inform Delbrück and Pauling that I had impetuously written of an idea which was only twelve hours old and lived only twenty-four before it was dead.

Pauling’s reaction was one of genuine thrill, as was Delbrück’s. In almost any other situation Pauling would have fought for the good points of his idea. The overwhelming biological merits of a self-complementary DNA molecule made him effectively concede the race. He did want, however, to see the evidence from King’s before he considered the matter a closed book. This he hoped would be possible three weeks hence.