James Watson wrote The Double Helix fifteen years after he and Francis Crick discovered the structure of DNA and six years after they shared a Nobel Prize with Maurice Wilkins. By then, scientists widely understood DNA’s importance in determining individual traits and genetic inheritance (the way that parents pass traits down to their offspring). As Watson writes in The Double Helix, DNA is “the Rosetta Stone for unraveling the true secret of life”—it’s the code that makes every organism distinct. But when Watson and Crick began their research in 1951, many chemists, biologists, and even geneticists didn’t appreciate DNA’s significance at all. Most thought that proteins were the key to genes, not DNA. Watson and Crick’s unusual confidence in DNA’s importance made their eventual success possible. While they were discovering DNA’s double helix structure, their more experienced colleagues were busy studying much less significant topics. In fact, not only did Crick and Watson’s intuitions about DNA turn out to be right, but the structure of DNA also proved their intuitions: the double helix was specifically suited to perform key genetic functions, like replication and encoding information. Thus, Watson and Crick’s didn’t just accurately model DNA—they also proved that DNA did exactly what they hoped that it would. In other words, Crick and Watson’s discovery was significant not only because they showed the scientific establishment the structure of a new molecule, but also because they showed why the molecule’s structure revealed its function as the “secret of life.”
The first important step in Watson and Crick’s research was their interest in DNA: they understood its central significance for genetics before almost anyone else. Watson explains that this began with their interest in O.T. Avery’s experiments on bacteria in the 1940s. Avery showed that DNA molecules could transfer hereditary traits between different bacteria, which suggested that these traits—and the genes that underly them—are located in DNA. However, most biologists and geneticists overlooked or discounted Avery’s studies at first. Instead, they continued to think that proteins were responsible for genes, so they tried to understand heredity by studying proteins. For instance, at an important London conference, Watson presented Al Hershey and Martha Chase’s work showing that phages (bacterial viruses) use DNA to infect bacteria and reproduce themselves. This strongly supported the results of Avery’s study. But, with the exception of three French virologists, most of the people at the conference didn’t care about the result. This illustrates how, when Crick and Watson entered biology, most of the scientific establishment was looking for genes in the wrong place. But as young newcomers to the field, Crick and Watson could easily see the evidence in favor of DNA. Of course, they weren’t the only people studying DNA. For instance, Herman Kalckar was studying its biochemistry in Copenhagen—but Watson didn’t consider his research interesting or applicable enough. Similarly, Maurice Wilkins and Rosalind Franklin were studying DNA in London, but Watson emphasizes several problems with their research. For instance, they didn’t get along and they didn’t treat DNA with the urgency it deserved. Worse still, they insisted on understanding it using experimental X-ray diffraction studies alone—not the molecular models pioneered by Linus Pauling. Thus, when Watson and Crick began their research, they clearly saw that most researchers were ignoring DNA, and most DNA researchers were ignoring the methodology most likely to uncover the truth about it.
When Crick and Watson discovered DNA’s double helix structure, they also provided very strong evidence for their hypothesis that DNA carries genes and is responsible for genetic inheritance. First, Crick and Watson proved that DNA can have a regular, consistent shape despite having a long, irregular sequence of nitrogenous bases. This supported Crick and Watson’s hypothesis that different people’s DNA could have a different sequence of bases but the same overall molecular form. Second, Crick and Watson established that DNA could replicate itself. They proved this by showing that DNA’s two strands are complimentary mirror images: adenine always bonds with thymine, and guanine always bonds with cytosine. For example, if one strand has adenine, then guanine, then cytosine, the other strand will have thymine, then cytosine, then guanine. This means that either of the two strands can serve as a template for creating a totally new strand of DNA. Thus, if the strands separate, the organism to which they belong can create new DNA molecule. By repeating this process, it can replicate its own DNA millions of times. (Several years after discovering the double helix structure, Crick and Watson discovered that this process happens through mRNA, a molecule similar to DNA.) This feature strongly supported Crick and Watson’s hypothesis that DNA was the “secret to life” because it explained how a person could develop from a small collection of fertilized cells to a complex organism with the same DNA in every cell.
In The Double Helix, Watson doesn’t explain how the discovery of DNA’s structure has revolutionized biology and genetics—his readers are likely to already know. Instead, he points out how things could have been otherwise: DNA could have simply been just another molecule, with no special function or structure. There would have been no Nobel Prize and no revolution. Thus, Watson emphasizes that his and Crick’s discovery wasn’t merely revolutionary because it revealed the molecule that was eventually proven to be the key to life. Instead, they revealed the molecule and showed why it was the key to life all at once.
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Of course there were scientists who thought the evidence favoring DNA was inconclusive and preferred to believe that genes were protein molecules. Francis, however, did not worry about these skeptics. Many were cantankerous fools who unfailingly backed the wrong horses. One could not be a successful scientist without realizing that, in contrast to the popular conception supported by newspapers and mothers of scientists, a goodly number of scientists are not only narrow-minded and dull, but also just stupid.
Knowing he could never bring himself to learn chemistry, Luria felt the wisest course was to send me, his first serious student, to a chemist.
He had no difficulty deciding between a protein chemist and a nucleic-acid chemist. Though only about one half the mass of a bacterial virus was DNA (the other half being protein), Avery’s experiment made it smell like the essential genetic material. So working out DNA’s chemical structure might be the essential step in learning how genes duplicated. Nonetheless, in contrast to the proteins, the solid chemical facts known about DNA were meager. Only a few chemists worked with it and, except for the fact that nucleic acids were very large molecules built up from smaller building blocks, the nucleotides, there was almost nothing chemical that the geneticist could grasp at.
I proceeded to forget Maurice, but not his DNA photograph. A potential key to the secret of life was impossible to push out of my mind. The fact that I was unable to interpret it did not bother me. It was certainly better to imagine myself becoming famous than maturing into a stifled academic who had never risked a thought.
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.
The moment was thus appropriate to think seriously about some curious regularities in DNA chemistry first observed at Columbia by the Austrian-born biochemist Erwin Chargaff. Since the war, Chargaff and his students had been painstakingly analyzing various DNA samples for the relative proportions of their purine and pyrimidine bases. In all their DNA preparations the number of adenine (A) molecules was very similar to the number of thymine (T) molecules, while the number of guanine (G) molecules was very close to the number of cytosine (C) molecules. Moreover, the proportion of adenine and thymine groups varied with their biological origin. The DNA of some organisms had an excess of A and T, while in other forms of life there was an excess of G and C.
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.
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.
The instant I saw the picture my mouth fell open and my pulse began to race. The pattern was unbelievably simpler than those obtained previously (“A” form). Moreover, the black cross of reflections which dominated the picture could arise only from a helical structure. […] The real problem was the absence of any structural hypothesis which would allow them to pack the bases regularly in the inside of the helix. Of course this presumed that Rosy had hit it right in wanting the bases in the center and the backbone outside. Though Maurice told me he was now quite convinced she was correct, I remained skeptical, for her evidence was still out of the reach of Francis and me.
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.
[Maurice Wilkins] emphasized that he wanted to put off more model building until Rosy was gone, six weeks from then. Francis seized the occasion to ask Maurice whether he would mind if we started to play about with DNA models. When Maurice’s slow answer emerged as no, he wouldn’t mind, my pulse rate returned to normal. For even if the answer had been yes, our model building would have gone ahead.
My aim was somehow to arrange the centrally located bases in such a way that the backbones on the outside were completely regular—that is, giving the sugar-phosphate groups of each nucleotide identical three-dimensional configurations. But each time I tried to come up with a solution I ran into the obstacle that the four bases each had a quite different shape. Moreover, there were many reasons to believe that the sequences of the bases of a given polynucleotide chain were very irregular. Thus, unless some very special trick existed, randomly twisting two polynucleotide chains around one another should result in a mess. In some places the bigger bases must touch each other, while in other regions, where the smaller bases would lie opposite each other, there must exist a gap or else their backbone regions must buckle in.
Despite the messy backbone, my pulse began to race. If this was DNA, I should create a bombshell by announcing its discovery. The existence of two intertwined chains with identical base sequences could not be a chance matter. Instead it would strongly suggest that one chain in each molecule had at some earlier stage served as the template for the synthesis of the other chain. Under this scheme, gene replication starts with the separation of its two identical chains.
As the clock went past midnight I was becoming more and more pleased. There had been far too many days when Francis and I worried that the DNA structure might turn out to be superficially very dull, suggesting nothing about either its replication or its function in controlling cell biochemistry. But now, to my delight and amazement, the answer was turning out to be profoundly interesting. For over two hours I happily lay awake with pairs of adenine residues whirling in front of my closed eyes. Only for brief moments did the fear shoot through me that an idea this good could be wrong.
Suddenly I became aware that an adenine-thymine pair held together by two hydrogen bonds was identical in shape to a guanine-cytosine pair held together by at least two hydrogen bonds. All the hydrogen bonds seemed to form naturally; no fudging was required to make the two types of base pairs identical in shape.
[…]
The hydrogen-bonding requirement meant that adenine would always pair with thymine, while guanine could pair only with cytosine. Chargaff’s rules then suddenly stood out as a consequence of a double-helical structure for DNA. Even more exciting, this type of double helix suggested a replication scheme much more satisfactory than my briefly considered like-with-like pairing.
Rosy’s instant acceptance of our model at first amazed me. I had feared that her sharp, stubborn mind, caught in her self-made antihelical trap, might dig up irrelevant results that would foster uncertainty about the correctness of the double helix. Nonetheless, like almost everyone else, she saw the appeal of the base pairs and accepted the fact that the structure was too pretty not to be true. Moreover, even before she learned of our proposal, the X-ray evidence had been forcing her more than she cared to admit toward a helical structure. The positioning of the backbone on the outside of the molecule was demanded by her evidence and, given the necessity to hydrogen-bond the bases together, the uniqueness of the A-T and G-C pairs was a fact she saw no reason to argue about.
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.
For a while Francis wanted to expand our note to write at length about the biological implications. But finally he saw the point to a short remark and composed the sentence: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”
