DNA Term Analysis

As I hope this book will show, science seldom proceeds in the straightforward logical manner imagined by outsiders. Instead, its steps forward (and sometimes backward) are often very human events in which personalities and cultural traditions play major roles. To this end I have attempted to re-create my first impressions of the relevant events and personalities rather than present an assessment which takes into account the many facts I have learned since the structure was found. Although the latter approach might be more objective, it would fail to convey the spirit of an adventure characterized both by youthful arrogance and by the belief that the truth, once found, would be simple as well as pretty.

I feel the story should be told, partly because many of my scientific friends have expressed curiosity about how the double helix was found, and to them an incomplete version is better than none. But even more important, I believe, there remains general ignorance about how science is “done.” That is not to say that all science is done in the manner described here. This is far from the case, for styles of scientific research vary almost as much as human personalities. On the other hand, I do not believe that the way DNA came out constitutes an odd exception to a scientific world complicated by the contradictory pulls of ambition and the sense of fair play.

I have never seen Francis Crick in a modest mood.

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.

Max Perutz was in his office when I showed up just after lunch. […] I explained that I was ignorant of how X-rays diffract, but Max immediately put me at ease. I was assured that no high-powered mathematics would be required: both he and John had studied chemistry as undergraduates. All I need do was read a crystallographic text; this would enable me to understand enough theory to begin to take X-ray photographs.

[…]

When Max realized that I had come directly to the lab from the station and had not yet seen any of the colleges, he altered our course to take me through King’s, along the backs, and through to the Great Court of Trinity. I had never seen such beautiful buildings in all my life, and any hesitation I might have had about leaving my safe life as a biologist vanished.

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.

The wrong person had been sent to hear Rosy. If Francis had gone along, no such ambiguity would have existed. It was the penalty for being oversensitive to the situation. For, admittedly, the sight of Francis mulling over the consequences of Rosy’s information when it was hardly out of her mouth would have upset Maurice. In one sense it would be grossly unfair for them to learn the facts at the same time. Certainly Maurice should have the first chance to come to grips with the problem. On the other hand, there seemed no indication that he thought the answer would come from playing with molecular models. Our conversation on the previous night had hardly alluded to that approach. Of course, the possibility existed that he was keeping something back. But that was very unlikely—Maurice just wasn’t that type.

Most annoyingly, her objections were not mere perversity: at this stage the embarrassing fact came out that my recollection of the water content of Rosy’s DNA samples could not be right. The awkward truth became apparent that the correct DNA model must contain at least ten times more water than was found in our model. This did not mean that we were necessarily wrong—with luck the extra water might be fudged into vacant regions on the periphery of our helix. On the other hand, there was no escaping the conclusion that our argument was soft. As soon as the possibility arose that much more water was involved, the number of potential DNA models alarmingly increased.

Sir Lawrence had had too much of Francis to be surprised that he had again stirred up an unnecessary tempest. There was no telling where he would let loose the next explosion. If he continued to behave this way, he could easily spend the next five years in the lab without collecting sufficient data to warrant an honest Ph.D. The chilling prospect of enduring Francis throughout the remaining years of his tenure as the Cavendish Professor was too much to ask of Bragg or anyone with a normal set of nerves.

[…]

The decision was thus passed on to Max that Francis and I must give up DNA. Bragg felt no qualms that this might impede science, since inquiries to Max and John had revealed nothing original in our approach.

My first X-ray pictures revealed, not unexpectedly, much less detail than was found in the published pictures. Over a month was required before I could get even halfway presentable pictures. They were still a long way, though, from being good enough to spot a helix.

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.

At High Table John kept the conversation away from serious matters, letting loose only the possibility that Francis and I were going to solve the DNA structure by model building. Chargaff, as one of the world’s experts on DNA, was at first not amused by dark horses trying to win the race. Only when John reassured him by mentioning that I was not a typical American did he realize that he was about to listen to a nut. Seeing me quickly reinforced his intuition. Immediately he derided my hair and accent, for since I came from Chicago I had no right to act otherwise. Blandly telling him that I kept my hair long to avoid confusion with American Air Force personnel proved my mental instability.

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.

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.

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.

However, we both knew that we would not be home until a complete model was built in which all the stereo-chemical contacts were satisfactory. There was also the obvious fact that the implications of its existence were far too important to risk crying wolf. Thus I felt slightly queasy when at lunch Francis winged into the Eagle to tell everyone within hearing distance that we had found the secret of life.

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.

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.

All of these people, should they desire, can indicate events and details they remember differently. But there is one unfortunate exception. In 1958, Rosalind Franklin died at the early age of thirty-seven. Since my initial impressions of her, both scientific and personal (as recorded in the early pages of this book), were often wrong, I want to say something here about her achievements.

[…]

We both came to appreciate greatly her personal honesty and generosity, realizing years too late the struggles that the intelligent woman faces to be accepted by a scientific world which often regards women as mere diversions from serious thinking. Rosalind’s exemplary courage and integrity were apparent to all when, knowing she was mortally ill, she did not complain but continued working on a high level until a few weeks before her death.