What Mad Pursuit

by Francis Crick

  It might be argued that since a helices are found almost exclusively in biological molecules, a model of a polypeptide backbone should not be rejected merely because it is ugly. I would prefer to say that because of its molecular simplicity the basic a helix is nearer to physical chemistry than to biology. At that level there are few alternatives for evolution to work on. It is only when we consider the side-chains, and the many ways a long polypeptide chain can fold back on itself, that a very large variety of structures become possible. Simplicity is then likely to yield to sophistication. Elegance, if it exists, may well be more subtle and what may at first sight seem contrived or even ugly may be the best solution that natural selection could devise.

  This failure on the part of my colleagues to discover the a helix made a deep impression on Jim Watson and me. Because of it I argued that it was important not to place too much reliance on any single piece of experimental evidence. It might turn out to be misleading, as the 5.1 Å reflection undoubtedly was. Jim was a little more brash, stating that no good model ever accounted for all the facts, since some data was bound to be misleading if not plain wrong. A theory that did fit all the data would have been “carpentered” to do this and would thus be open to suspicion.

  People have sometimes stated that Pauling’s model of the a helix or his incorrect model for DNA gave us the idea that DNA was a helix. Nothing could be farther from the truth. Helices were in the air, and you would have to be either obtuse or very obstinate not to think along helical lines. What Pauling did show us was that exact and careful model building could embody constraints that the final answer had in any case to satisfy. Sometimes this could lead to the correct structure, using only a minimum of the direct experimental evidence. This was the lesson that we learned and that Rosalind Franklin and Maurice Wilkins failed to appreciate in attempting to solve the structure of DNA. That, and the necessity for making no assumptions that could not be doubted from time to time. It should also be said that Jim and I were highly motivated to succeed, even if we approached problems in a relaxed manner, were quick to spot success when we saw it and to learn what lessons we could draw both from successes and from failures.

  The α helix was an important milestone on the rocky path of molecular biology but it did not have the same impact as the DNA double helix did. We initially hoped that, given the basic folds of the α helix and β sheets, we might be able to solve the structure of a protein by straightforward model building. Unfortunately most proteins are too complex and too sophisticated for that. In short, these two structural cliches alerted us to what to expect in some parts of a protein but did not immediately reveal the secret of the specificity and catalytic activity of a particular protein. The structure of DNA, on the other hand, immediately gave the game away, suggesting only too vividly how nucleic acid could be replicated exactly. DNA is, at bottom, a much less sophisticated molecule than a highly evolved protein and for this reason reveals its secrets more easily. We were not to know this in advance—it was just good luck that we stumbled onto such a beautiful structure.

  Pauling was a more important figure in molecular biology than is sometimes realized. Not only did he make certain key discoveries (that sickle cell anemia is a molecular disease, for example), but he had the correct theoretical approach to these biological problems. He believed that much that we needed to explain could be done using the well-established ideas of chemistry and, in particular, the chemistry of macromolecules and that our knowledge of the various kinds of atoms, especially carbon, and of the bonds that hold atoms together [the homopolar bond, electrostatic interactions, hydrogen bonds, and van der Waal’s forces] would be enough to crack the mysteries of life.

  Max Delbrück, on the other hand, who started as a physicist, hoped that biology would enable us to discover new laws of physics. Delbrück also worked at Cal Tech, where Pauling was. He had pioneered important studies of certain viruses, called bacteriophage (“phage” for short), and was one of the leaders of the very influential Phage Group, of which Jim Watson was a more junior member. I don’t think Delbrück much cared for chemistry. Like most physicists, he regarded chemistry as a rather trivial application of quantum mechanics. He had not fully imagined what remarkable structures can be built by natural selection, nor just how many distinct types of proteins there might be.

  Time has shown that, so far, Pauling was right and Delbrück was wrong, as indeed Delbrück acknowledged in his book, Mind into Matter. Everything we know about molecular biology appears to be explainable in a standard chemical way. We also now appreciate that molecular biology is not a trivial aspect of biological systems. It is at the heart of the matter. Almost all aspects of life are engineered at the molecular level, and without understanding molecules we can only have a very sketchy understanding of life itself. All approaches at a higher level are suspect until confirmed at the molecular level.

  6

  How to Live with

  a Golden Helix

  THE DOUBLE HELIX is indeed a remarkable molecule. Modern man is perhaps 50, 000 years old, civilization has existed for scarcely 10, 000 years, and the United States for only just over 200 years; but DNA and RNA have been around for at least several billion years. All that time the double helix has been there, and active, and yet we are the first creatures on Earth to become aware of its existence.

  So much has already been written about our discovery of the double helix that it is difficult for me to add much to what has already been said. “Every schoolboy knows” that DNA is a very long chemical message written in a four-letter language. The backbone of each chain is almost entirely uniform. The four letters—the bases—are joined to the backbone at regular intervals. Normally the structure consists of two separate chains, wound around one another to form the double helix, but the helix is not the real secret of the structure. That lies in the way the bases are paired: adenine pairing with thymine, guanine with cytosine. In shorthand, A=T, G≡C, each dash representing a weak chemical bond, the hydrogen bond. It is this specific pairing between bases on opposite strands that is the heart of the replication process. Whatever sequence is written on one of the chains, the other chain must have the complementary sequence, given by the pairing rules. Biochemistry is mainly based on organic chemical molecules fitting closely together. DNA is no exception. (See appendix A for a slightly more detailed account.)

  DNA was not always a familiar term, but even thirty years ago it was not entirely unknown. The physical chemist Paul Doty told me that shortly after lapel buttons came into style he was in New York and to his astonishment saw one with “DNA” written on it. Thinking it must refer to something else, he asked the vendor what it meant. “Get with it, Bud,” the man replied in a strong New York accent. “Dat’s the gene.”

  Nowadays most people know what DNA is, or if they don’t they know it must be a dirty word, like “chemical” or “synthetic.” Fortunately people who do recall that there are two characters called Watson and Crick are often not sure which is which. Many’s the time I’ve been told by an enthusiastic admirer how much they enjoyed my book—meaning, of course, Jim’s. By now I’ve learned that it’s better not to try to explain. An even odder incident happened when Jim came back to work at Cambridge in 1955. I was going into the Cavendish one day and found myself walking with Neville Mott, the new Cavendish professor (Bragg had gone on to the Royal Institution in London). “I’d like to introduce you to Watson,” I said, “since he’s working in your lab.” He looked at me in surprise. “Watson?” he said. “Watson? I thought your name was Watson-Crick.”

  Some people still find DNA hard to understand. I recall a singer in a. nightclub in Honolulu telling me how, when she was a schoolgirl, she had cursed Watson and me because of the difficult things about DNA she had to learn in biology classes. Really the ideas needed to grasp the structure are, if properly presented, ridiculously easy, since they do not violate common sense, as quantum mechanics and relativity do. I believe there is a good reason for the simplicity of the
nucleic acids. They probably go back to the origin of life, or at least very close to it. At that time mechanisms had to be fairly simple or life could not have started. Of course the very existence of chemical molecules can only be explained by quantum mechanics, but fortunately the shape of a chemical molecule can be embodied rather easily in a mechanical model, and it is this that makes the ideas easy to understand.

  For those who have not already heard how the double helix was discovered, the following brief outline may help. Astbury, at Leeds University, had taken some poor but suggestive X-ray diffraction photographs of DNA fibers. After the Second World War Maurice Wilkins, working in Randall’s laboratory at King’s College, London, had obtained some rather better ones. Randall then hired an experienced crystallographer, Rosalind Franklin, to help solve the structure. Unfortunately Rosalind and Maurice found it difficult to work together. He wanted her to pay more attention to the wetter form (the so-called B form), which gave a simpler X-ray pattern but a more revealing one than that given by the slightly drier form (the A form), though the latter gave more detailed X-ray pictures.

  At Cambridge I was working on a Ph.D. thesis about the X-ray diffraction of proteins. Jim Watson, a visiting American, then age twenty-three, was determined to discover what genes were and hoped that solving the structure of DNA might help. We urged the London workers to build models, using the approach Linus Pauling had used to solve the α helix. We ourselves produced a totally incorrect model, as did Linus Pauling a little later. Finally, after many ups and downs, Jim and I guessed the correct structure, using some of the experimental data of the London group together with Chargaff’s rules about the relative amounts of the four bases in different sorts of DNA.

  I first heard of Jim from Odile. One day when I came home she said to me, “Max was here with a young American he wanted you to meet and—you know what—he had no hair!” By this she meant that Jim had a crew cut, then a novelty in Cambridge. As time went on Jim’s hair got longer and longer, as he tried to take on the local coloration, though he never got so far as to sport the long hair that men wore in the sixties.

  Jim and I hit it off immediately, partly because our interests were astonishingly similar and partly, I suspect, because a certain youthful arrogance, a ruthlessness, and an impatience with sloppy thinking came naturally to both of us. Jim was distinctly more outspoken than I was, but our thought processes were fairly similar. What was different was our background knowledge. By that time I knew a fair amount about proteins and X-ray diffraction. Jim knew much less about these topics but a lot more about the experimental work on phages (bacterial viruses) and especially those associated with the Phage Group, led by Max Delbrück, Salva Luria, and Al Hershey. Jim also knew more about bacterial genetics. I suspect our knowledge of classical genetics was about the same.

  Not surprisingly, we spent a lot of time talking over problems together. This did not pass unnoticed. Our group at the Cavendish had started with very little—for a brief period in 1949 we all worked in one room. By the time Jim joined us, Max and John Kendrew had a tiny private office. At this point the group was offered an extra room. It was not clear at first who should have this till one day Max and John, rubbing their hands together, announced that they were going to give it to Jim and me, “… so that you can talk to each other without disturbing the rest of us,” they said. A fortunate decision, as it turned out.

  When we met Jim had already obtained his doctorate, whereas I, though some twelve years older, was still a graduate student. Maurice Wilkins, in London, had done much of the initial X-ray work, which was then taken over and extended by Rosalind Franklin. Jim and I never did any experimental work on DNA, though we talked endlessly about the problem. Following Pauling’s example, we believed the way to solve the structure was to build models. The London workers followed a more painstaking approach.

  Our first attempt at a model was a fiasco, because I thought, quite erroneously, that the structure contained very little water. This mistake was partly due to ignorance on my part—I should have realized that a sodium ion was likely to be heavily hydrated—and partly due to Jim’s misunderstanding of a technical crystallographic term that Rosalind had used in a seminar she gave. [He mixed up “asymmetric unit” and “unit cell.”]

  This was not our only mistake. Misled by the term tautomeric forms, I assumed that certain hydrogen atoms on the periphery of the bases could be in one of several positions. Eventually Jerry Donohue, an American crystallographer who shared an office with us, told us that some of the textbook formulas were erroneous and that each base occurred almost exclusively in one particular form. From that point on it was easy going.

  The key discovery was Jim’s determination of the exact nature of the two base pairs (A with T, G with C). He did this not by logic but by serendipity. [The logical approach—which we would certainly have used had it proved necessary—would have been: first, to assume Chargaff’s rules were correct and thus consider only the pairs suggested by these rules, and second, to look for the dyadic symmetry suggested by the C2 space group shown by the fiber patterns. This would have led to the correct base pairs in a very short time.] In a sense Jim’s discovery was luck, but then most discoveries have an element of luck in them. The more important point is that Jim was looking for something significant and immediately recognized the significance of the correct pairs when he hit upon them by chance—"chance favors the prepared mind.” This episode also demonstrates that play is often important in research.

  During the spring and summer of 1953 Jim Watson and I wrote four papers on the structure and function of DNA. The first appeared in Nature on April 25 accompanied by two papers from King’s College, London, the first by Wilkins, Stokes, and Wilson, the other by Franklin and Gosling. Five weeks later we published a second paper in Nature, this time on the genetic implications of the structure. (The order of the authors’ names on this paper was decided by the toss of a coin.) A general discussion was included in the volume that came from that year’s Cold Spring Harbor Symposium, the subject of which was viruses. We also published a detailed technical account of the structure, with rough coordinates, in an obscure journal in the middle of 1954.

  The first Nature paper was both brief and restrained. Apart from the double helix itself, the only feature of the paper that has excited comment was the short sentence: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” This has been described as “coy,” a word that few would normally associate with either of the authors, at least in their scientific work. In fact it was a compromise, reflecting a difference of opinion. I was keen that the paper should discuss the genetic implications. Jim was against it. He suffered from periodic fears that the structure might be wrong and that he had made an ass of himself. I yielded to his point of view but insisted that something be put in the paper, otherwise someone else would certainly write to make the suggestion, assuming we had been too blind to see it. In short, it was a claim to priority.

  Why, then, did we change our minds and, within only a few weeks, write the more speculative paper of May 30? The main reason was that when we sent the first draft of our initial paper to King’s College we had not yet seen the papers by the researchers there. Consequently we had little idea of how strongly their X-ray evidence supported our structure. Jim had seen the famous “helical” X-ray picture of the B form reproduced by Franklin and Gosling in their paper, but he certainly had not remembered enough details to construct the arguments about Bessel functions and distances that the experimentalists gave. I myself at that time had not seen the picture at all. Consequently we were mildly surprised to discover that they had got so far and delighted to see how well their evidence supported our idea. Thus emboldened, Jim was easily persuaded that we should write a second paper.

  I think what needs to be emphasized about the discovery of the double helix is that the path to it was, scientifically speaking, fairly
commonplace. What was important was not the way it was discovered but the object discovered—the structure of DNA itself. You can see this by comparing it with almost any other scientific discovery. Misleading data, false ideas, problems of personal interrelationships occur in much if not all scientific work. Consider, for example, the discovery of the basic structure of collagen, the major protein of tendons, cartilage, and other tissues. The basic fiber of collagen is made of three long chains wound around one another. Its discovery had all the elements that surrounded the discovery of the double helix. The characters were just as colorful and diverse. The facts were just as confused and the false solutions just as misleading. Competition and friendliness also played a part in the story. Yet nobody has written even one book about the race for the triple helix. This is surely because, in a very real sense, collagen is not as important a molecule as DNA.

  Of course this depends to some extent on what you consider important. Before Alex Rich and I worked (quite by accident, incidentally) on collagen, we tended to be rather patronizing about it. “After all,” we said, “there’s no collagen in plants.” In 1955, after we got interested in the molecule, we found ourselves saying, “Do you realize that one-third of all the protein in your body is collagen?” But however you look at it, DNA is more important than collagen, more central to biology, and more significant for further research. So, as I have said before: It is the molecule that has the glamour, not the scientists.