What Mad Pursuit

by Francis Crick

  The program closely follows the main lines of the story. It shows Rosalind in Paris, with her friend and scientific advisor Vittorio Luzzati, before she moved to King’s College, London, to work on DNA in John Randall’s lab there. It rather overemphasizes the differences Rosalind found, as a woman, between Paris and London. Maurice and Rosalind’s failure to collaborate is brought out clearly. At Cambridge we see Jim being introduced to the college scene by Max Perutz, then meeting me. The fiasco of our first model-building attempt and the reactions of the King’s workers are clearly delineated, though our telling-off by Bragg is quite fictitious. Other scenes include our meeting with Chargaff and our discussion with John Griffith about base pairing. Brash young Peter Pauling, Linus’s son, is seen arriving in Cambridge. A little later he produces a copy of his father’s scientific paper with the incorrect three-chain model of DNA. Rosalind loses her temper with Jim when he comes to London to show her Linus’s paper. Maurice, in sympathy, shows Jim the revealing photograph of the B form, which Rosalind had taken but had put aside while she plodded on with the more detailed photos of the A form. Viewers had previously been prepared, so that they would appreciate the significance of this photo, by a little lecture I give to Jim on the diffraction of X rays by a helix. There is no doubt that seeing this dramatic photo prodded us into action, but in fact much of its data were made available to us in other ways.

  Finally we see Jerry Donohue telling us that we had the wrong formulas [tautomeric forms] for the bases, so that Jim was able to hit on the correct base pairs. After that the model was almost inevitable. We see a very hyped-up version of this climax, followed by a stream of visitors, while the model of the double helix appears to rotate to celestial music. The film ends with Rosalind viewing the model and Jim chatting to his sister on a bridge over the Cam.

  It is difficult for me to pass judgment on Life Story because I had been so close to the actual events. Almost everyone enjoys watching the tale as it unfolds on the screen. In spite of the intention to soft-pedal the science, a surprisingly large amount has been included, though I doubt if most viewers realize that DNA is not a short fat molecule but a long thin one. If we had made our model a more typical length it would have reached well above the clouds. The model we built was only a tiny fraction of the sort of lengths found in nature.

  It is obviously unfair to criticize the BBC for not achieving complete factual accuracy. Anyone interested in knowing what really happened will get much closer to the truth by reading the printed accounts described earlier. What Life Story was trying to do was to get over the general nature of the discovery and to show in broad terms how it was done and how it was received.

  The BBC, while striving to be factually correct, had no qualms in telescoping incidents and shifting scenes. The conversation among Maurice, Jim, and myself, shown as taking place in the college gardens near the river, actually occurred in my dining room at home. The party, with the men dressed as clergymen, in reality took place at Peter Mitchell’s house; but the conversation between John Griffith and myself at that party occurred in a quiet pub. Nor did we meet Chargaff over a college dinner. But these translocations seem to me to be perfectly acceptable, since they get over important parts of the story and also the local atmosphere, even if the combinations shown were not the real ones.

  There are a few more significant errors. Surprising as it may seem, I don’t believe that Chargaff’s rules were in the forefront of Jim’s mind when he first stumbled on the correct base pairs. A more serious mistake are the words put into Rosalind’s mouth. She says to Maurice Wilkins, “But you may be guessing right or you may not. We won’t know until we’ve done the work. When we’ve done the work we won’t need the guesses because we’ll know the answer. [So] what’s the point of the guesses?”

  This argument appears, on the surface, to have considerable force, but it is incorrect. As explained earlier, the X rays provide only half the required data. For this reason a good model is worth its weight in gold, especially if, as in the DNA case, the X-ray reflections are rather few. Rosalind is unlikely to have said such words. If she had, it would have shown that she had not adequately grasped the problem confronting her.

  It is implied, but not actually stated, that Rosalind and her Paris companion were lovers. I would be very surprised if this were true. Vittorio, who is a more lively character than the one portrayed in the film, was in fact a married man. Rosalind was friendly with both the Luzzatis, as she was later with Aaron Klug and his wife and with Odile and myself. I think Rosalind rather liked such friendships, since she could interact scientifically with the husband while enjoying the company of both partners. She would be friendly and relaxed without any danger of sexual involvement. Vittorio was at that time her closest scientific advisor, but he had little experience of solving structures of organic molecules in the Pauling manner so that his advice, though superficially sound, was in fact somewhat misleading.

  The treatment has a number of interesting weaknesses. The scriptwriter, Bill Nicholson, was delighted to learn about the fiasco of our first model, because this seemed to fit a standard dramatic format. As he put it, “Boy meets girl; boy loses girl; boy gets girl,” or, as he explained to me, a failure in the middle of the action gets the audience’s sympathy on the side of the two “heroes.” I could not help reflecting that when we made our blunder about the water content we were not trying to give dramatic shape to our efforts. We were hoping we had arrived at the correct structure.

  The rapid cutting backward and forward between London and Cambridge as the climax approaches does correspond to the facts, even though the excitement is in a god’s-eye view of the action, but the whole flavor of the ending has been distorted to make a theatrical climax. Although we were excited when we discovered the double helix, neither we nor anybody else thought of it as a wild success. Indeed Jim worried that it might be all wrong and that we’d again made fools of ourselves. Consequently the celebrations and the congratulations are figments of the scriptwriter’s imagination. Most people would have described the structure as “interesting” or “very suggestive,” but few would be confident at that stage that the double helix was really correct. Even less excusable is the “literary” twist given at the end. The idea that Jim was sobered (during the fictitious conversation on the bridge with his sister) because he had achieved all his aims is quite untrue to life. Moreover it fails to get over the true “ending"—that the double helix was not an ending but a beginning, because of all the ideas it suggested about gene replication, protein synthesis, and so on. This is what we worried about for the rest of the summer and for many years to come. Talk of prizes and success only came much later. When I returned to Cambridge from the States in the late summer of 1954 the Medical Research Council did not feel they had to give me tenure, although by then I was thirty-eight. They offered me a seven-year appointment, though a year or so later they converted this to an indefinite appointment (equivalent in the MRC to tenure).

  As to the actors, I think Jeff Goldblum is too manic as Jim and far too interested in girls. “Nobody told me Jim didn’t chew gum,” Mick Jackson complained to me, but if he had looked carefully he would have discovered that almost no scientists chew gum, not even brash young American ones. Jim’s natural manner was more subdued. Goldblum caught it rather well in the costume party scene, when he is asked if he is a real vicar (an Anglican clergyman). Incidentally, at the actual party Jim replied that he was. His questioner, a young American woman, quizzed him for half an hour about the spiritual upbringing of her children and was rather cross when she eventually discovered that he was not a clergyman at all.

  As to the other actors, Max Perutz, Raymond Gosling, Maurice Wilkins, Peter Pauling, and Elizabeth Watson are immediately recognizable, but the really key performance is that of Juliet Stevenson as Rosalind. She is not only the true center of the film—she is almost the only person who really appears to be doing science—but we have a more complex inside view of her than of most of the o
ther characters. I don’t think this interpretation of Rosalind was an accident. Miss Stevenson’s comments, quoted in the Radio Times, show that she had considerable insight into Rosalind’s abilities and character. Moreover the scriptwriter has conveyed the general nature of Rosalind’s error of judgment about the best method for solving the problem.

  What, then, is one to make Life Story? It certainly gets over the obvious fact that scientific research is performed by human beings, with all their virtues and weaknesses. There is no trace of the stereotyped emotionless scientist, solving problems by rigid logic. It shows, at least in outline, how one kind of science is done, though most research is more plodding and less dramatic than the discovery of the double helix. It even puts over, in an elementary way, a certain amount of basic scientific information. Most important of all, it tells a good story at a good pace, so that people from all walks of life can enjoy it and absorb some of these lessons in the process. All in all, in spite of its limitations, Life Story must be considered a success. In other hands it could easily have been nothing quite as good.

  8

  The Genetic Code

  WITH THE DOUBLE HELIX clearly in view, the next problem was, what did it do—how did it influence the rest of the cell? We already knew the answer in outline. Genes determined the amino acid sequence of proteins. Because the backbone of the nucleic acid structure appeared so regular we assumed, correctly, that it was the base sequence that carried this information. Since the DNA was in the nucleus of the cell and since protein synthesis seemed to take place outside the nucleus, in the cytoplasm, we imagined that a copy of each active gene had to be sent to the cytoplasm. As there was plenty of RNA there, and no apparent trace of DNA, we assumed that this messenger was RNA. It was easy enough to see how a stretch of DNA would make an RNA copy—a simple base-pairing mechanism could do the trick—but it was less easy to see how the resulting messenger RNA (as we would now call it) could direct protein synthesis, especially as very little was then known about this latter process.

  Moreover there was an informational problem. We knew there were about a couple of dozen different kinds of amino acids—the little units from which protein chains were made—yet there were only four different kinds of bases in DNA and RNA. One solution would be to read the nucleic acid sequence two bases at a time. This would yield only sixteen (4 × 4) possibilities, which seemed too few. Another alternative was to read them three at a time. This would give sixty-four (4 × 4 × 4) possible combinations of the four bases A, T, G, and C. This seemed too many.

  It may help you to understand what follows if I outline our present knowledge of the genetic code. Unfortunately the phrase “genetic code” is now used in two quite distinct ways. Laymen often use it to mean the entire genetic message in an organism. Molecular biologists usually mean the little dictionary that shows how to relate the four-letter language of the nucleic acids to the twenty-letter language of the proteins, just as the Morse code relates the language of dots and dashes to the twenty-six letters of the alphabet.

  I shall use the term in this latter sense. The details are set out in appendix B, which displays the little dictionary in the form of a table. The details of the table need not concern the lay reader. All you need to know is that the genetic message is read in non-overlapping groups of three bases at a time (for RNA, the bases being A, U, G, and C). Such a group is called a codon, a term invented by Sydney Brenner. It turns out that just twenty kinds of amino acids are coded for. In the standard code two amino acids have only one codon apiece, many have two, one has three, several have four, and two of them have six codons. In addition there are three codons for “end chain” (“start chain” is a bit more complicated). These add up to sixty-four codons in all. No codon is unused.

  The proper technical term for such a translation rule is, strictly speaking, not a code but a cipher. In the same way the Morse code should really be called the Morse cipher. I did not know this at the time, which was fortunate because “genetic code” sounds a lot more intriguing than “genetic cipher.”

  An important point to notice is that although the genetic code has certain regularities—in several cases it is the first two bases that encode one amino acid, the nature of the third being irrelevant—its structure otherwise makes no obvious sense. It could well be that it is mainly the result of historical accidents in the distant past. Of course none of this was known in 1953 when the double helix was first discovered.

  Jim and I had discussed the problem of protein synthesis in a desultory fashion that summer, but DNA itself was giving us so much to worry about—was the structure really correct? how exactly did it replicate itself?—that we had not seriously come to grips with it.

  One day a letter arrived from America written in a large, round, unknown hand. We found we had already heard of its author, the physicist and cosmologist George Gamow, but the contents of the letter were quite new to us. Gamow had been intrigued by our papers in Nature. (Indeed we sometimes felt that physicists took more notice of them than biologists.) He jumped to the conclusion that the DNA structure itself was a template for protein synthesis. He noticed that, looked at in a certain way, the structure could have twenty different kinds of cavities, depending on the local sequence of the bases. Since there are about twenty different kinds of amino acids used to form the chains of proteins, he boldly assumed that there was just one type of cavity for each amino acid.

  As we sat and studied Gamow’s letter at the Eagle, Jim and I realized that we had never actually counted the exact number of types of amino acids found in proteins. It was not a completely straightforward matter, since there are many possible amino acids, only a few of them are found in living creatures, and not all of these occur in proteins. Protein chemists had discovered well over twenty amino acids in one protein or another, but some of these, such as hydroxyproline, were found in only one or two proteins and not in the general run of them.

  Gamow had given his list of the magic twenty, but we immediately saw that some of them were unlikely and that he had left out some obvious candidates, such as asparagine and glutamine. There and then we wrote out our own list. I don’t recall that Jim knew a lot about the finer points but fortunately I had by then acquired a detailed knowledge of many aspects of protein structure. The basic idea we used was that the amino acids that had been claimed to be in proteins should be classified either as members of a “standard” set or as “freaks.” Any amino acid that was known to occur in many different proteins, such as alanine, was accepted as one of the standard set. An amino acid that occurred in only a few odd proteins, such as bromotyrosine, we classified as a freak. We also rejected any amino acid that, although it occurred in a polymer in the cell, had not yet been shown to exist in a true protein. Diaminopimelic acid, which is found in the cell walls of certain bacteria, fell into this class.

  We did not insist that every protein had to have all the members of the standard set, since in a small protein one of the less common ones might be missing by chance, because its polypeptide chain contained rather few amino acids (the lack of tryptophan and methionine in insulin would be an example). To our astonishment, we arrived at exactly twenty. Rather remarkably, our list has turned out to be essentially correct. Unknown to us, Dick Synge, one of the inventors of modern chromatography, had drawn up a similar list, but his had one extra candidate—cystine as well as cysteine—which was fairly obviously unlikely.

  It is worth noting that all the writers of biochemical textbooks had a much longer list. In the early part of the century, the discovery of a new amino acid that occurred in proteins was an important event. While those days were past, the glamour of the quest still hung around. A new amino acid, once its occurrence in a protein had been firmly established experimentally, was still deemed an important discovery and, as such, went into the textbooks. The idea that there might be a standard set of amino acids and that the rest were, in some sense, freaks had not penetrated to most biochemists, though obviously some protein chemis
ts thought that way even if they had not formulated their ideas explicitly. We now know the proteins are synthesized by a very special mechanism that can handle only a limited number of amino acids. The others, the “freaks,” are mostly standard amino acids that have been modified by extra processes after the polypeptide chain has been synthesized.

  This is a nice example of complexity of nature produced by natural selection. It shows how easily one can be misled if one takes too straightforward a view of a biological problem. Of course, we were fortunate to have hit on the correct standard set at our first attempt. It was a lucky guess and needed to be confirmed by many additional experiments. While it took some years for biochemists to do this, that our list was correct was never seriously in doubt. Although there was occasional conflicting evidence, our list has stood the test of time. The only omission was the use of formylmethionine for chain initiation in prokaryotes, and this would have been impossible for us to foresee.

  I cannot remember whether Gamow’s first letter included a manuscript (I think this arrived a little later), but when we did get a copy—I still have it somewhere—we were surprised to see that Gamow had listed Tomkins as a coauthor. Gamow was well known as a popular science expositor, with a somewhat whimsical style. Mr. Tomkins, Gamow’s Everyman, was a character in several of his books and usually appeared in the title (Mr. Tomkins Explores the Atom, for example). Alas, before the paper was finally published the mythical Mr. Tomkins was removed by a stern editor.