Brilliant Blunders: From Darwin to Einstein - Colossal Mistakes by Great Scientists That Changed Our Understanding of Life and the Universe

by Livio, Mario

  When I talked to Alex Rich and Jack Dunitz, who were Pauling’s postdocs at the time, both agreed that had Pauling seen Rosalind Franklin’s X-ray photograph 51 of the B form of DNA, he would have realized immediately that the molecule possessed a two-fold symmetry, pointing to a double-stranded rather than a three-chain structure. As we have seen, however, Pauling made no special effort to see Franklin’s photographs.

  In January 2011, I asked James Watson how surprised he was when he saw Pauling’s erroneous triple-helix model. Watson laughed. “Surprised? You could not have written a fictional novel in which Linus would have made an error like this. The minute I saw that structure, I thought, ‘This is wacko.’ ”

  A close examination of the many potential causes for Pauling’s calamitous model raises a series of questions at a deeper level: How can we explain the haste, the apparent lack of exertion, the forgetfulness, and the disregard for some of the basic rules of chemistry?

  On the face of it, the haste is particularly puzzling if we accept Peter Pauling’s testimony that there never was a “race” to solve the DNA structure. In the same entertaining account in which he noted that to his father DNA was just another interesting chemical, Peter added, “The story of the discovery of the structure of DNA has been described in the popular press as ‘the race for the double helix.’ This could hardly be the case. The only person who could conceivably have been racing was Jim Watson.” Peter explained further that “Maurice Wilkins has never raced anyone anywhere,” and that Francis Crick simply liked “to pitch his brain against difficult problems.” I asked Alex Rich and Jack Dunitz about it, and neither of them thought that there was a race as far as Pauling was concerned. Why, then, did he hurry so much to publish? “Because he was always competitive,” Rich suggested. This is certainly true, but it can be only part of the explanation, since Pauling had shown so much more caution and patience in the case of the alpha-helix. Ironically, his triumph with the alpha-helix had no doubt contributed to his defeat with the triple helix, since Pauling assumed, based on his success with the former, that he could reproduce the accomplishment with the latter. In this sense, this was a classical case of inductive reasoning: the common strategy of probabilistic guessing based on past experience—taken way too far.

  Everyone engages in inductive reasoning all the time, and usually it helps us make correct decisions based on relatively little data. Suppose I ask you, for instance, to complete this sentence: “Shakespeare was a uniquely talented ___.” Most people would probably answer “playwright,” and they would be perfectly justified in doing so. While there is nothing illogical with completing the sentence with “cook,” or “card player,” chances are that the word sought for was indeed “playwright.” Inductive reasoning is what allows us to use our cumulative experience to solve problems through the choice of the most likely answer. Like experienced chess players, we do not typically analyze every possible logical answer. Rather, we opt for what we think is the most probable one. This is an essential part of our cognition. Psychologist Daniel Kahneman described the process this way: “We can’t live in a state of perpetual doubt, so we make up the best story possible and we live as if the story were true.” However, because inductive reasoning involves probabilistic guesswork, it also means that sometimes it gets things wrong, and occasionally, it can get things very wrong. Pauling thought that he could take a shortcut, because past experience had shown him that all of his structural hunches turned out to be correct. In the DNA failure, the blunderer was a victim of his own previous brilliance.

  Why, however, did he feel that he needed to cut corners at all? Certainly not because of Watson and Crick—he was barely aware of their endeavors—but because he did know that King’s and perhaps even the Cavendish had access to superior X-ray data. He must have assumed that it would not be too long before his old rivals Bragg, Perutz, Kendrew, or perhaps Wilkins would figure out the correct structure. He decided to gamble, and he lost.

  But there is very little doubt that had Pauling significantly delayed publication of his model, some researchers from Cambridge or London would have published their correct model first. Even though Pauling did not think specifically about Watson and Crick, he did know that the competition had the better hand. Therefore, taking a calculated risk may not have been altogether crazy.

  On a more speculative note, Pauling’s decision to rush publication may also have been related to a human cognitive bias known as the framing effect, which reflects a strong aversion to loss. Have you ever wondered why stores generally advertise ground beef as being “90 percent lean,” rather than “10 percent fat”? People are much more likely to buy it with the former label, even though the two labels are equivalent. Similarly, people are more likely to vote for an economic agenda that promises 90 percent employment than for one that emphasizes 10 percent unemployment. Numerous studies show that the degree to which we perceive loss as devastating is higher than the degree to which we perceive an equivalent gain as gratifying. Consequently, people tend to seek risks when presented with a negative frame. Pauling may have preferred to take the risk when faced with the possibility of a probable loss.

  There is also the puzzling issue of Pauling’s forgetting the Chargaff rules and, more importantly, his own insights on the self-complementarity of the genetic system. I believe that the latter was a strong manifestation of the fact that even when he finally decided to work on DNA, Pauling was still not entirely convinced that this molecule truly represented the very secret of life—the mechanism of cell division and heredity. Four main clues lead me to this conclusion: (1) There is Peter’s testimony that to his father DNA was just another interesting chemical and nothing more. Pauling was, after all, a chemist and not a biologist. (2) In his letter to the president of the Guggenheim Foundation announcing his “discovery” of the structure of DNA, Pauling added this, rather lukewarm, sentence: “Biologists probably consider that the problem of the structure of nucleic acid is fully as important as the structure of proteins” (note the noncommittal flavor of the phrase “Biologists probably consider”). (3) We have the pointed question that Pauling’s wife, Ava Helen, asked him after all the hoopla surrounding the publication of the Watson and Crick model had subsided: “If that was such an important problem, why didn’t you work harder on it?” (4) The Pauling and Corey paper itself (on the triple helix) provides what is perhaps the most convincing piece of evidence for Pauling’s lack of confidence in DNA’s importance. Pauling and Corey discuss the biological implications of their model only obliquely. In the opening paragraph of their paper, they mention halfheartedly that evidence exists that the nucleic acids “are involved” in the processes of cell division and growth, and that they “participate” in the transmission of hereditary characters. Only in the last paragraph of the original manuscript do they vaguely address the topic of coding of information (but not of copying), noting, “The proposed structure accordingly permits the maximum number of nucleic acids to be constructed, providing the possibility of high specificity.” I believe that this lack of conviction on Pauling’s part about the crucial role of DNA was at the core of the reality that the topic of heredity—and Pauling’s important pronouncements on it—apparently remained largely disconnected in his mind from the problem of the structure of DNA.

  Forgetting Chargaff’s rules is, in my opinion, less mysterious. First, Pauling’s personal dislike for Erwin Chargaff surely contributed somewhat to his lack of attention to Chargaff’s results. Second, recall that Pauling was continuously distracted during his work on DNA. Enmeshed in his attempts to complete the work on proteins and in his bitter political struggles with McCarthyism, he barely had any time left to concentrate. Actually, on March 27, 1953, just two months after Peter received the manuscript on DNA, Pauling wrote a letter to Peter in which he commented, “I am just putting the final touches on my paper on a new theory of ferromagnetism.” He was already thinking of something else! This hardly could have helped. Extensive studies by Swedish researc
hers showed that natural memory problems (known as benign senescent forgetting) occur much more frequently when attention is divided or has to be shifted rapidly. Therefore, Pauling’s not remembering Chargaff’s rules is not very surprising.

  Finally, there is the truly dumbfounding question of why Pauling ignored some basic rules of chemistry in his model, such as those concerning the acidity of DNA. The world’s most celebrated chemist fumbling in some elementary chemistry?

  I asked molecular biologist Matthew Meselson about his thoughts on this aspect of the blunder. Meselson, Pauling’s graduate student at the time, conjectured that Pauling might have considered the problem and had convinced himself that it could somehow be overcome. This would certainly be consistent with Pauling’s general frame of mind throughout the entire DNA model-building episode. His thought process must have been something like this: He had a highly successful model for proteins, which consisted of a helical strand with side chains on the outside. He therefore thought that the model for DNA would be that of interwoven strands, also with side chains (the bases, in this case) on the outside. This created a packing problem along the axis, but all the rest of the characteristics, in Pauling’s mind, were in some sense details to be sorted out later. Again, his previous success with the alpha-helix apparently had a blinding effect. Unfortunately, as we know only too well, the devil is often in precisely those details.

  In my conversation with Jack Dunitz, he recalled that Pauling had once told him something that summarized beautifully his attitude toward scientific research:

  Jack, if you think you have a good idea, publish it! Don’t be afraid to make a mistake. Mistakes do no harm in science because there are lots of smart people out there who will immediately spot a mistake and correct it. You can only make a fool of yourself and that does no harm, except to your pride. If it happens to be a good idea, however, and you don’t publish it, science may suffer a loss.

  Dunitz added that indeed the three-stranded structure did no harm, except to Pauling’s reputation. He commented further that Pauling had made enough major contributions that we should simply forgive and forget. I must say that I fully agree with the “forgive” part, but I actually think that we should not forget. As I have attempted to show, there are many insights that can be gained from analyzing such blunders by brilliant individuals.

  Seeing Double

  The rest of the story of the discovery of the structure of DNA has been told and retold numerous times, but the recently discovered correspondence of Francis Crick does shed some new light on the frantic activity that preceded the publication of the Watson and Crick model.

  Pauling’s blunder served as the catalyst that convinced Bragg to allow Watson and Crick to go back to DNA modeling. Within a couple of weeks, Watson went to London, where Wilkins, also pleased with Pauling’s glitch, took the liberty of showing him Franklin’s famous photograph 51 of the B form of DNA (figure 14), without Franklin’s knowledge. Much ink has been devoted to the question of the ethical nature of this particular act. In my humble opinion, three main parts to this story deserve attention. First, there was apparently no problem with Wilkins himself having a copy of the photo (given to him by Gosling), since Franklin was about to leave King’s to work at Birkbeck College, and she had been informed by the lab director, Sir John Randall, that the results of all the DNA work belonged exclusively to King’s. Second, there is little doubt (in my mind at least) that Franklin should have been consulted before her unpublished results were shared with members of another laboratory. Finally, there is disagreement on whether or not Watson and Crick acknowledged Franklin’s contribution adequately in their paper. You can be the judge of that. They wrote, “We have also been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr. M. H. F. Wilkins, Dr. R. E. Franklin and their co-workers at King’s College, London.” Be that as it may, the effect the photo had on Watson was dramatic: The dark cross was the unmistakable sign of a helical structure. No wonder that, as he later described, his “mouth fell open,” and his “pulse began to race.”

  Watson and Crick spent the following weeks trying frantically to build models in which the bases would form the rungs of the helical ladder they had in mind. The first attempts were unsuccessful. Ignoring the clue from Chargaff’s ratios, Watson mistakenly thought that he should pair every base with its twin, forming rungs composed of adenine-adenine (A-A), cytosine-cytosine (C-C), guanine-guanine (G-G), and thymine-thymine (T-T). However, since the bases C and T were different in length from G and A, this created rungs of unequal lengths, which was inconsistent with the symmetric pattern exhibited in photograph 51. There was also the question of the bond between the two bases in each rung and between the rung and the “legs” of the ladder (which were supposed to be composed of sugars and phosphates). Here again Watson and Crick were heading the wrong way, but their office mate Jerry Donohue came to the rescue. As a former student of Pauling’s, Donohue knew everything there was to know about hydrogen bonds. Donohue pointed out to Watson and Crick that even many textbooks had the hydrogen atoms in the wrong positions in thymine and guanine. Placing these atoms in their correct locations opened new possibilities for bonding the bases to each other. By shifting the bases in and out of other pairing possibilities (than the like-with-like), Watson suddenly realized that an A-T pair held together by two hydrogen bonds was identical to a G-C pair held similarly. The rungs became of equal length. Moreover, this pairing provided a natural explanation to Chargaff’s rules. Clearly, if A always paired with T, and G with C, then the numbers of A and T molecules in any section of DNA would be equal, and similarly for G and C. Another source of valuable information became available around that time via Max Perutz: a copy of Franklin’s report, written for a visit of the Medical Research Council biophysics committee to King’s. From the symmetry of the crystalline DNA described in that report, Crick concluded that the two strands of DNA were antiparallel—they ran in opposite directions.

  Figure 15

  The resulting structure was the celebrated double helix, in which the two helical strands (the backbones) were made of alternating phosphates and sugars, with the paired bases attached to the sugars and making the rungs (figure 15). At this point, Watson and Crick were so convinced of the correctness of their model that they were eager to submit a short paper to Nature to announce it. Even before that, according to Watson’s by-now-famous description, Crick interrupted patrons’ lunchtime at the Eagle to make public that he and Watson had “discovered the secret of life.” Figure 16 shows the spot in the Eagle where Crick made the announcement. On March 17, 1953, Crick sent a copy of the paper to Wilkins. One of the recovered documents in Crick’s “lost” correspondence is a draft of the letter that was to accompany the manuscript. Part of it reads:

  Figure 16

  Dear Maurice,

  I enclose a draft of our letter. As it has not yet been seen by Bragg I would be grateful if you did not show it to anyone else. The object of sending it to you at this stage is to obtain your approval of two points:

  a) the reference number 8 to your unpublished work.

  b) the acknowledgement.

  If you would like either of these rewritten, please let us know. If we don’t hear from you within a day or so we shall assume that you have no objection to their present form.

  This draft and another one addressed to one of the editors of Nature (which apparently was never mailed) show that Crick and Watson were at first under the impression that theirs was the only manuscript to be submitted at that time. Actually, the two groups at King’s submitted papers to Nature as well. In a brief note to Crick probably written on the same day, Wilkins says, “Herewith almost uncorrected draft. How should we refer to your note?” This accompanied a draft of Wilkins’s own manuscript. The third paper was by Rosalind Franklin and Raymond Gosling.

  Once he realized the situation, Crick expressed his view that everyone should see everyone else’s manuscript: “It is not
reasonable for letters to be sent jointly to Nature without having been read by all concerned. We want to see hers [Franklin’s], and I’ve no doubt she wishes to see ours.” Wilkins agreed. In a newly found letter dated “Mon.,” probably referring to Monday, March 23, he said, “We will post a copy of Rosy’s thing to you tomorrow,” adding, “Raymond and Rosy have your thing so everybody will have seen everybody else’s.”

  Perhaps the most fascinating part of the new correspondence, however, is related to Pauling. First, Crick expressed his displeasure with the fact that Franklin might want to see Pauling on his forthcoming visit to England. “It is not impossible,” he wrote to Wilkins, “that she might consider turning over the experimental data to Pauling. This would inevitably mean that Pauling would prove the structure and not you.” To which Wilkins responded with irritation: “If Rosy wants to see Pauling, what the hell can we do about it? If we suggested it would be nicer if she didn’t that would only encourage her to do so. Why is everybody so terribly interested in seeing Pauling . . . Now Raymond [Gosling] wants to see Pauling too! To hell with it all.” This exchange is a perfect demonstration of the awe that Pauling continued to inspire even at one of the lowest moments in his career.