Brilliant Blunders: From Darwin to Einstein - Colossal Mistakes by Great Scientists That Changed Our Understanding of Life and the Universe (21 page)

There were only two things left to do that day. First, Crick hurried to Perutz and Kendrew to convince them that urgency was of the utmost importance. Unless he and Watson got busy with modeling immediately, he argued, it wouldn’t be long before Pauling discovered his mistake and revised his model. Crick estimated that they had no more than about six weeks to come up with a correct model. Watson and Crick’s second action was equally obvious to the two young men:
They went to celebrate at the Eagle Pub on Bene’t Street. Watson later recalled, “As the stimulation of the last several hours had made further work that day impossible, Francis and I went over to the Eagle. The moment its doors opened for the evening we were there to drink a toast to the Pauling failure.”

How could this blunder have happened? Why was Pauling’s model-building approach so spectacularly successful with the alpha-helix and so disastrously ineffective with the triple helix?

Let’s attempt to analyze, one by one, the causes for Pauling’s failing. First, there was the issue of how much time and how much thought he had actually put into solving DNA. Pauling started to think about some aspects of the DNA structure following Ronwin’s paper in November 1951. However, it wasn’t until November 1952, a full year later, that he commenced working earnestly on the problem. Yet by the end of December 1952, after just about a month’s work, he’d already submitted his paper! Compare this to his exertion on the polypeptide structure, where he thought about the issues for about thirteen years, delaying publication several times until he was fairly confident in his model. So, even just in terms of the time invested into thinking about DNA, there is no escape from the conclusion that the DNA model was a rush job. Maurice Wilkins certainly thought so. In an interview on the history of the discovery of DNA structure, he remarked,
“Pauling just didn’t
try.
He can’t
really have spent five minutes on the problem himself.” We shall return later to the question of the possible reasons for this haste and apparent lack of focus.

Second, there was a huge difference between the quality of the data on the basis of which Pauling constructed his model for proteins and his model for DNA. In the case of the alpha-helix, Pauling’s collaborator, Robert Corey, had produced a vast arsenal of structural information on sizes, volumes, and angular positions for amino acids and simple peptides. For DNA, by contrast, Pauling was operating almost in a vacuum. The only X-ray photographs available to him were of poor quality and had been produced from a mixture of the A and B forms (unbeknown to him), rendering them almost useless. Worse yet, Pauling was unaware of the high water content of the preparations from which the X-ray diffraction photos were taken. By neglecting the fact that more than one-third of the material in the DNA specimens was water, Pauling obtained a wrong density, which led him to the wrong conclusion of three strands. Lastly, unlike Corey’s extensive work on the building blocks of proteins, there was no equivalent effort on the bases—the subunits of the nucleotides.

Then there were the two astounding memory lapses: one about Chargaff’s base ratios and one about Pauling’s own self-complementarity principle. Chargaff’s findings that the amount of the A base was equal to that of T, and the amount of C equal to that of G, argued for the bases somehow pairing with each other and producing two strands rather than three. Pauling claimed later that he had known about these ratios but had forgotten. Chargaff himself thought that this was
the
reason for Pauling’s blunder, saying, “Pauling in
his
structural model of DNA
failed to take account
of my results. The consequence was that his model did not make sense in the light of the chemical evidence.”

Pauling’s second memory failure was even more astonishing. Recall that Pauling had said in 1948 that if genes consisted of two parts that were complementary to each other in structure, replication was relatively straightforward. In that case, each of the parts
could serve as a mold for the production of the other part, and the complex of the two complementary parts as a whole could serve as a mold for a duplicate of itself.
Clearly, this principle of self-complementarity suggested strongly a two-stranded architecture, and it was markedly at odds with a structure consisting of three strands. Yet Pauling had apparently completely forgotten this principle by the time he constructed his DNA model.

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 researchers 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.