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

by Livio, Mario

  Meanwhile, in England

  Three separate events, all happening in 1951, proved to be fateful for the “race” to uncover the structure of DNA. In that year, Francis Crick, at age thirty-five, was working at Cambridge toward a PhD degree in biology after having been bored with physics. (He later described his work on the viscosity of water as “the dullest problem imaginable.”) His mathematical background would be crucial for the discoveries to come. In the same year, James Watson, then twenty-three, arrived at Cambridge to learn about X-ray diffraction from Max Perutz. Watson had completed his PhD at the University of Indiana on the effects of X-rays on viruses and later had some training in nucleic acid chemistry at the University of Copenhagen. Also in 1951, Rosalind Franklin, then thirty-one, came to King’s College, after having completed three years of research in Paris, where she became proficient in X-ray diffraction techniques.

  Franklin, who came from an erudite banking family, had earned her PhD from Cambridge in 1945. When she arrived at King’s College, physicist Maurice Wilkins was hoping that by virtue of her being an accomplished crystallographer, she would help him in his studies of molecular structure. That Wilkins would expect that of Franklin was not at all surprising, since at the time, according to Watson’s account, “molecular work on DNA in England was, for all practical purposes, the personal property of Maurice Wilkins.” This was not at all, however, what Franklin had in mind when she signed up to come to King’s, and she had good reasons for her different presumption. Sir John Randall, director of the college’s Biophysics Research Unit, had written her a letter in which he described her job as follows: “This means that as far as the experimental X-ray effort is concerned there will be at the moment only yourself and Gosling [Raymond Gosling, who was a graduate student at the time], together with the temporary assistance of a graduate from Syracuse, Mrs. Heller.” Franklin was therefore under the logical impression that she was going to be her own boss as far as the DNA work was concerned—an attitude that clearly conflicted with Wilkins’s assumptions. Consequently, Franklin and Wilkins were bound to clash, and they did. Later, they ended up working separately, even though they shared the same laboratory quarters.

  By contrast, Watson and Crick, who were sharing an office at Cambridge, hit it off right away. Watson described Crick as “no doubt the brightest person I have ever worked with and the nearest approach to Pauling I have ever seen.” The two men brought together rather different but complementary expertise, traits, and temperaments. As Crick noted in an interview, “The interest was that his [Watson’s] background was in phage work which I had only read about and did not know first hand and my background was in crystallography which he had only read about and did not know first hand.” It is amusing to read how they described each other’s personality. Referring to Crick’s assuredness, puckish wit, and habit to speak his mind, Watson wrote about him, “I have never seen Francis Crick in a modest mood.” He also added that Crick “talked louder and faster than anyone else.” On the other hand, Crick wrote about Watson, “Jim was distinctly more outspoken than I was.” Despite the different backgrounds, something clicked immediately between the two. Crick suspected that this was “because a certain youthful arrogance, a ruthlessness, and an impatience with sloppy thinking” came naturally to both of them. Their thought processes were also fairly similar. In Crick’s words, “He was the first person I had met who thought the same way about biology as I did . . . I decided that genetics was the really essential part, what the genes were and what they did.”

  There was something else that made the Watson-Crick collaboration truly powerful. Because neither of them was professionally senior to the other, they could afford to be brutally honest in criticizing each other’s ideas. This type of intellectual honesty is sometimes missing in relationships burdened by formal politeness, bowing to one’s superiority, or by one or the other pulling rank. This is how Crick himself described his interaction with Watson: “If either of us suggested a new idea, the other, while taking it seriously, would attempt to demolish it in a candid but nonhostile manner.” According to Crick, Watson “was determined to discover what genes were and hoped that solving the structure of DNA might help.” This turned out to be absolutely true.

  One may still wonder what it was that convinced Watson and Crick that the DNA structure was at all solvable rather than being an irregular mess. Conceivably, it was a talk Maurice Wilkins had given at a meeting in Naples, Italy, in the spring of 1951—a meeting that Watson attended. Wilkins succeeded in pulling extremely thin fibers of the sodium salt of DNA, and in producing X-ray photographs that were significantly superior to the ones by Astbury and Bell. The pictures showed a crystalline form of DNA, which indicated to Watson that the structure was regular. These were the same pictures that Pauling had requested from Wilkins.

  Upon receiving Pauling’s letter, Wilkins, who was fully aware of Pauling’s abilities when it came to molecular structure, did not quite know what to do about the request. Eventually, he replied politely that his pictures were not ready to share until he had the opportunity to carry out some additional investigations. Pauling did not give up, and he decided to try his luck with Randall, only to be refused again on the grounds that “it would not be fair to them [Wilkins and his collaborators], or to the efforts of our laboratory as a whole, to hand these over to you.” So by the end of 1951, Pauling was still unable to see any X-ray diffraction images of reasonable quality.

  Meanwhile, Watson and Crick were becoming increasingly obsessed with the desire to beat Pauling at deciphering the structure of DNA. The Austrian-American biochemist Erwin Chargaff, who met Watson and Crick in May 1952, gave a humorous description of the dynamic duo: “One, thirty-five years old; the looks of a fading racing tout, something out of Hogarth . . . The other, quite undeveloped at twenty-three, a grin, more sly than sheepish; saying little, nothing of consequence.” Even funnier was Chargaff’s depiction of the burning ambition of the two scientists: “So far as I could make out, they wanted, unencumbered by any knowledge of the chemistry involved, to fit DNA into a helix. The main reason seemed to be Pauling’s alpha-helix model of a protein.” Indeed, even though Pauling was unaware of it, Watson (in particular) and Crick (to some extent) saw themselves as participating in a race against him.

  One should not get the impression that Pauling was the first to introduce helical models, but he certainly had a major role in making such models the choice for molecules of biological significance. By introducing a non-integer number of amino acids per turn in his alpha-helix model, Pauling expanded further the horizons of traditional structural crystallographers. Consequently, research into the interpretation of the X-ray diffraction patterns from helical structures received a huge boost, establishing the tools for the eventual deciphering of DNA. As Crick described the general thinking around that time: “You would be eccentric, looking back, if you didn’t think DNA was helical.”

  Toward the end of 1951, events started to progress rapidly. On November 21, 1951, Watson made a trip to London to hear a colloquium by Rosalind Franklin. Even though he did not learn much new from that lecture, barely a week passed before he and Crick produced their first model for the structure of DNA. The model consisted of three helical strands and had a sugar-phosphate backbone on the inside, with the bases pointing outward. The main motivation for this particular design was simple: Since the bases were of different sizes and shapes (two were single ringed and two were double ringed; see figure 13), Watson and Crick didn’t see how the crystalline DNA could produce a highly regular pattern unless the bases were relatively uninvolved in the central architecture.

  On John Kendrew’s advice, the energized pair invited the King’s College team to see their model, even though Crick later admitted that he had felt somewhat uncomfortable to issue the invitation so soon. The overture was accepted immediately: The group of Maurice Wilkins, Rosalind Franklin, Raymond Gosling, and William Seeds (another member of the Biophysics Research Unit) showed up in Ca
mbridge the very next day.

  The presentation of the first Watson and Crick model proved to be a total disaster. Not only did Franklin question all of the basic assumptions, from the helical structure to the forces that were supposed to hold together the core, but she also pointed out that the reported water content was completely wrong—DNA was a rather “thirsty” molecule—invalidating all of Watson’s density calculations. Apparently, part of the mistake was due to Watson’s misunderstanding of a crystallographic term that Franklin had used in her seminar a week earlier. This unfortunate confusion led Crick to believe that the number of possible configurations was rather limited.

  The fiasco had meaningful consequences: Watson and Crick were essentially banned from continuing their DNA work, and all the DNA research was supposed to be confined exclusively to King’s College in London. It has usually been assumed that the directors of the two labs, Randall and Bragg, called for the moratorium on additional DNA work by Watson and Crick. However, in 2010 Alexander Gann and Jan Witkowski of the Cold Spring Harbor Laboratory in New York discovered some long-lost correspondence of Francis Crick’s. As it turned out, the missing letters had become mixed with papers of biologist Sydney Brenner, with whom Crick shared an office between 1956 and 1977. The recovered correspondence provides a new perspective on the circumstances of the suspension of the DNA research. In a formal letter dated December 11, 1951, Maurice Wilkins wrote to Crick:

  I am afraid the average vote of opinion here [at King’s College], most reluctantly and with many regrets, is against your proposal to continue to work on n. a. [nucleic acids] in Cambridge. An argument here is put forward to show that your ideas are derived directly from statements made in a colloquium and this seems to me as convincing as your own argument that your approach is quite out of the blue.

  Wilkins, continuing to assume the role of the mediator between King’s and the Cavendish, then added, “I think it most important that an understanding be reached such that all members of our laboratory can feel in future, as in the past, free to discuss their work and interchange ideas with you and your laboratory. We are two M. R. C. [Medical Research Council] Units and two Physics Departments with many connections.” Wilkins suggested further that Crick should show the letter to Max Perutz, and he informed Crick that he was giving a copy to Randall. On the same day, Wilkins also sent Crick a more personal, handwritten letter in which he confessed that he “had to restrain Randall from writing to Bragg complaining about your behavior.” A draft reply written by Watson and Crick two days later indicates that “we’ve all agreed that we must come to an amicable arrangement.” Watson however, was not going to be deterred from at least cogitating over DNA by an administrative decision.

  Meanwhile, Franklin, on her part, was making significant progress. First, she discovered that DNA occurred in two somewhat different configurations. One form, which she labeled “A,” was crystalline. The other, the “B” form, was more extended and contained more water. One of the consequences of the existence of these two conformations was that the X-ray diffraction photos of DNA samples looked confused unless produced from one pure form. Franklin spent the first five months of 1952 generating pure samples of both the A and B forms, managing to pull out single fibers of each form, and designing and reconfiguring her X-ray camera to take high-resolution pictures. As we shall see shortly, one of the photographs she had produced of the “wetter” B form, which was tagged photograph 51 (see figure 14), was about to become key for understanding the structure of DNA. Unfortunately, because Franklin decided to use a particular method of analysis, she and Gosling concentrated first on the more detailed X-ray pictures of the A form, neglecting the simpler but truly revealing X-ray pattern in photograph 51 for almost nine months!

  Figure 14

  In all of her research endeavors, Franklin exhibited a striking difference between her way of thinking and Pauling’s. Franklin abhorred “educated guesses” and heuristic methods. Rather, she insisted on relying on the X-ray data to lead her to the right answer. For instance, although she did not object in principle to helical structures, she absolutely refused to assume their existence as a working hypothesis. In contrast, Watson and Crick emulated Pauling’s approach and methods to the fullest, and they were not going to be bogged down in formal methodology. In Crick’s words, “He [Watson] just wanted the answer, and whether he got it by sound methods or flashy ones did not bother him one bit. All he wanted was to get it as quickly as possible.”

  Surprisingly, neither Watson and Crick nor Pauling knew at the time that already in 1951, Elwyn Beighton in Astbury’s lab at the University of Leeds had produced excellent X-ray photographs of the B form by stretching the DNA fibers and wetting them. However, since Astbury and Beighton apparently thought that this represented a mixture rather than a pure configuration (because the X-ray pattern was simpler than in the Astbury-Bell pictures), they did not advertise the existence of these photos at all. Unfortunately for Astbury and Beighton, neither of them was familiar with how a helix would appear in X-ray photographs. Just like that, the Leeds lab missed an opportunity to play a significant role in the DNA story.

  Back in the United States, Pauling was trying to work his magic again with DNA, in an attempt to replicate his feat with proteins. The available X-ray photos showed a strong reflection at about 3.4 angstroms, but nothing much else. As a starting point, Pauling reexamined Ronwin’s paper. Even though he was convinced that Ronwin’s proposed structure for the DNA, with the phosphorus atom connected to five oxygen atoms, was completely wrong, something in Ronwin’s suggestion attracted his attention. Ronwin had the four bases on the outside of the structure and the phosphates down the middle. This seemed to make sense to Pauling, precisely for the same reason that Watson and Crick placed the bases on the outside in their first attempt. (Pauling was unaware of that totally off-target model.) Following this line of thought, Pauling embarked again on what has become known as his “stochastic method.” The idea was to use chemical principles to pare down the list of possible structures to the most plausible ones and then to construct three-dimensional models of those in order to eliminate configurations that were packed either too tightly or too loosely. He could then check the emerging “best-bet” arrangement against the experimental X-ray diffraction pattern.

  Having had great success with this method on previous occasions, Pauling thought that he knew exactly which steps to follow. First, he had little doubt that the molecule was helical, and the Astbury-Bell photographs seemed to be generally consistent with this assumption. Second, two of the bases were double ringed and two were single ringed. The different constructions and dimensions made it difficult, at least at first glance, to have the core of a helix—which appeared to be regular—be composed of the bases. The next step was to figure out how many strands the helix should have. Pauling decided to attack this problem by calculating the density of the structure. However, before he was even able to start, an unexpected distraction stopped him in his tracks.

  Life Under McCarthyism

  In the Cold War atmosphere that followed World War II, and in particular after the passage of the Internal Security Act of 1950, the US State Department’s Passport Division was given almost unlimited authority to deny passports to anyone it deemed to be too “leftist.” Pauling applied to renew his passport in January 1952, as he was preparing to attend a Royal Society meeting in London the following May. Pauling and Corey had both been invited to present their work on proteins and the alpha-helix at that conference, and Pauling was also planning to take advantage of this trip to Europe to visit a few universities in Spain and France. Then on February 14, 1952, Ruth B. Shipley, head of the Passport Division, sent Pauling a letter that could hardly be considered a Valentine’s Day card. She informed him that his passport could not be issued, since the department was of the opinion that his travel “would not be in the best interest of the United States.”

  In the then-prevailing mood, given Pauling’s many pacifist speeches,
his activism against nuclear weapons, and his declaration that “the world now stands at a branch in the road, leading to a glorious future for all humanity or to the complete destruction of civilization,” it was perhaps not entirely shocking that Shipley would surmise that “there is good reason to believe that Dr. Pauling is a Communist.”

  At first, Pauling regarded the refusal merely as an annoying inconvenience, and he was convinced that the problem would be resolved easily. To speed things up, he immediately sent a letter to President Harry Truman, to which he attached a copy of his 1948 Presidential Medal for Merit, signed by Truman. Pauling wrote in frustration, “I am confident that no harm whatever would be done to the Nation by my proposed travel.” The president’s secretary replied politely that the Passport Division had been asked to reevaluate its judgment. Still, the decision was not reversed. In April, with an increasing sense of urgency, Pauling took a series of actions: First, he asked for the assistance of a lawyer. Second, he supplied the Passport Office with loyalty oaths and affidavits declaring he was not a Communist. Finally, he arranged to meet in person with Ruth Shipley. All of this was to no avail. The conclusive denial of the appeal was announced on April 28, and the next day, Pauling notified the organizers of the Royal Society meeting of his inability to attend.

  Predictably, Pauling’s passport trials and tribulations infuriated scientists worldwide. Sir Robert Robinson, the Nobel laureate chemist from England, wrote a letter to the London Times expressing his “consternation.” Leading American and British scientists, including physicists Enrico Fermi and Edward Teller, biologist Harold Urey, and crystallographer John Bernal, wrote letters in protest, and French biochemists elected Pauling to be the honorary president of an International Biochemical Congress scheduled to take place in Paris in July.