Genes, Girls, and Gamow

by James D. Watson

  The week that followed was initially dominated by the removal of a lower wisdom tooth. I masked the resulting discomfort by browsing through the mammoth 900 pages of In the Matter of J. Robert Oppenheimer, the verbatim transcript of the Atomic Energy Commission (AEC) hearings that had just led to the removal of Oppenheimer’s security clearance. Before leading the Los Alamos team, which built the first atomic bomb, Oppenheimer taught both at Caltech and Berkeley and still had many Caltech friends. The hearing centered on whether Oppenheimer’s reluctance to work on much more powerful hydrogen bombs reflected a hidden pro-Soviet agenda. In the 1930s Oppenheimer’s politics were far to the left, and the question arose whether several brief meetings with American communist friends after he went to Los Alamos had transferred vital information to the Soviets about our two-billion-dollar Atom Bomb Project. Although many of his fellow physicists strongly testified for Oppenheimer’s loyalty, there were several others—in particular, George Gamow’s close friend Edward Teller—who counter-argued that Oppenheimer’s behavior, in opposing trying to build a hydrogen bomb, had the smell of a communist. In contrast, Hans Bethe, also close to Gamow, testified strongly for Oppenheimer, stating that “the super” could so easily wipe out modern civilization.

  The pervasive unease felt at Caltech with the Oppenheimer verdict was subsequently heightened by our learning from George Beadle that two Caltech scientists had recently been denied non-classified research grants from the National Institutes of Health (NIH) because of putative communist leanings. Deeply disturbed by political loyalty requirements, George thought Caltech must make a public stand and should possibly refuse more NIH grants until the recent decision made by the Secretary of Health and Welfare, Oveta Culp Hobby, was reversed. The first Caltech grant application to run into trouble, not surprisingly, was from Linus Pauling. His highly visible opposition to nuclear weapons, and appearances at so-called Communist Front Peace Rallies, was a deepening thorn in the sides of the many deeply pro-military Caltech trustees. In contrast, until Biology professor Henry Boorsok’s grant ran into trouble, no one thought of him in political terms.

  Before this political cancer spread further, George (“Beets”) wanted his faculty’s concurrence in letting Mrs. Hobby know the shortsightedness of her position. It too easily brought to mind political reliability tests imposed on Nazi-era German professors. Linus, perhaps feeling the government’s distrust of him would never end, had his grant resubmitted under the name of his co-worker, Robert Corey. As such, it was soon funded. Henry Boorsok, however, did not have this way to stay scientifically alive. Fortunately Secretary Hobby soon reversed her decision, and the political litmus test vanished from the awarding of NIH grants. Here Beets’s forceful intervention was helped by the publicly announced decision of the greatly respected Harvard protein chemist, John Edsall, to give back his NIH monies if Boorsok’s grant was not funded.

  Over the next several November weeks, Leslie and I returned to how RNA molecules form cavities specific for the side groups of the 20 different amino acids. None of the potential helical fold we considered for single-stranded RNA molecules generated even half-good holes into which the specific side groups would bind. Even subsequent daily visits of Dick Feynman to our model-building table did nothing to break our mental road jam. After an hour or so of looking at potential amino acid-binding surfaces, he invariably gave up and returned to meson theory frustrations. The week before, Dick and I had received essentially the same letter from a California rabbi asking our views on religious revelation and spiritual guidance. As an escapee from the Catholic religion, I wrote back that I had no interest in religion. But Dick wrote back a much stronger response, believing that calling crap, crap was the Brooklyn way to make your mark on this world.

  Gamow was by then the possessor of the sole RNA tie so far made. Earlier in the week, he sent me an urgent telegram asking me to dispatch it to Washington by special delivery. He wanted to wear it to a coming weekend meeting of the National Academy of Sciences, where he was going to speak about his code-finding efforts. There he would pass the tie on to Melvin Calvin, the Berkeley chemist who was to talk at NIH several days later.

  By Thursday evening, feeling mentally stale, I came into the Athenaeum expecting to eat quickly but noticed Victor Rothschild eating alone. He explained that much too often he found himself next to impassive souls interested only in their work, college football, and new cars. With Tess back in England, he was spending most of his days and nights at the lab. This evening, however, he wanted out from Caltech life. So we drove the Pasadena Freeway into the center of Los Angeles and then up Wilshire Boulevard to see the new Italian film Bread, Desire, and Dreams. Gina Lollobrigida starred. Our fantasies took off and we came back to Pasadena with much-improved morales.

  The following Tuesday night, Leslie, Victor, and I had a very alcoholic occasion at The Stuffed Shirt. This was, in effect, a farewell dinner for Victor. To my surprise, he started talking about his British philosopher friend, Stuart Hampshire, with whom Tess had had dinner in New York on her way back to London. That morning Christa’s latest letter had told me of listening to, but not understanding, Hampshire at a Swarthmore lecture. Over cognac at Leslie’s flat, we talked more about Cambridge. To his delight, Leslie had just received one of its lectureships in Chemistry. This was totally unexpected because only rarely did Cambridge offer positions to Oxford graduates, and vice versa. In going back to the Athenaeum, Victor encouraged me to get back to Cambridge as soon as possible. Later, telling Beets of Victor’s advice, I found him sympathetic to my wish to be near Francis again.

  Several letters a week from Geo Gamow were then barraging me, one excitedly telling me of help from the Los Alamos computer whiz Nic Metropolis. Through him the powerful bomb-making Maniac Electronic Computer was also working on the genetic code. At the same time, Geo’s life at home with Rho had become hellish, and he was moving temporarily into the Cosmos Club in Washington. To divert himself, he had started circulating a chain letter to the now-17 members of the RNA Tie Club asking them to choose an amino acid whose abbreviation would be inscribed on their respective RNA tie pins. Geo picked Alanine so he would be ALA, leading me to choose Proline so that I could be PRO. With the design already in hand, the tie pin could soon be made in Washington, giving Geo the opportunity to trap new acquaintances into asking why he had misleading initials all over his tie. Later he was the victim of his own joke when a hotel cashier in Chicago refused to honor his check, noticing that ALA did not correspond to George Gamow.

  More seriously, Geo kept trying to find support for his original “diamond” code through examination of the newly available 165 amino acid sequences of the polypeptide hormone ACTH. Frustratingly, two double-letter sequences, Lys–Lys–Arg–Arg, ruled out his beloved diamonds. So he had moved on to a crazy triangular code that would simultaneously generate two polypeptide chains from a single DNA sequence. In this way, he hoped to explain similarities between the A and B chains of insulin. This was a mad idea that died almost as soon as it was born. Geo went on to construct empirical curves relating the number of different amino acid neighbors found to the total number of already sequenced amino acids. Hopefully, the new calculations coming off Maniac would point to restrictions in the number of neighbors that any given amino acid possessed. If no restrictions existed, then completely different sets of base pairs must be used to code for successive amino acids along the polypeptide. Geo disliked this possibility because, if true, there would be no way to guess the nature of the genetic code through examining amino acid sequences—the only tool at his disposal.

  Geo also remained bothered by the DNA—>RNA—>protein relation and soon posted me a cartoon message asking why cells with DNA rich in AT base pairs contained RNA that had predominantly G and C bases. But this fact, which was already well known, only mildly disturbed me. I could explain it by postulating that genes rich in G and C are more commonly expressed than genes rich in A and T bases. Why this is so, I didn’t know. But I saw
no reason to doubt that RNA molecules are the templates that order amino acids during protein synthesis.

  After seeing Victor Rothschild—now suitably dressed in a dark pinstriped suit for his return to “civilization”—off to the airport, Leslie came up with a bizarre idea that double-stranded DNA, not RNA, had the surface for attracting amino acid side groups. By slipping the two DNA chains past each and holding them together, not by hydrogen bonds but by divalent ion bridges, Leslie thought that amino acid side groups might be bound. But suspecting it was an extremely long shot, Leslie’s brainstorm totally left my mind during an Italian meal cooked for André and Marguerite Lwoff on Saturday night by Renato Dulbecco’s wife, Enucia. The next day the Lwoffs and I walked through the expansive Italianate grounds of the nearby Huntington Library, peeking into the building itself to see its two main artistic treasures—Thomas Gainsborough’s exquisite Blue Boy and Pinkie. Smiling broadly, André admitted they were good enough for the Louvre.

  Three days later, the warmth of southern California vanished as Leslie and I crossed over the Tejon Pass and descended into the foggy cold of the Central Valley. We were on our way to a Thanksgiving feast with Gunther and Inga Stent in Berkeley. The next day we went to the Virus Lab, hoping that Robley Williams’s electron microscope would give vital clues about the shape of his TMV RNA molecules as well as some animal-cell RNA I had brought from Caltech. But both our samples gave rise to flat puddlelike masses, and we left no wiser than when we arrived. That evening, we predictably did not find gaiety in what Gunther enthusiastically proclaimed as San Francisco’s most existentialist night club.

  Upon arriving back at Caltech, I faced the fact that in only a month I must give my Harvard job seminar. I was uncertain about what new ideas I could talk about. With each passing day, Leslie and I got colder feet about our phosphoanhydride RNA model that the month before had seemed so perfect. Although Leslie seldom doubted his acumen as a theoretical inorganic chemist, he had little feel for organic chemistry and its biochemical offshoots. There was no way to predict whether our DNARNA scheme had any chance of surviving expert scrutiny. In particular, the fact that we were using only one hydrogen bond to attract an RNA base to its corresponding DNA base pair was bound to raise questions of whether our scheme had the requisite accuracy needed for RNA synthesis. We were resigned to delaying submission of our completed manuscript to Nature until we had solid evidence. We had no clue about how to move ahead experimentally and my frustration was compounded further by our continuing inability to twist an RNA chain into any shape with true template properties.

  At best I was in a restrained mood when I went to the big Friday night Athenaeum faculty banquet held to honor Linus just before he and Ava Helen flew off to Sweden. When he and I briefly chatted the day before, his very tweedy suit was perfect for the now almost cool weather, and he was very pleased with his circumstances. Highlighting the banquet was a skit satirizing Linus entitled “The Road to Stockholm.” Its clever lyrics put everyone in a light mood, especially Linus, who announced this to be the happiest evening of his life.

  Dick Feynman and I sat next to each other. Although we could not say it to others, we felt we might be Caltech’s most obvious candidates for future Nobel awards. More privately the next afternoon, Dick told me that his contributions to physics were still insignificant compared with the great minds from the Bohr-Heisenberg era. Although now no theoretician outshone him, he wanted to come up with a more profound contribution to physics before he went to Stockholm. In the same way I felt the need to have more than the double helix below my belt before winning the prize. I did not want to be overpraised for what was not very difficult science.

  The next evening I drove up to the Altadena home of Stuart Harrison, a British-born physician with many Caltech friends. In the mid-1930s, he helped establish the student health service but now he specialized in radiology and could afford his smart ranch-style house. Some months before at Mariette Robertson’s house we had fun talking, and at the Pauling banquet he said I must come up soon to his and his wife’s foothills’ home. Finding they had no plans for the next night I asked “Why not then?” and, to my relief, was invited. I needed desperately to talk to a real physician. Persistent anxieties about Christa, heightened by the tone and decreasing frequency of her letters, were affecting my ability to concentrate either on model-building or preparing for my impending talk at Harvard. Falling asleep was becoming a nightly struggle, and without medical help I feared a nervous breakdown that would not only foreclose any offer from Harvard but also give Christa the message that I was emotionally fragile.

  Spotting my unease upon my arrival, Stuart gave me two Scotch and sodas. Soon I no longer felt terminal anxiety and was being reassured that my plight was not unusual. He told me about the mid-thirties Caltech and its bohemian underlife that moved to a very different drummer than that governing the self-assured solemnity of its founding president, Robert Millikan. Many couples who then knew each other too well had cause for much anxiety. In particular, Stuart related the turmoil that accompanied the affair of his left-leaning first wife, Kitty, with Robert Oppenheimer, whom she subsequently married just before Oppenheimer began leading the Los Alamos atomic-bomb lab.

  With my nerves no longer jangling, I returned to the Harrisons’ home a week later for a dinner honoring a couple from Italy. A cheerful letter earlier in the week from Christa had put me back on the sleep track. No hint came through that anyone else was in her life, and she was looking forward to seeing me after Christmas. No longer in panic, I stopped intellectually freezing when looking at my RNA model and came up with a new single-chain RNA helix that repeated every 12 angstroms. It had the phosphate groups on the outside and the bases stacked next to each other 45 degrees to the perpendicular position. Tentatively this model had the potential for at least several good amino-acid binding holes. But with the Orgels off camping in Death Valley, the weekend passed before Leslie had a chance of seeing it. Later we realized that there was not enough time before I left for Christmas to see if the model actually had template features. Later I enjoyed Geo’s quickly penned response comparing my potential template holes to a tiger’s mouth.

  Leslie and I, however, were still model-gazing when a thick letter arrived from Francis Crick containing a draft of the article on plant-virus structure that he and I had long planned to write. Full of flamboyant Crickisms, I saw the need to write them out of the final manuscript. Meanwhile, I was much enjoying words that Mariette Robertson sent me from Paris, where she now was living with her parents. Earlier in the fall she had spent several weeks travelling about the south of France with Linda Pauling—Linus and Ava Helen’s daughter. More recently, Linda couldn’t understand why Mariette had not yet congratulated her and Peter on their papa’s prize. But Linus’s prize had been for his chemistry, and Mariette saw no reason to see Linda on a pedestal whose base was the attractive personality that Linus had passed on to her and Peter. Reminding me that I was always warning her against the wiles of charm, Mariette revealed her concern that someday I might fall under Linda’s blue-eyed blond spell. But she noted that during their recent travels the European students who flocked around Linda were not interested in her, and vice versa. So she thought I was unlikely later to fall for Linda. That night I easily fell asleep not that certain.

  Northern Indiana, Cambridge (Mass.), and Washington D.C.: December 1954–January 1955

  AN OFFER FROM Seymour Benzer to give a talk at Purdue University let me practice my Harvard job seminar the day after I flew to Chicago for Christmas. I drove my parents’ car—the first they had had since the depths of the depression—to Lafayette. My journey took 90 minutes, most of them spent anticipating Christa, whom I would see in less than a week. Before my talk, Seymour happily told me more details of his elegant new genetic tricks for determining the location of mutational changes within a phage T4 gene. Utilizing the observation that T4r2 mutants do not grow in an E. coli strain containing phage?, over the past year he had dem
onstrated the strictly linear order of several hundred different r2 mutations, each of which he believed represented base-pair changes along DNA molecules.

  Invariably, Seymour worked late into the night and seldom arrived at his lab before lunchtime. But the day I arrived Seymour was there by 11:30 a.m. to take me home for a lunch prepared by his always upbeat, diminutive wife, Dottie. As it was the last day of classes before the Christmas recess, Seymour warned me that my audience might be thin. So I was pleasantly surprised by a totally filled lecture room. The moment I started speaking, I became excited again by the beauty of the double helix and how its complementary base sequences should provide the structural basis for DNA replication. I went on to argue that RNA must be the information-bearing molecule that carries genetic information from the chromosomal DNA to cytoplasmic sites of protein synthesis.

  For most of my lecture, I talked about how single-stranded RNA chains might be made on DNA templates as well as how they in turn might serve as the templates for ordering the amino acids along polypeptide chains. Then I made it more than clear that no experimental support existed as yet for any aspect of our RNA triplet model: single RNA chains might well be formed upon single-stranded DNA templates using the base-pairing rules of double-helical DNA. Almost in passing, I mentioned that base quartets could be formed in which two base pairs related by a parallel diad are held together by two hydrogen bonds. When thinking about how DNA replicates, I said, we should not automatically rule out intact DNA double helices serving as templates for a second double helix. On the other hand, the resulting quadruple helix was not a regular structure with its exact configuration a function of its underlying DNA sequences. I ended my talk by emphasizing the positive role model-building would have in investigating such alternative template mechanisms. When the questioning started, I worried that some true chemist would pronounce my paper chemistry schemes not worthy of public presentation. No one in the audience, however, proved the slightest bit unpleasant, and I drove back to my parents’ home feeling upbeat about my forthcoming Harvard debut.