Genes, Girls, and Gamow
Page 13
Although the phage-oriented lab of Max Delbrück and Renato Dulbecco’s animal-virus group bustled with after-vacation vitality, I was most relieved not to be attached to Delbrück’s group anymore. Instead I was on my own in a big office room on the floor above, just across from George Beadle’s office. It provided the space for serious model-building now that Alex Rich was at the National Institutes of Health and Linus Pauling’s chemistry department benches were no longer at my disposal. With Leslie leaving just after Christmas, though, I worried about my shortcomings in chemistry. In 1953, they might easily have cost Francis and me the double helix. If Jerry Donohue, the Caltech-grown chemist, had not had a sabbatical year at the Cavendish, we might not have been the first to appreciate the structural significance of Erwin Chargaff’s base pairs. Learning some real chemistry now could only be for the good. So before the weekend started, I arranged with Linus’s secretary for a Monday-morning appointment.
Fearful of exposing the true depth of my lack of chemistry, I anxiously entered his large office in the Crellin Laboratory. But Linus soon put me at ease and let us talk as if we were almost equals. Quickly we moved from DNA to RNA and my feeling that only after we had solved the RNA structure would we understand how RNA templates order amino acids during protein synthesis. The trouble was, our current X-ray pictures were too disordered to give us a reasonable chance of finding the helical parameters for successful model-building. Seeming more relaxed than I had ever seen him, Linus cautioned me about being in too much of a hurry for another big breakthrough. Instead he urged me to spend the coming year beefing up my knowledge of statistical mechanics and quantum mechanics. Unclear whether Linus had any idea how little physics birdwatchers usually learn, I rapidly seized his alternative suggestion that I attend his fall-term lecture course on the “Nature of the chemical bond.” His first lecture was at 9 the next morning, and I left his office knowing that I would be there.
Crick had already written from England saying how wonderful Cambridge still was and offering me a place there should I want to go back. And, remembering the Gordon Conference, he wrote, “How is Christa?”, a question that I feared might take longer to settle than the RNA structure itself. Here I took comfort that Margot Schutt, my shipboard Henry James girl from Vassar, still had me—at least slightly—on her mind. A new letter from her revealed that she was off the next day to teach history in what I took to be a posh girls’ school in the fox-hunting region west of Washington.
With Sydney still around, there was no point for Leslie Orgel and me to get serious until he left. We also had Rosalind Franklin briefly on hand, a visit that we feared might easily go awkward. She had come down to Woods Hole late in August just after her arrival from England. Learning of her plans to go West, I asked her if she wanted to accompany Sydney and me to Pasadena. But with her six-week travel plans fixed, she declined, knowing she would see us at Caltech. To my relief, she now proved the opposite of unpleasant, eagerly telling me about her recent X-ray diffraction studies on tobacco mosaic virus (TMV). Happily, they both confirmed and greatly extended my 1952 Cambridge proposal that the protein subunits of TMV were helically arranged. Observing her current friendliness, Leslie took us aside to say that Rosalind’s past reputation as difficult to get along with was unbelievable. In his mind, she had been judged most unfairly when working on DNA. Sydney and I had to agree, but still wondered whether our trip West would have been so lighthearted if Rosalind had been with us.
Before Rosalind went on to Berkeley, she and I had dinner with the Paulings in their expansive foothills ranch-style house. It was still largely surrounded by desert plants except for a well-manicured broad lawn beneath the glass-fronted living-room doors. Our invitation was last-minute, given during a brief, clear respite from the thick smog so characteristic of Pasadena’s early fall. The 6000-foot San Gabriel Mountains above us stood out magically as Rosalind and I drove up from Caltech. Before arriving at the Paulings’, I wondered what to say to Ava Helen. My concerns were needless as both she and Linus seemed pleased to learn more about me. In turn, I wanted to learn more about Linda, Peter’s younger sister. She had just departed for Europe to be near Peter, much in the same way as my sister followed me to Europe in 1951.
Later, our conversation turned to Francis and his recent article in the October Scientific American. I had been jealous earlier when I saw that he, not I, had been asked to write about the double helix. But then my, not his, picture was in Vogue with its readership of stylish women, who had never read, much less heard of, Scientific American. In it, Francis’s prose was clean and concise. Only in describing the base pairs did he let himself go, writing that he expected that an enthusiastic biologist would someday call his twins Adenine and Thymine. When Erwin Chargaff learned of Crick’s exuberance, he agreed that this would probably happen but questioned whether enthusiastic was the right adjective.
Pasadena: October 1954
WITH SNOW SOON forecast for the High Sierra, Leslie Orgel and I used the first weekend in October 1954 to drive north to Lone Pine and from there to the pine tree–surrounded campground that lay 8000 feet below the summit of Mt. Whitney, the highest mountain in California. On our second night, neither of us slept well in our sleeping bags, partly due to the 12,000-foot altitude of our campsite but also because of some wretched bouillon that made our stomachs feel filled with lead. When a trace of morning lightness hit, we climbed upwards under cloudless conditions, finding only the last 200 feet difficult. Not enough sleep and too little oxygen had made us slightly dizzy. After quick looks from the flat, rocky, 14,496-foot top to the expansive scenery below, we retraced our steps towards more oxygen.
The 13-mile descent took less than four hours, and we were down to Lone Pine in time for a coffee-shop lunch. On the ride back, we talked about Rosalind Franklin’s new X-ray data that questioned our simplistic picture of tobacco mosaic virus’s RNA component forming a solid cylindrical core. From what Rosalind had just told us, combined with more convincing X-ray data that came later in a letter from Yale, it became clear that TMV’s center was filled with water, not RNA. And because there was not enough RNA in a single TMV particle to form an external shell, the RNA chains within TMV particles must be tightly inter-digitated into its helically arranged protein components (molecular weight 17,000).
Back at Pasadena, Leslie and I began making molecular models to explore whether it was possible chemically for intact double-stranded DNA molecules to serve as templates for the single-stranded RNA molecules. We wanted to see if single base pairs might function as template bits that specifically attract single RNA bases to generate base triplets. If so, we should be able to use our Pauling–Corey space-filling models to build a pretty triple helix consisting of a DNA double helix hydrogen-bonded to a single-stranded RNA molecule. Soon we focused on a scheme whereby adenine–thymine (A–T) base pairs attract adenine, T–A bases bond to uracil, guanine-cytosine (G–C) base pairs attach guanine, and C–G base pairs bond cytosine. Conceivably the single hydrogen bonds underlying the selection of specific RNA bases were strong enough for an accurate RNA-making scheme. No longer bored, we celebrated by walking several blocks after dinner to Lake Street for hot fudge sundaes. Afterwards, I penned a brief progress report to Christa Mayr, which I took the next morning to the post office. By then, to my great relief, her letters from Swarthmore ended “I love you.” And I replied likewise.
Already, I had given Dick Feynman our triplet scheme for making RNA but quickly sensed during subsequent lunchtime talk that he wanted solid facts, not dreams. So our conversation shifted to the Gravity Research Foundation, with which, to my surprise, Dick was well acquainted. It gave physicists license for far-out antigravity schemes without any of their friends thinking that they had gone off the deep end. Already some of Dick’s friends had submitted prize essays. Quickly Dick spun out a proposal that he knew was no better than crap and could never dignify with his name. We thought it might be fun to see how it would fare under Leslie’s and my attr
ibutions. Briefly anticipating its prize money, we soon learnt the same idea had already won an award several years before.
The prospect of yet another dead Pasadena weekend led me back to the Sierra by Friday evening, this time going with Renato Dulbecco and his adolescent son, Pietro. Hiking in from Mineral King, we were alone except for deer hunters, amazed that we were there only for walking. The crystal-clear air of our two nights on the high open meadows was in total contrast to the hellish thick smog that greeted us on our return to the Los Angeles basin. Making the smog even harder to take was the fact that I could not come up with an RNA backbone model that did not have impossibly close atomic contacts. With deep frustration, Leslie, a Swiss chemist friend, and I drove north one afternoon into the San Gabriel Mountains until, at 7000 feet, the smog vanished. There on a roadside table our Swiss friend read about quantum mechanics, while Leslie and I wrote an introduction to the triplet paper that we knew might never see the light of day.
The following morning I still saw no way to save our new scheme and our lunch was of unmitigated gloom. There seemingly was no way to get the RNA backbone atoms out of each other’s way when they were confined to a radius of 7.5 angstroms. Only back alone in my office did I suddenly see a beautiful way out of our dilemma. If the nascent RNA chain was based on anhydride phosphate groups, formed by splitting a water molecule from each sugar–phosphate group, the resulting triple-esterified sugar–phosphate backbone formed a very compact RNA helix that fitted perfectly into the DNA double helix. The thought that RNA might be synthesized in the anhydride form, while radical, nonetheless was chemically possible because triplet-esterified organic compounds, though unstable, can be synthesized and studied. In fact, an inherent instability of the backbone, while bonded to its template, might be a great advantage. As soon as the cyclic bonds break, the hydrogen bonds holding the base triplets would also break and the complete RNA chains peel off their DNA templates.
Later, Leslie was predictably bowled over by the beauty of the structure. Like me, he saw the need to explain why the cyclic bonds always break to form 3’–5′ bonds as opposed to 2′–5′ bonds. But some 2′–3′ cyclic nucleotides enzymatically break this way and so he was not overly concerned. Immensely relieved that my brain was still capable of a big leap, I no longer felt the need to leave Pasadena for the weekend. Suddenly I had much to do and decided not to join Leslie and Alice on their coming trip to the Sierra so that I would have the time to work out the coordinates of the anhydride backbone as well as finish the short manuscript that Leslie and I had rashly started on the smog-free Angeles Crest Highway the weekend before.
Tess and Victor Rothschild
Meanwhile, the first RNA tie had just been finished, and I unabashedly wore it to dinner that night at the Athenaeum. By then Victor Rothschild and his wife Tess had just arrived from England and were staying in the suite for important guests. A British member of the illustrious Rothschild banking family, Victor had trained as a zoologist and had come to Caltech for a month to do experiments with Caltech’s sea-urchin specialist, Albert Tyler. In Cambridge, Victor had worked closely with Av Mitchison’s brother, Murdoch, and it was in their Zoology lab that I first met him. Hopefully that night he and Tess would see the RNA Tie as a thinking brain’s response to academic dullness. But, perhaps because of jet lag, they were not up to appearing and feigning pleasure that they had exchanged the coal-fire smell of English air for the automobile-generated yellow acridity of Pasadena.
By Sunday night I had a handwritten first draft of our manuscript, hoping to have it typed by the next afternoon so that Leslie and I could give Linus Pauling a copy after his morning lecture on chemical bonds. When he first read the manuscript, Linus warned us not to publish until we had more evidence. Like Dick Feynman, whom we saw later in the day, his first reaction was complete disbelief. But after we had fully explained our arguments, Linus slowly became more open-minded and thought publication might be worth the gamble. He saw the beauty of a template with an inherently unstable product that would automatically peel away from its generating surface. While we might be far out, he said, we might also be right. In particular, Linus recalled that several years before he had proposed an analogous argument about the transition-state nature of the intermediates in enzyme-catalyzed reactions. In spite of some opposition, Linus thought it was one of his best contributions to chemistry. After seeing Linus, however, I worried whether our anhydride RNA backbones really existed. Would any structure known either as OW (Orgel–Watson) or WO (Watson–Orgel) ever sound convincing?
George Gamow’s original cutout-paper design for the RNA Tie Club tie
For the rest of the week I talked much with Gunther Stent, then down from Berkeley, about his recent experiments using heavily 32P-labelled bacteriophage particles to test whether the two strands of the double helix came apart during DNA duplications. Because his results were not easy to explain, Leslie and I spent Sunday heretically exploring the possibility that the two strands of the double helix never separate but instead serve as the template for two-stranded, base-paired daughter products. Underlying this heresy was the possibility of creating base quarters formed by specifically hydrogen bonding two base pairs to each other. The fact that we could not see how to build a perfectly regular four-chained DNA helix might, in fact, be a plus—its inherent instability would cause the daughter double helix to untwist away from its parental double helix. But our enthusiasm was soon dampened when we realized that Gunther’s experiments were still far too preliminary to interpret.
The first real social life of the Caltech fall had come the day before when the Paulings gave a large tea party at their home to which 150 people were invited. My mind then did not easily lend itself to small talk and I had a long conversation instead with André and Marguerite Lwoff. They had just come from Paris to use new animal-virus plaque techniques being developed in Dulbecco’s lab. Sensing my lack of enthusiasm for Pasadena, André suggested I spend a year with them at the Institut Pasteur. Later that evening, at a small square dance in the Delbrücks’ living room, André asked why I didn’t join in—I had been such a keen square dancer at Cold Spring Harbor the year before. Then he asked where my brown-haired muse of that year had gone, hinting that he knew why I was not in a mood to dance.
I continued faithfully to get to Linus’s early-morning lectures, but was too excited by our RNA thoughts to spend any noticeable time reading the outside class assignments. So with each subsequent lecture I found myself understanding less and less. Even more incomprehensible was the public lecture Dick Feynman gave on quantum mechanics and whether physical phenomena are chance events. Given Dick’s irresistible personality, the lecture was total fun, given in the Physics Department to a packed audience that applauded before he even began speaking—respect that no other lecturer at Caltech then commanded. Physics also entered my life with a cheerful communication from George Gamow, excited by his apparent finding of a financially rich backer for the RNA Tie Club. The U.S. Army Quartermaster Corps would not have been my sponsor of choice, but their promise to fund biannual gatherings of the club was not to be sneezed at.
One Friday morning late in October, rumors began to float that Linus had been awarded the 1954 Nobel Prize for Chemistry. Such reports often proved false for others, but by the afternoon he was receiving official congratulations and I got word from his secretary of a celebratory cocktail party at his home. When I was in England, at Cambridge, Peter Pauling had told me that the annual October awarding of the prizes had become a source of much tension in the Pauling household. It had been more than 20 years since Linus had used quantum mechanics to provide fundamental insights about the nature of the chemical bond. Particularly seminal had been his 1931 breakthrough in understanding the tetra-hedral manner in which carbon atoms form chemical bonds. Although he had received many other prizes, the failure of the Swedish Academy to give him due recognition was increasingly a source of deep rankle.
But no sense of past hurt was evident
at the party the Paulings gave the next night: champagne flowed copiously. Linus and Ava Helen had already decided to fly over the North Pole to Copenhagen and then on to Stockholm. All their family would join them in Sweden, and then Linus and Ava Helen would afterwards go on alone around the world, stopping in India and Japan for Linus to give lectures. Most of the guests were Linus’s age, and I felt myself out of place by being 10 years younger than any of the other celebrants. Victor Rothschild was there alone, as Tess had flown back to England to be with their children, and I had somebody to gossip with. Later, the Lwoffs and I speculated on how Linus’s life might be altered by the prize.
I had thought the occasion would have been one where Ava Helen was surrounded by the wives of Linus’s long-time chemistry department colleagues. But they did not flutter about her, and we had the time to speak about Peter and the danger of his going too long without a firm direction in his research. Sensing that I had not yet found myself socially, Ava Helen suddenly revealed that she had long found herself bored by the heaviness of Caltech social life in contrast to the liveliness of more political occasions across Los Angeles in Hollywood. Soon after, she moved on to a nearby Caltech couple and our frankness, possibly too close to home for comfort, was lost in the ample champagne that remained available long into the night.
Pasadena and Berkeley: November–December 1954
WITH MY HEAD still heavy from not enough sleep and too much alcohol, Manny Delbrück, Renato Dulbecco, and I early the next morning drove east along the base of the San Gabriel Mountains to the foot of Mt. Baldy. We wanted to climb it before winter snows converted its upper slopes into a site for skiing. At its 10,000-foot summit, the bright sun and sweaters kept us from feeling too cold as we peeled oranges and ate cheese sandwiches. I tried not to think how much more fun I would be having if Christa were with me. Nor was this the occasion to dwell on my relief at having just received a letter from the Harvard Biology Department, inviting me to give a job-seeking seminar. Already I had written back that I would go to Cambridge after I had visited my parents at Christmas. Leslie and I thus had a pressing deadline to clarify our ideas on how protein synthesis occurred. Even if our new model for how RNA is made upon double-stranded DNA templates proved to be correct, the much bigger question remained of how RNA itself functions in amino acid ordering.