Genes, Girls, and Gamow Read online

  Continuing on to Harvard later that night, I went to Paul and Helga Doty’s new home on Kirkland Place the next morning to tell my bad news over coffee. Paul warmly tried to reassure me saying that, with my new life at Harvard about to start, I was bound to find an even more suitable girl from Radcliffe, the women’s college near Harvard. Helga then, to my immediate pain, told me that with time I would realize my news was not so bad. For reasons she couldn’t define in words, she had long felt that it would never work out well for me with Christa. Far better that it was now over definitely than to go through more years of emotional turmoil.

  I had to see Christa before she left and did so one evening when she had been back for a week. If she had weakened in her determination to have the baby, by then it would have happened. Ernst and Gretel left us alone and we had the living room to ourselves. Both of us tried to smile and talk like good friends catching up on each other’s last six months. The boy she was marrying was already a trained engineer who wanted to work on nuclear reactors and she felt confident for his future. Most importantly, he was not tense and almost instinctively knew how to keep her happy. That she knew him so briefly did not matter. He was good for her. There was nothing I could say in reply: Christa had made her choice. To argue that she was acting stupidly would have done no good, and my visit would have ended on an angry note. After wishing her well and not being sure but shaking hands, I was off into the street. I got into my MG and slowly drove to Divinity Avenue, where I parked outside the Biological Laboratories that were to prove my effective home for many years to come.

  Not capable of being alone then in my new office, I walked towards Harvard Yard, where just a trace of early-fall evening light remained. Slowly I calmed down, the outlines of the giant elms above me giving the feeling that those who chose to walk beneath them go on to rightful destinies. The fall katydid sounds were everywhere, and I was virtually alone as I walked back and forth along the yard’s diagonal paths not wanting to go further out into the noise and light of Harvard Square.

  Epilogue

  October 1956–March 1968

  THE PERSONAL AGONIES that for many of us dimmed the glamour of the double helix’s first glory days did not last much longer. For the most part, they were replaced by much happier emotional commitments. Likewise, the intellectual disappointments that accompanied our attempts to jump beyond the double helix before experimental facts had firmly gripped our feet soon ceased. Just seven years were to intervene between the 1953 finding of the double helix and the 1960 understanding of the basic ways that RNA is involved in protein synthesis. With messenger RNA and transfer RNA at our disposal, the genetic code took only six more years to crack and complete.

  Mariette Robertson left England, in June 1956, for Paris, where she spent the following year at the Sorbonne. But she returned permanently to her Caltech roots, marrying the Harvard- and Oxford-trained historian of India and the Opium Wars, Peter Fay, in 1958. Later, the couple and their four children spent two years in India. Meanwhile, Linda Pauling married geophysicist Barclay Kamb, recently appointed to the Caltech faculty of which later he served for several years as its Provost. In 1964, after Linus left Caltech, the Kambs and their four sons moved into the foothills home where Linda was raised.

  Linus’s departure from Caltech followed the awarding to him, in late 1963, of the Nobel Peace Prize in recognition of his efforts to prevent the use of nuclear weapons. His widely acclaimed second Nobel award, sadly, was ungraciously received by Caltech’s trustees, who perceived him as aiding communist causes. By then Linus had become increasingly frustrated by Caltech’s cutbacks of his research space, and he accepted a position at the Center for Democratic Institutions in Santa Barbara directed by Robert Hutchins.

  Av Mitchison was also married soon, to Lorna Martin, a student at Edinburgh University. Her parents lived on Skye, to which I went in July 1957 to be Av’s best man at the ceremony in Portree. I took my father, much at loss after my mother’s sudden death in May of that year, to the wedding. Mother’s heart, long faulty from a childhood streptococcal infection, could go on no longer. My Harvard lab had moved by then into high gear through the arrival the past March of Alfred Tissières and his Bentley—all too soon to be sold to a Harvard Law professor. Celia Gilbert, by then, had retired from her job with me and took comfort that she no longer had to think in terms of factors of 10. Instead, she was happily anticipating the impending birth of her and Wally’s first child.

  Av and Lorna Mitchison after their wedding on Skye in August 1957; JDW was best man. Nou Mitchison is second left.

  With Alfred Tissières in front of the Biology Laboratories at Harvard

  Then living near Harvard was Margot Schutt, whose Henry James manners so fascinated me on the boat that brought me back from England as the summer of 1953 ended. She was working for the book publishers Ginn & Company. In mid-April I drove her to Woods Hole to let Marta Szent-Györgyi see me with a girl who knew the consequences of vulgarity. The meeting between these two ladies—one young, one middle-aged—did not go well, in part because Margot had not thawed from the wind rushing through my transparent MG. Whether my unexpected re-emergence into Margot’s life had anything to do with her decision a month later to take a job in London, I was not given reason to know.

  Over the 1957–58 academic year, Alfred and I found that the E. coli ribosomes were not structurally like spherical RNA viruses but had a bipartite structure with one subunit twice the size of the other. In the presence of sufficient magnesium ions, the two subunits stick together but fall apart at lower Mg2+ ion levels. Subsequently, we were puzzled by observations that both subunits contain single RNA molecules, that of the larger subunit being twice the size of the one within the smaller sub-unit. We had expected to find heterogeneously sized ribosomal RNA molecules, reflecting the greatly different lengths of the polypeptide chains they reputedly coded for.

  In July 1958, Alfred married the spirited Virginia Wachob, who had been living in Paris but was from Denver. I was a best man again. Colorado also did well for Geo Gamow, who after arriving in Boulder in 1956 wanted to hold a molecular genetics meeting in August the following year. In December 1956, he wrote with more details of the conference and mentioned he was finishing off his latest book, Matter, Earth and the Stars. Two years later he made a second marriage to the similarly aged Barbara Perkins. Her past life had been in publishing and over the next 10 years she assisted Geo in the publication of several more books. In 1968, aged only 64 years old, he died prematurely from alcohol-induced liver failure.

  Just after I left England to go to Harvard in the summer of 1956, Sydney Brenner left South Africa to join Francis Crick in Cambridge, adding extraordinary genetic zip to the Cavendish site. During the next few years, experiments both from my lab and Sydney and Francis’s, where Leslie Orgel’s wife Alice also contributed significantly, began to show how mutagenic agents act at the DNA level. At Harvard, key work was done by Ernst Freeze, who had trained as a theoretical physicist in Germany under the famed Werner Heisenberg and had afterwards moved into biology through a year with Seymour Benzer at Purdue. There, Ernst showed that the sites of 5-bromouracil-induced mutations differ from those where spontaneous mutations occur. After coming to Harvard, he went on to demonstrate that two quite different types of mutation exist. Those caused by base analogs he interpreted correctly as “transitions” (replacements of one pyrimidine by another pyrimidine or one purine by the other purine). The other class of mutation, induced by DNA-binding dyes, like proflavin, he called “transversions,” thinking them substitutions of purines for pyrimidines, and vice versa. Here time would prove him wrong.

  Early in June 1959, Francis, Sydney, and Ernst came together for a meeting at Brookhaven National Lab. Francis and Odile were temporarily living in Cambridge, Mass., staying with the Riches, while Francis was a visiting professor in Harvard’s Chemistry Department. The Riches had by then been ensconced in a Linnaean Street house for some six months after Alex’s move from
the National Institutes of Health in Bethesda to MIT. Francis radiated enthusiasm about the now-universal acceptance of his “Adaptor Hypothesis.” No one, including himself for a time, thought it on the right track until the fall of 1956. Then, soon after my arrival at Harvard, Paul Zamecnik at the Massachusetts General Hospital told me about his studies with Mahlon Hoagland showing that amino acids on the way to being incorporated into proteins are first covalently bound to RNA molecules. Mystified by what their result meant, I suggested to them that they had discovered the “RNA adaptors” that Francis had postulated in his 1955 note to the RNA Tie Club.

  In the spring of 1959, Aaron Klug was having difficulty in being admitted to the States. Rosalind Franklin had died the year before at the young age of 37 from the ovarian cancer that had been diagnosed after an operation 18 months previously. After her second such operation, she recuperated in the home of Francis and Odile. She felt more comfortable with the Cricks than with her parents, with whom she too easily found herself at odds. Aaron, now in charge of Rosalind’s former lab, wanted to share ideas again with Don Caspar, by then at the Children’s Hospital attached to Harvard Medical School. But Aaron’s supposed political past in South Africa had made him suspect by our State Department officialdom. I wrote on his behalf to the U.S. Embassy in London, hoping to reverse their paranoia. To the relief of those of us embarrassed by our country, he soon got his visa.

  Later in 1959, in August, a meeting in Copenhagen brought together 30 of the key figures trying to unravel how DNA provided the genetic information for protein synthesis. In his talk, Jacques Monod emphasized the puzzling results that he, François Jacob, and Art Pardee had just obtained at the Institut Pasteur in Paris. They had found that the synthesis of an induced enzyme takes off maximally, within minutes of its coding gene’s entry into a cell. If new ribosomes have to be synthesized, he said, several subsequent cell divisions would have to occur before synthesis at the maximum rate. Then Jacques wondered whether induced enzymes represent proteins that are directly made on DNA templates. To me, this was a horrid possibility.

  Much easier to interpret were the elegant experiments done the year before at Caltech by Matt Meselson and Frank Stahl, which showed unequivocally that the two strands of the double helix separate during DNA replication. As soon as his Ph.D. thesis with Linus Pauling was complete in 1956, Matt focused with Frank on how heavy isotopes might be used to distinguish parental from progeny strands. This they achieved by separating parental E. coli DNA labeled with the heavy isotopes 15N and 14C from progeny DNA labeled with the lighter 14N and 12C isotopes in density gradients of the heavy salt cesium chloride. Experiments done soon afterwards by Julius Marmur in Paul Doty’s Harvard lab were almost as exciting. They showed that separated single strands, made by exposing double helices to high denaturing temperatures, can subsequently come together under lower annealing temperatures to form hydrogen-bonded double helices.

  The new technique of sucrose gradient centrifugation had by then begun to dominate ribosome studies in our lab. Developed in Washington by the Carnegie Institute biophysics group, sucrose gradients allow centrifuged extracts to be sampled for radioactively tagged cellular components. By the fall of 1959, at Illinois University, Masayasu Nomura and Ben Hall, Paul Doty’s former student, were using them to look at the “DNA-like” RNA synthesized after phage T2 infection. Because of Masayasu’s impending move to Seymour Benzer’s lab, they had little time for experiments and thought that T2 RNA became part of a smaller ribosomal subunit. When I read the resulting manuscript, I was not so convinced and had my first graduate student, Bob Risebrough, do further experiments early in 1960. Within two months, he showed that ribosomes are not templates but are instead molecular factories to which T2 RNA RNA (later to be called messenger RNA, or mRNA, by Jacob and Monod) binds as a template and directs the ordering of amino acids during the synthesis of polypeptide chains. We now saw why our previous three years’ work on ribosomes had yielded so many unwanted results and we began a search for mRNA in uninfected E. coli cells.

  Such experiments began in late May 1960 after François Gros arrived at Harvard from the Institut Pasteur. Soon he and I were joined by Wally Gilbert, now an assistant professor of physics. Learning of mRNA over a Celia-cooked supper, Wally, then fearing that his “dispersion theory” forays in physics were going nowhere, thought he would have much more fun trying to find the templates that order amino acids within bacterial proteins. By the time our first such E. coli experiments succeeded, we knew the “ribosomes as factories not templates” concept had been independently demonstrated at Caltech. Earlier, a mid-spring visit to Cambridge, England, by François Jacob brought him to Sydney Brenner’s rooms in King’s. There they, with Francis Crick, batted about the idea that short-lived RNA molecules, like those synthesized after T2 infection, might be templates for the induced enzymes then under study at the Institut Pasteur. Excited by their possibly important brainstorm, Sydney and François went soon afterwards to Matt Meselson’s Caltech lab. Through his cesium chloride sedimentation tricks, they also found that T2 RNA binds to ribosomes synthesized before viral infection.

  The fall of 1961 was for me dominated by the presidential race between John Kennedy and Richard Nixon. I joined Alfred and Virginia around their TV set to see the presidential debates. After Kennedy’s victory, McGeorge Bundy went with him to Washington as the White House National Security Advisor. Paul Doty and I breathed a sigh of relief that Bundy had not left Caltech earlier, because only with him as Dean would Matt Meselson have been offered and have accepted a position in Harvard’s Biology Department. Matt was now married to a girl he met at the Aspen Music Festival and had arrived at Harvard just before Dick Feynman came through to give a Biology Seminar in early February 1961.

  I had previously learned from Matt that Dick was about to get married and that he had become a part-time biologist doing phage experiments. So I wrote Dick asking him to come to Harvard to give a talk about his work. He quickly accepted, writing me during his honeymoon in San Francisco and ending with his RNA Tie Club code name “Glycine.” He and his new wife, Gweneth, had met first on a beach near CERN, the big European physics lab outside Geneva. She was temporarily away from her au-pair responsibilities when Dick first spotted her. He urged her first, unsuccessfully, by mail to come to Pasadena as his au pair. Now he had the wife that would be his for the remainder of his life.

  Harvard was covered with a foot of new snow the day Dick arrived in early January, causing me to rush to the Riches’ to borrow the snow boots that made Harvard so different from Caltech. Later, in his lecture on February 6, Dick talked about new experiments with phage T4 r2 mutants induced by proflavin, an acridine dye. To his surprise, he found that the revertants back to wild types themselves were not mutations at the same site but suppressor mutations at nearby sites in the same gene. Interestingly Dick had noticed that the r2 suppressor mutant, when alone, had the same phenotype as the mutants they suppressed. Present together, they somehow neutralized each others’ effect. Later that spring, I arranged for Geo Gamow to lecture on the “Origin of the Universe.” The large audience on April 26 almost filled the Burr Hall lecture room with students attracted by his “Mr. Tompkins” popularization of physics and astronomy.

  Six weeks later, the June 1961 Cold Spring Harbor Symposium was dominated by messenger RNA’s recent discovery. The “ribosomes as factories” papers from Harvard–Pasteur and Caltech–Cambridge had just been published in Nature, and soon to appear would be the long review paper by Jacob and Monod in the Journal of Molecular Biology. Brand new, and particularly important, was the use of Julius Marmur and Paul Doty’s DNA annealing procedures by Sol Spiegelman’s lab in Illinois to make hybrid double helices containing DNA chains hydrogen-bonded to their mRNA molecule products.

  In late July 1961, Peter Pauling stayed with me in my Appian Way flat. He was in good form, his unwanted move five years before to the Royal Institution being a blessing in disguise. There, he got out of prot
ein crystallography and did an inspired thesis on inorganic molecules that led him to a lectureship in Chemistry at University College London. He and Julia had recently had a new daughter, Sarah, to complement their son, Thomas, and were living up from the Notting Hill Gate tube station in Lansdowne Crescent. Stricken with tonsillitis upon his arrival, he went for help to three Radcliffe College girls ensconced for the summer in the small home that my father, now living near me, had vacated for the summer. The sweet Emily had no idea what she was doing when she offered to help nurse Peter through his recovery. Not wanting to know how this care was given, I felt relief when Peter flew on to Denver for the annual meeting of the American Crystallographic Association.

  Peter’s research was then supported by the Office of Naval Research (ONR), whose travel orders often let him get lifts on military airplanes. Going on to Seattle for more lectures, he used his travel orders to get on a flight to San Diego, but not being on the manifest, upon his arrival he was fingerprinted and questioned by security personnel as to his right to be on military aircraft. Finally convinced that he was not defrauding the Federal Government, they let him hop on a bus to Los Angeles and his parents’ home above Pasadena. Later, the sum of $135.51 flew him to Pittsburgh for more crystallography and a further $14.41 got him to Washington, where at ONR he got further travel orders to London, soon exchanged for a TWA ticket to London. Peter wrote me that perhaps he is an army man after all.

  Peter Pauling on a visit to JDW’s office, c. 1966

  At the beginning of August 1961, Wally Gilbert and I stopped off in Helsinki and then Leningrad on our way to the International Congress of Biochemistry being held in Moscow. In the midst of the congress, there was a large parade through Red Square celebrating the triumph of the second Russian cosmonaut, Titov, who had just circled Earth. Luckily I was able to watch it through a window of the adjacent Hotel National. While I and most congress participants were condemned to rooms in the Hotel Ukraine across the Moscow River, Robert Maxwell, whose Pergamon Press was publishing the proceedings, occupied a National Hotel suite once occupied by Lenin. Paul Doty, who knew Maxwell through the Harvard chemist Bob Woodword, thought there would be no problem in my viewing the festivities from Maxwell’s rooms. Francis Crick, however, was not sure that he also would be welcome until the heavyset swarthy publisher told him that any friend of Jim Watson was Robert Maxwell’s friend too.