Genes, Girls, and Gamow

by James D. Watson

  The dejection, which inevitably hit me on my return to Pasadena, was not helped by my need to give, two nights later, a pepless Sigma Xi lecture before a general audience that included physicists and chemists as well as biologists. Speaking about DNA alone would have depressed me, so I ended my talk with the dilemmas coming out of finding viruses with RNA as their genetic material. It was key to find out whether each TMV particle contained just one RNA molecule, whose length, in turn, defined the 2800-angstrom length of infectious TMV particles. Unfortunately the measured molecular weights of TMV RNA suggested each TMV particle might contain some 10 to 20 separate RNA molecules. If so, I wondered whether the basic RNA unit in TMV might be two RNA chains. While later doodling on paper in my flat, I madly hypothesized that two such chains might be held together by P–O–P phosphotriester linkages. This was a wacky thought because it could only complicate how these RNA molecules were ever copied. But desperate for some way out of our RNA void, I got to the lab early the next morning to see if such a two-chain RNA structure could be built using Pauling–Corey space-filling models.

  Straight away, I found myself putting together a seemingly perfect structure where all the atoms fit snugly together with just the right interatomic distances. Happily, there was a hint in the literature of unstable TMV structure becoming more acidic upon breaking down. Although these were crude 1937 data, my new model could be quickly proved or disproved by isolating RNA from TMV in the presence of 18O-containing water. If phosphotriester linkages existed, then 18O molecules should be found in the resulting purified RNA. But I realized that getting the answer might take many months to several years.

  Previously I had taken my elegant-looking two-chained ribbon to the Chemistry lab for Linus Pauling’s longtime coworker, Robert B. Corey, to look at. He had to admit it was indeed pretty, but would aesthetics win? Corey’s “American Gothic” demeanor went along with his long-subservient role to Linus. I was surprised, therefore, when he candidly implied that Linus, then touring India, was far too out of touch with his experimental helpers.

  Total frustration with his meson theories was bringing Dick Feynman to my office most afternoons. Recently he had spent an entire evening staring at his ceiling trying to make sense of the data that seemingly had no rhyme or reason. An unexpected invitation to go to Moscow for an “All Union Conference on Quantum Mechanics Electrodynamics” initially diverted him, until he realized that the State Department might not want him on the other side of the Iron Curtain. Close to the date that he was due to depart, his passport was withheld.

  My morale increasingly was on a roller coaster, the inherent shakiness of my ideas particularly hitting home when more than a week would pass without a letter from Christa. But I was kept sane for the lectures I was then giving to a Virus course by the prospect of flying East to give a March 17 lecture in Baltimore at the yearly Biophysical Society Meeting. Not at all sure what would happen when I saw Christa afterwards, I penned another letter to Foxcroft School in the hope that Margot Schutt and I might meet in Washington. Its cherry blossoms would be out and a perfect time for the aesthetically tuned Margot to see that I go for more than molecules. These hopes, however, never went anywhere. On the day I was to speak in Baltimore, she would be in New York seeing “mommy and daddy” sail for a spring in Italy. Then she was going on to Boston to help decide whether to go to graduate school or seek a career in publishing.

  My trip took on a completely new dimension when, just after my arrival East, I got word that the Harvard biology professors had voted to offer me an Assistant Professorship starting on July 1. Before they made up their minds, they had sent out letters to several prominent scientists asking, among other matters, whether the low voice I used in my job seminar might later be equally inaudible to Harvard students. One such letter went to Fritz Lipmann, long notorious for giving such incomprehensible lectures that the Harvard Chemistry Department had appointed Konrad Bloch, not him, to introduce biochemistry into their undergraduate course offerings. In reply to the botanist John Raper’s letter, Fritz wrote “that if I have something important to say, the students will hear me.” Soon after receiving the letter from Frank Carpenter, the Biology chairman, I quickly let him know that I would end my East Coast visit at Harvard to see its laboratory space and facilities. Of course, I would accept his offer.

  The East Coast, Pasadena, and Woods Hole: March–June 1955

  WHEN I ARRIVED in Baltimore for the Biophysical Society Meeting I found Geo Gamow keen to talk about the new manuscript we had each separately received from Crick. In the 17 mimeographed pages entitled “On degenerate templates and the adaptor hypothesis: a note for the RNA Tie Club,” Francis conveyed a radical new thought about how the genetic code works. Never intended for actual publication, it reflected Francis’s opinion that neither DNA nor RNA had the structural features that would let them act as direct templates for the ordered assembly of amino acids into polypeptide chains. Instead he regarded nucleic acids as molecules that like to form hydrogen bonds but not to make the hydrophobic interactions necessary for distinguishing the water-repelling side chains of amino acids such as valine or leucine.

  Francis first focused on this dilemma when driving early in September 1954 from the Nucleic Acid Gordon Conference to New York City, to sail back to England and his family. On the road, he clicked onto the bold idea that each amino acid, before its incorporation into a protein, is chemically bound to a small, possibly RNA-like, molecule with a specific hydrogen-bonding surface that in turn binds specifically to sets of RNA bases. When learning of this idea in December, Sydney Brenner called it the “Adaptor Hypothesis” because it proposes that each amino acid is fitted with an adaptor to attach it to the template. In its simplest form, there would be 20 different kinds of adaptor molecules, as well as 20 specific enzymes to join the amino acids and their respective adaptors. Although no such small adaptors had been found, Francis argued that they could easily be present in small amounts and had been overlooked. Furthermore, the energy that must be supplied to join the amino acids together to form peptide bonds might be supplied by bonds uniting the adaptors with their amino acid.

  Geo saw no reason yet to accept Francis’s reasoning, but he was not averse to considering it—better a still-untested new idea than an old one going nowhere. In contrast, I did not like the idea at all. If correct, it meant that Leslie Orgel and I had been naive chemists when unsuccessfully we tried to fold RNA chains into helical structures with hydrophobic cavities complementary in shape to the hydrophobic amino acid side chains. More to the point, the adaptor mechanism seemed to me too complicated to have ever evolved at the origin of life.

  On the other hand, I had to admit that we had never come close to making a helical model where the hydrophobic backsides of the purine and pyrimidine bases formed even the simplest of cavities—say one into which the methyl side group of alanine would snugly fit. So maybe the first real meeting of the RNA Tie Club should be devoted to the merits of the Adaptor Hypothesis. But now the club’s National Science Foundation (NSF) funding was problematical. Those in charge wanted to be sure that those invited would actually show up in Boston. Much worse, they wanted a book out of the meeting to justify the $3500 we had asked to cover travel and subsistence costs. Common sense told us that more hassle than pleasure would come from further pursuit of such funding.

  What the next day would bring with Christa was never far from my mind. I sensed that all might not be perfect when I learnt that she would be coming down on Saturday morning, not on the Friday afternoon when her classes at Swarthmore were over. I went back to Washington with Geo to spend the night with the Riches. Not knowing what Christa was up to kept me from sleeping well and I was still worrying when she came off the platform carrying her overnight possessions on her back. The kiss I wished to give her evaporated into an awkward hug. As we rode the trolley out to Georgetown, I talked as neutrally as I could about Geo’s reaction to Francis’s adaptor idea.

  My objective in Geor
getown was an arty bookstore. After entering I stared at a large Gauguin reproduction of Tahitian women. Before then, Christa’s face had seemed to me a Renoir painting, but from this moment on I saw her as a Tahitian beauty. My saying so, however, did not have my desired effect. At lunch in a nearby coffee shop, neither of us was at ease and soon we were back outside for a desultory walk along Wisconsin Avenue. We arrived sooner in Cabin John than the Riches expected, and passed more awkward moments walking several miles along the towpaths of the Chesapeake Canal. It was all too clear that my honest, twice-weekly letters to Christa had backfired. Better would have been brisk reports of my activities, not outpourings of unhappiness at her absence.

  During dinner Alex and Jane sensed that our weekend was not on course, particularly after Christa told them that unexpected homework required her to be back at Swarthmore by Sunday suppertime. My psyche took another hit the next morning when she said that she could easily get back to Union Station by herself. Then Alex came to my rescue by offering to take all of us there in his car, thereby letting our lunch be less hurried. Only on the platform walking her to her coach did I sense a lightening of her mood. Then to my surprise, I realized that our past plans for her to come up to New Haven the following weekend were still on course. We were to stay at my uncle and aunt’s house just off the Yale campus. Given my aunt Betty’s longstanding preoccupation with dead ancestors, the visit might be the emotionally neutral occasion I badly needed.

  The following morning I thought I made a good impression on Lawrence Blinks, the NSF biology chairman, whose good graces could help bring about the NSF grant to let me return to England. Most important to him was that I would soon have a Harvard position. This should allow the NSF to give me a grant as a member of the Harvard faculty that in turn I could use to fund my time in Cambridge, England. I still had to convince Harvard’s Biology Department that my academic appointment start with a NSF-funded sabbatical-like year. But a week later I found its chairman, Frank Carpenter, happily agreeable to the first year of my five-year appointment being spent abroad. With NSF funds for my time in England, Harvard would save the money it otherwise would have to use for a later, more conventional sabbatical leave.

  Only a little Harvard departmental money would be available to let me equip and run my lab a year hence. But I anticipated no difficulty in getting more NSF support that would let me do science at full tilt. The only substantial Harvard issue to settle was the space in the Biological Labs to suit my position as an Assistant Professor. Because several major professors were soon retiring, there was free space galore, even excluding the unfinished north wing. Several large, square, corner offices were out of bounds except to full professors, but I was shown the almost as large, third-floor office soon to be vacated by Frederick Bailey, long revered as America’s best plant anatomist. No chemical hoods were present in his accompanying microscopy lab, but I still saw great advantage in taking over his modest facilities. The office faced west out over large trees and grass to the architecturally pleasing nineteenth-century Divinity Dormitory. Moreover, it was just above the formal entranceway flanked by two life-size bronze rhinoceroses that, in 1934, the soon-to-retire President Lowell had judged appropriate symbols of biological research.

  In New Haven with Christa, it was as if the past weekend had never occurred. Why she was less tense, and so naturally put her arm around me on my aunt’s newspaper-strewn couch, I had the good sense not to ask. Christa’s natural good looks were soon noted by my uncle. In turn, my aunt took comfort in reporting to friends that my girlfriend was the daughter of a prestigious Harvard professor. And I now had the warm inner glow from Christa happily telling me that from Swarthmore she would be mailing me an appropriate present for my forthcoming birthday on April 6.

  The thought of her gift kept my morale high through the tiring journey back to Caltech. Needing to change planes in Chicago, I briefly saw the Orgels—Leslie back again being a pure chemist with Robert Mulliken. When my birthday passed without receipt of Christa’s present, I grew anxious until I saw her writing on a long cylindrical parcel. Savoring its opening until I was back in my flat, I found the reproduction of Gauguin’s Ta Matate that I had so admired in the Georgetown bookstore. With its three Tahitian women’s faces looking wonderfully serene, I placed it in a prominent place on the wall above the table that I used as my writing surface.

  Afterwards in carefree spirits I went off with the Delbrück’s, the Dulbeccos, and their German-born friend, Marguerite Vogt, then working on polio with Renato, for an Easter camping trip. Our objective was the desert sand dunes on the eastern side of Baja California, just south of the Mexican fishing village of San Felipe. The heat was not quite that of the parching summer, but the grunion-filled water was already tepid and Manny Delbrück, still girlishly formed at 36, saw no reason for swimming suits. Modesty initially made me keep my head largely under the water, but Max and Manny showed no such inhibitions nor did Marguerite, whom I found particularly awkward to view at close distance. But by dusk, it was obvious to everybody from my burnt skin that I had not been completely modest. A week passed before my fried look vanished.

  Now that I had formally accepted Harvard’s position, I could enjoy looking forward to a brief visit from George Wald. It soon was punctuated by an awkward moment when Max, in an uncharacteristically gentle manner, pilloried the mathematics behind George’s new theory of how the eye adapts to light. Although little time remained for me at Caltech, I still wanted a serious manuscript to emerge from this year’s academic efforts. By then, however, both Leslie and I felt our triplet scheme for RNA synthesis too speculative to publish, and I knew that it would be likewise dangerous to announce my more recent RNA ribbon structure unless future experiments with 18O-water demonstrated RNA phosphotriester bonds. For the moment, I felt semi-comfortable with the theoretical paper about tobacco mosaic virus (TMV) RNA that Don Casper and I had started writing. Using symmetry arguments for the existence of protein subunit dimers, I first favored the existence of some 12 RNA two-chain ribbons running the whole length of the 2800-angstrom-long TMV particles. But it implied an RNA chain molecule weighing only half the 200,000 value measured over the past month by Norman Simmons in Los Angeles. So we might not yet have a good paper in our grasp.

  Gunther and Inga Stent had urged me to visit Berkeley one last time before leaving California, and I chose a late-April date that coincided with my sister Betty and her husband Bob’s arrival in San Francisco by ocean liner from Japan. Proudly they showed off their almost one-year-old son, Timothy, while I expressed excitement about spending another year with Francis in England before having to start teaching at Harvard. Betty and Bob had been living well as part of the U.S. government’s occupying force in Japan, successively in two stylish homes—one built for a member of the powerful Mitsui family near International House in Tokyo, the other to the south in a beach home near the Great Buddha at Kamakura. What Bob had done for whom in his office at our big naval base in Yokohama, I saw Betty didn’t want me to ask.

  After putting them on a plane for Chicago, I crossed the Bay Bridge to Berkeley to give a seminar. I first talked about RNA ribbons and then, even more speculatively, about possible DNA structures generated during genetic recombination. That evening Gunther reported rumors that RNA had recently been enzymatically synthesized in the New York laboratories of the Spanish-born biochemist Severo Ochoa. Marianne Grunberg-Manago, a postdoc from Paris, had apparently found a bacterial enzyme that made RNA chains using nucleotide diphosphates as precursors. DNA was said to have no role in this reaction, which generates RNA chains with random sequences of the four different nucleotide building blocks. The absence of a role for DNA made Gunther and me wonder whether the true cellular role for this enzyme was the breakdown, not the synthesis, of RNA. In any case, we were keen for Alex Rich to get his hands on this enzymatic product soon to see whether it gave the RNA X-ray diffraction pattern that we had found common to both viral and cellular RNAs.

  Back a
t Caltech, my last weeks passed quickly. Even a brief stench of awful smog failed to dampen my spirits. One weekend, I went into the Mojave Desert with Matt Meselson, who just had been given a Thunderbird convertible by his affluent father. With ease we sped along at 100 mph, and as we drove back I sensed that an open roadster would greatly enhance my forthcoming return to England. For several days, Robert Oppenheimer set the Caltech campus abuzz with his two lectures on meson theory. Without any hesitation, I joined the curious mob that packed the Physics lecture hall and like most was not qualified to follow his arguments. But his lucid mannerisms mesmerized many of us into temporarily believing we knew what he wanted his theory to achieve. The day before his lecture, his porkpie hat silhouette suddenly cut across my path to the Athenaeum, his face so familiar that I felt as if he had been part of my personal world for a long time.

  An infinitely less appealing treat was several hours of Erwin Chargaff. His May visit was his first to Caltech, and in no way did he compromise his still-vitriolic feeling towards Francis and me. Referring to us as “The Thinkers,” Dick Feynman kept jabbing me in the side as Chargaff rose to new heights of disdain. Newcomers to DNA might have suspected that Chargaff’s bilious remarks reflected his failure to be the first to appreciate the significance of his A = T and G = C base ratios. I knew otherwise, remembering well his petulant attitude to Francis and me in John Kendrew’s Peterhouse rooms the summer before we found the double helix.

  For my last two California weekends, I went with friends to the mountains to the east of Caltech, first going up the 11,500-foot San Gorgonio and a week later reaching the slightly higher San Jacinto peak above Palm Springs. There was still snow on both peaks but not too much to confuse our paths and make us wish that we were back in safer lower elevations. Without much formality, I was effectively closing out my Pasadena existence. Saying good-bye to George Beadle was the most painful moment. In every way possible, Beets had been on my side. But knowing that my long-term self-interest likely lay at Harvard, he was invariably gracious when my departure came up. In the 1930s, a year of Harvard had been one too many for his Wahoo, Nebraska-bred mind. He now hoped I had the sense not to value Harvard for more than it was.