The most striking of David's guests that afternoon was the Radcliffe senior Diana de Vegh. Quickly making a move to her side, I learned that her investment banker father, Imre de Vegh, was a Hungarian, while her mother was a Social Register Jay. As such, she had sampled both Brearley and Miss Porter's School before being admitted to Rad-cliffe, where she had effectively managed to avoid any science. Now she lived in one of the off-campus houses favored by her fellow private school friends. Her comings and goings were much less conspicuous than would have been those of an inhabitant of one of the large red brick dorms surrounding the Radcliffe Quad up Garden Street. David, in observing Diana give me her telephone number as she went off to another party, took immediate pleasure in telling me that she had earlier attracted the attention of Senator John Kennedy. His official car recently had been sent from Boston to fetch her upon one of his recent returns to check in on his Massachusetts constituents.
Soon I was to phone Diana to ask her to lunch after one of my Biology 2 lectures. This new course, a one-term offering, was intended for students already possessing some background in biology. They would have benefited most from a coherent series of lectures given by one person, in the manner of the long-successful Chemistry 2 taught by Leonard Nash. But my department had opted for Biology 2 to have four instructors, thereby ensuring a virtual potpourri of facts and ideas for its students to master. But with me as one of its four instructors, DNA was bound to be much talked about.
The theme running through all my talks was the need to understand biological phenomena as expressions of the information carried within DNA molecules. Many, and I hoped most, students must have been desperate after nine lectures presented by the physiologist Edward Castle. The tall, thin Castle was bright but sad, habitually seen hurrying home by bike early each afternoon to a wife long stricken with multiple sclerosis. His lectures were a time warp back into the thirties. After listening to his opening talk, I could not have preserved my sanity listening to another. Three weeks later, before the same one hundred students in the Geological Museum auditorium, my first words were a promise that they would hear nothing more about the rabbit. The loud laughs that roared back assured me that I had broken the ice. After my last lecture, which was to be about cancer, I took Diana de Vegh to Henri IV, the French restaurant on Winthrop Street just off Harvard Square, run by the formidable Genevieve McMillan. Genevieve had masterminded the transformation of a modest wooden house into a popular space to have stylish French food with conversationally inclined companions. Looking into Diana's big eyes, I was in high spirits, for my lectures had gone well, with my impromptu attempts at humor appreciated.
Course notes for Biology 2, Lecture 1: “What Is Life”
That term Francis Crick was at Harvard as a visiting professor of chemistry. Even now, six years after the double helix had been found, Cambridge University had yet to provide him and his new South African-born collaborator, the prodigiously clever experimentalist Sydney Brenner, decent research space. Their experiments were being done in a wartime hut erected next to the Austin wing of Cavendish Lab, where the DNA base pairs had come together. The Harvard Chemistry Department, always wanting the best, had just offered Francis a professorship, but without much expectation of his acceptance. Here they were right, as Francis soon got news that the Medical Research Council would provide funds for the construction of a new laboratory building expressly for molecular biology. In fine intellectual fettle because his long-ignored adaptor hypothesis was now a widely accepted fact, Francis conversed endlessly on the details of how specific amino acids first become attached to their respective tRNA molecules. When he and I were awarded the Warren Triennial Prize at Massachusetts General Hospital, my talk surely was much less convincing than his, as I took the opportunity to propose my as yet unproven theory that the essence of DNA tumor viruses was their possession of genes that initiated DNA synthesis.
Ribosomal particles were proving much more structurally complicated than we anticipated, and Alfred Tissières persuaded the Welsh protein chemist Ieuan Harris to come over temporarily from Cambridge to help us. We initially had thought the particles would have the molecular simplicity of small plant viruses. But from his first amino end group analysis, Ieuan saw that ribosomes contained many more proteins than he could effectively cope with using current separation methodologies. So he took solace for the remainder of the spring in sampling American beers still new to him.
My lab group's size was steadily expanding despite the unwanted fleeing of my first graduate student, Bob Risebrough, to sea on the Woods Hole oceanographic sailing boat Atlantis. Much more content at their first contacts with molecular biology were two new graduate students, David Schlessinger and Charles Kurland. After working with Alfred to more firmly establish the two-subunit composition of ribosomes, David briefly went to Caltech to see if Matt Meselson's CsCi banding technique would reveal how long these subunits stayed together during multiple rounds of protein synthesis. That he came back empty-handed reflected his finding that even the ribosomal sub-units are unstable in high levels of CsCi. But the visit was far from a total loss: at Caltech David met the girl that he would later marry. He also discovered David Zipser, a very disenchanted first-year graduate student eager for a fresh chance at happiness at Harvard.
Chuck Kurland's first results on ribosomal structure were not at all what I expected. He found single RNA chains in each ribosomal sub-unit, with those present in the larger subunit twice the length of those in the smaller subunits. Before his observations we had anticipated a variety of RNA chain lengths, reflecting their respective functions to convey information for different-sized polypeptide chains. A year later, Matt Meselson and Rick Davern discovered that once made, these ribosomal RNA chains were very stable under optimal conditions for protein synthesis. Yet at the time of our discoveries, Francois Jacob, Jacques Monod, and Arthur Pardee at the Institut Pasteur in Paris had evidence that the RNA templates for so-called induced enzymes had fleeting lives of only a few minutes. This apparent contradiction came to a head at a Copenhagen meeting in the late summer of 1959, at which Jacques Monod questioned the view that RNA had to be the template for all protein synthesis. Could, in fact, DNA molecules be the templates for the synthesis of the so-called induced enzymes? I rejected this hypothesis during my terse report of our ribo-some discoveries. Unfortunately, my talk's only lively moment came at its start, and not from its content. Everyone in the front row brought out a copy of the New York Times to read—a brainchild of Sydney Brenner, who had long noticed with envy my ability to follow talks while simultaneously keeping abreast of daily events.
Earlier in the summer the Japanese biochemist Masayasu Nomura, then a postdoc in Sol Spiegelman's Urbana lab, came briefly to my lab on his way to the 1959 phage course at Cold Spring Harbor. He had spent the previous summer with me and Alfred characterizing abnormal ribosomes made under conditions of chloromycetin inhibition of protein synthesis. Now a year later and still unable to judge their biological significance, I suggested to Masayasu that he use his forthcoming phage course experience to look at the molecular form of the unstable RNA made during T2 infection. I had been long attracted to T2 RNA because its base composition was almost identical to that of the T2 phage DNA and possibly represented RNA copies of the information present in T2 DNA genes. Though potentially very important, the phenomenon eluded further characterization. What T2 RNA was should at last be revealed by the new techniques of sucrose gradient centrifugation, which required only small amounts of RNA and would potentially provide information about its function through measurements of the sedimentation rate of its radioactively labeled molecules.
We were greatly benefiting from David Zipser's transfer from Cal-tech. From the moment he arrived, David, soon to be called Zip, homed in on the sucrose gradient centrifugation procedure that had been recently developed at the Carnegie Institution of Washington biophysics lab. He was an indisputable asset, but a period of some acquaintance revealed that Zip's unhappiness a
t Caltech may have had a basis in his character: he did not play well with others. After a particularly inappropriate remark about another student's girlfriend, Zip was put on social probation: I told him to stay away from our afternoon tea and cookie sessions, a ban maintained for much of the year. Tellingly, no one came to his defense. His cause was not later helped by his cheering when Gary Powers's U2 was shot down in May 1960 and Eisenhower had to cancel his visit to Moscow later that month. Zip was the product of a New York communist family, fully aware that an easing of tensions between the United States and the USSR would give the family less purpose.
Everyone in the Biolabs was also now benefiting from the insect physiologist Carroll Williams's becoming the new chairman of biology. In July 1959, he got money from University Hall to repaint the corridor of the Biolabs, using bright shades of red, yellow, and blue at focal points. Much more important, McGeorge Bundy told Carroll that he wanted the Biology Department to propose five names for consideration by a super ad hoc committee to be formed in midwinter. Our department's failure over the past year to attract a distinguished geneticist had made Bundy realize that he would have to take the bull by the horns if he indeed wanted to force our Biology Department into the modern age. Not all the appointments were to be molecular biologists, but each should represent a significant advance over the past.
More a conciliator than I might have hoped, Carroll wanted the five candidates to have the department's unanimous backing. My elation at Bundy's proposal was tempered when I saw the department was soon to make offers to the animal and plant embryologists Aaron Moscona and John Torrey As I believed embryology would remain an antiquarian pursuit until revived by better understanding of how DNA expression is controlled, I feared these offers would amount to two more nonwinners. More hope lay in the department's wish to hire an electron microscopist who could teach a modern cell biology course, and I was happy that they decided to try to pinch the spirited Keith Porter from Rockefeller University. For someone to teach modern microbiology, there seemed no one better than Mel Cohn at Stanford, a former protege of Jacques Monod in Paris. Best of all, there was universal enthusiasm for trying to get Matt Meselson to defect from Caltech. Earlier Matt had mesmerized the department with a lecture on how his experiments with Frank Stahl demonstrated the semicon-servative replication of DNA.
Conceivably, a major impediment to our effort lay in Jonas Salk's impending creation of a new high-powered research institute for biology at La Jolla. He bragged about its future oceanfront location on a stopover at Harvard in the fall of 1959 on his way to visit his son at school at Exeter. There he envisioned recruiting leading biologists, including me, to engage in cutting-edge research with no teaching responsibilities. Behind Jonas's Utopian vision was Leo Szilard's desire to create a first-class environment that he could use as a permanent base for his simultaneous forays into biology and nuclear weapons politics. Leo strongly wanted Jonas as its head, believing his fame would make Hollywood Jewish money easy to get. My counterargument that Jonas's intellectual distinction was not much greater than Nathan Pusey's did not faze him. Leo countered that the bylaws of the new institute could be set up to put control of appointments and finances in the hands of its leading scientists. I was, in fact, more intrigued by the recent offer to be one of the founding biologists at a new University of California campus also to be located in idyllic La Jolla. It was to be adjacent to the land that Jonas coveted for his purposes.
My formal visit to see the proposed site of the U of C's new La Jolla campus occurred in early March 1960, timed to coincide with a gathering of prospective appointees to what later would be called the Salk Institute. Awaiting me at the San Diego airport was Jonas with a white stretch limousine to take us to a motel on the Pacific Ocean. The wheels, Jonas explained, had been provided by his longtime patron, the National Foundation for Infantile Paralysis, still then headed by former Franklin Roosevelt lawyer and confidant Basil O'Connor, who believed that only by such grand conveyance would Jonas get the respect due him for his role in stopping polio. Upon arriving at the oceanview site of the future Salk Institute, I saw that Matt Meselson and Mel Cohn also had been called to La Jolla by Jonas. I quietly told everyone that Meselson and Cohn would both soon also be receiving offers from Harvard. Unusually tense was a final luncheon jointly hosted by Jonas and the oceanographer Roger Revelle, head of the venerable Scripps Institution of Oceanography and the main instigator of the new U of C campus. Roger, who had married into the Scripps newspaper fortune, did not take kindly to Jonas's opening remarks that he and Jonas respectively play mama and papa at the occasion.
I left San Diego not at all tempted to move to its perfect climate. Instead I was keen to return to Harvard in anticipation of the impending visit of Peter, Jean, and Caroline Medawar. Three years had passed since we were all together on Skye and in the meanwhile Caroline had almost finished her Cambridge education. Peter was to give that year's Prather Lectures in the Biology Department. After the last of his three lectures was delivered, I made the mistake of inviting Caroline to go skiing in Vermont. Her awkwardness as a beginner was compounded by the seemingly fearless downhill glide of a young Radcliffe student I had also asked along. In a sulk at being outclassed by a girl who also had brains, Caroline went off to join her parents in New York, leaving me to realize once again that you shouldn't pay simultaneous attention to two girls. Fortunately, a major conceptual breakthrough was soon to emerge from my lab. Late in 1959, as an editor of the newly founded Journal of Molecular Biology, I received a manuscript from Urbana by Masayasu Nomura, Ben Hall, and Sol Spiegelman on T2 RNA. My initial reading immediately led me to doubt its central conclusion, that the T2 RNA sedimented as if it were a special form of the small ribosomal subunit. Believing the experimental facts should be known widely, even if they were possibly wrongly interpreted, I accepted the manuscript for publication. Soon afterward I suggested to Bob Risebrough, just back from more than a year on the Indian Ocean, that he repeat the experiments done at Urbana in the hope that we might at long last see the RNA templates for protein synthesis. It had long mystified me why Bob had so precipitously vamoosed to sea. Now I took comfort in learning that it was not from my lab and its experiments that he had fled but from an entanglement with a married woman. Hoping this mess was now behind him, Bob wanted to get back in the game.
In the Harvard Biolabs
Within six weeks, Bob cut to the heart of the T2 RNA's special nature. Using sucrose gradients containing high (10”2M) levels of Mg++ ions, all the T2 RNA was seen to have bound to the 70S ribosome complex of the big and small ribosomal subunits. In contrast, when Bob followed sucrose gradients containing lower (io”4M) Mg++ levels, the T2 RNA sedimented as free RNA and not as part of either the smaller or larger ribosomal subunits. Excitedly we realized that ribosomal RNA never orders amino acids during protein synthesis. Instead their respective ribosomes are nonspecific “factories” in which the T2 RNA templates order amino acids during protein synthesis. That such messenger RNA had not been seen before reflected the fact that, in most cells, much more ribosomal RNA is made than messenger RNA. But following infection of bacteria by T2-like phages, all host-specific RNA synthesis stops. All the RNA molecules synthesized during phage infection are made on T2 DNA templates.
A week later I flew down to New York City, trying without success to resume my friendship with Caroline Medawar, who was spending the weekend with her parents at Rockefeller University. Over the same weekend I visited Leo Szilard, at this time a patient at Memorial Hospital. Just before Christmas the awful news had reached me that Leo had bladder cancer and that diagnosis might have come too late. Fortunately, by the time I saw him he had taken charge of his radiation therapy and was soon to emerge totally cured. He immediately wanted to gossip about my recent visit to San Diego, while I wanted to talk about our big T2 RNA breakthrough. He said he would take my idea seriously only when messenger RNA molecules were shown to exist in uninfected as well as phage-infected cells. I told him
this was to be our next research objective. A young French biochemist from the Institut Pasteur, Francois Gros, was to come to Harvard for the summer to search for messenger RNA in uninfected E. coli cells.
My main goal soon became persuading Matt Meselson to accept Harvard's offer, not Jonas Salk's. His visit to look us over came during a week of fortuitously perfect April weather, a seduction in itself compared with Pasadena smog. Matt, unlike Benzer, quickly said yes to Harvard, telling Paul Doty and me that he would arrive as soon as appropriate research space could be renovated. Mel Cohn, in contrast, opted for the Salk Institute, and Aaron Moscona, to my never hidden delight, decided to remain in Chicago. Also to Harvard's long-term benefit was the acceptance of Keith Porter. In contrast, John Torrey's decision to leave England meant that botany at Harvard would likely continue intellectually vapid.
During that time, Celia Gilbert often invited me for vodka-dominated meals at which one of Wally's young colleagues, the theoretician Sheldon Glashow, was often present. Wally was then twenty-eight years old and had been an assistant professor of physics for two years. Surprisingly, he now found himself more excited by our T2 RNA experiments than by his own attempts at high-level physics. Eagerly he was soon to drive up with Alfred Tissières, Francois Gros, and me to the 1960 Gordon Conference on Nucleic Acids in New Hampshire, afterward assisting Francois in his summer pursuit of a T2-like RNA in uninfected bacterial cells. Most conveniently, Francois and his wife, Francoise, also a scientist, were living in the tiny 10^ Appian Way flat that my father had moved into two years before upon his early retirement from his job in Chicago. Dad was off on a lengthy tour of Europe, having enjoyed a similar trip the year before. To my delight these trips showed that he could now be on his own for long periods, coping with if never quite moving beyond the loss of my mother.
Avoid Boring People: Lessons from a Life in Science Page 15