From 1971 to 1973, my main teaching responsibility was a yearlong introductory undergraduate course on biochemistry and molecular biology (Biochemistry 10). In preparing for a spring 1972 lecture on DNA replication, I saw the need to point out the commonly accepted 5'→3’ DNA chain elongation mechanism led to incomplete double helices with single-stranded tails. Some molecular mechanism had to prevent DNA molecules growing ever shorter during each round of replication. Until then, no one understood why identical, redundant DNA sequences were found at the two ends of all linear phage DNA molecules. Suddenly I knew why. Redundant ends allowed right and left single-stranded DNA tails to hydrogen-bond to each other to form dimers. Further cycles of DNA replication would lead to ever longer phage DNA molecules. No longer mysterious to me was why replicating phage DNA molecules are many times the length of infecting phage DNA molecules. Excited by my brainstorm, I told it to my Biochem 10 students and, afterward, wrote it up for an article in an October 1972 issue of Nature.
Salvador Luria, Nancy Hopkins, and David Baltimore at the MIT Cancer Center in 1973
Soon my main concern at Harvard turned to making the Biological Laboratories another major site for tumor virus research; after coming strong into the molecular age, Harvard was risking again being behind the curve. In April 1973, however, the National Cancer Institute turned down Harvard's application for construction monies for animal cell facilities. The proposal's reviewers were not convinced that the building addition would be used in a way that well served NCI's mission. True enough, given my Cold Spring Harbor responsibilities, I would likely never directly oversee a tumor virus lab in Cambridge. Nor was it clear whether Mark Ptashne would abandon gene regulation in bacteria to work on retroviruses. And Klaus Weber might go back to Germany were he offered a high-level appointment. In contrast, MIT's application for NCI construction funds was approved without a hitch.
Actually, it was a shoo-in with David Baltimore and Salvador Luria as its main drivers. Soon they would conscript two Cold Spring Harbor initiates into tumor virus research: Nancy Hopkins, after two years in Bob Pollock's lab, and Phil Sharp, after three highly productive years in James Lab.
Moving much too slowly were the joint efforts of the Biology Department and BMB to recruit a tenure-level RNA retrovirologist. Though discussions began in the fall of 1972, letters seeking advice from eleven referees did not go out until six months later, in February. The referees were asked to compare as candidates Mike Bishop, Peter Duesberg, Howard Temin, Peter Vogt, and Robin Weiss. Temin's name was high on most lists, although with the caveat that he was not a consistently good lecturer. Two respondents advised that we also consider Harold Varmus. Mike Bishop was not on top of any list except for Bob Huebner's, who called him a highly intelligent biochemist as well as a lucid teacher.
On July 10, 1973, I went to University Hall to see the economist Henry Rosovsky, who had just replaced his fellow economist John Dunlop as dean of the Faculty of Arts and Sciences. Dunlop had hurriedly taken on the role during the April 1969 University Hall occupation when Franklin Ford suffered a mild stroke. I was then BMB's new chairman, a task I was to have only until February 1975, when Matt Meselson replaced me. During my brief tenure, I wanted to ensure that Harvard somehow acquired animal cell facilities equal to those MIT would have in eighteen months. That morning with Rosovsky, I stressed how important it was for him to ensure Klaus Weber's return to Harvard, a commitment Klaus could not make until up-to-date animal cell facilities were available in the Biological Laboratories or, better still, in the proposed new animal cell annex. Six weeks later, I took Klaus to Henry's offices to give Henry personal assurance that Klaus would come back to Cambridge if he could continue the experiments he and Mary Osborn had started at Cold Spring Harbor. By then Harvard decided to resubmit its application to NCI for construction monies, now opting for a completely separate new building on roughly the same site proposed for the annex. Several of the Biology Department faculty had become queasy about living with possible biohazards in their midst.
Harvard's president, Derek Bok, became actively involved on November n when the ad hoc committee met to consider whether Howard Temin should be offered tenure. I appeared as an early witness, sensing there would be no objection. Soon the question became whether he would agree to come. To answer it, he and his wife came to visit Harvard in mid-December. Their main host was Matt Meselson, a close friend of Howard's since their days together at Caltech in the late 1950s. I was worried from the start that his population geneticist wife, Rayla, would not want to leave the University of Wisconsin at Madison. Matt, however, thought we had a good chance of getting them to join us.
In January 1974, Henry Rosovsky scheduled a day to hear everyone out about the proposed NCI grant resubmission. Carroll Williams expressed concern that receipt of NCI monies would force Harvard to use all of the government-financed space for work with cultured animal cells and their viruses. If the federal funds came forth, he thought BMB should relinquish some of its space in the Biolabs to let the Cellular and Developmental Biology subdepartment increase its numbers. In contrast, I argued for Harvard's quickly recruiting several animal cell hotshots who would create a high-powered cancer center like the one at MIT. It was my belief that all outstanding research on animal cells would easily fall within the purview of the NCI mission. Until we understood how cells sent out and received molecular signals to divide, we could not get at the essence of cancer, and understanding the mechanism was plenty to keep an animal cell group busy. I then told Henry the building would function best with a director reporting directly to the dean, which Carroll Williams resisted, seeing it would diminish the power of department chairmen. But I felt the chair's usual three-year term did not allow him or her to take on necessary long-term funding objectives.
The animal cell building proposal went to NCI in January just ahead of the deadline. The cover letter, signed by Derek Bok, was essentially written by me, with the requested construction money adjusted to $5.76 million, reflecting our architect's prediction of further inflation, which was then bedeviling the entire American economy. In its final form, the proposal was my vision—not Carroll Williams's—of how animal cell science should proceed at Harvard. But its realization much depended upon whether Howard Temin joined our faculty. More than a month of uncertainty passed before Howard finally turned us down, saying his wife saw her life diminished by moving to Harvard. No job she might find in Boston would be as good as the one she had with the population geneticist Jim Crow in Madison. To keep our NCI application alive, an offer was made to the English retrovirologist Robin Weiss. But soon he turned us down, as he had MIT the year before. My dominos continued to fall when Klaus Weber in early April formally accepted an offer to head a Max Planck Institute in Göttingen, Germany. It would provide even better facilities than could be fixed up for him within the confines of the Bio-labs. Harvard then had no choice but to tell NCI it no longer could claim a future in tumor viruses.
Klaus's decision was already 90 percent made when Derek and Sissela Bok invited Liz and me for a late March Friday night dinner at Elmwood, the gracious old wooden house just off Fresh Pond Parkway where they lived with their four children. Upon Derek's becoming president, they chose not to live in the formal Quincy Street fishbowl successively occupied by Lowell, Conant, and Pusey Two years younger than I, Derek had concluded three very successful years as dean of Harvard's Law School. A graduate of Stanford, he was the first president of Harvard not a product of the college. That evening I tried to forget about the animal cell biology fiasco and Harvard's lack of a tumor virus future. I realized there was no longer a good reason for Cold Spring Harbor and Harvard to remain closely connected. Derek graciously kept our conversation on other matters, knowing only too well that my heart was now mostly at Cold Spring Harbor. Harvard had no one leading it into the future in the way David Baltimore was blazing the way for MIT biology.
Two weeks later, I drove over to the glass-faced MIT biology building for a meeti
ng hosted by Paul Berg. There, with David Baltimore's help, he assembled a small group to discuss implications of the powerful new recombinant DNA technology developed at Stanford. Phil Handler, the president of the National Academy of Sciences, had asked Paul to come up with an appropriate response to a letter published in the September 21,1973, issue of Science. The academy had been called on to offer guidelines for recombinant DNA experiments that might create biohazards not only for the lab worker but also for the general public. That morning our small group, which included Dan Nathans and Norton Zinder, concluded the matter would best be dealt with by a much larger group assembled at the same Asilomar, California, site where we had considered potential biohazards of tumor virus research the year before. Until Asilomar II could be held, likely early the next year, we proposed a worldwide moratorium on recombinant DNA experiments in a letter to the journals Nature and Science. I then visualized the Lab publishing Asilomar II's proceedings. Unlike our first biohazard book, this one I expected to make real money.
All the world's major tumor virologists assembled three months later for the Lab's annual early June symposium. Joe Sambrook organized the DNA tumor virus sessions, and David Baltimore put together the ones on RNA retroviruses. Between Renato Dulbecco's introductory talk and David's concluding summary, there were 116 presentations, out of which 101 manuscripts were generated. They would fill our first two-volume symposium proceedings, consisting of almost twelve hundred pages. Though no scientific bombshell exploded, the meeting's highly charged atmosphere made it likely that a deep truth would emerge at any moment. More presentations came from Cold Spring Harbor scientists than from the faculty of any other institution, even London's better-funded Imperial Cancer Research Labs in Lincoln's Inn Fields. Klaus Weber and Mary Osborn notably reported upon their purification of the SV40 antigen. In their talk they provided strong presumptive evidence that the T antigen was the product of SV4o's A gene, one that functions early in the SV40 life cycle as well as in SV4o-transformed (cancerous) cells. Further studies might soon convincingly show it to be the primary cancer-causing genetic unit on SV4o's small circular chromosome.
I spent much of the remainder of the summer on Martha's Vineyard preparing the third edition of The Molecular Biology of the Gene.
Next to our old farmhouse was a small barn, whose large central room provided an ideal writing space. I was getting invaluable feedback from several science-oriented Harvard and Radcliffe students, who later extended the glossary and corrected the final proofs. Doing the many needed new illustrations was Keith Roberts, by then running his own plant cell biology lab at the John Innes Institute in Norwich, England. As a postdoc at Cambridge five years before, he had created the new drawings for the second edition as well.
Over the following academic year, I was again on leave, working full time at Cold Spring Harbor at a salary identical to what Harvard would have paid me for teaching. Our settled residence in Cold Spring Harbor allowed Liz to take two classes per week at the New York School of Interior Design. Often sitting near her was the petite, blond Barbara Lish, wife of the writer Gordon Lish, then America's most influential arbiter of fiction, whom we befriended. Most unexpectedly we bumped into the Lishes at an early December gathering of intellectuals on the Florida coast. Arthur Schlesinger, Gunnar Myrdal, Saul Bellow, Vernon Jordan, and I had all been assembled just north of Daytona Beach with the unexpressed purpose of drawing attention to ITT's big beachfront development called Palm Coast. It was still a day when public intellectuals could sell real estate. Attracting us to this most unlikely gathering was the generous $4,000 honorarium, a much more substantial monetary award than normally given for intellectual chitchat. Barbara and Gordon were there in pursuit of Truman Capote. At the meeting, Gordon persuaded Capote to let Esquire, where he reigned as “Captain Fiction,” to serialize his newest opus, Answered Prayers. Before arriving at Palm Coast, we visited Disney World, where Duncan, just shy of his third birthday, screamed all through the jungle boat ride.
We were just a month settled into Airslie, its new picture windows alluringly draped with Swedish cloth we found in the D&D building on Third Avenue. Its many rooms let Liz invite her parents and her two brothers and sister, as well as her aunt from California and grandmother from Philadelphia, to spend Christmas day with us. But the big Christmas feast, preparation for which included many hours basting two geese, did not go as planned. By the time the fowl were on the dining table everyone except the schoolteacher aunt and physician dad had come down with twenty-four-hour retching flu. The night before, we had received all the families in Lab housing for warm Christmas grog. I didn't know whether they had brought the contagion or whether one of Liz's family members was its origin. Fortunately, there was no sign of a Boxing Day epidemic.
That year, the newly winterized Davenport Lab was utilized by three supermotivated yeast geneticists on sabbaticals: David Botstein from MIT, Gerry Fink from Cornell, and John Roth from the University of California at Berkeley.
After Christmas, our yeast trio and the tumor virologists began to discuss what should happen at Asilomar II, scheduled for February 1975.1 increasingly worried about restrictions that might be imposed on the use of recombinant DNA technologies to clone putative cancer-causing genes. In fact, these procedures would greatly reduce whatever risks we were now incurring using live SV40 virus or adenovirus 2. Our call for a moratorium, however, created the mistaken impression, magnified by each successive press conference, that working with recombinant DNA was a potential major public health hazard possibly equal to nuclear weapons. Even before the meeting started, Joe Sambrook had been asked to join fellow tumor virologists in coming up with guidelines that could only retard the development of recombinant DNA technology.
When I arrived at Asilomar, I found that virtually all the 140 participants were inclined toward accepting restrictions of one sort or another. Only Stanley Cohen, Joshua Lederberg, and I thought they were the wrong way to go. To no avail we voiced the impossibility of regulating an unquantifiable risk. Harm to someone or something had to be demonstrated before regulation could be rational, and to our knowledge no tumor virologist had come down with a cancer likely to have been caused by lab exposure. But for Paul Berg and his Asilomar II co-organizers, there seemed no way out of accepting some form of NIH-imposed guidelines. If we attendees did not accept them, the wrath of public opinion would surely descend upon all of us. And if we did not propose them they would be imposed upon us in more draconian form. At the meeting's end, virtually all participants warily voted to approve the mildly restrictive rules prepared by the several working groups. If the public found them satisfactory, recombinant DNA experimentation should not be too badly set back. On the small feeder plane taking participants back to the San Francisco airport, however, I was full of foreboding. I believed that trying to look good, as opposed to doing good, could only backfire.
A week after Asilomar I flew up to Boston to speak at the dedication of MIT's Cancer Center. In my talk, I offered my view on how to fight the escalating “war on cancer.” I proposed that money would be best spent initially on creating centers filled with Ph.D.'s, as opposed to M.D.'s. I did not see the big clinical cancer centers then as having the potential to attract the very bright young scientists who could find the molecular essences of cancer. And without those molecular keys all the money in the world would only little improve what clinicians could do. Only after my speech did I learn that an inexperienced young stringer for the Washington Post had been in the audience. To my horror, the next day the Post ran his story over the headline “Nobelist Calls War on Cancer a Failure.” I immediately wrote Dick Rauscher, the RNA tumor virologist now heading the NCI, to say that I had been badly misquoted. Fortunately, someone on his staff, Phil Stansley, also heard my talk, and backed me up.
With my $1,000 MIT honorarium I soon acquired for the Lab a Milton Avery-like abstract painting by the talented Long Island artist Stan Brodsky. It gave real style to the fireplace room of Blackford Hall un
til it was damaged by a large spoon thrown during a summer banquet food fight. After repairs costing almost half the original purchase price, it went back on the same wall until the next food fight damaged it again. This time the harm was slight, and it was only a few days before its subtle red, pink, and blue colors could again be admired.
In the fall of 1975, I resumed teaching at Harvard, flying up to Boston to spend Sunday and Monday nights at the Harvard Faculty Club. My lectures on tumor virus and animal cells were updated versions of those I had given three years before, using as a text the Lab's monograph The Molecular Biology of Tumor Viruses. This was to be the last course I would teach at Harvard. Matt Meselson was unwilling to appeal to the dean for an exception to Harvard's long-standing prohibition against sharing faculty with other institutions. And so I was informed that, as of July 1,1976, I would no longer be a professor at Harvard. It was a situation of my own making, but all the same I was much annoyed, if not insulted, since Jack Strominger had recently become director of research at the Dana Färber Cancer Institute across the river while retaining his professorship in our department. Jack, moreover, now was being paid by both institutions, while I would have been content with only one salary if I could keep both jobs. There were many things I knew I would miss about Harvard, but by far the first would be its students; the obligation to lecture to them forced me to extend my own thinking, and occasionally the most extraordinary ones came down for research at Cold Spring Harbor, enriching the intellectual fellowship there.
Avoid Boring People: Lessons from a Life in Science Page 31
