Avoid Boring People: Lessons From a Life in Science (33 page)

Less than a week passed before Dick heard that Ekke Bautz at Rutgers and his student John Dunn had obtained the same results using GG and PC enzymes following the protocol he had sent them in July. At my suggestion, Dick immediately contacted Bautz to see whether they would like their work included in a joint lab paper on the σ factor to be submitted to
Nature.
Liking the idea, they came up to Harvard on November 6. For me their presence was also a distraction from the unbearable cliffhanger of the presidential elections that day. Richard Nixon's victory over Hubert Humphrey would become clear only late that night. Even the discovery of σ factor did not alleviate the gloom I felt the rest of the week at the prospect of a Nixon presidency.

At the 1970 Cold Spring Harbor symposium: Jeff Roberts with Ann Burgess (left) and John Richardson with Dick Burgess (right)

On Monday morning, November 11, a silver lining briefly presented itself. In that day's
Crimson
I read the supersize headline “Pusey to Quit Harvard.” The accompanying article reported that Presidentelect Nixon had paid an unannounced visit to Harvard, coming secretively at 9:00 P.M. the night before, to ask Pusey to become his Postmaster General. After a frank and comradely conversation, during which tea and vanilla wafers were served, Pusey accepted later declared to be “the greatest moment of my life.” All too soon, however, the happy glow permeating my being dissipated. Lower on the page was another story reporting that the proposed JFK Library was to be moved from Cambridge to Bayonne, New Jersey, making me realize I was reading one of the hoax issues
Crimson
editors occasionally created, perhaps to assure themselves that no want of wit had consigned them to the
Crimson
rather than the
Lampoon.
After this monumental letdown nothing in the
Crimson
ever seemed funny.

When the manuscript announcing σ factor was submitted to
Nature
on December 2, it contained only data obtained at Harvard. The equivalent experiments from Rutgers had been done fewer times and were less complete. “Factor Stimulating Transcription by RNA Polymerase,” by Burgess, Travers, Dunn, and Bautz, speedily appeared as a full article in January 1969. Before publication, I announced our lab's breakthrough in a lecture to Arthur Kornberg's perennially self-congratulatory Biochemistry Department at Stanford. It was a moment I never dreamed would come: our Harvard Biolabs demonstrating the biochemical competence to take on and best mighty Stanford.

In mid-December, Dick and Andrew had heard from Ekke Bautz and John Dunn that σ molecules disappear from cells infected with T4 phage, explaining why host bacterial RNA synthesis stops soon after phage infection. Phage DNA molecules likely coded for phage-specific σ factors that directed core RNA polymerase molecules to specific signals on their respective DNA. Over the next six months, Andrew Travers confirmed this conjecture and sent a paper to
Nature
in August called “Bacteriophage Sigma Factors for RNA Polymerase.” In its conclusion, he speculated that σ-like transcription factors might be responsible for the massive shifts in RNA transcription patterns underlying the development of higher organisms. Sensing again a major paper on their hands,
Nature
editors rushed it into print in just over a month.

By early February, Dick had defended his thesis and started a Helen Hay Whitney postdoctoral fellowship that would let him remain at Harvard until his intelligent, blond wife, Ann, finished her Ph.D. thesis. She hailed from a prosperous, hardworking Wisconsin family and did her experiments on bacteriophage ΦX174 down the hall in Dave Denhardt's lab. By then, Dick knew that not one but two ß chains existed in the core (PC) RNA polymerase particle whose structure was α
₂
ββ He and Andrew, furthermore, had preliminary evidence pointing to how σ functioned in the initiation of RNA synthesis. Its role was to direct the core α
₂
ββ
¹
complex to appropriate starting sites to the DNA for RNA synthesis. RNA polymerase's enzymatic property is solely owing to its α
₂
;ββ
¹
core component.

The relative importance in controlling gene regulation of repressore and operators versus σ factor shifts still remained open. Bernie Davis at Harvard Medical School bet me a case of wine that my group would not discover a second bacterial σ factor over the next two years. Andrew then had let Bernie know of his tentative evidence for a σ factor controlling ribosomal RNA synthesis. Here time was not on his side, costing me a case of cabernet. But Richard Losick, a newly appointed junior fellow, had begun experiments in the Biolabs on how
Bacillus subtilis
forms spores, soon getting hints of a possible σ factor specific to bacterial sporulation.

The first visible recognition of σ factor's importance came in November 1969 at a meeting in Florence, Italy, on RNA polymerase and transcription. Dick Burgess gave the opening talk, coming from Geneva, where he was now a postdoc in Alfred Tissières's lab. Sponsoring the meeting was Lepetit, the Milan drug company whose rifamycin and rifampicin antibiotics had been shown to inhibit bacteria through binding to the ß subunit of RNA polymerase. At this meeting, Jeff Roberts announced his recent discovery of a protein called p that halts RNA synthesis at specific stop signals on DNA molecules. Just before coming to Italy, he sent off his manuscript “Termination Factors for RNA Polymerase” to
Nature,
which published it in December 1969.

Though the low sun was not optimal for picture viewing in the Uffizi Gallery, the Palazzo Vecchio provided a reception site equal in its satisfactions to the science of the three-day gathering. Even being forced to listen to a minister up from Rome could not diminish the pleasure of knowing that the Biolabs were still at the center of how genes are regulated.

    Remembered Lessons

1. Two obsessions are one too many

Experiments, like many speculative enterprises, are likely to require at least five times more effort than you initially guess. Being a really good anything—be it university president, violinist, securities lawyer, or a scientist—requires a virtually obsessive devotion to one's objectives. Dividing one's attention will give the edge to competitors who have the same talent but greater focus. For this reason, highly successful bankers who also claim to be accomplished cellists are often neither. Their banking reputation likely rests on the labors of talented associates working day and night, and their cello playing as likely suffers from the time lost to even the pretense of being a banker.

2. Don't take up golf

The moment golf clubs are first spotted in your trunk, you will be subject to constant ribbing. Only the rare few content to play occasionally with no fantasy of breaking 90 should even consider hitting the links. Once you become obsessive about bettering your personal best—say, now 94—your weekend science experiments cease. You have become a thank-God-it's-Friday scientist, always fighting not to fall too embarrassingly behind those peers who have sensibly chosen the less Zen but more aerobic thrill of hitting tennis balls.

3. Races within the same building bring on heartburn

A serious competitor aiming for the same objective inherently creates anxiety. It is emotionally draining to wish ill upon anyone constantly nearby, yet few, if any, human psyches are capable of turning off the visceral wish for an opponent to stumble. In science, the journey is not the destination; the destination is the destination. And so it is better that one's competitors be in a different city, if not country. Having them in the same building is a small model of hell, and not even an efficient one. Once Jacques Monod had two research teams working in adjacent labs attempt to make ß-galactosidase in the test tube. Maybe he knew their respective leaders already disliked each other. Anyway, in that spring 1962 race, no one crossed the finish line.

4. Close competitors should publish simultaneously

Science works better when the winners do not take all. The agony of losing a very close race may break the spirit of a competitor who may again bring out the best in you. And so when you beat someone across the line by only a nose, offer to publish at the same time, if not back to back, in the same journal. Those scorekeepers in the know usually are aware what happened and will think more highly of you. Doing unto others may also yield reciprocal benefits the next time you are oh-so-close.

5. Share valuable research tools

Do not hog powerful new research tools or reagents. If Dick Burgess had not shared his GG and PC RNA polymerase preps with his lab neighbor Jeff Roberts, he unlikely would have been the first to discover σ factor. One hand washes the other. Though it was sharing his RNA polymerase protocols with Ekke Bautz and John Dunn that brought them into his game, they later immediately shared their discovery that σ factor disappears following phage T4 infection. This openness further helped Andrew Travers get an early start in the hunt for phage-specific σ factors.

14. MANNERS FOR HOLDING DOWN TWO JOBS

I
N THE FALL of 1967, Harvard gave me permission to become the director of the Cold Spring Harbor Laboratory while remaining a full-time member of the faculty. They did so upon realizing that Cold Spring Harbor's precious research and educational resources were on the brink of disaster and would likely disappear unless someone stepped in to make this unique Long Island institution financially viable. I was already a member of its board of trustees and knew its shaky state through my close friendship with its sharp-minded director, John Cairns. Born and bred in North Oxford, John exuded an ironic intelligence as well as an inability to seek help from individuals who had more power than warranted by the agility of their brains.

Since arriving from Australia in July 1963, John increasingly had come to see the biochemist Ed Tatum, chairman of his Board of Trustees, as a personal nemesis. On paper he seemed an asset. Tatum, then a professor at Rockefeller, had done research at Stanford in the 1940s on gene-protein relationships that led to his sharing the 1958 Nobel Prize in Physiology or Medicine with the Nebraska-born geneticist George Beadle. But Tatum was a polite plodder who would have gone nowhere but for Beadle, and later at Yale he was propped up by his graduate student and protege Joshua Lederberg. The sharp intellectual crossfire of the geneticists and molecular biologists who spent summers at Cold Spring Harbor was not Tatum's cup of tea. Prior to his becoming chairman, he had attended only one summer symposium. Much to John Cairns's annoyance, Tatum arranged for all trustee gatherings to be held in New York City at Rockefeller University. Avoiding the thirty-mile trip east, the chairman spared himself and the other trustees having to see the decrepit state of the some twenty-five buildings on the Lab's almost one-hundred-acre campus. At board meetings, Tatum's demeanor reminded me ofthat of Nathan Pusey Neither knew how to handle individuals who presented unwanted facts.

John Cairns (center) at the 1968 symposium

By the time I joined the board, John operated in day-to-day uncertainty, even though he had converted the lab's $50,000 negative cash balance to a surplus of some $100,000. Three years of hard physical and mental effort had been required, including his oft cutting the Lab's many green lawns himself. At the same time, the Lab's endowment remained effectively zero, and its survival depended upon the success of its small number of scientists each obtaining one to several significant research grants, which supported not only their science but also the budget for administration, facilities maintenance, and the like. Apart from this grant income, the only other major barriers to insolvency were a few corporate sponsorships and the ever-increasing sales of the lab's annual symposium report, a must-have volume for anyone in molecular biology.

By mid-1966, John began to talk about quitting, and such talk only increased as Tatum showed himself entirely unperturbed by it. But several key junior scientists took note and in turn began to seek jobs elsewhere. In early 1967, John submitted his resignation, effective upon the selection of a successor. By then it was cold comfort to John that Ed Tatum would be gone even sooner. Replacing him as chairman was an H. J. Muller-trained geneticist from Texas, Bentley Glass, whose association with the lab went back to the late 1930s. Recently he had moved from Johns Hopkins to become provost of the new Long Island campus of the State University of New York, at Stony Brook.

Bentley knew that he alone could not dramatically improve the Lab's chances for survival. Though he was connected to innumerable government funding sources, no new monies would flow to Cold Spring Harbor until an appropriate new director was found. When I flew to New York City for the Lab's late October trustee meeting, I feared they might choose the German phage geneticist Carsten Bresch, then looking for an escape from an insecure job in Dallas. If Bresch were to come, he would continue the Lab's historically strong focus on molecular genetics. But I feared that he would see the job as a way station for him until a permanent, well-financed position was created in Germany.

Still, this was not an objection likely to sway my fellow trustees. Better a temporary leader than none, the others would counter. So I threw my hat into the ring, saying I would accept the directorship if I could simultaneously remain at Harvard as a full-time member of the faculty. In this way, the Lab trustees would be spared the need to find a source from which to pay the new director. Since his arrival, a five-year grant from the Rockefeller Foundation had covered John Cairns's $15,000 annual salary. But one could not count on an extension of this grant. As soon as I raised the possibility of my leading Cold Spring Harbor, further discussion about Bresch subsided. I sensed that if Harvard said yes, the job was mine.

Before coming down to New York, I had not consulted with anyone about the likelihood of Harvard's allowing me to hold two academic positions simultaneously. So immediately upon returning to Cambridge, I contacted Paul Doty, who had assumed his role as first chairman of the Department of Biochemistry and Molecular Biology. After receiving positive concurrence from its members, he wrote to Franklin Ford on November 22 proposing that I serve as director of the Cold Spring Harbor Laboratory for a five-year interval. During this time, I would continue my current Harvard teaching and committee responsibilities while being in Cold Spring Harbor for three days every two weeks on average. Only five days passed before Ford wrote with his approval, noting that he would have to pass my request on to the Harvard Corporation for official endorsement. I so wrote Bentley, who in turn asked other board members for a formal endorsement of my selection as director. On February 1,1968, my new responsibilities began.

My decision to take on Cold Spring Harbor's troubles was in no small part sentimental. When I was there I was home. To me it was science at its best, where finding deep truths mattered more than personal advancement. Never had I known anyone to pull rank there or to get above himself. I could not contemplate the thought of its demise. As director, moreover, I could test my 1958 hypothesis that the cancerous potential of DNA tumor viruses is owing to the presence in their genomes of genes encoding enzymes that turn on DNA synthesis. It was too good an idea not to have a high chance of being correct, but because of space and funding limitations it had no chance of being tested at Harvard.

The sad underutilization of lab space at Cold Spring Harbor could prove a blessing. Its scientific direction could be changed fast without the unpleasantness of alienating excellent scientists already there who were oriented in the old way. To move swiftly into molecular biology, MIT in the mid-1950s had effectively fired its entire Biology Department, a move that generated much bitterness. This would not be necessary at Cold Spring Harbor.

On Sunday, February 4,1 made my first public appearance as director. The occasion was the annual meeting of the Long Island Biological Association, whose membership initially was drawn from the owners of the great estates that had once dominated much of the landscape of the North Shore. Though the twenty years since the war had seen many big estates subdivided, there still remained, within a several-mile radius around the lab, the opulent homes of many of Harvard's most loyal and generous Wall Street benefactors. Thus, I thought, my Harvard professorship could prove as relevant as my Nobel Prize in mobilizing the local gentry behind our new cancer research objectives. Equally important was the high esteem in which John Cairns and his family were held by the Cold Spring Harbor community. That afternoon I publicly announced my hope that John would remain as a lab scientist and continue to live in Airslie, the large wooden manor house built for Major William Jones in 1806. Long part of the Henry deForest estate just to the north of the lab, it became the director's home in 1942. Being single and planning to be on site at most six to eight days a month, I did not need its many rooms. Before the association meeting started, I requested the even older Osterhout Cottage as my own residence. Alfred and Jill Hershey had lived there for several years before building a largely glass-walled house on land west of the lab.

At that time, my father was avoiding the winter cold in an old-fashioned resort on the west coast of Florida below Sarasota. This was his fifth winter there, the first having followed the mild stroke in November 1963. Once the awful shock of my mother's sudden death in 1957 had passed, Dad's broad, warm smile helped him make new friends among kindred souls, who valued books and Rooseveltian ideals. In particular, he met several quiet intellectuals associated with the experimental New College, on the grounds of the once expansive Ringling estate outside Sarasota. Two years before, he'd been proud to attend a lecture I gave to its students. The college's focus on the great books of Western civilization reminded me fondly of my University of Chicago years. His last Florida visit, however, had gone less well, as Dad's long-dormant stomach ulcer again opened up. Fortunately, it soon healed, and he felt confident enough to spend several spring weeks on a cruise to the Mediterranean before passing much of the summer on Martha's Vineyard in Edgartown's quaint Harbor View Hotel.

Still, he was only in middling health when he left my sister's Washington home after Christmas to again take up residence in Florida the year I became director. The persistent bad cough he'd developed over the holidays wouldn't abate in the Southland's warmth. But his Sara-sota physician reassured my sister, Betty, several times over the phone that Dad did not have a virulent pneumonia. He was otherwise in good spirits, particularly when two
Atlantic Monthly
issues serializing
The Double Helix
appeared without generating a firestorm of criticism. He was also proud that his New College friends got a kick out of seeing me on the
Merv Griffin Show.

Then, without warning, my sister called late one afternoon to report that Dad's persistent cough was never to go away. It was caused by an inoperable lung cancer, and the prognosis was that Dad had but a few months left. The two packs of Camels that he had smoked every day since college had finally caught up with him. Betty had gotten the grim news while I was en route to Cambridge from New York City after the lunch marking the publication date of
The Double Helix.
I was at my office when she finally reached me that afternoon. Then with me was the very pretty Elizabeth Lewis, the Radcliffe junior who on many afternoons assisted my secretary, Libby Aldrich's sister-in-law, Susie. Liz's appearance in the Biolabs several times a week to file reprints or to help me assemble successive drafts of
The Double Helix
invariably made me feel good. Conversely, I always felt lonely when she retreated back into her student life.

When she first came to Harvard, Liz thought about majoring in math, a subject that she had much enjoyed as a student at the Lincoln School in Providence, where her father, Robert Vickery Lewis, of Welsh and Yankee antecedents, practiced medicine. After his college years at Brown, he studied medicine at the University of Pennsylvania, where he met his future wife, the nurse Edith Mae Belle Irey, of Scots-Irish and Pennsylvania Dutch heritage. Being at a small Quaker school in no way prepared Liz for the Harvard math concentration, and she switched to physical science as a possible route to medical school.

At my cousin Alices wedding to James Houston in 1967; I am to the right of the bride, and next to me are Betty's husband, Bob Myers; my sister, Betty; my father; and William Weldon Watson.

Our first effective date was unplanned, she coming with me at the last moment for an early pre-supper get-together at Carl and Anne Cori's home off Brattle Street. Afterward we drove along the Charles River to Boston, where we saw an English movie at the Exeter Theatre. Her exams were finished, and she was about to depart for a summer job in Montana at a resort ranch above Yellowstone Park. It had seemed a long summer when in early August a brief note from her made me realize just how keenly I had been anticipating her return to my office in the fall. Just after she got back to Radcliffe, we ran into each other on Brattle Street near Sage's Market, which coincidence gave me my second chance to drive with her into Boston. After lunch on Newbury Street, we went into Bonwit Teller, the elegant shop spread over the several spacious floors of what had been a gracious city mansion.