Only late in May did Weidenfeld publish the British edition of The Double Helix. They had produced a much condensed version for the Sunday Times to publish, but I nixed the effort, saying that it lacked the character of the full book and would unnecessarily annoy Francis and Maurice. Even worse was the vulgar jacket, printed a month before publication without my input. It made Francis seem ridiculous, with such ludicrous attempts at seductive copy as: “1) Which winner of the Nobel Prize has a voice so loud it can actually produce a buzzing in the ears? 2) Who is the top Cambridge scientist who gossips over dinner about the private lives of women undergraduates? 3) Which eminent English biologist created a scandal at a costume party by dressing up as George Bernard Shaw and kissing all the girls behind the anonymity of a scraggy red beard?” Mortified by my publisher's stupidity and grossness, I immediately contacted Nicolas Thompson to have Weidenfeld replace the offensive jacket. With no argument they backed down, and George Weidenfeld personally reassured me that all the jackets were being destroyed.
The week I was in England to mark the official publication date was no time to try to see Francis and Maurice. But Peter Pauling was typically fun to be with, and I could deliver the English version to Naomi Mitchison, to whom I dedicated The Double Helix. I saw Lawrence and Alice Bragg at their country home near the Suffolk coast. In England, most of the reviews were favorable. The most critical was by the embryologist C. H. Waddington, who thought me verging toward Salvador Dali-like manic egocentricity. By the year's end, some seventy thousand books had sold in the United States and British sales approached thirty thousand. Given its generally high praise and wide visibility, Tom Wilson thought I would be a shoo-in for the 1969 National Book Award in science. But it went to Yale's Robert Jay Lifton for Death in Life: Survivors of Hiroshima.
Though I was disappointed, I no longer needed others to tell me I had written a book worth reading.
Remembered Lessons
1. Be the first to tell a good story
In 1953 the finding of the double helix by itself did not create the opportunity for an important new textbook. Any such book written the next year necessarily would have been dominated by other facts already well documented—and which still constituted most of what was known on the subject of life's nature. Twelve years had to pass before an almost complete, new story could be told of how the genetic information within DNA molecules is used by cells to order the amino acids in proteins. By contrast, the story of the quest for DNA's structure could be told immediately, although it took me almost a decade to figure out how to go about telling it. Many have had their objections to my version of characters and events, but the popular imagination was captured by it, not least on account of its having come first.
2. A wise editor matters more than a big advance
Assuming you are not being insultingly low-balled, choosing a publisher on the basis of the advance is like choosing a house builder solely on the basis of the lowest bid. An innovative book usually takes more time to write and may cost more money to produce than either you or your publisher would guess at the time of signing the contract. Better to have a seasoned and comprehending editor on your side when your manuscript takes many more years to finish than contractually stipulated. By then your editor, if not employed elsewhere, will be under pressure to curb production costs as much as possible. Your illustrations may be cut in number and fobbed off on the cheapest available commercial artist, but the chances of that are diminished if the publisher isn't already deep in the hole having paid you money you haven't yet earned. If you haven't been overpaid, your freedom to pay back the advance and take the book elsewhere is greater and so is your leverage in demanding that corners not be cut.
3. Find an agent whose advice you will follow
Publishers’ contracts invariably contain clauses that only publishing lawyers understand. Unless you want to become credentialed in this arcane specialty, another field that has seen its best days, let your prospective contract go through the hands of someone paid by you to see that you are not taken advantage of. It is too much to expect your publisher, no matter his reputation for rectitude, to look after your interests and his own equally. The 10 percent to 15 percent of the proceeds charged by a reputable agent are well worth whatever is saved trying to represent yourself.
4. Use snappy sentences to open your chapters
With so much on TV, a short, incisive first sentence is more important than ever in pulling your readers into a new chapter. Let your audience know where they will be going if they stay with you. In The Double Helix, I used openers such as “I proceeded to forget Maurice, but not his DNA photograph.” Equally important are ending sentences, in which I often sprinkled a touch of irony, as in “The remnants of Christianity were indeed useful,” or attempted Oscar Wilde-like epigrams: “The message of my first meeting with the aristocracy was clear. I would not be invited back if I acted like everyone else.”
5. Don't use autobiography to justify past
actions or motivations
A major reason for writing autobiography is to prevent later biographers getting the basic facts of your life wrong. If life has graced you with lots of memorable occasions, merely reporting them correctly and dispassionately will generate a book worth reading. Attempts at justifying your actions and apologizing for bad behavior long ago only consign your work to the dubious genre of apologetics. Better to tell it straight without vainglory or shame and let others praise or damn you, as they will inevitably do anyway.
6. Avoid imprecise modifiers
Modifiers such as very, much, largely, and possibly don't convey useful information and only reduce the impact of otherwise crisp language. Saying someone is very bright offers no further insight than just saying he is bright. To go further, you must be more creative; for example, comparing your subject's brightness (or stupidity) with that of a known person or somehow ranking him, saying for instance, “No one was brighter in the Cavendish Laboratory”—that's got to mean something.
7. Always remember your intended reader
From the start, I wanted The Double Helix to be read beyond the world of science. So I integrated paragraphs about science with ones dealing with people, their individual actions and motives. Technical facts not essential to the story I left out. Even so, I found certain highly paid lawyers annoyed by any paragraph too technical for them to understand. I savored the justice ofthat.
8. Read out loud your written words
To make The Double Helix read smoothly, I read aloud every sentence to see if it made sense when spoken. Long sentences that were hard to follow I broke into shorter ones. I also sometimes combined a few short ones, as one short sentence after another can obscure the significance of events that unfold over more than one day. Choppy language is better suited for cookbooks and lab manuals.
13. MANNERS REQUIRED FOR ACADEMIC CIVILITY
BY THE mid-1960s, more and more of the research being done in Wally's and my third-floor labs was directed toward understanding how gene functioning is regulated by specific environmental triggers. We were preoccupied by concepts emanating over the past decade from the Institut Pasteur in Paris. There Jacques Monod and Francois Jacob skillfully employed genetic analysis of the bacterium E. coli to study how its exposure to the sugar lactose induced the preferential synthesis of the lactose-degrading enzyme ß-galactosidase. They showed the existence of a lactose “repressor” whose presence negatively controls the rate at which ß-galactosidase molecules are made. Their work suggested that free lactose repressore bind to one or more regulatory regions on the ß-galactosidase gene, thereby preventing subsequent binding of the RNA-making enzyme RNA polymerase. In their 1961 Cold Spring Harbor Symposium paper, Jacob and Monod had proposed that the lactose repressor was an RNA molecule. Controversy by now existed as to whether they were correct, with others suspecting it to be a protein.
In 1965, Wally's main aim was to isolate the lactose repressor. As it was likely present only in a few molecules per bacter
ial cell, its identification was not a task for the faint-hearted. Two years before, Wally had spent several months unsuccessfully searching for it, believing it should specifically bind to ß-galactosidase inducers. Sensing then he was going nowhere, he turned to experiments with Julian Davies and Luigi Gorini that revealed streptomycin-induced misreadings of the genetic code, which offered possible explanations of how this powerful antibiotic kills bacteria.
Also keen to get the lactose repressor was the German biochemist Benno Müller-Hill, who was one year younger than Wally Coming from a politically liberal family, Benno gravitated further to the left as a chemistry student in the German socialist student scene, discovering that many teachers at the University of Munich had been Nazi sympathizers, though no one in authority seemed to care. In his hometown of Freiburg, Benno later did doctoral work in the laboratory of the sugar chemist Kurt Wallenfels. There he learned the essentials of protein chemistry through studying ß-galactosidase. He began to love science and became excited about Monod and Jacob's work on how lactose molecules induce the synthesis of ß-galactosidase. Later, in the fall of 1963, Benno began a postdoctoral position in Howard Ricken-berg's lab at Indiana University, to which he brought samples of the Wallenfels lab's glycosides to study their specificity in inducing ß-galactosidase.
In Bloomington, Benno never felt comfortable either as a German among its many Jewish biochemists or as a leftist among Americans whose paranoia about communists in their midst surprised him. But his experiments there, which gave him sufficient results for a talk at the August 1964 International Biochemistry Congress in New York, were an ample reward for such social unease. By then he wanted to move on to the lactose repressor and came up to me after my talk to see whether I would accept him into my Harvard lab. Explaining that it was Gilbert he needed to approach, I urged him to visit Harvard as soon as Wally returned from a lengthy visit to England. Upon their meeting, Wally instantly saw Benno as the collaborator he needed and offered him a research position starting as soon as he could politely leave Howard Rickenberg's lab.
In Bloomington, Benno had learned how to genetically manipulate E. coli. He ably deployed this newly acquired skill soon after he arrived at Harvard to show that the lactose repressor is indeed a protein, not an RNA molecule. By using chemical mutagens he generated almost two hundred E. coli mutants that made ß-galactosidase in the absence of any inducers. Two of the mutants represented change to “nonsense” codons leading to premature polypeptide chain termination. If the repressor was made of RNA, this class of mutants would not have existed. The simple elegance of Benno's experiment was not revealed in his first manuscript draft. After telling him it was heavy and Teutonic, I rewrote it before its October 1965 submission to the Journal of Molecular Biology. As one of the journal's editors, I knew the article would quickly appear in print.
Though both Benno and Wally had earlier independently failed to detect the lac repressor through its binding to potent ß-galactosidase inducers, this feature offered still the only approach at their disposal. To increase their chances of succeeding, Benno again turned to bacterial genetics, making a mutant repressor that had enhanced affinity for the chemical that induced isopropyl-ß-D-i-thiogalactosidase (IPTG). By growing E. coli cells in very low concentrations of IPTG, a much more effective repressor became available. To double repressor numbers in bacteria, Benno made a diploid derivative containing two copies of its respective gene. These genetic tricks by themselves, however, were not sufficient to pinpoint the lac repressor in cell-free bacteria extracts. Success came only through developing molecular separation procedures that yielded protein samples enriched in the lac repressor. The first positive results were achieved in May 1966, but they were barely credible. Only 4 percent more radioactively labeled IPTG was found in bacterial extracts containing repressore than in surrounding repressor-free solutions. Soon better fractionation methods led to a semipurified sample that drew the IPTG into a semipermeable dialysis sac at a concentration almost twice that found outside. These enriched extracts were not affected by the enzymes that break down DNA and RNA. In contrast, the protein-degrading enzyme pronase destroyed all binding activity, confirming Benno's genetic pinpointing of the repressor as a protein.
Until then, Wally and Benno faced the likely prospect of not being first to characterize a repressore molecular nature. On the fourth floor was twenty-six-year-old Mark Ptashne, who was feverishly trying to isolate the phage λ repressor. It blocks the functioning of all but one phage λ gene when phage is present as an inactive prophage on an E. coli chromosome. The only λ gene then functioning is that coding for the repressor. Though its existence became known through elegant genetic experiments at the Institut Pasteur, no one in Paris had come up with a workable approach for its molecular characterization.
Mark had arrived in the fall of 1960 to do his Ph.D. thesis work with Matt Meselson. As essential to his nature as his desire to do top science were his leather motorcycle jacket, his violin, and his golf clubs. In high school, Mark had spent summer vacations at the University of Minnesota working in the neurophysiology lab of a left-wing family friend. At Reed College, which he chose over Harvard for its exclusive devotion to undergraduate education, he moved from philosophy to biology, working during the summer before his senior year at the University of Oregon. There Frank Stahl told him to do his graduate work with Matt Meselson. Mark already knew that the λ repressor was the next big objective in the phage world. But this goal was too risky for an early 1960s Ph.D. thesis, and so Mark settled in for a semiroutine genetic analysis of phage λ. As his thesis experiments neared their end, Paul Doty and I strongly backed his appointment to a three-year stint in Harvard's Society of Fellows. This would give him a shot at the λ repressor. As a candidate, he proved a shoo-in, since Wassily Leontief, the new head of the Society of Fellows, saw in Mark an agreeable conversationalist for the society's Monday night dinners. His term as a junior fellow commenced in July 1965.
That August, I submitted a $55,000 grant application to the National Science Foundation to pay Mark's salary and lab expenses for the three years, including a $5,000 yearly salary for a technician. The funding would allow him to work independently from his boss, Matt Meselson, who by now had despaired of Mark's sometimes sloppy work habits. In fact, my application stated that Mark intended to use DNA-RNA hybridization techniques to detect the λ repressor, which was yielding messy results even before the grant came through. Not enough was known about how RNA polymerase transcribes genes in cell-free extracts.
Mark's game plan soon changed. He began to look for differences in the proteins synthesized when heavily irradiated bacteria are infected with different types of λ phage. He guessed that λ repressor synthesis constituted only 0.01 percent of the protein synthesis in cells carrying λ prophages. To make scarce repressor molecules visible, he needed to drastically reduce synthesis of most bacterial proteins, as well as to inhibit the synthesis of all λ-specific proteins that were not the repressor. He reasoned he could cut back the routine synthesis of cellular proteins by irradiating the bacterial host cells with massive doses of ultraviolet light.
Mark Ptashne lobs a Softball at the 1968 Cold Spring Harbor symposium.
With Wally Gilbert's and my students and postdocs on the Biology Department rhino in 1965
Though Mark's experimental design was elegant, making it work would be no cakewalk. Though he received hints of early success, these were cruelly followed by failures to spot a radioactively labeled protein. In the summer of 1966, virtually all of Mark's experiments were crashing while Wally and Benno provided mounting proof that they were looking at the lac repressor. Happily, Mark's world would brighten immeasurably through the sudden unanticipated arrival of my former Radcliffe tutee, Nancy Haven Doe.
Nancy had been intrigued by repressore ever since learning about them during my spring 1963 Biology 2 lectures. Until then, she had expected her life to be largely that of the wife of a social male, very likely Brook Hopkins, Harvard ‘6
3, whom she had met as a freshman and with whom she had persevered through five years of “understood engagement.” During her senior year, noticing Nancy's intellectual vitality, I strongly encouraged her to go to graduate school. Aiming her toward the best, I wrote to Rockefeller University's president, Detlev Bronk, in support of her admission. Perhaps because she had come to science so recently, Bronk did not take the bait. Nancy's fate instead became Yale, possibly pushed ahead by my recommendation letter describing her as a quick learner who happened also to be cheerful and pretty.
Nancy's first year in New Haven was a typical full load of four courses during both the fall and spring terms. She mastered the Schrödinger wave equation as well as many facts of chemistry that with luck she would never need to use. Eight straight A's left Alan Garen no choice but to accept her into his molecular genetics lab, where she wanted to go for the repressor. Soon, however, she realized Alan to be a man of few words, little time for mentoring, and an excess of caution. He told her he was not up to the repressor; it was too hard a problem for someone over thirty-five. The dull alternative he proposed held little hope of sustaining and exciting her as a scientist. Writing to me early in March 1966, she remained resolute about resisting contentment in mediocrity. By late spring, she could take no more of her New Haven abode and decamped with an equally disenchanted aspiring female academic to the island of Mykonos.
Upon coming back to the States, she feared that staying at Yale would condemn her to work in Bill Konigsberg's lab on dull, dull hemoglobin. In August, she wrote to me proposing to join Mark Ptashne's lab as his technician. There her three-and-a-half-year-long obsession to work on repressore could find a proper outlet. Only several days before, she'd visited Harvard and found Mark so clearly in need of intelligent help that he would forgive her several blessings of heredity including a six-inch advantage in height. Nancy found it infinitely more gratifying to work as a technician on the repressor than to be a graduate student not working on the repressor. Wanting my opinion about her potential new career, she made it clear she had not at any time been, nor ever would be, in love with Mark Ptashne. With that reassurance, I gave her my blessing.
Avoid Boring People: Lessons from a Life in Science Page 25