Brave Genius

by Sean B. Carroll

  Such progress, however, gave birth to new questions: Where and how did the prophage hide out in the bacterial host? What determined whether it was induced by ultraviolet light or not? Such questions often arose through conversations in the corridor, by bouncing results and ideas off one or more of his floor mates—all of whom had different backgrounds and were of various nationalities and contrasting personalities. While there were relatively few permanent staff members, the attic hosted many scientists from abroad who came to work for some period of time. In 1951, Seymour Benzer, an American, came for a year’s sabbatical at Lwoff’s invitation and moved into Jacob’s crowded lab. Benzer had a good deal of experience working with bacteriophages, as he had previously worked at Caltech with Max Delbrück, a pioneer in the field.

  Jacob came to Benzer’s rescue early on in his stay. When Benzer and his family first arrived in Paris, they had no permanent place to live and went to a hotel, the same hotel in fact where Sartre was staying, although they never saw the famous existentialist. They eventually found a small artist’s studio to lease, with an open-air bathtub and a communal toilet that was just a hole in the floor. They were told that everyone in France lived that way and that as Americans, “you have to lower your standards a little bit.” When Jacob came to visit him, he was shocked and asked Benzer, “Why are you living like this?”

  “Well, we want to live like the French,” Benzer said.

  “The French don’t live like this,” Jacob informed his lab mate. The family broke their lease and eventually found a nice apartment near the Pasteur.

  Jacob came to appreciate Benzer’s sharp and creative mind, and they eventually teamed up to do some experiments together. He also enjoyed Benzer’s vast curiosity and mischievous sense of humor. Accustomed to the more casual atmosphere of American labs, Benzer had some fun with Lwoff’s rituals and formalities. Partly out of his sense of adventure, and partly for its shock value, Benzer liked to bring exotic things for lunch—whatever he could find in Parisian markets, such as sea urchin, bull testicles, or dried South African caterpillars. When Lwoff teased him by asking, “Did you ever try tétine de vache [cow’s udder]?” Benzer tracked down the delicacy at the butcher shop, cooked it for lunch on a laboratory Bunsen burner, and declared it “quite delicious.”

  While most were not as colorful as Benzer, Jacob discovered that his floor mates were largely just as bright, curious, and helpful. And some carried a more tragic war story than his own. Elie Wollman was another member of Lwoff’s group working on bacteriophage. He was not a mere visitor to the Pasteur; he was born into the institution. His parents, Eugène and Elisabeth Wollman, began working at the Institute in 1909, eight years before he was born. His godfather and namesake was Elie Metchnikoff, a great Russian scientist who went to Paris to work with Pasteur in the late 1880s and whose discoveries concerning the cellular basis of immunity earned him a share of the 1908 Nobel Prize. Eugène and Elisabeth Wollman were in fact two of the very few researchers who worked on bacteriophage in the 1920s and 1930s, and they also described the phenomenon of lysogeny. Despite their Jewish backgrounds, and Nazi restrictions that precluded them from publishing their work after 1940, they remained in Paris and at the Institute during the Occupation. In December 1943, despite great efforts by the Pasteur’s director to intercede, the couple was arrested by the Germans and died during their deportation to Auschwitz.

  Elie had earlier escaped Paris for the south of France, joined the Resistance, and worked as a doctor under an alias. After the war, he returned to Paris and the Pasteur, where Lwoff, who was close to the elder Wollmans and grieved their murder, saw to it that Elie had a scientific home. Jacob found Wollman to be a font of knowledge about both the Pasteur and the world of bacteriophage research. They became good friends.

  Surrounded by such enthusiastic, sharp, and rigorously critical people as Wollman, Benzer, Lwoff, Monod, and Cohn, Jacob had the sense that he had found the right place, the right address. And that he had done so at the right time, when so much was beginning to happen in biology. Those feelings were familiar: the atmosphere at the Pasteur, the sense of being where something was happening, stirred him up “as much as had being part of a Free French combat unit in the war.”

  And while working in the lab gave Jacob a great sense of purpose, his family life gave him boundless joy. In the spring of 1952, fraternal twins Laurent and Odile were born. Every evening, Jacob hurried home to his beautiful wife and growing clan. A fourth child, Henri, would be born in 1954. Each birth was, for Jacob, a rebirth, an affirmation of life. And each moment together with his family helped him replace bitter memories, as if each were “a revenge on the war, on death.”

  MEMBERSHIP IN THE CLUB

  In order to obtain bona fide research credentials, to earn the “legal right to practice science,” as he put it, Jacob pursued a doctoral degree under Lwoff’s supervision. That would require both substantial time—almost four years—and original research. It would also require staying on top of what everyone else was doing that was relevant to his research. And the best ways to do that were to attend gatherings of scientists outside of France, and to hear and meet with the stream of visitors who passed through Paris.

  In early 1952, Jacob attended his first international conference, the Society for General Microbiology meeting held in Oxford, England. Lwoff had been invited to give a talk on lysogeny; he brought Jacob and Benzer with him. Jacob discovered that much of the intelligence to be gathered was not so much from the presentations as from the rumors that one picked up in informal chats during breaks, at mealtimes, or in the pub in the evening.

  But there were talks that Jacob had anticipated, a chance to see and hear those giants whose names he knew from his reading. Salvador Luria was the most famous on the schedule, but he did not show up. The rumor was that Luria, although living and working in the United States, had been denied a passport for the meeting—another victim, like Monod, of the Internal Security Act. British politesse forbade any blunt announcement of such a controversial fact, so it was handled indirectly. An English scientist in the audience referred a question to Luria, and another audience member asked the chairman, “There is a rumor that Dr. Luria has been prevented from attending by being refused a passport. Are you in a position to scotch that rumor?”

  “No sir, I am not,” said the chairman.

  Luria instead sent his paper to be read by his former student Jim Watson, then a twenty-four-year-old postdoctoral fellow at Cambridge. Watson posed a startling image to Jacob and most attendees—tall and gangly, with wild hair, his shirttails out, socks down around his ankles, he looked like he had literally run over from Cambridge. He had a bewildered look about him, eyes bulging and mouth half open, and spoke in short, choppy bursts. Convinced by Oswald Avery’s original evidence that DNA was the genetic material, Watson had recently begun working on the chemical structure of DNA (a change in his research plans that the Merck Fellowship board did not approve, and thereby revoked his fellowship). Luria’s paper, however, explained his rationale for thinking that proteins were the genetic material, as they, and not DNA, were the first molecules to be produced after phage infection. But Watson boldly decided not to read it, and instead he explained to the audience that he had just received a long letter from Alfred Hershey, another prominent bacteriophage researcher then working at Cold Spring Harbor, that described new experimental evidence that DNA, and not protein, was the genetic material. Jacob listened intently to this unorthodox American, who was in effect arbitrating the conflicting views of two eminent, but absent, researchers.

  Watson explained how Hershey and his collaborator Martha Chase had exploited the fact that phage proteins contain sulfur but that DNA does not, while phage DNA contains phosphorus while phage proteins do not. By growing phage in the presence of precursors containing radioactive phosphorus or radioactive sulfur, Hershey and Chase were able to “label” the DNA and protein components of the phage, respectively, and then follow where each label went in
the course of phage infection of bacterial cells. They found that, after infection, DNA quickly wound up inside the bacterial host, while the protein remained outside stuck to the surface of the bacteria. The protein, but not the DNA, could be liberated by stirring the cells in an ordinary kitchentype Waring blender. The results indicated that the phage, which resembled the shape of a hypodermic needle when seen magnified in the electron microscope, “injected” its DNA into bacteria shortly after infection, while the empty vessel remained outside.

  It was a clever but simple experimental design, and it yielded results that clearly distinguished between two alternatives. It was, therefore, the best kind of experiment, and would become a classic in the annals of molecular biology. To Jacob, two implications were clear: DNA was the genetic material; and the prophage he was studying must be in the form of DNA inside the bacteria, and not in the form of intact virus particles. Although no one had ever seen a prophage, the mental picture had become clearer.

  Jacob was merely a spectator at Oxford; a bigger step was to present his own work, his own discoveries, before a critical audience. And he was making some intriguing progress toward that goal. Working with phage day after day, he was expert at inspecting plates of bacteria in which phage left their telltale pinholes, called plaques. Normally, every plaque was just a bit cloudy due to some bacteria that overgrew the plaque but did not lyse. When those bacteria were isolated and analyzed, they turned out to be lysogenic—they were harboring prophage. One day, Jacob spotted a completely clear plaque. When he isolated bacteriophage from the plaque, they produced only clear plaques. The phage were mutants: able to reproduce in bacteria and lyse them, but unable to hide out in bacteria as prophage, unable to form lysogens.

  What was the nature of such a mutation? The question demanded more experiments. When Jacob added the mutant virus to a lawn of lysogenic bacteria, he found that instead of producing clear plaques, it produced no plaques at all. The result demonstrated that lysogenic bacteria were “immune” to infection with other phage. Something in the lysogenic bacteria prevented the clear-type phage from reproducing. That same something could be made by the bacteria or by the prophage. Yet more experiments to do.

  Jacob’s first opportunity to present his own work came in the summer of 1952, just as the Sartre-Camus split was unfolding. Lwoff hosted a meeting of the First International Congress on the Bacteriophage at the elegant thirteenth-century Cistercian abbey at Royaumont, twenty miles north of Paris. All of the top phage scientists were invited, including Delbrück, Hershey, and Luria, the latter of whom had finally managed to secure a passport. Watson attended as well. Some thought that Watson’s attire—shorts and tennis shoes with their laces usually untied—was a deliberate effort to annoy Lwoff. The truth was that his luggage was stolen en route to France and the only clothes he had were a few things he’d bought at an Army PX and those intended for a subsequent hiking trip in the Italian Alps. Watson prudently borrowed a jacket and tie for a garden party held at the country estate of Baron Edmond de Rothschild. At the end of the evening, Baroness Rothschild told some guests that she regretted that the “mad Englishman from Cambridge” of whom she had heard had not attended. Lwoff had apparently forewarned her that a partially clad eccentric might appear.

  Watson had managed to pass his inspection without anyone noticing. Jacob’s test came when he gave an account of his work in front of the “jury” of phage luminaries, with Delbrück sitting in the front row. Jacob was surprised when he first saw the former physicist. He’d been expecting a stereotypical paunchy, aging, balding German professor. Instead, he saw a young-looking athletic man, with a full head of hair, wearing steel-rimmed glasses, listening intently to the speakers. Despite the intimidating audience and his inexperience, Jacob’s nervousness disappeared once he started speaking. The talk actually went over well.

  Even better, Delbrück subsequently invited Jacob to the next Cold Spring Harbor Symposium, a meeting on viruses that was to take place in the summer of 1953. Jacob was thrilled. The invitation was like receiving his “membership card to the club”—the club of insiders, of those in the know, of those who mattered in the very small and select group of international scientists probing the nature of life.

  THE DOUBLE HELIX

  Membership in that club meant hearing about discoveries before others, and well before they appeared in journals. Some members in Lwoff’s attic were made privy to some very big news when Jim Watson came through Paris again in March 1953.

  The breakthrough had happened just a couple of weeks earlier.

  For more than a year, Watson had been working with Francis Crick in Cambridge, trying to solve the structure of DNA. Watson was certain that the structure was the most important riddle of genetics, indeed of all biology. The central mystery that the correct structure had to solve was how such a molecule was copied, and thus how genetic information was transmitted faithfully generation after generation. Their efforts had stalled repeatedly as they hit various kinds of impasses. Some were caused by a shortage of data; others appeared when they attempted to build models and discovered that they were chemically impossible.

  Several things were known about DNA: it was an acid; it contained four different bases—adenine (A), guanine (G), cytosine (C), and thymine (T); and it was a polymer with a sugar phosphate backbone. It had also been reported that within any given species, the ratio of adenine to thymine was always equal, and the ratio of cytosine to guanine was always equal. This chemical analysis, however, had not been sufficient for anyone to decipher the arrangement of atoms within DNA’s three-dimensional structure. The critical unknowns were the number of chains in the molecule and the relative arrangement of the bases and the backbone. Crucial clues to those features came from a technique called X-ray crystallography, in which a beam of X-rays was trained on a crystal of DNA, causing the beam to scatter and diffract according to the detailed structure of the crystal. The interpretation of the resulting patterns required a rare expertise.

  After struggling for many months, and rejecting one flawed structure after another, the penny finally dropped on the morning of Saturday, February 28, 1953. Tinkering with cardboard-cutout models of the bases in his lab at Cambridge, Watson realized that the A and T bases, and the C and G bases, could form bonded pairs (base pairs) with very similar shapes that fit neatly within and could hold together a two-chain, double helix. Moreover, if A always paired with T, and C with G, then the copying of DNA was easy to explain: the identity of the base on one chain would determine the identity of its complement on the other.

  Watson and Crick started building a physical model of DNA right away, and writing up their discovery for publication. A few days later, and despite Crick’s objections, Watson decided that it was a good time to make a previously postponed visit to Paris. In addition to the food and fun, the excursion gave him the chance to share the news.

  Although Watson did not have a full model of the structure, just of the two base pairs, Monod understood instantly. As the most biochemically inclined of the attic’s residents, Monod could best appreciate Watson’s chemical and structural reasoning. Moreover, Monod grasped right away that Watson had solved the copying problem.

  Jacob, however, did not have the background to weigh Watson’s explanations. In fact, he only skimmed Watson and Crick’s historic article on the structure of DNA that appeared the following month in Nature. The arguments based on the X-ray crystallographs were beyond him. It was not until six weeks later, when he went to Cold Spring Harbor and heard Watson present the complete story, that he understood the full, profound significance of the double helix.

  It was Jacob’s first trip to the United States. He went by boat with André Lwoff.

  At the meeting, Jacob was struck by the contrast with European gatherings. At Cold Spring Harbor, there were no lofty speeches, no formalities whatsoever. The scientists sat where they liked, no matter how eminent their neighbor might be. And students and junior scientists did not hesitate to ask
challenging questions of their seniors.

  Jacob’s talk went fine. He described some new work he had been doing in collaboration with Elie Wollman on a bacteriophage called lambda that infected E. coli. He reported on the properties of some mutant phage, including different kinds of clear-plaque mutants that could not infect lysogenic bacteria, and another rare mutant that could. The unquestionable star of the meeting, however, was Watson.

  Wearing shorts again, and with his shirttail out as usual, Watson gave a detailed explanation of the evidence for the double helix, and the biological consequences that followed from it. The arrangement of the bases implied not only how DNA was copied but also how mutations arose by the substitution of other bases, and that the sequence of bases must somehow encode the characteristics of every organism. The normally feisty and skeptical audience offered no criticisms, no objections. Jacob now appreciated that the structure was both simple and beautiful, and explained so much that he thought, “All this could not be false.” Even though the technical background was still beyond him, he understood that the double helix illuminated on the screen above Watson accounted for the fundamental mystery of heredity—“one of the oldest problems posed since antiquity by the living world.”

  The first secret of life had been revealed.

  BEFORE RETURNING TO France, Jacob purchased a Waring blender as a gift for Lise.

  Fewer than three years into the research game, he could not have possibly imagined that the next big secrets of life would belong to him and his attic neighbor Monod, nor that to get to them, that Waring blender would come in very handy.