Brave Genius

by Sean B. Carroll

  Between working in the lab, and her crash “education” with all of those books to read, “I didn’t sleep for six weeks,” Ullmann recalled.

  Agnes Ullmann in Paris, winter 1958, headed to a party outside the city, driver is unidentified. (Courtesy of Agnes Ullmann)

  ULLMANN WORKED IN the lab right up until the last minute of her stay. A Hungarian-born colleague took her back to the Gare de l’Est. The prospect of returning to Budapest made her miserable. But she could not defect at that moment, for Tamás would surely be punished if she did.

  When she arrived home, she told Tamás about the plan hatched in Paris. Tamás was cautious. He said, “We shall see.”

  CHAPTER 29

  MAKING CONNECTIONS

  Creating a new theory is not like destroying an old barn and erecting a skyscraper in its place. It is rather like climbing a mountain, gaining new and wider views, discovering unexpected connections between our starting point and its rich environment.

  —ALBERT EINSTEIN, The Evolution of Physics

  THE PAJAMA PAPER THAT PROPOSED THAT ENZYME SYNTHESIS WAS controlled by a repressor was just a short note in French—barely three pages long and with only one graph. A much longer paper with more meaty details, and in English, was still a year away. The note appeared at the end of May 1958.

  And with its publication came the end of the French Fourth Republic.

  Five prime ministers had attempted to deal with the Algerian crisis in the four years since the war erupted. Concerned over a perceived weakening resolve of the central government to maintain Algeria as part of France, a coalition of generals and the Army seized power in Algiers on May 13. Other members of the group plotted a coup d’état in which they would seize Paris, remove the French government, and demand the return of Charles de Gaulle as head of state.

  Jacob was summoned to an emergency meeting of the Compagnons de la Libération. It was to be a gathering of the faithful to call for the return of the great leader of the Free French, the only person who, many believed, could save France again from the quagmire. Jacob joined about two hundred fellow Compagnons to listen to fiery speeches and emotional debates. Finally, a vote was taken to confirm the group’s support for their general. De Gaulle received all but one vote cast. Jacob, however, did not get caught up in the fever: he abstained.

  On May 29, de Gaulle agreed to serve.

  SUMMER ARRIVED, AND most of the Pasteur group dispersed for their ritual vacations. By late July, Monod was sailing in the Mediterranean, and Wollman was in the United States. Jacob, however, remained in Paris, overloaded with preparations for a series of talks to which he had committed—an upcoming genetics congress in Montreal, a symposium in Copenhagen, and a set of Harvey Lectures in New York City. The latter was a great honor, a mark of having become one of the leading figures in experimental biology through his work on bacterial viruses and genetics.

  One Sunday afternoon, with the children away enjoying their vacation, Jacob was home with his wife, Lise, working on the lectures. While Lise played the piano, Jacob was pacing in his study, trying to formulate his talks on the “Genetic Control of Viral Functions.” He was getting nowhere; this would be one of those rare days “with no taste for work.” He gave up late in the afternoon and took Lise to the movies.

  Jacob was no more interested in the film than he had been in his work. Slumped in his seat, he started to daydream. His mind, however, returned to the subject of the lectures that he had been trying to escape. He shut out the picture on the screen to let the insistent images take shape. Jacob then felt “invaded by a sudden excitement mingled with a vague pleasure … And suddenly a flash. The astonishment of the obvious. How could I not have thought of it sooner? Both experiments—that of conjugation done with Elie on the phage … and that done with Pardee and Monod on the lactose system, the PA JA MA—are the same! Same result. Same conclusion.”

  For years, no one had seen any meaningful connection between what had begun and lived at the opposite ends of Pasteur’s attic. They were two separate research programs studying two separate phenomena, until that moment in the movie theater.

  Provoked by the new idea of a repressor controlling enzyme synthesis, Jacob connected that idea to the control of the prophage—the phenomenon that first prompted Lwoff to admit him into the attic. Perhaps the virus’s genes were controlled in the same fashion: “In both cases, a gene governs the formation … of a repressor blocking the expression of other genes and so preventing either the synthesis of the galactosidase or the multiplication of the virus. In both cases, one induces by inactivating the repressor, either by lactose or by ultraviolet rays. The very mechanism that must be the basis of the regulation.”

  Jacob then drew mental pictures of the repressors, one sitting on a bacterial chromosome, the other on a viral chromosome. He thought: “With the phage it is not simply two or three proteins whose synthesis is blocked, but at least fifty … Where can the repressor act to stop everything all at once? The only simple answer, the only one that does not involve a cascade of complicated hypotheses, is: on the DNA itself! In one way or another, the repressor must act on the DNA of the prophage to neutralize it, to prevent the activity of all its genes. And by way of symmetry, the repressor of the lactose system must act on the DNA containing its genes.”

  Jacob now had a new theory with which to work. He was exhilarated, as if he “had climbed a mountain, attained a summit from which [he] saw in the distance a vast panorama.” His brainstorm made a cascade of predictions that needed to be tested, on colleagues as well as in the laboratory.

  Lise saw him stir in his seat. “You’ve had enough?” she asked. “You want to leave?”

  Out on the broad boulevard Montparnasse, Jacob told her, “I think I’ve just thought up something important.”

  But Monod was away and would not be back before Jacob had to leave for New York. He would have to wait more than a month to try his new ideas out on the one person he needed most to convince.

  JACOB ARRIVED BACK from New York in mid-September. Without pausing to sleep after the overnight flight, he had lunch with his family and then hurried to the Pasteur to see Monod. He’d had weeks to refine his ideas, and had grown more convinced that he was on the right path. But he had not yet tested the full story on anyone. He was very excited, but exhausted, punchy, and bleary-eyed from the long trip.

  He started to tell Monod about all of the similarities between induced enzyme synthesis and induction of the prophage. Jacob did not get very far. Monod barely seemed to pay attention. He smiled faintly before breaking into booming laughter. He thought the idea that the two phenomena had a common explanation was silly, even “childish,” and told Jacob that he could think of at least five arguments against it. Jacob decided not to press further, and to try again the next day. He went home to get some rest.

  The following day, refreshed from a long sleep, Jacob launched again into his story. This time Monod was more patient and receptive. Jacob enumerated the parallels between enzyme induction and prophage induction. In both cases, a set of silent genes was triggered and became expressed. In both cases, the silencing was due to a single gene: in the lactose system it was the i gene; in the case of phage lambda, it was due to the “clear” gene that he had discovered when he isolated phage that could not form lysogenic bacteria. In both cases, genetic analysis had shown that the normal function of these genes was to produce a repressor that somehow blocked the expression of the lactose enzymes or the viral proteins. To Jacob, the analogy seemed so strong that a similar mechanism seemed inescapable.

  If that were true, Jacob continued, then virus induction seemed to place some constraints on the possible ways that repression could work. Unlike the lactose system, which used just 2 or 3 different proteins, the phage made perhaps 50 to 100 different proteins to produce new copies of itself. Yet the synthesis of all these proteins was blocked by the phage repressor. To Jacob, it seemed very unlikely that the production of each protein would be blocked indivi
dually. Rather, it was more logical that repression would operate “as if it closed a single lock to bolt in a single action, the activity of the whole viral chromosome.”

  Monod continued to listen attentively. Jacob then suggested that the one place that a repressor could lock down a whole chromosome was by acting on the DNA. This idea had an additional implication that there was some order of genetic organization higher than the gene. Jacob called them “units of activity” (for the time being)—perhaps comprised of several genes that were expressed together. All of these ideas were driven by Jacob’s insight into the logic of the phage. He asked Monod’s opinion about whether he thought that the lactose system might have a similar logic in which the regulation of enzyme production was governed “like a switch, by an all-or-none, stop-or-go mechanism.” The analogy had occurred to Jacob while he watched his son Pierre playing with an electric train.

  Monod was not sold on the switch idea or most of Jacob’s proposals. But he admitted, “Actually, there is no direct evidence either for or against the idea of repression at the level of DNA, and we should keep this possibility in mind.” As the discussion went on, Monod grew more animated, getting up to draw on the chalkboard, and pacing back and forth. Monod considered the consequences of the models, and the experimental predictions that followed from them. Jacob sensed that he had hooked his partner.

  The conversation lasted into the late afternoon. Jacob was drained. Monod broke out a bottle of scotch, and other lab members joined the lively discussion.

  From that day forward, results were considered and experiments were planned in the new light of Jacob’s proposal that there was symmetry between the two systems such that phenomena observed in the phage had a counterpart in the lactose system, and vice versa. Jacob and Monod talked nearly every day, often for hours, sketching out experiments and diagrams on a dark-green chalkboard. Jacob’s lab was upstairs, still in the attic; Monod’s was two floors below on the ground floor. Jacob spent so much time going up and down that he figured he should have an office in the stairwell. Conversations always wound up in Monod’s office.

  The game was to devise experiments that would rigorously test every facet of Jacob’s proposal; it was a game at which Monod excelled. One day, Monod pointed out that if the switch acted as an acceptor site on the chromosome for the repressor, then that site should be subject to genetic mutation. Furthermore, the predicted behavior of mutations in the acceptor site would be that they would break the switch and no longer be subject to repression; they would cause continuous “constitutive” expression of the lactose enzymes. The isolation of such a mutation would be technically daunting but a critical test of the model.

  In the middle of the discussion, Jacob realized that he and Elie Wollman had isolated the very equivalent mutation in phage lambda. Normal phage could not infect a bacterium already containing a prophage; their genes were kept silent like those of the prophage. However, in the so-called virulent mutant that Jacob and Wollman had isolated years earlier, the phage grew on prophage-containing bacteria. This was exactly the property expected of phage in which the repressor could no longer bind to its acceptor site on the phage chromosome, because the site was altered by a mutation. Once he realized that he had held crucial evidence without recognizing it, Jacob thought, “How stupid I had been not to have thought of it before!”

  But it was a happy embarrassment; the existence of a mutant that fit the prediction gave Monod and Jacob greater confidence in the model, as well as the impetus to identify its counterpart in the lactose system. Jacob jumped on the search for acceptor-site mutations that affected lactose enzyme synthesis.

  Jacob likened his exchanges with Monod to an intellectual Ping-Pong match: serve, return, and volley, all at top speed, until a concrete experiment manifested itself. They divided up the experiments according to their interests and expertise. Then the experiments were performed, the results obtained, and the volleying started all over again. The repartee was more than scientific; there was a lot of good-natured ribbing served in both directions about literary or political preferences; each other’s training as a zoologist or medical student; or the merits of the respective generals under whom they served, de Gaulle or de Lattre de Tassigny.

  During the winter of 1958–59, there were many new experimental results, and all were remarkably consistent with the various proposals Jacob had made—about repressors blocking the expression of sets of genes, and of the parallels between the control of the lactose system and the control of phage lambda.

  In March 1959, Monod and Jacob felt secure enough to call attention to the analogies. They completed the writing of the full-length version of the PaJaMa story—a much more extensive account in English of the short note published in French the year before. The authors were far more expansive about the roles of repressors than in the previous paper. In addition to accounting for their observations concerning the induction of galactosidase, they argued that the repressor model “may lead to a generalizable picture of the regulation of protein synthesis,” and pointed to the “formal analogy” between the lactose system and the induction of bacteriophage lambda as being “so complete as to suggest that the basic mechanism might be essentially the same.”

  The technical prowess of the experiments, the explicit reasoning, the bold connections, and Monod’s command of English combined to produce what readers recognized almost immediately as a tour-de-force.

  The duo was just beginning to hit their stride.

  EXTRACTING BIOCHEMISTS, PLAN A: THE BOAT

  In March 1959, Agnes Ullmann was able to return to the Pasteur for a visit of several months. Monod had arranged some lecture invitations that allowed her to leave Hungary. Tamás, however, stayed behind and remained under the watchful eye of the authorities, subject to arrest and imprisonment again at any time. With Ullmann in Paris for a length of time, there was now a window of opportunity during which, if Tamás could somehow be brought out of Hungary, Ullmann could defect and both would then be free. The great difficulty with that general scenario was that the borders were very heavily guarded; at the time, no one was sneaking out of Hungary.

  Monod was committed to helping Ullmann and Erdös, he just did not have any specific ideas of how to go about it. But once Ullmann returned to Paris, an old acquaintance from Hungary came to visit who had some promising connections.

  Andre Kövesi was a young journalist and writer who had written articles critical of the Hungarian system before the revolution. Kövesi left the country immediately after the first week of the revolution, when it was still possible to get out. It was his second escape from extreme danger. As a child during the Nazi occupation of Hungary, Kövesi and hundreds of other Jewish children were sheltered in a network of thirty-two homes established by Lutheran minister Gábor Sztehlo, and given papers identifying them as Christians. Despite the Nazis’ searching, none of those homes were discovered. Kövesi, however, lost his parents in the Holocaust. After the war, Tamás, who was many years his senior, became a sort of second father to Kövesi.

  Now living in Vienna, the tall, handsome, and very personable writer came to Paris to see a girlfriend. Ullmann invited him to the lab and introduced him to Monod. Kövesi was charmed by Monod, and when he learned that Monod wanted to help get his friends out of Hungary permanently, Kövesi offered to be the link between Monod and Ullmann in Paris and Tamás in Hungary. Kövesi was very familiar with the Austria-Hungary border and knew people who had business going in and out of Hungary.

  There were several great challenges in getting Tamás out of Hungary. The first was to identify some mode for smuggling him—car, truck, boat, or train. The second was engaging whoever might be willing to carry out the operation. The third was coming up with enough money to pay the smugglers for the risks they would take. The fourth was to communicate with Tamás inside Hungary, to make him aware of any plan, and to notify him when he would need to be ready.

  Within a few weeks after returning to Austria, Kövesi had sketc
hed a plan. He knew some characters who were affiliated with a smuggling business in Linz, Austria. This group was willing to arrange to have Tamás smuggled out of Hungary on one of the ships that made regular trips up and down the Danube and traveled through Budapest on their way to or from Austria and Yugoslavia.

  Kövesi explained to Monod in a letter from Vienna on April 18, 1959, in his broken English, that the operation would be expensive: “Last year prices are—as far as my informations go—about 3,000 US $ for one, though it is said that the Goverment is getting hard on the business … which may mean a rise in prices this year. Also there is no routine price for our way of making it.”

  Kövesi phoned Monod two days later at his Pasteur office to explain why the costs were necessary. Monod stirred quickly into action, soliciting Pasteur colleagues and contacts abroad for donations. Ullmann, too, wrote to some of Tamás’s friends who had fled Hungary. Monod reported to Kövesi on April 21, also in English (as were all of their communications): “We have been busy here trying to arrange financial matters, but we have already arranged to have your account in Vienna credited of 3,000 dollars … We hope that more may be coming shortly … I[n] any case, you may count on a total of at least 5,000. Good luck to you.” The sum was more than half a year’s pay for a Pasteur scientist.

  One week later, Monod reported that according to his “books,” Kövesi would have $4,700 directly available to him, and another $2,500 held in reserve, in case it was needed. The donations came from the Pasteur itself, Tamás’s cousin, and other concerned parties. Monod told Kövesi, “I have entire confidence in your ability to perform the operation if you find it feasible or to halt it if you eventually find it unadvisable.”