Tag Archives: lysogeny

The Converging Lives of Jacques Monod, Francois Jacob, Andre Lwoff, and Albert Camus in Wartime France

In the 1950s and 1960s, two French biologists at the Pasteur Institute, Francois Jacob and Jacques Monod, explained how genes are regulated in bacteria. Their studies of the “lac operon” of E. coli indeed opened up the field of gene regulation, and were a key development in the new science of molecular biology. Their experimental findings also implied the existence of an unstable intermediate between genes and protein synthesis, which eventually led to Jacob’s discovery, in collaboration with Sydney Brenner and Matt Meselson, of messenger RNA (1).

Jacob and Monod shared in the 1965 Nobel Prize for physiology or medicine for their breakthrough studies on gene regulation. Fellow Pasteur Institute scientist, Andre Lwoff, received a share of the award for his pioneering studies on the nature of lysogeny (i.e., how a bacteriophage’s genome can be incorporated into the genome of a host bacteria, and remain latent until being activated by an inducing factor).

In 2013, evolutionary biologist Sean B. Carroll published a book—Brave Genius: A Scientist, a Philosopher, and their Daring Adventures from the French Resistance to the Nobel Prize—that relates how wartime circumstances brought together Jacques Monod and his scientific colleagues Francois Jacob and Andre Lwoff (2). But while much of that story is already known (3), Carroll also tells us of the little known, but remarkable coming together of Monod and philosopher/writer Albert Camus, one of the intellectual giants of the 20th century. Coming from very different intellectual backgrounds, Monod and Camus forged a deep friendship, united in their opposition to tyranny and oppression. Carroll’s book was the inspiration for this post.

When Albert Camus learned that he had won the Nobel Prize for Literature in October 1957, he wrote to a few well-wishers, including an old friend in Paris:

My dear Monod,

      I have put aside for a while the noise of these recent times in order to thank you from the bottom of my heart for your warm letter. The unexpected prize has left me with more doubt than certainty. At least I have friendship to help me face it. I, who feel solidarity with many men, feel friendship with only a few. You are one of these, my dear Monod, with a constancy and sincerity that I must tell you at least once. Our work, our busy lives separate us, but we are reunited again, in one same adventure. That does not prevent us to reunite, from time to time, at least for a drink of friendship! See you soon and fraternally yours.

                                                                                                                                             Albert Camus

Camus appears somewhat downcast in his note to Monod. At 43-years-in-age, he was the second youngest writer ever to receive the Nobel Prize for literature (Rudyard Kipling at 42 was the youngest), and he was worried that the ballyhoo surrounding the award might distract him from his writing. And, he was concerned that the prize might stir up additional contempt from critics of his writing, as well as from his leftist colleagues who opposed his condemnation of Soviet communism.

But, why did philosopher/writer Camus—an intimate of some of the greatest writers and artists of the mid-twentieth century, including Sartre and Picasso—write to scientist Monod, and acknowledge the special importance he placed on their friendship? Likewise, why did he assert: “I have known one true genius, Jacques Monod.” And, what is the same adventure that Camus refers to?

A brief background to our tale is as follows. In March 1939, Hitler took control of Czechoslovakia. Next, on September 1, Germany invaded Poland. On September 2nd, Poland’s allies, Britain and France, issued an ultimatum to Germany: withdraw or face war. On September 3rd, the ultimatum expired, Britain and France declared war on Germany, and the Second World War was underway; sort of. Although Germany went on to conquer Poland in a mere eight days, several months passed without further action. Then, in May 1940, Nazi Germany invaded and overran France in just six weeks. Marshall Pétain surrendered to the Germans, the French Forces were disbanded, the pro-Nazi Vichy government was put in place under former prime minister Pierre Laval and the 84-year-old Pétain, and the Nazi occupation of the defeated French nation began.

A few months before the Nazis invaded France, thirty-year old Jacques Monod was a doctoral student in zoology at the Sorbonne. [A polymath, he also founded a Bach choral group, and was an accomplished cellist, and seriously considered a career in music (4).]  But as war with Germany loomed, Monod enlisted in the army—in the communication engineers—where he thought he might use his scientific talents if war were to break out. Consequently, Monod was serving on the front lines when the Germans invaded. France suffered the most colossal military disaster in its history, and Monod returned to his studies in Paris.

Life in France grew progressively harsher under the Nazis; beginning with subjugation, and followed by deportations, enslavement, and mass murder. Early on, Monod joined one of the first units of the French Resistance; a group of ethnologists and anthropologists at the Musée de l’Homme (Museum of Man).

One of Monod’s duties for the Musée de l’Homme group was to distribute its newspaper, at night. This seemingly simple task was extremely dangerous since capture could mean deportation to a concentration camp or execution. Monod, in fact, had several close escapes. On one occasion, the Gestapo raided his laboratory at the Sorbonne. Fortunately, since they were fearful of the viruses and radioactive isotopes in the lab, they didn’t search it as thoroughly as they might have. Otherwise, they might have found sensitive documents that Monod would hide inside the leg of a mounted giraffe outside his office. In any case, the Germans soon routed the short-lived Musée de l’Homme group

Monod’s wife, Odette, was the granddaughter of Zadoc Kahn, the former chief rabbi of France. Since the Vichy government soon began enacting Nazi policies, including anti-Jewish laws, and because of homegrown French anti-Semitism, Odette sought refuge for herself, and for her and Jacque’s twin sons (born in August 1939, four weeks before the war broke out), under assumed names, in a village outside of Paris. Meanwhile, Jacques had to register with the Vichy authorities as the spouse of a Jewish person.

With Odette and the children concealed, Monod joined the most militant unit in the Resistance; the Communist-led Franc-Tireurs (Free Shooters) group. Monod was not then a Communist Party member. Nonetheless, he joined the Franc-Tireurs since they actually were fighting the Germans—assassinating German officers in the streets and carrying out sabotage. One of his missions for the Franc-Tireurs took him to Geneva—through the Alps to avoid arrest—to request money for arms from the United States Office of Strategic Services; the precursor of the present Central Intelligence Agency.

By this time, Monod had gone completely underground. He wore a disguise during the day, slept in safe houses at night, and stayed away from his laboratory at the Sorbonne. But then, Andre Lwoff, the head of microbial physiology at the Pasteur Institute, offered Monod a refuge and a place to work in his laboratory at the Pasteur Institute. Monod then led a double-life. By day, as Monod, he worked on his experiments at the Pasteur Institute. At night, he carried out his duties for the Franc-Tireurs, as “Marchal” (from a character in a novel by Stendhal), and as  commander “Malivert.” [Lwoff too had been active in the Resistance, gathering intelligence for the Allies, while also hiding downed American airmen in his apartment.]

Jacques Monod’s identity card for the French Forces of the Interior (FFI), in his nom de guerre ‘Malivert.’

Monod was resolutely committed to the Resistance, while also maintaining a productive research program. At the Pasteur Institute, he and his student, Alice Audureau, made key discoveries that would lead to the later breakthroughs he would make with Jacob. [For instance, Monod and Audureau discovered mutations in E. coli genes that caused the induction of lactose metabolism; a finding that would have important implications concerning gene action and regulation.] Moreover, he was devoted to Odette and their twin sons, and managed to make frequent clandestine visits to see them.

Monod took on increasing responsibilities in the Franc-Tireurs, as more members of the group were discovered and executed by the Germans. In fact, by the time of the allied invasion of Normandy in June 1944, Monod, had become chief of staff of the operations bureau for the National Resistance Organization; a position from which his three predecessors had disappeared (4). As such, Monod prepared battle plans for the allied surge to Paris. He also arranged parachute drops of weapons, railroad bombings, and mail interceptions.

Interestingly, Monod also recruited to the Resistance renowned French chemist, John Frédéric Joliot-Curie (Aside 1), who devised a unique recipe for Molotov cocktails, which were the Resistance’s principal weapon against German tanks. In addition, Monod organized the general strike that facilitated the liberation of Paris. Then, after the liberation of Paris, he became an officer in the Free French Forces, and a member of General de Lattre de Tassigny’s general staff.

[Aside 1: John Frederick Joliet was working as an assistant to Marie Curie, when he married Marie’s daughter, Irene. Afterwards, both John Frederick and Irene changed their surnames to Joliot-Curie. In 1935, the couple was awarded the Nobel Prize in Chemistry for their seminal research on radioactivity. John Frederick then worked at the Collège de France on controlled chain reactions. His work on that was cited by Albert Einstein in his famous 1939 letter to President Franklin Roosevelt, warning Roosevelt of the possibility of a nuclear weapon: “In the course of the last four months it has been made probable through the work of Joliot in France as well as Fermi and Szilard in America—that it may be possible to set up a nuclear chain reaction in a large mass of uranium, by which vast amounts of power and large quantities of new radium-like elements would be generated. Now it appears almost certain that this could be achieved in the immediate future…This new phenomenon would also lead to the construction of bombs…” The Nazi invasion ended Joliet-Curie’s nuclear research. Nevertheless, he managed to smuggle his research notes out of France to England.]

Francois Jacob, a Jewish, nineteen-year old 2nd-year medical student, was planning on a career in surgery when the German occupation of France began in the Spring of 1940. Resolved to carry on the fight against Hitler, Jacob left medical school and boarded one of the last boats for England. In London, he was one of the first of the French to join Charles de Gaulle’s Free French Forces. He wanted to enroll in a combat unit, but, despite his incomplete medical training, he was commissioned as a medical doctor, and then served as a medical officer in North Africa. His surgical career was prematurely cut short in August 1944, when he was severely wounded at Normandy; by a bomb dropped from a German Stuka dive bomber. At the time, he was tending to a dying officer.

For their wartime service, Jacob and Monod were each awarded France’s highest honors for valor. Jacob was awarded the Cross of Liberation, as well as the Légion d’Honneur and the Croix de Guerre. Monod likewise received the Légion d’Honneur and the Croix de Guerre, as well as the American Bronze Star.

Unable to practice surgery after the war because of his wartime wounds, Jacob eventually turned to a career in science. He was accepted at the Pasteur Institute, where he beseeched Lwoff (Monod’s host at the Pasteur Institute) to serve as his mentor. Lwoff rebuffed Jacob several times, but finally agreed to take the young doctor under his wing. Then, in the cramped quarters of Lwoff’s laboratory at the Pasteur, Jacob and Lwoff’s student, Elie Wollman, began a fruitful collaboration that produced key insights into bacterial conjugation and the regulation of lysogeny (Aside 2). After that, Jacob and Monod forged their extraordinary collaboration that would lead to their Nobel Prizes. Note that Jacob’s earlier work with Wollman, on lysogenic induction, would provide the underpinning for his later work on gene regulation with Monod (3).

[Aside 2: Elie Wollman, born in 1917, was Jewish. In 1940, he escaped from the Nazis in Paris and then worked underground in the Resistance as a physician. His parents, Eugene and Elizabeth Wollman, were Pasteur Institute scientists who were seized by the Nazis in 1943 and sent to Auschwitz. They were never heard from again (3).]

In December of 1939, our other main protagonist, twenty-six-year-old Albert Camus, was an unknown, aspiring writer, working as a reporter and editor for a newly founded left-wing newspaper, Alger Republican, in his native Algeria; which was then under French control. Camus was completely opposed to the war, which he saw as “another unnecessary, avoidable, disastrous, absurd chapter of history that would consume the lives of those who did not make it or wish for it.” His antiwar editorials in the Alger Republican outraged French government officials who were calling for unity against Germany. The government finally shut down the newspaper, leaving Camus unemployed. So, Camus returned to France, where the prospects for employment were now better because wartime mobilizations had left many businesses shorthanded. See Aside 3.

[Aside 3: Camus started writing The Stranger while in Algeria, basing it on people and places he knew there. His purpose in The Stranger was to express how one might react to his philosophical notion of the “absurd”—the disconnect between our desire for a rational existence, and the actual world, which appears confused and irrational—in the form of a novel. Meursault, the narrator, and principle character in The Stranger, shows no grief over his mother’s death, no remorse over having committed an unintended murder, and no belief or interest in god. Even while Meursault was awaiting the guillotine, he was reconciled to “the tender indifference of the world.” Meursault’s honesty in describing his feelings makes him a ‘stranger’ in the setting of the novel, and seals his fate.]

Camus was not called up for military service when he returned to France, because he had contracted tuberculosis in Algeria, when he was 17 (Aside 4). Nonetheless, he twice attempted to enlist—the second time when the French Army was on the verge of surrender to the Nazis—to express his solidarity with those who were being drafted. In any case, the military rejected him each time because of his tuberculosis. So, he managed to get a job in Paris as a layout designer for the newspaper Paris-Soir.

[Aside 4: In the pre-antibiotic era, tuberculosis was often fatal, and the 17-year-old Camus indeed had a close brush with death. That experience had a profound effect on the “precocious philosopher,” who made notes on the question of “how, in the light of the certainty of death, one should live life.”]

Parisians began fleeing from their city when the German invasion began in May of 1940. Then, in June, as the Germans were on the verge of entering Paris, the stream of refugees became a flood, with about 70 percent of the city’s metropolitan population of nearly five million eventually taking flight from the city. All Parisian newspapers stopped publishing. However, Paris-Soir hoped to resume its operations in the south, with a reduced staff. Thus, Camus joined the stream of refugees, driving an automobile (almost all the paper’s regular drivers had been drafted), with a Paris-Soir executive as his passenger. After Camus and his passenger were well on their way, Camus suddenly realized that in the rush to vacate from Paris, he may have left his manuscript for The Stranger behind in his room. “He jumped out of the car and threw open the trunk, and was relieved to find in his valise the complete text of The Stranger.” See Aside 5.

[Aside 5: In 1885, Joseph Meister, at nine-years-of-age, was the first recipient of Louis Pasteur’s rabies vaccine and, as an adult, was caretaker of the Pasteur Institute; a position that he still held at the start of the Nazi occupation in 1940.  In despair over the fall of France, and wrongly believing that German bombs killed his family after he sent them away, he went to his apartment, closed the windows, and turned on the gas in his stove (5, 6).]

Camus went with Paris-Soir to Clermont-Ferrand. There, the paper began to publish again, using printing facilities made available by Pierre Laval, the former premier, and now architect of the Petain Vichy government. But with the paper now under Laval’s control, it began publishing anti-Semitic articles, and other articles in support of the Vichy government. Camus did not write any of these items. In any case, he was let go by Paris-Soir after the draftees of the 1940s were discharged and could return to work. Camus then went back to Algeria, where he completed The Stranger.

In 1942, with The Stranger about to be published in France, Camus suffered a nearly fatal relapse of his tuberculosis. He wanted to return to France for treatment in the Massif Central mountain range, but several months would pass before Algerian authorities gave him permission to do so. Then, upon returning to Paris, he would have a purpose that would totally engage him.

One night, under an assumed name (because of the need for secrecy in the Resistance), Camus stole into the clandestine headquarters of Combat (the journalistic arm and voice of the French Resistance), to implore the staff to take him on since he “had already done a little journalism” and would be happy to help in any way. Like Monod, Camus then led a double-life, carrying out his duties at Combat, as “Bauchard.” At first, he helped to select and edit articles, and prepare the paper’s layout. Then, in 1943 he became the paper’s editor, and wrote stirring editorials, exhorting Frenchmen to act against the German occupiers. By the time The Stranger was published in 1942, his recognition as Camus led to his acceptance into the literary and artistic circle that included Sartre, Simone de Beauvier, and Picasso.

Albert Camus’s false identity card, in the name of Albert Mathé, writer. All of the information on the card — birthdate, place, parents — is false.

Camus was suffering from recurrent bouts of tuberculosis all the while that he was carrying out his work at Combat. Nonetheless, as Camus, he also published his essay, The Myth of Sisyphus, which, like The Stranger, contemplates the experience of the Absurd (see Aside 3, above). And he also wrote The Plague, which depicts a city’s response to an outbreak of bubonic plague; perhaps a metaphor for the Nazi occupation. Remarkably, no one at Combat had an inkling that the man who at first had been editing and arranging pages for them as Bauchard was in fact the now renowned Camus. See Aside 6.

[Aside 6: Among laypeople, Jacques Monod is perhaps best known for his “popular” book, Chance and Necessity, published in 1970, and a bestseller in its day. Monod’s Chance and Necessity, and Camus’ The Myth of Sisyphus, are each relevant here because they point up how Camus influenced Monod’s view of the meaning of life. While Camus took a philosophical approach to that issue, Monod’s assessment was also informed by his knowledge of life’s fundamental molecular mechanisms. With the 1953 discovery by Watson and Crick of the molecular structure of DNA, it was apparent how accidental, random, unpredictable mutations in the sequence of bases in DNA were the source of all biological diversity. Thus, Monod knew that all living forms, including humans, are the products of chance genetic mutations and circumstances: “Man at last knows that he is alone in the unfeeling immensity of the universe, out of which he emerged only by chance. Neither his destiny nor his duty have been written down. The kingdom above or the darkness below: it is for him to choose.” [Monod’s title, Chance and Necessity, is from Democritus’ dictum “Everything in the universe is the fruit of chance of chance and necessity.”]  

That we live in a world that is indifferent to our hopes and suffering was the reason for Monod to inquire into the meaning of life, which, for Camus, was “the most urgent of questions.” Camus was often branded an existentialist, but unlike many contemporary existentialist thinkers, Camus vehemently rejected nihilism. In The Myth of Sisyphus, he wrote that Sisyphus gave his life meaning by choosing to believe that he remained the master of his own fate, even though he was condemned to rolling his rock uphill each day, only to have it roll back down.

On the opening page of Chance and Necessity, Monod includes a lengthy quotation from the closing paragraphs of The Myth of Sisyphus. “The struggle itself towards the heights is enough to fill a man’s heart…One must imagine Sisyphus happy.” Camus is advocating that we oppose the certainty of death in an uncaring Universe by living life to the fullest. For Monod, life is like Sisyphus, pushing its rock uphill. The end might be bleak, but “the struggle towards the heights is enough to fill a man’s heart.”]

By 1944, the liberation of Paris was imminent, Combat went from a monthly publication to a daily one, and the paper chanced to circulate in the open. Camus was still writing his editorials anonymously. And when his identity was finally revealed, his inspiring, eloquent words resulted in his widespread public acclaim.

Monod and Camus were very likely aware of each other at this point in our saga, but they had not yet met. Their meeting would happen after the liberation of France, and it would be in response to a new totalitarian threat; from the Soviet Union. It transpired as follows.

In 1948, Monod was working full-time on his research at the Pasteur Institute, when events in the Soviet Union moved him to write a stirring editorial that appeared on the front page of Combat. [Camus had left Combat the previous year, after it became a commercial paper.] Monod’s piece was in response to a pseudoscientific doctrine advanced by Stalin’s head of Soviet agriculture, Trofim Lysenko, which asserted that organisms could swiftly change their genetic endowment in response to a new environment. [Lysenko’s doctrine is reminiscent of discredited Lamarckian doctrine, also known as heritability of acquired characteristics—i.e., the premise that if an organism changes to adapt to an environment, it can pass on those changes to its offspring.] Lysenko based his doctrine on his purported discovery of a means to enable winter wheat to be sown in the spring.

Stalin embraced Lysenkoism—during an acute grain shortage in Russia—since it was in accord with his ideology to create the New Soviet Man. Stalin also banned all dissent against Lysenko’s doctrine. Consequently, traditional Russian geneticists were exiled or murdered, Mendelian genetics was no longer practiced in the Soviet Union, and Soviet agriculture suffered severely.

Monod was roused to write his editorial after French Communist newspapers began to widely disseminate Lysenko’s doctrine in France. One Party newspaper proclaimed Lysenko’s discovery “A Great Scientific Event,” and further asserted that the notion of evolution by natural selection was a racist form of thinking, in harmony with Nazi doctrine (7). Another Party newspaper condemned Mendelian genetics for being “bourgeois, metaphysical and reactionary,” while claiming that it must be false because it is reactionary; having been invented by an Austrian monk. In Contrast, Lysenkoism is true because it is progressive and proletarian.

A Party member’s position on Lysenko indeed had become a gauge of his commitment to Stalin’s Soviet cause. But for Monod, the Soviet embrace of Lysenko was “senseless, monstrous, unbelievable.” As expected, Monod’s article was strongly condemned by the powerful French Communist Party, which enjoyed broad support from both intellectuals and workers; many of whom saw the Soviet Union as a model for a French socialist state. In any case, the Party’s strong backlash inspired Monod to “make his life’s goal a crusade against anti-scientific, religious metaphysics, whether it be from Church or State.” Importantly, a separate consequence of the Lysenko affair was that it influenced François Jacob to focus his research in the field of genetics. See Aside 7.

[Aside 7: Ironically, the observation that Jacob and Monod initially set out to explain looked remarkably like Lysenkoism. When E. coli are fed a solution of glucose and lactose, they grow rapidly until glucose—their preferred carbon source—is depleted. Only then, they turn to metabolizing lactose. But, in contrast to Lysenko’s doctrine, Jacob and Monod showed that when E. coli “adapts” to lactose, it does so without changing its genes. Instead, the genes encoding the enzymes that metabolize lactose lie dormant until lactose induces them, under conditions in which glucose is not available. That is, Jacob and Monod determined that lactose regulates lactose metabolism in the cell by acting as an inducer of genes that already exist in the cell; as opposed to lactose causing the cell to undergo a Lamarckian acquisition of a genetic characteristic. In so doing, Jacob and Monod created the now well-established paradigm of inducers, regulators, regulator genes, and operators.]

While Monod was crusading against Lysenkoism, Camus was having his own feud, in public, with Sartre, who had chastised him for his anti-Soviet stance. Camus had once been a Communist, in Algeria, mainly because he was troubled by the way in which the European French treated the native Algerians. However, he was never very sympathetic to the Marxist cause. Monod too had once been a member of the Communist Party; but only because it enabled him to have a voice in the running of the Resistance. In any case, Camus seized upon Monod’s condemnation of Lysenkoism in his feud with Sartre.

Our two main protagonists finally met when Camus co-founded the anti-Stalin, anti-totalitarian Groupes de Liaison Internationale. Monod attended one of the group’s meetings. There, he, and Camus, discovering that they shared much in common, forged their friendship. Carroll writes: “Camus, who so treasured the sense of solidarity that existed among the Resistance, had in Monod a new comrade who shared both the deep bond of that wartime experience and an unqualified opposition to a new common enemy.”

As noted, Monod’s views on the meaning of life owed much to Camus. Likewise, Camus learned from Monod. Camus not only used Monod’s case against Lysenko in his dispute with Sartre, but he also “borrowed” from Monod in The Rebel; in which Camus argued that revolution inevitably leads to tyranny. In any event, after Camus and Monod had separately fought the Nazis, they were now united against another oppressor—the totalitarian state run by Stalin. [Camus’ anti-Soviet stance cost him the friendships of many French intellectuals on the left. He and Sartre never spoke to each other again.]

Monod was also troubled by the situation of scientists working under Eastern European Soviet regimes. In 1959, he organized the escape into Austria of Hungarian biochemist Agnes Ullman (who participated in the failed Hungarian uprising of 1956), and her husband, also a scientist. Earlier, in 1958, Agnes Ullman managed to visit Monod at the Pasteur Institute, and confided to him that she and her husband wanted to defect from Hungary. Monod maintained contact with the Ullmans in Hungary, using coded messages, written in invisible ink, which turned blue when exposed to iodine. The Ullmans finally crossed into Austria, hidden underneath a bathtub, in a compartment of a pull-along camping trailer. See Aside 8.

[Aside 8. Agnes Ullmann, became Monod’s long-time close collaborator at the Pasteur Institute. Now retired, she was carrying out research at the Pasteur Institute as recently as 2012; 53 years after her rescue from Hungary. At the Institute, she collaborated with Monod on characterizing the lac operon promoter, on complementation between β-galactosidase subunits, and on the role of cAMP in overcoming the repressive effect of glucose (catabolite repression) on lactose metabolism in E. coli.]

There are numerous other instances in which Monod stepped forward to fight injustice and defend human rights. In 1952, he wrote a letter in Science that might have been “ripped from today’s headlines.” It protested the U.S. government’s rejection of visa requests for himself and other Europeans who had once been Communists. Monod also condemned the treatment of Jews in the Soviet Union, while continuing to speak out against Soviet totalitarianism in general. And, in 1965, shortly after Monod, Lwoff, and Jacob received word of their Nobel Prizes, they publicly appealed to the French government to allow the use of contraceptives, and the legalization of abortion. See Aside 9.

[Aside 9: Jacob too was devoted to the defense of human rights. He chaired a committee of the French Academy of Sciences that supported persecuted scientists living under totalitarian regimes, and he worked for the release of those who had been imprisoned for their political views. Moreover, he forcefully advocated for the public support of the biological and medical sciences. What’s more, Jacob also had a distinguished writing career that produced a series of acclaimed books, including The Logic of Life: A History of Heredity; Of Flies, Mice and Men; The Possible and the Actual, and his memoir, The Statue Within. In Joshua Lederberg’s review of the latter for The Scientist, he stated:As a work of literature, it evokes unmistakable overtones of Rousseau, Proust, and Sartre.” In Jon Beckwith’s view, all of Jacob’s books are “written in a fluid and elegant style” Others refer to the “clarity and grace” of Jacob’s writing. See reference 8 for more on Jacob.]

In 1966, Martin Luther King Jr. and Harry Belafonte visited France to raise funds for the Southern Christian Leadership Conference (SCLC). Remarkably, Monod was chosen to introduce King to a crowd of 5,000 people at Paris’ Palais des Sports. Belafonte was introduced by French singer and actor Yves Montand (9).

Coretta Scott King shaking hands with Jacques Monod, as Martin Luther King Jr. looks on. From l-r: French actress Simone Signoret, Harry Belafonte, French actor and singer Yves Montand. 29 March 1966, at a meeting of the “Movement for the Peace.”

The intellectual lives of Monod and Camus played out in entirely different areas. Yet the parallels were striking. Each, in his way, searched for meaning in life. Moreover, each put his life on the line to oppose ignorance, injustice, and totalitarianism. And, it is clear from their correspondences that they were dear to each other. Here is the note from Monod that elicited Camus’ response at the top of this post.

My dear Camus,

My emotion and my joy are profound. There were many times when I felt like thanking you for your friendship, for what you are, for what you managed to express with such purity and strength, and that I had likewise experienced. I wish that this dazzling honor would also appear to you, in some small part, as a token of friendship and of personal, intimate recognition. I would not dare coming to see you right now, but I embrace you fraternally.

Jacques Monod

This piece ends with a few personal thoughts. Jacques Monod was a Nobel Prize-winning scientist, a hero of the French Resistance, a rescuer of persecuted scientists from behind the Iron Curtain, and a leading voice against tyranny and oppression. And, he was also blessed with dashing good looks. I remember well the women among my fellow graduate students in the 1960s finding him to be very attractive. But, on a more serious note: Today, when political and religious blocs dismiss evidence-based science in favor of alternative ‘facts’ in order to advance their ideologies, and when they are tacitly aided by a press that all too often gives equal validity to all points of view, and while scientists seem to be groping for an effective response, one can hope that scientists with the courage, eloquence, and eminence of Jacques Monod and Francois Jacob might emerge to take up the cause of science and reason. Meanwhile, it is especially important for young scientists, and the public, to be aware of the examples set by these men. See Aside 10.

[Aside 10: The following is from a March 8, 2017 editorial in Nature.  “Last week, state legislators in Iowa introduced a bill that would require teachers in state public schools to include ‘opposing points of view or beliefs’ in lessons on topics including global warming, evolution and the origins of life… Since last month, Indiana, Idaho, Alabama, Texas, Oklahoma and Florida have all introduced and discussed similar tweaks to the way in which they want to educate their children… Although these proposed changes are typically presented by their supporters as giving teachers the chance to discuss genuine scientific controversies, in truth they are (very) thinly veiled attempts to pursue political and religious agendas that have no place in school science lessons — for whatever age. They seek to import the alternative facts and misleading rhetoric of the new federal government and to impose it on children who deserve much better from those elected to serve them.”]

References:

  1. A Most “Elegant” Experiment: Sydney Brenner, Francois Jacob, Mathew Meselson, and the Discovery of Messenger RNA , Posted on the blog October 6, 2016.
  2. Sean B. Carroll, Brave Genius: A Scientist, a Philosopher, and their Daring Adventures from the French Resistance to the Nobel Prize, Crown, 2013.
  3. Genealogies and a Selective History of Lysogeny: Featuring Friedrich Loeffler, Emile Roux, Andre Lwoff, Elie Wollman, and Francois Jacob, Posted on the blog January 28, 2015 (8).
  4. Agnes Ullmann, In Memoriam: Jacques Monod (1910–1976), Genome Biology and Evolution 3:1025-1033. 2011, DOI: https://doi.org/10.1093/gbe/evr024.
  5. Louis Pasteur: One Step Away from Discovering Viruses, Posted on the blog January 7, 2015.
  6. Dufour, H. D., and S. B. Carroll, History: Great myths die hard, Nature 502:32–33, 2013.
  7. John Marks, Jacques Monod, François Jacob, and the Lysenko Affair: Boundary Work, L’Esprit Créateur: Genetics and French Culture. 52:75-88.
  8. Beckwith, J., and M. Yaniv, Francois Jacob (1920-2013), Current Biology 23:R422-R425, 2013.
  9. Remembering Dr. Martin Luther King Jr., CBS Minnesota, January 19, 2013, 3:51 PM.

Genealogies and a Selective History of Lysogeny: Featuring Friedrich Loeffler, Emile Roux, Andre Lwoff, Elie Wollman, and Francois Jacob

I am intrigued by the genealogies of our leading scientists, since their mentors too were often preeminent scientists. Earlier postings noted the example of Jonas Salk, who did postgraduate studies under Thomas Francis; one of the great pioneers of medical virology, perhaps best known for developing the first influenza vaccine (1, 2). James Watson, who did his doctoral studies in Salvatore Luria’s laboratory, and Renato Dulbecco, who trained under both Luria and Max Delbruck (3), are other examples. In fact, Watson and Dulbecco shared a lab bench in Luria’s lab. Howard Temin did his doctoral (and postdoctoral studies too) in Dulbecco’s lab (4). And Delbruck, who hugely influenced the new science of molecular biology, did his doctoral studies under Max Born, the 1954 Nobel Laureate in physics. Moreover, Delbruck later served as an assistant to Lisa Meitner (5).

Important research paths were undertaken, and major contributions were made, which resulted from less formal interactions between budding young scientists and top scientists of the day. Howard Temin’s chance encounter with Harry Rubin, while on a mission to Dulbecco’s lab, is a case in point (4).

Our last posting told how Louis Pasteur came within a whisker of adding the discovery of viruses to his list of extraordinary achievements (6). Robert Koch played a part in that story for developing his famous postulates, which provided the standard for demonstrating that a particular microbe causes a particular disease.

The Pasteur article also noted that in 1898 Friedrich Loeffler and Paul Frosch isolated the foot and mouth disease virus; the first virus isolated from animals. However, the piece did not point up that Loeffler had trained under Robert Koch. Also, it did not underscore the special significance of what Loeffler and Frosch achieved. In brief, by the 1890s Dmitry Ivanovsky and Martinus Beijerinck had independently discovered that the agent responsible for tobacco mosaic disease passes through bacterium-proof filters. Nevertheless, neither Ivanovsy nor Beijerinck appreciated the implication of their observation. Ivanovsky believed his filters might be defective, while Beijerinck thought the disease was caused by a “living liquid.” In contrast, Loeffler and Frosch, in addition to isolating the first virus that is pathogenic in animals, also carefully considered all possible explanations for their experimental findings, and then were the first to conclude the existence of a kind of microbe too small to be retained by bacterium-proof filters, and too small to be seen under a microscope, and that will not grow on laboratory culture media. They also correctly predicted that smallpox, cowpox, cattle plague, and measles are similarly caused by a “filterable virus.”

Loeffler made another major discovery, fourteen years earlier, in 1884, when he used his mentor’s postulates to identify the bacterium that causes diphtheria, Corynebacterium diphtheriae. Importantly, Loeffler also discovered that when he injected C. diphtheriae into animals, the microbe did not need to spread to the tissues it damaged. This observation led Loeffler to propose the bacteria were secreting a poison or toxin that spread to the remote sites and caused disease there.

Loeffler’s idea of a toxin was a new concept that subsequently was confirmed by Emile Roux, who had been Louis Pasteur’s assistant (6). Using bacterium-proof filters developed by Charles Chamberland in Pasteur’s lab, Roux showed that injecting animals with sterile filtrates of C. diphtheriae cultures caused death with a pathology characteristic of actual diphtheria. Roux was also a co-founder of the Pasteur Institute, where he was responsible for the production of diphtheria anti-toxin; the first effective diphtheria therapy. See Aside 1.

[Aside 1: Earlier, Roux suggested the approach Pasteur used to generate attenuated rabies virus for the Pasteur rabies vaccine (aging spinal cords from rabbits that succumbed to experimental rabies infections of their spinal cords). Roux later withdrew from the rabies project because of a disagreement with Pasteur over whether the rabies vaccine might be safe for use in humans (6).]

So, Loeffler and Roux trained under Koch and Pasteur, respectively. But why might toxin production by C. diphtheriae interest virologists. Well, in 1951, Victor Freeman at the University of Washington showed that the lethal toxins produced by C. diphtheriae (and by Clostridium botulinum as well) are the products of lysogenic bacteriophage carried by the bacteria. This was shown by the finding that avirulent strains of these bacteria became virulent when infected with phages that could be induced from virulent strains. So, are diphtheria and botulism due to bacteria or to viruses? Our chain of genealogies continues with a selective history of lysogeny.

Almost from the beginning of phage research (bacteriophage were discovered independently by Frederick Twort in Great Britain in 1915 and by Félix d’Hérelle in France in 1917), some seemingly normal bacterial cultures were observed to generate phage. Initially, this phenomenon was thought to be a sign of a smoldering, steady state kind of persistent phage infection. Then, during the 1920s and 1930s, the French bacteriologists, Eugene Wollman and his wife Elizabeth, working together on Bacillus megatherium at the Pasteur Institute, provided evidence that instead of a steady state infection, the phage actually enter into a latent form in their host cells; a form in which they might be harmlessly passed from one cell generation to the next. [Considering the state of knowledge back then, note the insightfulness of Eugene Wollman’s 1928 comment, “the two notions of heredity and infection which seemed so completely distinct and in some ways incompatible, . . . almost merge under certain conditions.”] See Aside 2.

[Aside 2: Since some bacterial strains would, on occasion, spontaneously undergo lysis and release bacteriophage, the cryptic bacteriophage they carried were called “lysogenic.” Thus, it is a bit odd that “lysogeny” eventually came to refer to the temperate relationship between these phages and their host cells.]

In the late 1930s, the Wollmans developed a close friendship with Andre Lwoff, their new colleague at the Pasteur Institute. The Wollmans introduced Lwoff to their ideas about lysogeny, but, as Lwoff confesses, he was not then impressed by bacteriophage (7).

The Nazi occupation of Paris during the Second World War began in 1940. From then on, the Jewish Wollmans were prevented from publishing their research findings. Nevertheless, they continued their research at the Pasteur Institute until 1943, when they were seized by the Nazis and sent to Auschwitz. They never were heard from again. Their friend, Lwoff, grieved their loss and became active in the French resistance, gathering intelligence for the Allies, while also hiding downed American airmen in his apartment.

After the war, Lwoff received several honors from the French government for his efforts against the Nazis. He also returned to his research at the Pasteur Institute, studying the genetics of Moraxella; a bacterial pathogen of the human respiratory tract. Because of his work as a microbial geneticist, he was invited to the 1946 Cold Spring Harbor Symposium, where he met Max Delbruck. And as happened to others, meeting Delbruck resulted in Lwoff being seduced by bacteriophage.

Andre Lwoff
Andre Lwoff

Back in Paris, Lwoff’s passionate interest in phages was heightened further by discussions with Jacques Monod, a friend of Max Delbruck, and Lwoff’s neighbor in the attic of the Pasteur Institute. Although Monod was Lwoff’s junior colleague (in fact, it was Lwoff who first stirred Monod’s interest in microbiology), Lwoff’s conversations with the future Nobel Laureate resulted in Lwoff becoming intensely fascinated by lysogeny, which he began to study in 1949 (7).

Because of Lwoff’s earlier friendship with the Wollmans, he chose to study a lysogenic strain of B. megatarium. And, making use of techniques he learned from Renato Dulbecco during a brief stint at Cal Tech, he was able to follow a single lysogenic bacterium, which enabled him to observe that a bacterium could go through multiple rounds of replication without liberating virus. What’s more, he discovered that the phages are released in a burst when the cell lyses, thereby dispelling the still current notion that phages are liberated continuously by lysogenic bacteria. Furthermore, Lwoff showed that lysogenic bacteria usually do not contain phage particles, since none are detected when the cells are experimentally lysed with lysozyme; confirming the earlier (1937) findings of the Wollmans.

Lwoff went on to show that temperate phage genomes are maintained in a previously unknown integrated state in their host cell, and he gave the integrated phage genomes a name, “prophage.” He also discovered, unexpectedly, that irradiating lysogenic bacteria with ultraviolet light could induce the temperate phages to emerge from their latent state, and then replicate in, and lyse their host cells. And, he discovered that the phages lyse their host bacterial cells by producing enzymes that destroy bacterial cell walls.

Prophage
Prophage

Lwoff’s elucidation of the fundamental nature of lysogeny in bacteria would later provide a paradigm for the DNA tumor viruses, the herpesviruses, the oncogenic retroviruses, and HIV. He was awarded a share of the 1965 Nobel Prize for physiology or medicine for his lysogeny research. He shared the award with his fellow Pasteur Institute scientists, François Jacob and Jacques Monod, who received their awards for their pioneering studies of gene regulation in E. Coli.

A rather intriguing aspect of this story is that Lwoff was joined in his research on lysogeny at the Pasteur Institute by Elie Wollman; the son of Eugene and Elizabeth. Elie, born in 1917, escaped from the Nazis in Paris in 1940 and worked in the French resistance as a physician. In 1946, after the war, he came to the Pasteur Institute, where he took its microbiology course and then became Lwoff’s research assistant. Then, in 1947, Elie too happened to meet Max Delbruck (in Paris in this instance) and was invited to join the Cal Tech phage group, where he spent the next two years. See Aside 3.

Elie Wollman
Elie Wollman

[Aside 3: By the early 1940s, the then young Cal Tech “phage group,” headed by Max Delbruck, was on its way to becoming the World’s great center for phage research (5). However, the American group had little interest in lysogeny, since Delbrück neither believed in it, nor saw its importance. Instead, Delbruck was totally committed to the study of lytic phages. Then, during the late 1940s, Delbruck began to lose interest in molecular biology and looked for new research directions. When he thought of turning his attention to brain function, he asked his group to put together a series of seminars based on papers written by prominent neuroscientists of the day. Elie Wollman was the only member of the Cal Tech group who declined to participate in that endeavor, since he was totally committed to bacteriophage. Moreover, Elie was the one who finally convinced Delbruck that “such a thing as lysogeny does exist (7).”

Elie himself tells us that when he looked into a bibliographical index at Cal Tech, he came across an index card referring to his parent’s 1937 paper, which reported their finding that lysogenic cells contain a non-infectious form of the phage (8). “Delbruck’s comment on the card was “Nonsense.”]

After Eli’s two-year stint with Delbruck in Pasadena, he returned to the Pasteur Institute. Meanwhile, Francois Jacob had come to the Institute in the hope of beginning a research career in genetics under the tutelage of either Lwoff or Monod. Before that, in 1940, Jacob, who also was Jewish, left medical school in occupied France to join Free French Forces in London. He then served as a medical officer in North Africa, where he was wounded, and was later severely wounded at Normandy in August 1944, ending his dream of becoming a surgeon.

Francois Jacob
Francois Jacob

Initially, Jacob was spurned by both Lwoff and Monod, but was finally taken on by Lwoff, who suggested that he, Jacob, start work on “the induction of the prophage.” Jacob confesses he had no idea what that meant, but he accepted the project. Thus it came to pass that Francois Jacob and Elie Wollman established a particularly close and friendly collaboration, in which they turned their attention to the lambda prophage of E. coli. Their initial goal was to clarify the events of bacterial conjugation so that they might then understand the phenomenon whereby a temperate phage carried by a lysogenic bacterium is activated to undergo vegetative replication when that bacterium conjugates with, and transfers its integrated phage genome to a non-lysogenic bacterium.

To accomplish their goal, Wollman and Jacob began with experiments to locate the lambda genome on the chromosome of the lysogenic cell, and to follow its transfer during conjugation into a non-lysogenic recipient cell. A key feature of their experimental approach was conceived by Wollman (8). It was simply to interrupt conjugation between a lysogenic donor (Hfr) cell and a non-lysogenic recipient (F-minus) cell, at various times, by using a kitchen blender to break the mating cells apart. Using the blender to interrupt conjugation, and also using bacterial strains in which the recipient bacteria contained a set of mutations, and plating the mating mixture on selective media, Wollman and Jacob were able to measure the length of time required for each of the corresponding wild-type genes to be transferred from the Hfr donor cells to the F-minus recipient cells. Indeed, the time intervals between the appearances of each wild type gene in the recipient cells directly correlated with the distances between the genes, as independently determined by recombination frequencies. Thus, the interrupted mating approach gave Wollman and Jacob a new means to construct a genetic map of the bacterium, while also enabling them to locate the integrated phage genome on that map. Their experimental approach also allowed Wollman and Jacob to establish that, during conjugation, the donor cell’s genome is transferred linearly to the recipient cell. [The designation “Hfr” was coined by William Hayes because Hfr strains yielded a high frequency of recombinants when crossed with female strains.]

Importantly, Wollman and Jacob’s study of the activation of a lambda prophage when it enters a non-lysogenic F-minus recipient (a phenomenon they called “zygotic induction”), showed that the temperate state of the lambda prophage is maintained by some regulatory factor present in the cytoplasm of a lysogenic bacterium, but which is absent from a non-lysogenic one. It led to the discovery of a “genetic switch” that regulates the activation of the lysogenic bacteriophage, and of a phage-encoded repressor that controls the switch. These findings are among the first examples of gene regulation, and are credited with generating concepts such as the repressor/operator, which were firmed up by Jacob and Monod in their Nobel Prize-winning studies of the E. coli lac operon. See Aside 4.

[Aside 4: At the time of Wollman and Jacob’s interrupted mating experiments, kitchen blenders had not yet made their way to European stores. Eli was aware of these appliances only because of his earlier stint at Cal Tech. He bought a blender for his wife before returning to France, and then “borrowed” it for these experiments.]

Wollman and Jacob went on to demonstrate that the fertility or F factor, which confers maleness on the donor bacteria, can exist either in an integrated or an autonomous state. Indeed, this was the first description of such a genetic element, for which they coined the term “episome;” a term now largely replaced by “plasmid.”

Wollman and Jacob also determined that the E. coli chromosome is actually a closed circle. The background was as follows. Only one F factor is integrated into the chromosome of each Hfr strain, and that integration occurs at random. And, since the integrated F factor is the origin of the gene transfer process from the Hfr cell to the F-minus cell, interrupted mating experiments with different Hfr strains gave rise to maps with different times of entry for each gene. However, when these time-of-entry maps were taken together, their overlapping regions gave rise to a consistent circular map. The discovery of the circular E. coli chromosome was most intriguing, because all previously known genetic maps were linear. See Aside 5.

[Aside 5: The bacterial strain used by Wollman and Jacob in their study of zygotic induction was, in fact, the original laboratory strain of E. coli (i.e. E. coli K12) that was isolated in1922 from a patient with an intestinal disorder. In 1951, Esther Lederberg discovered that K12 is lysogenic. The discovery happened when she accidentally isolated non-lysogenic or “cured” derivatives of E. coli K12 that could be infected by samples of culture fluid from the parental K12 strain, which sporadically produced low levels of phage. Esther gave the lysogenic phage its name, lambda.

Esther was the wife of Joshua Lederberg, who received a Nobel Prize in 1958 for discovering sexual conjugation in bacteria, and the genetic recombination that might then ensue. Prior to Lederberg’s discoveries, genetic exchange and recombination were not believed to occur in bacteria. Lederberg’s Nobel award was shared with George Beadle and Edward Tatum (the latter was Lederberg’s postdoctoral mentor) for their work in genetics.

Joshua Lederberg, working with Norton Zinder (9), also discovered transduction, whereby a bacterial gene can be transferred from one bacterium to another by means of a bacteriophage vector. And, working together with Esther, Joshua discovered specialized transduction, whereby lambda phage transduces only those bacterial gene sequences in the vicinity of its integration site on its host chromosome. Esther and Joshua also worked together to develop the technique of replica plating, which enabled the selection of bacterial mutants from among hundreds of bacterial colonies on a plate and, more importantly perhaps, to provide direct proof of the spontaneous origin of mutants that have a selective advantage.]

In 1954 Elie Wollman was appointed a laboratory head in his own right at the Pasteur Institute. He retired from research in 1966 to become vice-director of the Institute, which he then rescued from a severe financial crisis. He continued to serve in that role for the next 20 years, while garnering numerous prestigious awards for his research and service.

Francois Jacob earned his doctorate in 1954 for his lysogeny studies. Then, realizing that he and Jacques Monod, his senior neighbor in the Pasteur Institute attic, were actually studying the same phenomenon, gene repression, he entered into a hugely productive collaboration with Monod that led to the elucidation of the genetic switch that regulates beta-galactosidase synthesis in E. coli (9). Their collaboration established the concepts of regulator genes, operons, and messenger RNA, for which they shared in the 1965 Nobel Prize for physiology or medicine, as noted above. See Asides 6 and 7.

Jacques Monod
Jacques Monod

[Aside 6: One of Jacob and Monod’s first experiments was the famous 1957 PaJaMa experiment, carried out in collaboration with Arthur Pardee, who was then on sabbatical at the Pasteur Institute. In brief (for aficionados), a Lac-positive, Hfr strain was grown in an inducer-free media, and then mated, still in an inducer-free media, with a Lac-minus, F-minus strain. (Note that the deletion in the Lac-minus, F-minus strain included the LacI gene, which encodes the yet to be discovered lac repressor.) As expected, in the absence of inducer, no beta-galactosidase is detected initially. But, after the donor DNA sequence, which bears the normal Lac genes (including LacI), is transferred to the Lac-minus recipient, it initially finds no repressor in the recipient cell and begins to synthesize beta-galactosidase. Then, as the donor cell’s lac repressor gene begins to be expressed in the recipient cell, in the inducer-free media, expression of the donor cell’s beta-galactosidase gene ceases. The PaJaMa experiment thus showed that the genetic regulation of enzymatic induction depends on a previously unknown regulatory molecule, the repressor.

Notice the similarity between the rationale for the PaJaMa experiment and that of the earlier Wollman and Jacob experiment on zygotic induction. In each instance, a process regulated by a repressor is suddenly in the repressor-free environment of a recipient cell.]

[Aside 7: In June of 1960, Francois Jacob, Matt Meslson, and Sidney Brenner came together in Max Delbruck’s Cal Tech lab to carry out an experiment that confirmed the existence of messenger RNA. The key to the experiment was their ability to distinguish ribosomes present in the cell before infection from ribosomes that might have been made after infection. They cleverly did that by incorporating heavy isotopes into ribosomes before infection, so that they might be separated in a density gradient from ribosome made after infection. Then, they showed that RNA produced by T2 phage in E. Coli associates with ribosomes that were synthesized by the cell entirely before infection. Furthermore, the new phage-specific RNA directs the synthesis of phage-specific proteins on those “old” ribosomes. I vote for this experiment as the most elegant in the entire history of molecular biology (11).]

Incidentally, during the Nazi occupation of Paris, Monod too was active in the French Resistance, eventually becoming chief of staff of the French Forces of the Interior. In that capacity, he helped to prepare for the Allied landings in Normandy. Monod and Jacob each received France’s highest honors for their wartime service.See Aside 7.

[Aside 7: I am singularly intrigued by the experiences of Andre Lwoff, Elie Wollman, Francois Jacob, and Jacques Monod during the Second World War. References 3 and 5 recount the wartime experiences of Renato Dulbecco and of Max Delbruck, and of other great scientists of the time. Other posts on the blog give accounts of virologists courageously placing themselves in harm’s way under different circumstances. Examples include pieces featuring Ciro de Quadros, Carlo Urbani, Peter Piot, and Walter Reed.]

References:

(1) Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science, Posted on the blog March 27, 2014.

(2) Ernest Goodpasture and the Egg in the Flu Vaccine, Posted on the blog November 25, 2014.

(3) Renato Dulbecco and the Beginnings of Quantitative Animal Virology, Posted on the blog, December 4, 2013.

(4) Howard Temin: “In from the Cold,” Posted on the blog December 16, 2013
(5) Max Delbruck, Lisa Meitner, Niels Bohr, and the Nazis, Posted on the blog November 12, 2013.

(6) Louis Pasteur: One Step Away from Discovering Viruses, Posted on the blog January 7, 2015.

(7) Lwoff, Andre, The Prophage and I, pp. 88-99, in Phage and the Origins of Molecular Biology, J. Cairns, G.S. Stent, and J.D. Watson eds., Cold Spring Harbor Laboratory Press, 1966.

(8) Wollman, Elie L, Bacterial Conjugation, pp. 216-225, in Phage and the Origins of Molecular Biology, J. Cairns, G.S. Stent, and J.D. Watson eds., Cold Spring Harbor Laboratory Press, 1966.

(9) “The Phage in the Letter,” Posted on the blog November 4, 2013.

(9) Francois Jacob, Nobel Lecture, December 11, 1965.

(11) Norkin, Leonard C., Virology: Molecular Biology and Pathogenesis, ASM Press, 2010.

Andre Lwoff