Deep Reads Deep Reads: Strands in the History of Molecular Genetics

Andrew D. Chisholm* Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America

Mr. Elphinston talked of a new book that led to the deciphering of the genetic Nazis. The 3MP rests on a quantitative that was much admired, and asked code (Part II, ‘‘RNA: The Functions of the analysis of radiation mutagenesis in Dro- Dr. Johnson if he had read it. Structure’’). If you read one book on the sophila; while superseded in many places, JOHNSON. ’I have looked into it.’ history of modern genetics, this has to be the 3MP is well worth rereading for its ’What, (said Elphinston,) have you it! analytic rigor and its formulation of a gene not read it through?’ Johnson, offend- as a ‘‘physical-chemical unit.’’ The 3MP ed at being thus pressed, and so obliged Act I: Before What Is Life? takes a remarkably sophisticated view of to own his cursory mode of reading, the roles of genes in development, reject- Many of those interviewed by Judson answered tartly, ’No, Sir, do you read ing simplistic ideas of genes as the ultimate traced their interest in biology to reading through?’—James Boswell, units of life, in contrast to Schro¨dinger’s books Erwin Schro¨dinger’s What Is Life? The Life of Samuel Johnson more influential hardcore reductionism. (1943), which was based on lectures given Delbru¨ck was a theoretical physicist ‘‘Reading rots the mind’’—sign in at Trinity College Dublin. This influential whose interest in biology was stimulated Francis Crick’s office treatise, still highly readable, gives the first by Bohr’s speculations on complementar- encapsulation of the duality of the gene as ity. For its wonderfully evocative account The history of molecular genetics, its a physical structure (the ‘‘aperiodic solid’’) of the atmosphere of the Bohr circle and precursors and descendants, is rich in and as a ‘‘miniature code.’’ Not everyone the quantum mechanics group, I enjoyed events and colorful characters intertwining has had the same high opinion: Max Faust in Copenhagen: A Struggle for through the tumultuous history of the mid- Perutz commented that ‘‘what was true in the Soul of Physics (2007), by the 20th century. In this second iteration of his [Schro¨dinger’s] book was not original, physicist Gino Segre`. Bohr’s Institute for ‘‘Deep Reads,’’ I try to trace selected and most of what was original was known Theoretical Physics in Copenhagen held strands in the ancestry of the field as told not to be true.’’ Nevertheless, What Is famous annual meetings, of which perhaps in histories, biographies, and memoirs, Life? inspired many to start thinking about the most legendary was that held in 1932, some of which I have, unlike Johnson, the physical nature of genes, in large part the ‘‘miracle year’’ of quantum mechanics read through (Image 1). by bringing Delbru¨ck’s model of the gene and the centenary of Goethe’s death. The These recommendations form a tale of to the attention of a larger audience. book is structured around the entertain- three successive intellectual utopias. In the What was Delbru¨ck’s model? To find ment at the meeting, a parody of Goethe’s first act, the precursors of molecular out we have to go back to the fabled devised by none other than the genetics take hold among physicists, in Faust Dreima¨nnerwerk, or ‘‘Three-Man Paper’’ young Max Delbru¨ck. particular in those around Niels Bohr. In (3MP), of Nikolai Timofe´ev-Ressovsky, the second act, molecular genetics emerges Karl Zimmer, and Max Delbru¨ck, pub- Act II: War and Phage in the 1940s, spreading out from the phage lished in the Proceedings of the Go¨ttingen group and together with structural biology Academy of Sciences in 1935 and for Our middle act revolves around bacte- forming the nascent field of molecular many years well-nigh impossible to find, in riophage (and their bacterial hosts). Un- biology. In the third act, a diaspora English at least. An excellent scholarly known until about 1915–1917, phage were generation of geneticists applies the style translation is now available in Creating a not immediately seized on by physicists of phage genetics to a menagerie of Physical Biology: The Three-Man looking at biology: they are not mentioned organisms: Caenorhabditis elegans, Dro- Paper and Early Molecular Biology in the 3MP or in What Is Life?. Delbru¨ck sophila, zebrafish, and Arabidopsis, among (2011, eds. Phillip R. Sloan and Brandon first realized the importance of phage in others. Fogel), along with essays placing the paper 1936 in a chance conversation on a visit to First though, for an epic and accessible in its context as the urtext of molecular the California Institute of Technology history of molecular biology and genetics, biology. At the time, the rise of fascism (CalTech) (to work with Morgan on I, like Jane Gitschier in the 2013 ‘‘Deep already loomed: the 3MP arose from ). But where did the phage Reads,:Recommendations from Jane Drosophila Gitschier9s Bookshelf ’’ return again to informal seminars at the Delbru¨ck family come from? One starting point is with Horace Freeland Judson’s The Eighth home in Berlin, held for those recently the life of Felix d’Herelle, codiscoverer of Day of Creation (1979, expanded edi- expelled from their research posts by the phage and a nomadic eccentric whose life tion in 1996). I first read this as a teenager and remain captivated by Judson’s crisp, Citation: Chisholm AD (2014) Deep Reads: Strands in the History of Molecular Genetics. PLoS Genet 10(12): drama-filled accounts of discovery, based e1004887. doi:10.1371/journal.pgen.1004887 on countless interviews with the partici- Published December 18, 2014 pants. As well as recounting the eureka Copyright: ß 2014 Andrew D. Chisholm. This is an open-access article distributed under the terms of the moments, Judson also gives us the twists Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any and turns, the blind alleys, and the failed medium, provided the original author and source are credited. experiments. A high point is the story of Competing Interests: The author has declared that no competing interests exist. the maelstrom of experiment and theory * Email: [email protected]

PLOS Genetics | www.plosgenetics.org 1 December 2014 | Volume 10 | Issue 12 | e1004887 and Jacques Monod at the Pasteur Insti- tute in Paris. All had tumultuous experi- ences in war, Lwoff and Monod in the resistance and Jacob as a medical officer in the Free French Forces. Jacob’s autobiog- raphy The Statue Within (La statue inte´rieure, 1987), written in a deliberately fragmented montage style, focuses on his early life: boyhood, medical training, wartime service in Africa, a near-fatal shrapnel wound, and his postwar quest to become a biologist. Jacques Monod’s wartime exploits and his later rise to scientific eminence have been grippingly recounted in Sean B. Carroll’s double biography of Monod and Albert Camus, Brave Genius (2014). Monod and Camus both worked for the Resistance in Paris. Camus was the editor of the underground newspaper Combat; Monod (nom de guerre, Malivert) lived a double life, analyzing Escherichia coli growth curves by day and planning sabotage operations by night. Yet Camus Image 1. Some books consulted in the writing of this piece. Photo courtesy of Andrew D. and Monod did not meet until three years Chisholm. after the war, when Monod became well- doi:10.1371/journal.pgen.1004887.g001 known for his denunciation of the pseu- doscience of Lysenkoism. As a molecular story sounds stranger than fiction. d’Here- the development of molecular genetics as a biologist and a World War II buff, Carroll lle was a self-taught microbiologist whose discipline, has been told in several places, expertly covers a vast range of events, first published paper claimed that carbon although Delbru¨ck himself left no memoir. people, and ideas. was not an element. Early in his career, he For a vivid depiction of the ‘‘voices of In Cambridge in the late 1950s and was involved in ventures to distill whisky those involved,’’ the Festschrift volume early 1960s, phage geneticists, led by from maple syrup (in Canada), from Phage and the Origin of Molecular Sydney Brenner with a brief intervention rotting bananas (in Guatemala), and from Biology (1966) remains essential reading. by Francis Crick, used formal properties of the nonfibrous residue of sisal (in Mexico). The essays by Seymour Benzer, Andre mutagenesis in phage to decipher the In 1917 he discovered phage, became Lwoff, and Bob Edgar are lively mixtures genetic code. After reading Judson it is embroiled in priority claims with Frederick of amusing recollections with serious instructive to read Crick’s sharply opin- Twort, and then traveled the world using science. ionated semimemoir, What Mad Pur- phage therapy as a cure for bacterial As a counterpoint to such Delbru¨cki- suit: A Personal View of Scientific diseases. d’Herelle himself was a Lamarck- ana, it is worth seeking out Salvador Discovery (1990). Crick intersperses sci- ian with no affinity for the reductionist Luria’s autobiography, A Slot Machine, ence with brief autobiographical vignettes. geneticists who later took over his beloved a Broken Test Tube (1984, now sadly During WWII, Crick worked on the phage. The biography Fe´lix d’Herelle out of print). Luria gives an engagingly design of naval magnetic mines, a period and the Origins of Molecular Biology down to earth and at times confessional he passes over in his memoir but which is (1999) by William Summers is a nice account of his early life and his path to the discussed in absorbing detail in the official account of d’Herelle’s wildly diverse pur- momentous collaboration with Delbru¨ck biography, Francis Crick: Hunter of suits and peregrinations. on the fluctuation test. (This paper con- Life’s Secrets, by Robert Olby (2009). d’Herelle, or at least his work, may have tains one of the first and best author Crick’s naval warfare experience, while far been in part the inspiration for Arrow- contributions: ‘‘Theory by M.D., experi- from biology, taught him many important smith (1925) by Sinclair Lewis, the one ments by S.E.L.’’) Luria became the lessons valuable for his later scientific work of fiction I will recommend here (and founding director of the Massachusetts career: the need for constant improvisa- Seymour Benzer’s http://en.wikipedia. Institute of Technology (MIT) Center for tion and critical re-evaluation, how to org/wiki/Seymour_Benzer favorite book). Cancer Research. What is striking now is bypass bureaucracy, and the importance The portrayal of Martin Arrowsmith, an how active Luria was in progressive of creative rule-breaking. For a shorter obsessive idealist who gives up a lucrative politics, as a vocal opponent of the introduction to Crick’s life and work, Matt medical career to follow his research Vietnam War and a supporter of the labor Ridley’s breezy minibiography, Francis dreams, may perhaps not be completely movement. One wonders what Luria Crick: Discoverer of the Genetic out of date. Arrowsmith was supposedly would make of the current MIT cancer Code (2006), despite a somewhat inaccu- modeled after Paul de Kruif, author of the center with its Koch sponsorship. rate title, is a good thumbnail sketch. classic (but even more dated) Microbe Alongside the phage church, bacterial Crick and Brenner worked, and for Hunters (1926). genetics was entering its heroic postwar many years shared an office, at the The career of Delbru¨ck, his founding of period, which included the emergence of Medical Research Council’s Laboratory the phage group (or ‘‘phage church’’) and the team of Andre Lwoff, Franc¸ois Jacob, of Molecular Biology (LMB) in Cam-

PLOS Genetics | www.plosgenetics.org 2 December 2014 | Volume 10 | Issue 12 | e1004887 bridge, whose chairman, Max Perutz, Wiener adeptly uses the biography of Benzer I end these recommendations with a brief played an essential role in fostering the and his lab to explain the genetic basis of look at another important strand in modern environment and institutional support of complex behaviors. genetics, chromosome structure, and dy- phage and later C. elegans genetics. Perutz Other phage geneticists boldly explored namics. One of the towering figures here is was a pioneer of protein crystallography yet new animal genetic models, including the Barbara McClintock, and I recommend the also a cultured and prolific writer whose nematode C. elegans (Sydney Brenner) and excellent biography The Tangled Field: essays and book reviews combine erudition, the zebrafish (George Streisinger). Not all of Barbara McClintock’s Search for the sensitivity, and a dry humor; some are these ventures were successful; Delbru¨ck Patterns of Genetic Control (Nathaniel collected in I Wish I’d Made You Angry himself spent the last quarter century of his Comfort, 2003), preferably to be read in Earlier (2002), complete with Perutz’s career studying Phycomyces, to little avail. tandem with Evelyn Fox Keller’s AFeeling ‘‘commonplace book’’ of inspiring quota- One success story (and admittedly, I am a for the Organism (Jane Gitschier’s rec- tions. As a Jewish refugee from Vienna, bit biased here) was of course C. elegans. In ommendation). Comfort’s analysis pushes Perutz’s wartime experience began with The Beginning Was The Worm: Find- back at the myth of the marginalized internment in a camp for enemy aliens in ing the Secrets of Life in a Tiny ‘‘intuitive’’ female scientist (partly a creation Canada. He was eventually released, going Hermaphrodite (Andrew Brown, 2003) of Fox Keller and perhaps partly of on to perform military research, most is an appealingly chatty account of the McClintock herself). In place of the myth, notably in the quixotic attempt to convert development of the C. elegans field. Brown McClintock seems all the more awe-inspir- icebergs into floating airfields (Project Hab- describes the pioneer days as ‘‘a remarkable ing: a brilliant, highly analytical mind bakuk). Max’s witty letters are on a par with story of altruism, cooperation, and general following a profoundly unconventional path. his essays and are collected in What a niceness,’’ and while there may be some McClintock was one of the first to Time I am Having (2008). (For the Perutz mythologizing, some vestiges of the original recognize the special properties of chromo- communal spirit remain. completists, there is an excellent biography some ends, or telomeres. It was not until A central figure in the elucidation of C. by Georgina Ferry, Max Perutz and the decades later that Elizabeth Blackburn and elegans development and in the mapping Secret of Life, 2007). others, working in Tetrahymena,madethe and sequencing of its genome is John For many molecular geneticists, WWII critical breakthroughs in defining telomere Sulston, who went on to lead the publicly was the formative experience. In her structure and synthesis. Catherine Brady’s funded Human Genome Project. We take it fascinating study of Cambridge molecular biography Elizabeth Blackburn and the for granted that such genomic data is open biology, Designs for Life (2002), the Story of Telomeres (2007) gives a careful access, yet during the public-private race to historian of science Soraya de Chadare- and accurate account of the key experiments, vian traces how the expansion of molec- sequence the human genome in the 1990s, such an outcome was by no means assured. showing how Blackburn alternated between ular biology (and thus molecular genetics) bold imaginative leaps and rigorous tests of was an integral part of postwar recon- Sulston and Georgina Ferry’s The Com- mon Thread: A Story of Science, thesepredictions.Despiteherloveoflifein struction in Britain. A weighty academic the lab, Blackburn was willing to take on tome, Designs for Life is scattered with Politics, Ethics and the Human Ge- nome (2002) is a heartfelt polemic, told significant public service; her bruising expe- intriguing footnotes, such as when Crick’s rience on the highly politicized President’s application for the chair in genetics at from the side of the public good. It is a remarkable trajectory for one scientist, Council for Bioethics is an intriguing cau- Cambridge was turned down, on the tionary tale. This biography appeared before grounds that he did not know any genetics. from tracing divisions of worm neuroblasts to managing hundreds of scientists and tens Blackburn (with Carol Greider and Jack de Chadarevian emphasizes that the Szostak) was awarded the Nobel Prize and history of science is not simply the stories of millions of dollars to finally waging and avoids some of the hagiographical tendencies of a small circle of ‘‘hero figures,’’ either winning a high-profile battle to keep the of other laureate biographies. self-told or as told to journalists or official results in the public domain. Anyone reading the above in search of biographers, and she broadens the scope The founder of the modern C. elegans guidance on ’’how to win the Nobel Prize’’ to the roles of technical staff, administra- field, the iconoclastic, unconventional, and (to quote the title of an excellent memoir by tors, and the political milieu. ever-quotable Sydney Brenner, is best encountered in his own words, in a series J. Michael Bishop) may be disappointed. Each protagonist took their own uniquely Act III: The Diaspora of conversations with Lewis Wolpert collected as My Life in Science (2001, tortuous path to discovery and fame. Some Delbru¨ck described phage as ‘‘a fine eds. Errol Friedberg and Eleanor Laur- were academic prodigies (Brenner), and playground for serious children who ask ence). Brenner, like Crick (and despite the others were late bloomers (Crick) or unfo- ambitious questions.’’ In the mid-1960s, office sign), is a voracious reader. Two of cused (Monod). Some were politically com- many of the ‘‘serious children’’ began to his favorites are the autobiographies of the mitted (Brenner, Luria, and Monod), while ask their questions about development, the geneticist and nematode neuroanatomist others stayed aloof in the ivory tower. They nervous system, and behavior. Some re- Richard Goldschmidt and the physicist were all ambitious, but for many the turned to classical organisms, such as Max Born (Delbru¨ck’s thesis advisor). My existential crisis of war may have given Drosophila, adapting them for the more Life in Science is now out of print but is them a sense of the commitment needed to systematic genetic screens that were the partly subsumed in Friedberg’s recent take on the big problems. Chance and secret to success. An early migrant from Sydney Brenner: A Biography (2010). circumstance were important, yet luck had phage to Drosophila was Seymour Benzer, It is clearly a challenge to encompass little do with it: rather, as Pasteur said, who almost single-handedly founded mod- Brenner’s myriad activities, opinions, and chance favored the prepared mind—pre- ern Drosophila neurogenetics. In Time, schemes in a single volume, and if pared, that is, to make connections and take Love, Memory: A Great Biologist and Friedberg’s account is a little low on imaginative leaps by having maximized the His Quest for the Origins of Behavior analysis or penetrating psychological in- ‘‘inductive space’’ of observations, discus- (2000), the popular science writer Jonathan sights, the chronicle itself is fascinating. sions, and reading.

PLOS Genetics | www.plosgenetics.org 3 December 2014 | Volume 10 | Issue 12 | e1004887