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Home , Alfred Hershey, James Watson, Joshua Lederberg, Seymour Benzer, Thomas Hunt Morgan Medal, Torsten Wiesel

Forum TRENDS in Vol.17 No.8 August 2001 475

Science Chronicle From controlling elements to transposons: Barbara McClintock and the * Nathaniel C. Comfort

Why did it take so long for Barbara leaves and kernels indicated systematic McClintock to win the Nobel Prize? In alterations in rates. McClintock the mid-1940s, McClintock discovered concluded that she had disrupted the ’s genetic transposition in maize. She mechanism for regulating activity. published her results over several years By early 1948, difficulties in mapping the and, in 1951, gave a famous presentation loci led her to conclude that they were not, at the Cold Spring Harbor Symposium in fact, loci – sites on the – (Figs 1,2), yet it took until 1983 for her to but chromosomal elements that moved win a Nobel Prize. The delay is widely from place to place. It soon became clear attributed to a combination of gender bias that these new elements were capable of and gendered . McClintock’s results exerting a wide range of actions upon the were not accepted, the story goes, because . By 1950, McClintock had developed are marginalized, a theory about how controlling elements because the idea of transposition was too orchestrated development and far-fetched and because her scientific style differentiation of the organism. The key to was too intuitive, too holistic and too her theory was coordinated transposition. feminine to be believed. In each nucleus, platoons of controlling Most scientists I know detest this story. Fig. 1. Barbara McClintoch, 1983. Photograph by elements would transpose in concert, McClintock loathed it too. She was not David Miklos, courtesy of the Cold Spring Harbor inhibiting and modulating the effects of Laboratory Archives. scorned, insist, because she was the genes to execute the developmental a woman nor for any other reason, she program of the cell. was misunderstood. The intricacy of her and archived correspondence. From these Transposition was never in doubt. experiments, combined with her eccentric, and other materials, we can reconstruct the Other geneticists quickly confirmed elliptical style of presentation, made events leading up to the 1983 prize†. transposition in maize, but, at the time, her science difficult to understand. What are known today as transposable few considered it McClintock’s major Furthermore, her findings were limited to elements, McClintock called ‘controlling claim. Although McClintock was indeed maize, and their significance was not clear elements’. During the years 1945–1946, difficult to understand, all her peers until the late 1960s and early 1970s, when at the Carnegie Dept of Genetics, Cold grasped that her real point was control. transposition was found to be widespread Spring Harbor, McClintock discovered a Yet, to most scientists, transposition in and of general importance. The pair of genetic loci in maize that seemed seemed a random process. By ~1953, Nobel Prize was not late; McClintock was to trigger spontaneous and reversible once McClintock had thoroughly early, ahead of her time. in what had been ordinary, documented the fact of transposition, she Both of these stories are myths. Both stable alleles. In the language of the day, worked hard to prevent her controlling assume that, had things gone differently, they made stable alleles into ‘mutable’ elements from moving because their the transposition prize might have been ones. The resulting patterns in the maize effects were difficult to study when they awarded sooner. Both neglect the fact that jumped around. She never had any McClintock did not win the prize for what inclination to pursue the she thought was most important in her of transposition. work. A closer look at how McClintock Current understanding of how gene came to receive the Nobel Prize reveals activity is regulated, of course, springs that she won only after her major from the operon, François Jacob and contribution to science was recast to fit ’s 1960 model of a block of better with the current understanding structural genes under the control of an of the . adjacent set of regulatory genes (Fig. 3) The McClintock papers in the Nobel archive will not be accessible until 2033. *Commissioned by Trends in Biochemical and However, nominators retain the rights to published in the July issue of TiBS. their nominations. Several scientists have †A fuller account of McClintock’s and science, including the events leading up to the Nobel Prize, can be generously made their nominations and found in The Tangled Field: Barbara McClintock’s Search stories of McClintock available to me; other Fig. 2. Barbara McClintock sitting on the patio at the 1951 for the Patterns of Genetic Control by Nathaniel Comfort evidence I have gleaned from interviews Symposium. Photograph courtesy of Norton Zinder. ( Press, 2001).

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University of Rochester, wrote to her, (a)Controlling elements (b) Operon ‘I completely see that you are going to

Repressor have many calls for many activities. You are, after all, very famous now, and it is rather astonishing how your fame has Structural gene Ds P O Structural gene increased at a time of life where in most 3 Control sites people it is on the way down’ . Ac In 1976, McClintock was nominated for

Repressor the Nobel Prize by Judson van Wyk, an Structural gene Ds P O Structural gene endocrinologist at the University of North Carolina, Chapel Hill. Van Wyk had nominating privileges as a result of Ds Structural gene TRENDS in Genetics having spent the previous four years at the in Stockholm. Fig. 3. Both McClintock’s controlling elements (a) and Jacob and Monod’s operon (b) modeled gene regulation by the He nominated McClintock jointly with action of elements outside the structural gene. Here, transposition of Ds into the gene silences transcription. In the , best known for his work operon model, each set of structural genes had its own adjacent regulatory elements (O, operator; P, promoter). In on the fine structure of the gene. The this diagram, binding of a repressor to an operator sequence silences gene transcription. This figure is adapted, with permission, from Ref. 18. nomination form contained a box labeled ‘The nomination is based on the discovery of’. In this box, van Wyk entered ‘the Although subsequent studies revealed Rhoades had reservations about organization and function of the genome sometimes baroque variations in McClintock’s developmental-regulation in higher organisms’4.The summary eukaryotes, the operon remains the core theory (though not about transposition), description of McClintock’s work stated theme (also the textbooks’ historical he inserted the text. that it had led to ‘the first clear starting point) of gene regulation. That same year, James Shapiro, then enunciation of the distinction between Immediately following publication of the at the Postgraduate Medical School of structural and regulatory genetic operon model, McClintock wrote an article London, and Sankhar Adhya, at the elements’. An accompanying detailed for The American Naturalist on the University of Wisconsin, published description informed by Gordon Sato, a parallels between the control systems in their discovery of insertion sequence friend of van Wyk’s and a regular summer maize and bacteria1. For a time, she even (IS) elements in . IS elements visitor at Cold Spring Harbor, stated that referred to her elements as ‘operators’ and were discovered because of their ability McClintock had ‘laid the conceptual ‘regulators’. Jacob and Monod were not to produce strongly polar mutations groundwork for the historic achievements influenced by McClintock; when they in known operons. Subsequent recognized in the honor conferred on Jacob referred to controlling elements, it was as characterization showed distinctive and Monod by the Nobel Committee in extrachromosomal episomes, perhaps features that enabled these elements to or ’. After initial viral in origin, not as components of the remove themselves from and reinsert into review, the nomination was turned down. cell’s normal regulatory machinery. the bacterial . Meanwhile, transposable elements McClintock, however, saw her work as the and biochemistry revealed the existence were being reframed in molecular terms. conceptual predecessor of the operon. of unique base sequences – inverted In June 1976, at a Cold Spring Harbor Seven years later, in 1967, McClintock repeats – at either end of the elements meeting organized by Shapiro, Adhya and won the Kimber Medal, which was awarded that would be recognized by the enzymes muologist Ahmad Bukhari, transposable to distinguished geneticists by the National responsible for excision and ligation. By genetic elements or ‘transposons’ were Academy of Sciences each year from the mid-1970s, IS elements had been defined simply as pieces of DNA that can 1955 until 1970. McClintock had been on found in other organisms and shown to move from one place to another. By 1980, the short list since at least 1964. When function in a wide variety of ways. The transposons had become so important that the award was to be announced, Marcus rapid spread of -resistance introduced the proceedings Rhoades, the award committee chairman genes was perhaps the most spectacular, of a Cold Spring Harbor Symposium on and McClintock’s closest colleague, asked but work on phage mu, yeast mating-type mobile genetic elements by writing that Tracy Sonneborn, the geneticist best switching and other areas of research, all such a meeting had become ‘virtually known for his investigations of cytoplasmic contributed to a rapidly developing view unavoidable’5. By now, mobile elements inheritance in Paramecium, to review the that the movement of genetic elements were mainly a subfield of microbial proposed press release. Sonneborn, familiar within and between was a genetics. Papers at Cold Spring Harbor with McClintock’s interpretation, suggested mechanism of major importance. that summer touched on infectious inserting ‘that her studies of controlling The new transposition workers disease, , immunology and systems of gene action were the precursors quickly discovered that McClintock recombinant DNA. However, one of the famous regulator–operon theory that had described transposition, in strictly area that was not discussed was won the Nobel Prize for its promulgators genetic terms, long before. McClintock, developmental regulation. and that their thinking was probably much then in her late sixties, experienced a In 1981, McClintock was besieged influenced by Barbara’s notion of two- scientific . In 1973, her with awards. In June, she was made member interacting controls’2. Although friend Ernst Caspari, a geneticist at the an honorary member of the Society for

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Developmental and was awarded forerunner of the operon theory and did is mentioned about gene regulation or the Medal of the not recall having said it was9. Indeed, it the control of development and Genetics Society of America. In October, is doubtful that he believed it in 1981; differentiation. Herskowitz and Alberts the Wolf Foundation, based in Israel, the words are probably those of Marcus mentioned recent work that had ‘shown awarded McClintock its $50 000 prize in Rhoades. A busy man, Lederberg likely that transposable genetic elements are medicine. On 17 November, the John D. wrote a gloss on Rhoades’ evaluation and present in essentially all organisms’. and Catherine T. MacArthur Foundation sent it off, rightfully pleased to have done In addition, they went on to note the named her its first MacArthur Laureate, a good deed for a deserving colleague. implications of transposition for cancer a now discontinued plum for senior In another nomination letter for 1982, research, yeast genetics and genome scholars, which awarded McClintock Heinz Saedler, a bacterial geneticist in . In short, the nomination $60 000 a year for life, tax free. The next Cologne working on insertion elements, presented genetic transposition as day, she won the Albert Lasker Basic wrote perceptively that McClintock’s universal, of basic importance to Medical Research Award. She had also contribution ‘lay in the introduction organisms and of great significance to been nominated for the Nobel Prize once of a completely new concept. In it, medicine. It had little in common with again, this time by Stanley N. Cohen and chromosomes are no longer rigid what McClintock herself had been arguing Howard Temin. But the 1981 prize went structures, but show flexibility and for decades. to neurobiologists Roger Sperry, thereby allow reorganization of the McClintock won the prize that year, David Hubel and . genetic material’. Shifting to a discussion solo, although the suggestion had been Meanwhile, Nobel nominations of transposable elements in bacteria, floated that she share it with Susumu continued to roll in. Herschel Roman, Saedler continued, ‘Such a reorganization Tonegawa, whose brilliant experiments a geneticist who had been a graduate of the ordering of genes is catalyzed by demonstrated genomic rearrangement student at the University of Missouri in transposable elements. These genetic among antibody genes. (Tonegawa won the late 1930s when McClintock was units not only jump from one place in the in 1987.) One cannot yet know whether there, and who was now at the University genome to another, they can also influence the Herskowitz–Alberts letter was the of Washington, began to canvass for her. the expression of other genes; because determining document; Nobel campaigns In September, apparently unaware of the of this McClintock at first named them often acquire a momentum and other, previous nominations, he wrote to ‘controlling elements’: ‘The “controlling independent nominations might well Marcus Rhoades that ‘It seems to several elements” were the first model system for have been submitted. But, regardless of of us that Barbara McClintock should the control of gene activity.’11 whether it defined or represented the get or share in the Nobel Prize, now that Saedler’s letter accomplished several shift, the Herskowitz–Alberts nomination transposons have been shown to be so things. It represented McClintock’s work expressed beautifully McClintock’s widespread and so important. I just had a reasonably accurately, describing contribution to science as being the letter from Beets [] and he transposition, influence on gene action discovery of genetic transposition, not agrees and would support a nomination. and McClintock’s recent emphasis on genetic control. This is the standard view He suggests that you lead the charge’6. genomic rearrangements. It also placed of her work today. Rhoades suggested Jim Watson as a her work in the context of contemporary McClintock seems to have been Nobel-laureate sponsor but Watson transposon research. Yet it retained the bittersweet about the Nobel Prize. demurred, saying he was already idea of genetic control. But 1982 was not Though, of course, she was glad of the supporting another candidate. Joshua to be her year. scientific recognition, Jim Shapiro Lederberg, however, assented happily to The next year, a nomination by Ira believes she was pained by the fact that Roman’s request: ‘Barbara for Nobel is of Herskowitz and reflected the recognition missed her central point. course an excellent idea although my own a change in strategy. Both Alberts and In 1999, he said, ‘She told me she wasn’t view is that Ac/Ds [her first controlling Herskowitz were in the biochemistry interested in transposition. She was element] was not even her most important faculty at the University of at interested in regulation.’12 McClintock work. I would be glad to endorse and San Francisco. Herskowitz led the lab herself expressed this opinion in forward a nomination that you and group that developed the cassette model interviews throughout the 1970s and Marcus prepared.’ Other affirmations of of yeast mating-type switching; Alberts, early 1980s. support came in from Nobelists Salvador today head of the National Academy of Barbara McClintock could not possibly Luria, and Francis Crick7. Sciences, used to study the have won a Nobel Prize for transposition Lederberg’s nomination, informed mechanism of DNA replication. In the box before 1976. Until then, her work since by Rhoades’s summary appraisal of ‘The nomination concerns the discovery 1944 had been understood as she had McClintock’s research, noted the of,’ Herskowitz and Alberts entered wished: a theory about development and importance of ‘her work on the mechanism simply, ‘Transposable genetic elements’11. differentiation. That theory had never been of control of gene action in maize, The nomination began, ‘Barbara widely accepted and, by the 1970s, it had involving the action and interaction of two McClintock discovered that discrete pieces been solidly refuted. Between 1976 and independent loci. This system was the of genetic information are capable of 1983, her Nobel nominations gradually forerunner of the regulator-operon theory movement from one chromosomal location overcame a quarter-century of inertia, as of Jacob and Monod’8. When I interviewed to another and that this movement of transposition was reframed as the basis of Lederberg in the late 1990s, he did not “transposable elements” can lead to major genomic rearrangement. Any delay for her believe McClintock’s work was the alterations in gene expression.’ Nothing award seems to be a consequence of

http://tig.trends.com 478 Forum TRENDS in Genetics Vol.17 No.8 August 2001 residues of that old developmental 2 Tracy Sonneborn to Marcus Rhoades, 21 March 11 and Bruce Alberts, ‘Nomination framework clinging to her nominations. 1967; press release dated 17 April 1967, box 12, for the 1983 Nobel Prize in Physiology or folder 12, Marcus Rhoades collection, Lilly Medicine,’ 26 January 1983, from Herskowitz’s This view in no way diminishes either Library, private collection McClintock or the prize. The reframing of 3 Ernst Caspari to McClintock, 27 June 1973, folder 12 James Shapiro, interview with the author, great discoveries could, in fact, be common, ‘McClintock, Barbara,’ Ernst Caspari Collection, 14 July 1999 and might sometimes happen repeatedly: American Philosophical Society Library, 13 Barkan, A. and Martienssen, R.A. (1991) recently, in some circles, dogmatic Philadelphia, PA, USA Inactivation of maize transposon Mu 4 Judson Van Wyk, nomination for 1976 Nobel Prize suppresses a mutant phenotype by activating opposition to transposon-mediated gene in Physiology or Medicine, 28 January 1976, from an outward-reading promoter near the end of regulation has softened(For examples, see van Wyk’s private collection Mu1. Proc. Natl. Acad. Sci. U. S. A. Refs 13–17). What does seem rare is for a 5 Watson, J.D. (1980) Foreword. Cold 88, 3502–3506 scientist to live to see her work take on new Spring Harbor Symposia on Quantitative 14 Martienssen, R.A. (1996) Epigenetic phenomena: meaning. McClintock was fortunate in Biology 45, xiii paramutation and gene silencing in plants. Curr. 6 Herschel Roman to Marcus Rhoades, Biol. 6, 810–813 earning the admiration of junior colleagues 2 September 1981, folder 16, box 12, Marcus 15 The Cold Spring Harbor Laboratory, Washington who, within her lifetime, rewrote history to Rhoades collection, Lilly Library, Indiana University Genome Sequencing Center and PE ensure due, but not overdue, credit to one of University Biosystems Arabidopsis Sequencing Consortium the century’s great geneticists. 7 Herschel Roman to , 1 October (2000) The complete sequence of a 1981; Lederberg to Roman, 5 October 1981; heterochromatic island from a higher eukaryote. Roman to Lederberg, 30 December 1981; folder Cell 100, 377–386 Nathaniel C. Comfort 16, box 12, Marcus Rhoades collection, Lilly 16 Dimitri, P. and Junakovic, N. (1999) Revising the Center for History of Recent Science, Dept of Library, Indiana University selfish DNA hypothesis: new evidence on History, The George Washington University, 8 Joshua Lederberg, undated nomination letter, accumulation of transposable elements in Washington, DC, USA. box 12, folder 16, Marcus Rhoades collection, Lilly heterochromatin. Trends Genet. 15, 123–124 e-mail: [email protected] Library, Indiana University 17 Buckler, E.S. et al. (1999) Meiotic drive of 9 Joshua Lederberg, interviews with the author, chromosomal knobs reshaped the maize genome. References 12 March 1996, 1 July 1999 Genetics 153, 415–426 1 McClintock, B. (1961) Some parallels between 10 Heinz Saedler ‘Nomination: Nobel Prize for the 18 Comfort, N. (2001) The Tangle d Field: Barbara gene control systems in maize and in bacteria. year 1982: Dr. Barbara McClintock,’ 25 January McClintock’s Search for the Patterns of Genetic Am. Nat. 95, 265–277 1982, from Saedler’s private collection. Control,

Book Review

themselves on one level and, at another satisfactory. Whether this was merely Telling genetic stories level, the hidden curriculum in the genetic my personal response to reading content conveyed within the stories material with which I was already Abraham Lincoln’s DNA and Other The first four chapters deal with familiar, or whether other, lay readers Adventures in Genetics history. They aim to instruct the would find the same, I am not sure. It by Philip R. Reilly interested lay person in such matters felt to me as though Reilly had used his Cold Spring Harbor Laboratory Press, as patterns of inheritance, and the best cards – the best stories – early on. 2000. £19.00 hbk (xx + 339 pages) nature of genetic diseases and metabolic After that, the balance between story ISBN 0 87969 580 3 pathways. The pegs on which the and content shifted to the detriment technical content is hung are attractive – of the story. A similar effect occurs in I found this I think the stories about the Romanov Sophie’s World1, where the author collection of essays family, Abraham Lincoln, Toulouse tries to lure readers into the world of both interesting and Lautrec and others will interest many philosophy by stringing them along informative. Indeed readers. This is also true of the next with a story line. However, both books it contains many section. Here, the subject matter shifts increasingly shift to become more anecdotes that I to Justice, and the stories within it relate content with less sugar coating, may store and to the investigation of several murders. becoming less palatable to those who re-use in lectures. As in the first section, Reilly is to be are not already interested and at least However, I remain congratulated on introducing a variety partly informed. uncertain as to the of difficult issues alongside the technical Reilly seems to have regarded this intended audience of ones. Among them, the possible book as his one chance to educate the the book as a whole. contribution of genetics to criminality public; every essential fact and every Reilly, a prominent geneticist trained and the potential implications of such important issue had to be crammed in. in both medicine and law, declares in his an effect are dealt with. He also looks at This feeling grew progressively stronger introduction that there is a book within the most appropriate possible framework as I read the second half of the volume. the book. His concept is to use the for police DNA banks to be used for I have to admit to a personal interest 24 chapters as stories to sweeten the forensic purposes. in this problem, because I would like to pill of instruction for non-scientists, Reading further into the book, write a book that could be accessible to and consequently, we have the stories however, I found it becoming less members of the general public, and I am

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