From Controlling Elements to Transposons: Barbara Mcclintock and the Nobel Prize Nathaniel C
Total Page:16
File Type:pdf, Size:1020Kb
454 Forum TRENDS in Biochemical Sciences Vol.26 No.7 July 2001 Historical Perspective From controlling elements to transposons: Barbara McClintock and the Nobel Prize Nathaniel C. Comfort Why did it take so long for Barbara correspondence. From these and other to prevent her controlling elements from McClintock (Fig. 1) to win the Nobel Prize? materials, we can reconstruct the events moving because their effects were difficult In the mid-1940s, McClintock discovered leading up to the 1983 prize*. to study when they jumped around. She genetic transposition in maize. She What today are known as transposable never had any inclination to pursue the published her results over several years elements, McClintock called ‘controlling biochemistry of transposition. and, in 1951, gave a famous presentation elements’. During the years 1945–1946, at Current understanding of how gene at the Cold Spring Harbor Symposium, the Carnegie Dept of Genetics, Cold activity is regulated, of course, springs yet it took until 1983 for her to win a Nobel Spring Harbor, McClintock discovered a from the operon, François Jacob and Prize. The delay is widely attributed to a pair of genetic loci in maize that seemed to Jacques Monod’s 1960 model of a block of combination of gender bias and gendered trigger spontaneous and reversible structural genes under the control of an science. McClintock’s results were not mutations in what had been ordinary, adjacent set of regulatory genes (Fig. 2). accepted, the story goes, because women stable alleles. In the term of the day, they Though subsequent studies revealed in science are marginalized, because the made stable alleles into ‘mutable’ ones. sometimes baroque variations in idea of transposition was too far-fetched The resulting patterns in the maize leaves eukaryotes, the operon remains the core and because her scientific style was too and kernels indicated systematic theme (also the textbooks’ historical intuitive, too holistic and too feminine to alterations in mutation rates. McClintock starting point) of gene regulation. be believed. concluded that she had disrupted the cell’s Immediately following publication of the Most scientists I know detest this story. mechanism for regulating gene activity. operon model, McClintock wrote an article McClintock loathed it too. She was not By early 1948, difficulties in mapping the for The American Naturalist on the scorned, biologists insist, because she was loci led her to conclude that they were not, parallels between the control systems in a woman nor for any other reason, she was in fact, loci – sites on the chromosomes – maize and bacteria1. For a time, she even misunderstood. The intricacy of her but chromosomal elements that moved referred to her elements as ‘operators’ and experiments, combined with her eccentric, from place to place. It soon became clear ‘regulators’. Jacob and Monod were not elliptical style of presentation, made her that these new elements were capable of influenced by McClintock; when they science difficult to understand. exerting a wide range of actions upon the referred to controlling elements, it was as Furthermore, her findings were limited to genes. By 1950, McClintock had developed extrachromosomal episomes, perhaps maize, and their significance was not clear a theory about how controlling elements viral in origin, not as components of the until the late 1960s and early 1970s, when orchestrated development and transposition was found to be widespread differentiation of the organism. The key to in nature and of general importance. The her theory was coordinated transposition. Nobel Prize was not late; McClintock was In each nucleus, platoons of controlling early, ahead of her time. elements would transpose in concert, Both of these stories are myths. Both inhibiting and modulating the effects of assume that, had things gone differently, the genes to execute the developmental the transposition prize might have been program of the cell. awarded sooner. Both neglect the fact that Transposition was never in doubt. McClintock did not win the prize for what Other geneticists quickly confirmed she thought was most important in her transposition in maize, but, at the time, work. A closer look at how McClintock came few considered it McClintock’s major to receive the Nobel Prize reveals that she claim. Although McClintock was indeed won only after her major contribution to difficult to understand, all her peers science was recast to fit better with current grasped that her real point was control. understanding of the genome. Yet, to most scientists, transposition The McClintock papers within the seemed a random process. By ~1953, once Nobel archive will not be accessible until McClintock had thoroughly documented 2033. However, nominators retain the the fact of transposition, she worked hard rights to their nominations. Several scientists have generously made their *A fuller account of McClintock's life and science, including the events leading up to the Nobel Prize, can nominations and stories of McClintock be found in The Tangled Field: Barbara McClintock's Barbara McClintock in the late 1940s. Photo kindly available to me; other evidence I have Search for the Patterns of Genetic Control by Nathaniel provided by the American Philosophical Society Library, gleaned from interviews and archived Comfort (Harvard University Press, 2001). Philadelphia, USA. http://tibs.trends.com 0968-0004/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0968-0004(01)01898-9 Forum TRENDS in Biochemical Sciences Vol.26 No.7 July 2001 455 Karolinska Institute in Stockholm. He (a)Controlling elements (b) Operon nominated McClintock jointly with Repressor Seymour Benzer, best known for his work on the fine structure of the gene. The nomination form contained a box labelled Structural gene Ds P O Structural gene ‘The nomination is based on the discovery Control sites of’. In this box, van Wyk entered ‘the Ac organization and function of the genome 4 Repressor in higher organisms’ . The summary Structural gene Ds P O Structural gene description of McClintock’s work stated that it had led to ‘the first clear Ds Structural gene enunciation of the distinction between structural and regulatory genetic Ti BS elements.’An accompanying detailed Fig. 2. Both McClintock’s controlling elements (a) and Jacob and Monod’s operon (b) modeled gene regulation by the description informed by Gordon Sato, a action of elements outside the structural gene. In McClintock’s model, the regulatory elements (Ac and Ds) acted by friend of van Wyk’s and a regular summer transposing into or next to the structural gene. Here, Ac activates Ds, causing Ds to transpose to a new position next to a structural gene. Insertion of the Ds element inhibits transcription of the gene. In the operon model, each set visitor at Cold Spring Harbor, stated that of structural genes had its own adjacent regulatory elements [O (operator) and P (promoter)]. In this diagram, McClintock had ‘laid the conceptual binding of repressor to an operator sequence silences gene transcription. Figure is adapted, with permission, from groundwork for the historic achievements The Tangled Field: Barbara McClintock’s Search for the Patterns of Genetic Control, Harvard University Press. recognized in the honour conferred on Jacob and Monod by the Nobel Committee cell’s normal regulatory machinery. features that enabled these elements to in Physiology or Medicine.’After initial McClintock, however, saw her work as the remove themselves from and reinsert into review, the nomination was turned down. conceptual predecessor of the operon. the bacterial chromosome. Sequencing Meanwhile, transposable elements Seven years later, in 1967, McClintock and biochemistry revealed the existence of were being reframed in molecular terms. In won the Kimber Medal, which was unique base sequences – inverted repeats June 1976, at a Cold Spring Harbor awarded to distinguished geneticists by the – at either end of the elements that would meeting organized by Shapiro, Adhya and National Academy of Sciences each year be recognized by the enzymes responsible muologist Ahmad Bukhari, transposable from 1955 until 1970. McClintock had been for excision and ligation. By the mid- genetic elements or ‘transposons’ were on the short list since at least 1964. When 1970s, IS elements had been found in defined simply as pieces of DNA that can the award was to be announced, Marcus other organisms and shown to function in move from one place to another. By 1980, Rhoades, the award committee chairman a wide variety of ways. The rapid spread of transposons had become so important that and McClintock’s closest colleague, asked antibiotic-resistance genes was perhaps James Watson introduced the proceedings geneticist Tracy Sonneborn, the geneticist the most spectacular, but work on phage of a Cold Spring Harbor Symposium on best known for his investigations of mu, yeast mating-type switching and mobile genetic elements by writing that cytoplasmic inheritance in Paramecium, to other areas of research, all contributed to such a meeting had become ‘virtually review the proposed press release. a rapidly developing view that the unavoidable’5. By now, mobile elements Sonneborn, familiar with McClintock’s movement of genetic elements within and were mainly a subfield of microbial interpretation, suggested inserting ‘that between genomes was a mechanism of genetics. Papers at Cold Spring Harbor her studies of controlling systems of gene major importance. that summer touched on infectious disease, action were the precursors of the famous The new transposition workers quickly cancer, immunology and recombinant regulator–operon theory that won the discovered that McClintock had described DNA. However, one area that was not Nobel Prize for its promulgators and that transposition, in strictly genetic terms, discussed, was developmental regulation. their thinking was probably much long before. McClintock, then in her late In 1981, McClintock was besieged with influenced by Barbara’s notion of two- sixties, experienced a scientific awards. In June, she was made an member interacting controls’2.