Forum TRENDS in Genetics Vol.17 No.8 August 2001 475 Science Chronicle From controlling elements to transposons: Barbara McClintock and the Nobel Prize* 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 mutation rates. McClintock the mid-1940s, McClintock discovered concluded that she had disrupted the cell’s genetic transposition in maize. She mechanism for regulating gene 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 chromosomes – (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 science. McClintock’s results exerting a wide range of actions upon the were not accepted, the story goes, because genes. By 1950, McClintock had developed women in science 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, biologists 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 Nature 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. mutations 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 biochemistry 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 Jacques Monod’s 1960 model of a block of better with the current understanding structural genes under the control of an of the genome. 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 Sciences 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 life 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. (Harvard University Press, 2001). http://tig.trends.com 0168–9525/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0168-9525(01)02383-6 476 Forum TRENDS in Genetics Vol.17 No.8 August 2001 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 Karolinska Institute 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 Seymour Benzer, 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 bacteria. 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 Physiology or Medicine’. 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 chromosome. Sequencing 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 antibiotic-resistance James Watson 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.