Barbara McClintock

For the illustrator of the same name, see Barbara McClintock (illustrator).

Barbara McClintock (June 16 1902 – September 2 1992) was an American scientist who pioneered the use of cytogenetics to understand the structure of chromosomes and mechanisms of genetic recombination. Her later work began the science of gene regulation. Her accomplishments are particularly remarkable because she made them at a time when women were formally discriminated against in academic science. McClintock received her PhD in botany from Cornell University in 1927, where she was a leader in the development of maize cytogenetics. That field remained the focus of her research for the rest of her career. From the late 1920s, McClintock studied chromosomes and how they change during reproduction. Her work was groundbreaking: she advanced techniques to visualize chromosomes using light microscopy and used microscopic analysis to demonstrate many fundamental genetic ideas, including genetic recombination by crossing-over during meiosis—a mechanism by which chromosomes exchange information. She produced a genetic map for maize, linking regions of the maize chromosomes with physical traits, and she demonstrated the role of the telomere and centromere, regions of the chromosome that are important in the conservation of genetic information. She was recognized as amongst the best in the field, awarded prestigious fellowships and elected a member of the National Academy of Sciences in 1944.

During the 1940s and 1950s, McClintock discovered transposition and used it to show how genes are responsible for turning physical characteristics on or off. She developed theories to explain the repression or expression of genetic information from one generation to the next. Encountering skepticism of her research and its implications, she stopped publishing her data in 1953. Nonetheless, she continued in science, and later made an extensive study of the cytogenetics and ethnobotany of maize races from South America. McClintock's research became generally appreciated by the scientific community in the 1970s and 1980s, after other researchers confirmed the mechanisms of genetic change in other model systems. Awards and recognition of her contributions to the field followed, including the Nobel Prize in Physiology or Medicine awarded to her in 1983 for the discovery of genetic transposition; to date, she has been the first and only woman to receive an unshared Nobel Prize in that category.

Early life

Barbara McClintock was born in Hartford, Connecticut, the third of four children of physician Thomas Henry McClintock and Sara Handy McClintock. She was independent from a very young age, a trait McClintock described as her "capacity to be alone." From about the age of three until the time she started school, McClintock lived with an aunt and uncle in Massachusetts in order to reduce the financial burden on her parents while her father established his medical practice. The McClintocks moved to semi-rural Brooklyn, New York in 1908. She was described as a solitary and independent child, and a tomboy. She was close to her father, but had a difficult relationship with her mother.

McClintock completed her secondary education at Erasmus Hall High School in Brooklyn. She discovered science at high school, and wanted to attend Cornell University to continue her studies. Her mother resisted the idea of higher education for her daughters on the theory that it would make them unmarriageable. Family financial problems also worked against her admission, and Barbara was almost prevented from starting college. It was her father's intervention that allowed her to enter Cornell in 1919.

Education and research at Cornell

McClintock began her studies at Cornell's College of Agriculture. She studied botany, receiving a BSc four years later, in 1923. Her interest in genetics had been sparked when she took her first course in that field in 1921. Taught by C. B. Hutchison, a plant breeder and geneticist, this course was the only one of its type offered to undergraduates in the United States at the time . Hutchison was impressed by McClintock's interest, and telephoned to invite her to participate in the graduate genetics course at Cornell in 1922, despite her status as an undergraduate. McClintock pointed to Hutchison's invitation as the reason she continued in genetics: "Obviously, this telephone call cast the die for my future. I remained with genetics thereafter."

Women could not major in genetics at Cornell, and therefore her MA and PhD — earned in 1925 and 1927, respectively — were officially awarded in botany. During her graduate studies and her postgraduate appointment as a botany instructor, McClintock was instrumental in assembling a group that studied the new field of cytogenetics, choosing maize as their species for experimental research. This group brought together plant breeders and cytologists, and included Rollins Emerson, Charles R. Burnham, Marcus Rhoades, and George Beadle (who became a Nobel laureate in 1958 for showing that genes control metabolism). McClintock's cytogenetic research focused on developing ways to characterize the chromosomes in cells. She developed a technique using carmine staining to visualize chromosomes, and showed for the first time that maize had 10 chromosomes. This particular part of her work influenced a generation of students, as it was included in most textbooks. By studying the banding patterns of the chromosomes, McClintock was able to link to a specific chromosome groups of traits that were inherited together. Marcus Rhoades noted that McClintock's 1929 Genetics paper on the characterization of triploid maize chromosomes triggered scientific interest in maize cytogenetics, and attributed to his female colleague 10 of the 17 significant advances in the field that were made by Cornell scientists between 1929 and 1935.

In 1930, McClintock was the first person to describe cross-shaped interaction of homologous chromosomes during meiosis. During 1931, McClintock and a graduate student, Harriet Creighton, proved the link between chromosomal crossover during meiosis and the recombination of genetic traits. They observed by microscopy that the regions of paired chromosomes that are physically crossing-over during meiosis are concurrently involved in exchange of genes. Until this point, it had only been hypothesized that genetic recombination could occur during meiosis. McClintock published the first genetic map for maize in 1931, showing the order of three genes on maize chromosome 9. In 1932, she produced a cytogenetic analysis of the centromere, describing the organization and function of that chromosomal structure.

McClintock's breakthrough publications, and support from her colleagues, led to her being awarded several postdoctoral fellowships from the National Research Council. This funding allowed her to continue to study genetics at Cornell, the University of Missouri - Columbia, and the California Institute of Technology, where she worked with Thomas Hunt Morgan. During the summers of 1931 and 1932, she worked with geneticist Lewis Stadler at Missouri, who introduced her to the use of X-rays as a mutagen. (Exposure to X-rays can increase the rate of mutation above the natural background level, making it a powerful research tool for genetics.) Through her work with X-ray-mutagenized maize, she identified ring chromosomes, which form when the ends of a single chromosome fuse together after radiation damage. From this evidence, McClintock hypothesized that there must be a structure on the chromosome tip that would normally ensure stability, which she called the telomere. She showed that the loss of ring-chromosomes at meiosis caused variegation in maize foliage in generations subsequent to irradiation resulting from chromosomal deletion. During this period, she demonstrated the presence of what she called the nucleolar organizers on a region on maize chromosome 6, which is required for the assembly of the nucleolus during DNA replication.

McClintock received a fellowship from the Guggenheim Foundation that made possible six months of training in Germany during 1933 and 1934. She had planned to work with Curt Stern, who had demonstrated crossover in Drosophila just weeks after McClintock and Creighton had done so; however, in the meantime, Stern emigrated to the United States. Instead, she worked in Germany with geneticist Richard B. Goldschmidt. She left Germany early, amid mounting political tension in Europe, and returned to Cornell, remaining there until 1936, when she accepted an Assistant Professorship offered to her by Lewis Stadler in the Department of Botany at the University of Missouri - Columbia.

University of Missouri - Columbia

During her time at Missouri, McClintock expanded her research on the effect of X-rays on maize cytogenetics. McClintock reported the breakage and fusion of chromosomes in irradiated cells. She also showed that, in some plants, spontaneous chromosome breakage occurred in the endosperm. Over the course of mitosis, she observed that the ends of broken chromatids were rejoined after the chromosome replication. In the anaphase of mitosis, the broken chromosomes formed a chromatid bridge, which was broken when the chromatids moved towards the cell poles. The broken ends were rejoined in the interphase of the next mitosis, and the cycle was repeated, causing massive mutation, which she could detect as variegation in the endosperm. This cycle of breakage, fusion, and bridge, also described as the breakage–rejoining–bridge cycle, was a key cytogenetic discovery for two reasons. First, it showed that the rejoining of chromosomes was not a random event, and second, it demonstrated a source of large-scale mutation. As a cause of major mutation, it remains an area of interest in cancer research today.

Although her research was progressing well at Missouri, McClintock was not satisfied with her position at the University. She was excluded from faculty meetings, and was not made aware of positions available at other institutions. In 1940 she wrote to Charles Burnham, "I have decided that I must look for another job. As far as I can make out, there is nothing more for me here. I am an assistant professor at $3,000 and I feel sure that that is the limit for me." She was also aware that her position had been especially created for her by Stadler and may have depended on his presence. McClintock believed she would not gain tenure at Missouri, although according to some accounts she knew she would be offered a promotion by Missouri in the Spring of 1942. In the summer of 1941 she took a leave of absence from Missouri to visit Columbia University, where her Cornell colleague Marcus Rhoades was a professor. He offered to share his research field at Cold Spring Harbor on Long Island. In December 1941 she was offered a research position by Milislav Demerec, and she joined the staff of the Carnegie Institution of Washington's Department of Genetics Cold Spring Harbor Laboratory.

Cold Spring Harbor

After her year-long appointment, McClintock accepted a full-time research position at Cold Spring Harbor. Here, she was highly productive and continued her work with the breakage-fusion-bridge cycle, using it to substitute for X-rays as a tool for mapping new genes. In 1944, in recognition of her prominence in the field of genetics during this period, McClintock was elected to the National Academy of Sciences — only the third woman to be so elected. In 1945, she became the first woman president of the Genetics Society of America. In 1944 she undertook a cytogenetic analysis of Neurospora crassa at the suggestion of George Beadle, who had used the fungus to demonstrate the one gene–one enzyme relationship. He invited her to Stanford to undertake the study. She successfully described the number of chromosomes, or karyotype, of N. crassa and described the entire life cycle of the species. N. crassa has since become a model species for classical genetic analysis.

Discovery of controlling elements

Heavy spotting on corn kernels reveals the activity of the Mutator transposon system. Photo: Damon Lisch PLoS Biology Open Access License

In the summer of 1944 at Cold Spring Harbor, McClintock began systematic studies on the mechanisms of the mosaic color patterns of maize seed and the unstable inheritance of this mosaicism. She identified two new dominant and interacting genetic loci that she named Dissociator (Ds) and Activator (Ac). She found that the Dissociator did not just dissociate or cause the chromosome to break, it also had other specific effects on neighboring genes - as long as the Activator locus was also present. In early 1948, she made the surprising discovery that the Dissociator and Activator loci could both transpose, or change position, on the chromosome .

She observed the effects of the transposition of Ac and Ds by the changing patterns of coloration in maize kernels over generations of controlled crosses, and described the relationship between the two loci through intricate microscopic analysis. She concluded that Ac controls the transposition of the Ds from chromosome 9, and that the movement of Ds is accompanied by the breakage of the chromosome. When Ds moves, the aleurone-color gene is released from the suppressing effect of the Ds and transformed into the active form, which initiates the pigment synthesis in cells. The transposition of Ds in different cells is random, it may move in some but not others, and that random variation causes color mosaicism in kernals (the seeds of maize). The size of the colored spot on the seed is determined by stage of the seed development during dissociation. McClintock also found that the transposition of Ds and the is determined by the number of Ac copies in the cell.

Between 1948 and 1950, she developed a theory by which these mobile elements regulated the genes by inhibiting or modulating their action. She referred to Dissociator and Activator as "controlling units"—later, as "controlling elements"—to distinguish them from genes. She hypothesized that gene regulation could explain how complex multicellular organisms made of cells with identical genomes have cells of different function. McClintock's discovery challenged the concept of the genome as a static set of instructions passed between generations. In 1950, she reported her work on Ac/Ds and her ideas about gene regulation in a paper entitled "The origin and behavior of mutable loci in maize" published in the journal Proceedings of the National Academy of Sciences. In summer 1951, she reported on her work on gene mutability in maize at the annual symposium at Cold Spring Harbor, the paper she presented was called "Chromosome organization and genic expression".

Her work on controlling elements and gene regulation was conceptually difficult and was not immediately understood or accepted by her contemporaries; she described the reception of her research as "puzzlement, even hostility". Nevertheless, McClintock continued to develop her ideas on controlling elements. She published a paper in Genetics in 1953 where she presented all her statistical data and undertook lecture tours to universities throughout the 1950s to speak about her work. She continued to investigate the problem and identified a new element that she called Suppressor-mutator (Spm), which, although similar to Ac/Ds displays more complex behavior. Based on the reactions of other scientists to her work, McClintock felt she risked alienating the scientific mainstream, and from 1953 stopped publishing accounts of her research on controlling elements.

The origins of maize

McClintock works with Blumenschein and Kato on maize. From left to right: Blumenschein, Kato and McClintock. Photo courtesy of the National Library of Medicine (NLM)

In 1957, McClintock received funding from the National Science Foundation, and the Rockefeller Foundation sponsored her to start research on maize in South America, an area that is rich in varieties of this species. She was interested in studying the evolution of maize, and being in South America, where maize agriculture had originated, would allow her to work on a larger scale. McClintock explored the chromosomal, morphological, and evolutionary characteristics of various races of maize. From 1962, she supervised four scientists working on South American maize at the North Carolina State University in Raleigh. Two of these Rockefeller fellows, Almeiro Blumenschein and T. Angel Kato, continued their research on South American races of maize well into the 1970s. In 1981, Blumenschein, Kato, and McClintock published Chromosome constitution of races of maize, which is considered a landmark study of maize that has contributed significantly to the fields of evolutionary botany, ethnobotany, and paleobotany.

Rediscovery of McClintock's controlling elements

McClintock officially retired from her position at the Carnegie Institution in 1967, and was awarded the Cold Spring Harbor Distinguished Service Award; however, she continued to work with graduate students and colleagues in the Cold Spring Laboratory as scientist emerita. Referring to her decision 20 years earlier no longer to publish detailed accounts of her work on controlling elements, she wrote in 1973:

Over the years I have found that it is difficult if not impossible to bring to consciousness of another person the nature of his tacit assumptions when, by some special experiences, I have been made aware of them. This became painfully evident to me in my attempts during the 1950s to convince geneticists that the action of genes had to be and was controlled. It is now equally painful to recognize the fixity of assumptions that many persons hold on the nature of controlling elements in maize and the manners of their operation. One must await the right time for conceptual change

The importance of McClintock's contributions only came to light in the 1960s, when the work of French geneticists Francois Jacob and Jacques Monod described the genetic regulation of the lac operon, a concept she had demonstrated with Ac/Ds in 1951. Following Jacob and Monod's paper 1961 Nature paper "Genetic regulatory mechanisms in the synthesis of proteins", McClintock wrote an article for American Naturalist comparing the lac operon and her work on controlling elements in maize. McClintock's contribution to biology is still not widely acknowledged as amounting to the discovery of genetic regulation.

McClintock was widely credited for discovering transposition following the discovery of the process in bacteria and yeast in the late 1960s and early 1970s. During this period, molecular biology had developed significant new technology, and scientists were able to show the molecular basis for transposition . In the 1970s, Ac and Ds were cloned and were shown to be Class II transposons. Ac is a complete transposon that can produce a functional transposase, which is required for the element to move within the genome. Ds has a mutation in its transposase gene, which means that it cannot move without another source of transposase. Thus, as McClintock observed, Ds cannot move in the absence of Ac. Spm has also been characterized as a transposon. Subsequent research has shown that transposons typically do not move unless the cell is placed under stress, such as by irradiation or the breakage, fusion, and bridge cycle, and thus their activation during stress can serve as a source of genetic variation for evolution. McClintock understood the role of transposons in evolution and genome change well before other researchers grasped the concept. Nowadays, Ac/Ds is used as a tool in plant biology to generate mutant plants used for the characterization of gene function.

Honors and recognition

McClintock speaking at Nobel Conference, 8 December 1983. Photo courtesy of the National Library of Medicine (NLM)

McClintock was awarded the National Medal of Science by Richard Nixon in 1971. Cold Spring Harbor named a building in her honor in 1973. In 1981 she became the first recipient of the MacArthur Foundation Grant, and was awarded the Albert Lasker Award for Basic Medical Research, the Wolf Prize in Medicine and the Thomas Hunt Morgan Medal by the Genetics Society of America. In 1982 she was awarded the Louisa Gross Horwitz Prize for her research in the "evolution of genetic information and the control of its expression." Most notably, she received the Nobel Prize for Physiology or Medicine in 1983, credited by the Nobel Foundation for discovering 'mobile genetic elements', over thirty years after she initially described the phenomenon of controlling elements.

She was awarded 14 Honorary Doctor of Science degrees and an Honorary Doctor of Humane Letters. In 1986 she was inducted into the National Women's Hall of Fame. During her final years, McClintock led a more public life, especially after Evelyn Fox Keller's 1983 book A feeling for the organism brought McClintock's story to the public. She remained a regular presence in the Cold Spring Harbor community, and gave talks on mobile genetic elements and the history of genetics research for the benefit of junior scientists. An anthology of her 43 publications The discovery and characterization of transposable elements: the collected papers of Barbara McClintock was published in 1987. McClintock died near Cold Spring Harbor in Huntington, New York, on September 2, 1992 at the age of 90; she never married or had children.

Legacy

Barbara McClintock Stamp, released by the US Postal Service 2005

Since her death, McClintock has been the subject of a biography by science historian Nathaniel C. Comfort, The tangled field : Barbara McClintock's search for the patterns of genetic control. Comfort contests some claims about McClintock, described as the 'McClintock Myth', which he claims was perpetuated by the earlier biography by Keller. Keller's thesis was that McClintock was long ignored because she was a woman working in the sciences, while Comfort notes that McClintock was actually well regarded by her professional peers, even in the early years of her career. The initial lack of interest towards McClintock's discoveries in transposition and her ideas on gene regulation may well have had little or nothing to do with sex discrimination, but instead have been generated by the very forces that she herself had blamed: the inability of the scientific community to accept a revolutionary concept 'before its time'.

She has been widely written about in the context of women's studies, and most recent biographical works on women in science feature accounts of her experience. She is held up as a role model for girls in such works of children's literature as Edith Hope Fine's Barbara McClintock, Nobel Prize geneticist, Deborah Heiligman's Barbara McClintock: alone in her field and Mary Kittredge's Barbara McClintock.

On May 4 2005 the United States Postal Service issued the American Scientists commemorative postage stamp series, a set of four 37-cent self-adhesive stamps in several configurations. The scientists depicted were Barbara McClintock, John von Neumann, Josiah Willard Gibbs, and Richard Feynman. McClintock was also featured in a 1989 four stamp issue from Sweden which illustrated the work of eight Nobel Prize winning geneticists. A small building at Cornell University bears her name to this day.