After her year-long temporary appointment, McClintock accepted a full-time research position at
Cold Spring Harbor Laboratory. There, 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 elected. The following year she became the first female president of the
Genetics Society of America; she had been elected its vice-president in 1939. In 1944 she undertook a cytogenetic analysis of
Neurospora crassa at the suggestion of George Beadle, who 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. Beadle said, "Barbara, in two months at Stanford, did more to clean up the cytology of
Neurospora than all other cytological geneticists had done in all previous time on all forms of mold."
N. crassa has since become a
model species for classical genetic analysis.
Discovery of controlling elements s. In 11 to 13, one copy of
Ac is present;
Ds can move, and some anthocyanin is produced, creating a mosaic pattern. In the kernel in panel 14 there are two
Ac elements, and in panel 15 there are three. In the summer of 1944 at Cold Spring Harbor Laboratory, 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
Dissociation (
Ds) and
Activator (
Ac). She found that the
Dissociation did not just dissociate or cause the chromosome to break, it also had a variety of effects on neighboring genes when the
Activator was also present, which included making certain stable mutations unstable. In early 1948, she made the surprising discovery that both
Dissociation and
Activator could 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, which causes color mosaicism. 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 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
Dissociation 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 her work on the origin and behavior of mutable loci in maize at the annual symposium at Cold Spring Harbor Laboratory, presenting a paper of the same name. The paper delved into the instability caused by
Ds and
Ac or just
Ac in four genes, along with the tendency of those genes to unpredictably revert to the wild phenotype. She also identified "families" of transposons, which did not interact with one another. 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, acts in a more complex manner. Like
Ac/Ds, some versions could transpose on their own and some could not; unlike
Ac/Ds, when present, it fully suppressed the expression of mutant genes when they normally would not be entirely suppressed. Based on the reactions of other scientists to her work, McClintock felt she risked alienating the scientific mainstream, and from 1953 was forced to stop publishing accounts of her research on controlling elements.
The origins of maize in Washington, D.C. In 1957, McClintock received funding from the
National Academy of Sciences to start research on indigenous strains of maize in Central America and South America. She was interested in studying the
evolution of maize through chromosomal changes, and being in South America would allow her to work on a larger scale. McClintock explored the chromosomal, morphological, and evolutionary characteristics of various
races of maize. After extensive work in the 1960s and 1970s, McClintock and her collaborators published the seminal study
The Chromosomal Constitution of Races of Maize, leaving their mark on
paleobotany,
ethnobotany, and
evolutionary biology. See Kass (2024, Chapter 9), for extensive details of McClintock's research and influence on the cytogenetics of the Races of Maize in Mexico and South America.
Rediscovery McClintock officially retired from her position at the Carnegie Institution in 1967, and was made a Distinguished Service Member of the Carnegie Institution of Washington. This honor allowed her to continue working with graduate students and colleagues in the Cold Spring Harbor Laboratory as
scientist emerita; she lived in the town. In reference to her decision 20 years earlier to stop publishing detailed accounts of her work on controlling elements, she wrote in 1973: The importance of McClintock's contributions was revealed in the 1960s, when the work of French geneticists
François 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 1961
Journal of Molecular Biology 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. Even late in the twentieth century, McClintock's contribution to biology was still not widely acknowledged as amounting to the discovery of genetic regulation. See Kass (2024, pp. 189–191) for clarification of this legend. McClintock was widely credited with discovering transposition after other researchers finally discovered the process in bacteria, yeast, and
bacteriophages 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 by other scientists 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-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==