An Interview with Manuel and Ann Varela: Barbara McClintock and Jumping Genes

Nov 21, 2020 by

Barbara McClintock

Michael Shaughnessy

Over the many years, I truly enjoyed not being required to defend my interpretations. I could just work with the greatest of pleasure. I never felt the need nor the desire to defend my views. If I turned out to be wrong, I just forgot that I ever held such a view. It didn’t matter.”

– Barbara McClintock

If you know you are on the right track, if you have this inner knowledge, then nobody can turn you off… no matter what they say.”

–Barbara McClintock

1) Barbara McClintock was born in Hartford, Connecticut—when exactly was she born, and can you describe her formative years?

Dr. Barbara McClintock was a Nobel Laureate and founding pioneer of modern genetics who discovered transposons and genetic recombination in corn genomes. McClintock was born in Hartford, Connecticut, on June 16, 1902. She had one younger brother and two older sisters. McClintock was an energetic youth and liked to participate in sports such as volleyball, skating, and swimming. She was raised in Brooklyn, New York, by her parents, Thomas and Sara. However, she spent some of her childhood, from ages three to five, living with an aunt to lessen her parents’ financial responsibilities. At the same time, her father grew his medical practice. Her mother was a piano teacher and poet. Although McClintock had her sights on attending college, her parents were not supportive at first. Her mother feared her daughter would not be attractive to potential suitors if she partook in higher education. Eventually, her father changed his mind in time for McClintock to complete the admissions applications, and all ended well.

2) Her early education—where was she trained?

McClintock was an Erasmus Hall High School graduate in 1919. At the age of 17, McClintock enrolled in the New York State College of Agriculture at Cornell University. She attended Cornell for both her undergraduate and graduate degrees. At Cornell, McClintock began to enjoy the company of others, unlike when she was younger, and joined a jazz band and was even elected president of the woman’s freshman class. McClintock earned her B.S. in Agriculture in 1923, and her focus was on plant breeding and botany. Two years later, with financial help from a graduate scholarship in botany, she took her master’s degree. McClintock was selected for membership in the graduate student’s Honor Society, Sigma Xi.

In 1927, McClintock completed her Ph.D. from Cornell’s Department of Botany and was the graduate student of L. W. Sharp and laboratory assistant of L. F. Randolph. During that time, she dedicated herself to investigate cytology, genetics, and zoology. A microscope and the squash staining technique enabled McClintock’s intense study of maize. McClintock’s Ph.D. thesis was titled A Cytological and Genetical Study of Triploid Maize (1927).

3) McClintock’s very early contributions to the field of maize cytogenetics—seemed to set her on the road to success. What were her early contributions, and why were they significant?

Dr. McClintock’s early contributions to the cytogenetics of corn were significant. One of these studies was related to gene mapping of specific traits to the genome corn, the scientific name Zea mays. Another notable discovery was genetic recombination and the crossing over of corn genes as they proceeded with meiosis.

McClintock’s pioneering work stemmed early on, starting in 1924, soon after her admission to graduate school at Cornell University. Her graduate academic advisor, Dr. Lester W. Sharp, a botany professor, taught a cytology course. McClintock had flourished in the class and eventually became his teaching assistant. Sharp later became McClintock’s thesis supervisor. Professor and program director Rollins Adams Emerson, a leading corn geneticist, taught McClintock how to cultivate corn. Under Emerson’s tutelage, McClintock learned to keep track of and control self- versus cross-pollinations carefully. The new expertise made it possible for McClintock to advance the study of maize cytogenetics.

As a paid laboratory research assistant, McClintock, who was still also a graduate student, entered the laboratory of Professor Lowell F. Randolph, a noted cytologist. The new association would provide funding to McClintock for graduate school. Randolph taught McClintock how to perform the so-called “squash” technique, developed by cytogeneticist John Belling, for staining the chromosomes of corn cells that were fixed to a glass slide. She used Belling’s technique to examine the chromosomes that were stained with a chemical called aceto-carmin (known today as acetocarmine), containing iron.

McClintock harvested the corn, collected its anthers, removed their walls and flower parts, and squeezed anthers’ contents onto a glass slide containing the iron-aceto-carmin staining solution. Next, McClintock added a glass coverslip and applied a flame to heat-fix the stain onto the corn chromosomes. Then she dropped the heated slide into a solution of acetic acid. After the coverslip fell away on its own, McClintock placed the coverslips, and the stained chromosomes slide inside of a so-called Coplin jar filled with a mixture of alcohol and acetic acid. McClintock then washed the contents with the covers and slides using a series of acid-alcohol solutions. Using her thumb, she reapplied the coverslips onto the slides to flatten out the chromosomes (the squash) and better visualize them.

McClintock used the corn chromosome detection method and made it her own to produce significant discoveries in generic’s burgeoning field. She used the chromosomes’ observable characteristics, such as their so-called knobs, extensions, and constrictions, to tell them apart.

McClintock and Randolph worked well together, at first, during their study of the triploid corn plant. The particular plant strain was a rare variant of maize discovered growing in the cornfields of Cornell University. The triploid plant harbored three chromosome sets, instead of one group (haploid) such as those found in the sex cells (i.e., gametes like eggs and sperm), or two groups (diploid) such as in somatic cells.

During mitosis, the parental cell divides into two daughter cells, each somatic containing a diploid number of chromosomes. In contrast, during meiosis, haploid gametes are produced in a two-stage process. The first stage of meiotic division generates a diploid chromosome number. The second meiotic division manufactures a haploid chromosome component to the egg or sperm. See Figure 49.

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Figure 49. Meiosis versus mitosis.

The collaboration between McClintock and Randolph produced their first and only publication, which came out in the journal American Naturalist in 1926. The article was also McClintock’s first scientific publication. Afterward, McClintock and Randolph had a falling out and never collaborated again. Several explanations for the rift have been postulated.

Randolph was known to be a methodical and careful scientist. While McClintock was also a systematic and cautious scientist, she was also clearly talented and gifted. She would eventually be fully recognized as a genius by the world’s leading scientist. Still, as a graduate student, she was viewed negatively by Randolph. He had tried to distinguish an identity from the Zea mays corn’s chromosomes but failed, and McClintock succeeded. She improved the chromosome staining technique, publishing the work. Furthermore, McClintock chose another meiosis stage, called pachytene, rather than metaphase, as Randolph had examined. McClintock got immediate results in clearly distinguishing individual corn chromosomes.

She was also instantly astute in grasping the significance of new data, even those of others. It was apparent to those colleagues around her that McClintock was gifted. A fellow graduate student, George Beadle, complained to Emerson about this aspect of McClintock. Emerson was reported to have informed Beadle that he should be grateful for the insight she had provided. Randolph complained about McClintock, too. Emerson took Randolph’s complaints more seriously, however, as he was a faculty. At first, Emerson sympathized with Randolph and voiced his disapproval of McClintock. In the end, however, Emerson soon became one of McClintock’s strongest advocates after learning of her scientific findings.

Her thesis completed, McClintock took a Ph.D. at age 25 in 1927 from Cornell University and published her thesis in the journal Genetics in 1929. She had identified each of the ten chromosomes held in the maize plants. She had lined up the chromosomes in order of length, with chromosome number one as the longest and number 10 has the shortest.

4) In 1945—she was chosen as the very first woman President of the Genetics Society in America. Can you outline just some of her work that led to this award?

McClintock discovered genetic recombination and genetic crossing over of corn genes during the meiotic process of gametogenesis. After earning her doctorate, McClintock remained at Cornell University from 1924-1931. She was employed as a researcher, teaching assistant, and instructor. She resumed the work that concluded in discovering transposable elements published in 1950 with financial support from three contributors: the National Research Council, the Guggenheim, and the Rockefeller Foundations.

During the period beginning in 1929, McClintock collaborated with fellow graduate student Harriet Creighton to study genetic recombination and gene crossover during meiosis. Creighton and McClintock used a set of markers, e.g., knobs at chromosome ends, located on the corn chromosomes that harbored a collection of linked genes. These markers permitted Creighton and McClintock to follow chromosomal crossing-over events. They also exploited a set of genetic markers that expressed themselves in the form of easily observable corn phenotypes. These traits included pigmentation of corn aleurone, (C), colorless aleurone, (c), waxy kernel starch (wx), and shrunken (sh) endosperms. This set up permitted Creighton and McClintock to follow any crossing over movements of genes and chromosomes.

They had genetic markers adjacent to two distinctive genes present on the same corn chromosome, e.g., one tag had a knobbed chromosome with adjacent genes for aleurone color and waxy endosperm starch on the kernel (knobbed-C-wx). These makers allowed Creighton and McClintock to trace whether chromosome crossover and gene movement were co-occurring in the same event. They had to perform the necessary mating experiments to demonstrate genetic recombination and gene crossing over during gametogenesis.

The work was arduous. Creighton and McClintock worked in the experimental cornfield stations from sunup to sundown. They planted the kernels with their distinctive observable colors and characteristics in spring. They also had to water and weed the growing plants in the hot sun while maintaining careful records of each corn plant and their genetic histories. They also had no control over the weather, such as drought or rain deluges. If the corn plants failed to grow after all of these efforts, they would lose all of their work!

During corn plant growth, they had to take great care to prevent cross-fertilization (pollination from different plants) while maintaining self-fertilization (pollination on the same plant). The male sperm on the plant tops (tassels) would fall to the egg cells located at the corn plant’s base, and their fusion would create the embryo within the corn kernel. Each sperm-egg fusion produced one corn kernel. Creighton and McClintock prevented unwanted pollination and maintained the desired self-fertilization by covering the tassels and ears with bags and transferring the pollen from the bags by hand to the eggs on the same plant (self-fertilization).

After harvest, they began the painstaking cytological work. Creighton and McClintock made observations on the numbers of chromosome crossovers and diagramed the genetic exchanges during meiosis. They looked especially closely at normal knobbed chromosomes versus knobless and interchanged chromosomes with those for kernel endosperm characteristics and colors. For instance, on chromosome number nine of the Zea mays corn, they studied the standard parental gene constitutions. One parent had knobs that carried the pigmented aleurone gene C and the gene wx (knobbed-C-wx). The other parent corn plant had no knobs and carried the c gene and the Wx gene (knobless-c-Wx). In the progeny, they observed crossovers, such as knobbed-C-Wx and knobless-c-wx!

That is, they had observed movements of genes to new chromosomal locations. It was a historical first that genetic recombination had been observed during meiosis. It was a scientific discovery of epic proportion.

Upon the encouragement of the famous Thomas Hunt Morgan himself, Creighton and McClintock would publish their groundbreaking data in the prestigious Proceedings of National Academy of Sciences in 1931.

McClintock was awarded a Guggenheim Fellowship in 1933 to study in Freiburg, Germany. She ended up leaving before the fellowship ended due to the rise of Nazism. Once back in the United States, McClintock found out that Cornell University refused to hire a female professor. Luckily, the Rockefeller Foundation funded her research at Cornell for about three years until she acquired employment at the University of Missouri in 1936.

From 1936 to 1942, McClintock held positions at the University of Missouri and then the prestigious Carnegie Institution of Washington’s Department of Genetics located at Cold Spring Harbor, New York, where she worked until she died in 1992. McClintock felt that the University of Missouri would not promote her since they labeled her as a “maverick.” She did not measure up to the university’s impression of a “lady” scientist, so she gained employment elsewhere. A small number of science historians have attempted to downplay the sexism she encountered. Nevertheless, it is clear that she experienced sexism on a personal level and was deeply affected by its ramifications. The Nobel’s bestowment to McClintock so late in her life is a giant testament to that fact, compared to the many younger male Laureates.

5) McClintock was apparently at the Carnegie Institution and continued to investigate the mechanisms of chromosome breakage and fusion in maize and transposons. Why is each of these important in the big scheme of things?

In 1950, McClintock studied chromosome breakage and fusion in maize, which led to the famous discovery of transposons. In particular, she observed a breakage phenomenon in a specific location on chromosome number nine from corn. This particular chromosome locus had a high rate of breakages. McClintock referred to this breakage point as a “mutable” locus. The specific name of the mutable locus was given Ds, for dissociation of the chromosome. She discovered that the Ds locus appeared in different places within the genome of corn, having moved about, as if jumping from place to place. In one particular example, McClintock found that the Ds locus had jumped to the C gene’s center, which specified kernel color. The genetic jump mutated the C gene to inactivate it to c, causing it to produce a colorless kernel. McClintock concluded that the kernels with no color resulted from a transposition event of Ds occurring into the middle of the C gene to destroy it.

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Figure 50. Photograph of Barbara McClintock’s ears of corn (five) and a microscope.

Most of the ear’s corn kernels appeared white, but several also appeared speckled with red sectors. See Figure 50. On the other hand, McClintock correctly deduced that Ds transposed out of the C gene for the red speckled kernels in several of the cells. Thus, the loss of Ds allowed the two ends of the broken C gene to reconnect, reforming the C gene to its normal function. Hence, the result was a restoration of the red kernel color in sections of the overall kernel, producing a prevalent red speckled kernel trait.

McClintock’s 1950 discovery of transposition was met with great skepticism. It would be decades before she was proven correct and given credit. She would be in her 80s before she was awarded the Nobel Prize.

6). Apparently, in 1983—35 years after McClintock first published a report on transpositions and 33 years after her PNAS “Classic Article,” she was finally awarded the Nobel Prize. What exactly did she get the Nobel for—or was it to recognize her work of many years?

McClintock discovered transposons and transposition as a mechanism for gene expression regulation, and she would earn the Nobel for it. See Figure 51. At Cold Spring Harbor Laboratory, McClintock focused on the coloration of corn kernels and their possible genetic information link. More specifically, she researched the role of specific chromosomes and their effects on pigmentation and other characteristics. McClintock’s famous article title was “The origin and behavior of mutable loci in maize.” The paper would become the basis of her so-called “classic article” that was first ignored and widely disbelieved for decades and later gradually accepted and celebrated.

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Figure 51. McClintock is giving her Nobel Lecture at Karolinska Institute in Stockholm during the Nobel Prize ceremony.

In 1950, McClintock had just completed her studies of breakages in the chromosomes of corn. Her findings led to a discovery—transposons, known as the “Jumping Genes” for which she would be world-famous. During McClintock’s chromosome breakage studies, she found that one of these breakage loci could alter its position within a chromosome. These genetic elements were mobile, and they became known as transposons. McClintock discovered that when these mobile genetic elements are inserted into their new chromosomal positions, they could alter the nearby genes’ expression depending on the insertion location. She had called these transposons “controlling elements.”

The classic 1950 PNAS paper presented the world’s first transposons, which McClintock specifically called Ac for activator and Ds for dissociation. The Ac transposon had controlled gene expression. She showed that Ac was a locus on the genome that moved to another locus and influenced gene expression at its new location. The dissociated chromosome section, Ds, the dissociation locus, was controlled by Ac. The breakage event seemed to occur at Ds, and it appeared to be a so-called Ac-controlled mutable locus. McClintock further showed that the Ds locus could change its position within the corn chromosome. The Ac activator locus was required for the Ds locus to move to its new location. McClintock demonstrated that Ac and Ds could transpose and that their transpositions led to unstable chromosome mutations. She further explained that the transposition events from the detrimental mutated locations would restore gene function.

Reportedly, McClintock’s colleagues did not see the significance of her transposition work, so she ceased publishing and lecturing on her findings. However, she continued to conduct research. By the late 1960s and on into the 1970s, her work’s importance and relevance began to escalate due to scholars determining that the “controlling elements” (transposons) of which McClintock wrote about were DNA. She was presented with numerous awards and honors. Among those was the 1983 Nobel Prize for Physiology or Medicine.

7) After her formal retirement—did she continue to do research—and in what areas?

After 1967, when McClintock retired, she gained a long-awaited worldwide recognition of her transposition work. Not only was evidence mounting in support of her transposition phenomena, but also of her hypothesis that these jumping genetic elements had controlled gene expression patterns. New molecular and cellular mechanisms were later revealed on how these transposons moved about from chromosome to other chromosomes and epigenetic factors, like plasmids.

During these years, she would study the origin of corn in Latin America. She became a warrior in the Corn Wars. George Beadle had postulated that the central Mexican corn strain teosinte was the progenitor of modern corn. Beadle hypothesized that ancient humans domesticated teosinte, producing the contemporary corn we now enjoy as food worldwide. Beadle’s notion for the origin of corn was called the “teosinte hypothesis.” The prominent Paul Christof Mangelsdorf disagreed, who counter proposed that modern corn resulted from a cross between teosinte and a more-modern variant of the genus called Tripsacum. Hence, the Corn War was in a full-on mode of operation.

McClintock began collecting data to determine which of the various teosinte genomes available had contributed to the modern corn genome. She focused on the knob structures of the teosinte strains and the modern corn chromosomes. Soon Beadle’s results coincided with those of McClintock, who had found that the Rio Balsas section of Mexico was a likely area where ancient corn had arisen. In the end, McClintock’s data supported the now widely accepted notion proposed by her good friend George Beadle. Thus, in these later years, McClintock published influential studies relevant to ethnobotany, evolutionary biology, and paleobotany.

8) In a sense, what type of summative comments can be made about this pioneering female scientist?

In 1944, McClintock was the third woman to be nominated into the National Academy of Sciences. National Medal of Science (1970). She also received the Thomas Hunt Morgan Medal (1981) and the Louisa Gross Horwitz Prize (1982). McClintock won as the sole recipient of the Nobel Prize in Physiology or Medicine in 1983 for discovering transposable genetic elements in corn.

In May of 2005, the United States Postal Service issued a commemorative postage stamp series, the “American Scientists,” which was a set of four 37-cent stamps in several arrangements. The scientists depicted included Barbara McClintock, John von Neumann, Josiah W. Gibbs, and Richard Feynman. In addition, McClintock was featured in a 1989 four-stamp issue from Sweden, which illustrated eight Nobel Prize-winning geneticists’ work. A Cornell University building and a laboratory facility at Cold Spring Harbor Laboratory were named after McClintock. Near an “Adlershof Development Society” science park in Berlin, a street was named after her. McClintock has become the topic of several biographies and several children’s books intended to promote scientific study among young girls and give them a role model to follow in their educational and vocational quests.

McClintock’s work with genetic recombination explained a great deal about the internal workings of the living cell. When gametes were formed during meiosis, much of the genetic elements moved about, creating new variants in cellular and organismal traits. These were fundamental discoveries that are regularly included in all modern textbooks dealing with biology, genetics, biochemistry, molecular biology, biomedical sciences, and genomics.

Her discoveries of transposons, the “jumping genes,” has particular relevance to the field of microbiology. Bacterial antibiotic resistance genes have been found to reside within specific transposons. For example, the transposon called Tn10 carries a tetracycline resistance gene encoding an efflux pump transporter for the drug. The Tn10 transposon can transfer between various bacterial species present in the human gut or the soil of agricultural regions, permitting antibiotic resistance to move within human and farm animal populations.

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Figure 52A and 52B. Structure of a DNA transposon and its transposition mechanism (Mariner type).

In Figure 52A, The general structure of a transposon example is shown. In the Mariner type transposon, two so-called tandem inverted repeat (TIR) regions of the DNA flank the gene encoding the transposase enzyme. The transposon harbors two short tandem site duplications (TSD) on the inserted region’s two ends.

In Figure 52B, the mechanism of transposition is depicted. Here, two transposase enzyme molecules recognize and bind the TIR elements on the DNA. The two ends then come together and connect. The DNA then undergoes a double-stranded cleavage, breaking the DNA (indicated by the four arrows), just as McClintock had postulated. The complex formed by the DNA and the transposase enzyme then inserts the foreign DNA at specific sites. These insertion sites are called motifs located in other loci throughout the genome, generating new TSDs sections upon integration into new DNA places.

McClintock’s studies on the origins of modern corn have direct relevance in explaining human behavior. Her worked lent vital insight into the actions of over 5,000 years of human farming practices. Each succeeding human generation played a role in the cultivation of new corn variants. The social efforts led to the highly efficient and edible modern corn, an important food source for most humans on Earth.

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