by Anne E. Egger, Ph.D., Jessica Ruvinsky, Ph.D.
Science is based on data, and collecting lots of data often involves a lot of diligent work and attention to detail. In the study of genetics and heredity, for example, scientists from Gregor Mendel in the 1700s to Craig Venter in the 2000s have spent countless hours collecting data: carefully breeding pea plants and describing their offspring or combing through millions of DNA base pairs to sequence the human genome. But even the most carefully and diligently collected data does not interpret itself. Scientists must also interpret that data, and to do so, they need to be able to see both the details and the big picture, and be creative in their thinking. Barbara McClintock (Figure 1), a Nobel Prize-winning biologist, was renowned for her sometimes obsessive attention to detail in her observations and experiments, but her work is remembered today because of the creative leaps she was able to take to explain those details.
Figure 1: McClintock and her favorite research subject at Cold Spring Harbor.
When Barbara McClintock was born in 1902, there was no such thing as a “gene.” Gregor Mendel’s “characters” that made peas round or wrinkled were still only abstract concepts (see our Genetics I module). The Danish botanist Wilhelm Johannsen began calling these characters “genes” in 1909, when McClintock was a seven-year-old girl playing football in the streets of Brooklyn (Comfort, 2003). He derived the word from the same root as genus, meaning a class of things that share certain attributes; he meant that genes are what make offspring resemble their parents in discrete ways.>
Johannsen named genes based on what they did, but he still didn’t know what they were. The leading hypothesis when McClintock was growing up was that genes existed in some physical form on chromosomes, which were visible under the microscope as sausage-shaped blobs inside the nuclei of large cells, like the cells of maize. But even 20 years after genes were named, no one had yet demonstrated this. While an instructor at Cornell University in the late 1920s, McClintock spent a lot of time describing chromosomes in maize cells. Maize (or corn) was the subject of a lot of scientific research at the time because it was an economically important plant, it was simple to cultivate, and it has easily observable traits; these are some of the same reasons why Gregor Mendel studied pea plants nearly a century earlier (see our Scientists module for more on this topic). McClintock made a map of each chromosome, describing features like a dark-looking knob at one end of chromosome 9 (Figure 2). McClintock and a graduate student named Harriet Creighton then compared the features in the chromosome maps with visible hereditary traits, like whether the kernels on the ears of corn were red or yellow, waxy or not. They saw a strong correlation between some chromosome locations and particular visible traits, and the same locations were always associated with the same traits in different corn kernels. Their interpretation of that correlation was that these locations on the chromosomes were the physical form of Mendel’s “characters,” the genes that had been named 20 years earlier by Johannsen. They convincingly demonstrated that when corn inherits a given location on a chromosome - a gene - it also inherits the trait associated with that gene (Creighton and McClintock, 1931).
Figure 2: Photomicrographs (a and b) of chromosomes from Zea mays, or maize. Diagrams of the chromosomes are shown in c and d. From (Coe and Kass, 2005).
McClintock and Creighton established that chromosomes are made up of multiple genes, lined up one after another, apparently in a stable order. Looking only at their results, it may not seem significant that they determined that the spot on maize chromosome 9 nearest the dark-looking knob determines kernel color; next to that, kernel shape; and farther from the knob, waxiness (Creighton and McClintock, 1931), but their work built on that of other scientists like Gregor Mendel and Charles Darwin (see our modules on Charles Darwin) to develop a comprehensive theory of genetics and genetic inheritance.
McClintock had addressed the chromosome question by looking more closely at miniscule differences in maize better than anyone ever had. This attention to detail and her keen observational skills were essential to her work as a geneticist. She saw every irregularity in an ear of corn as a piece of evidence. Anything that didn’t fit was something left to discover, and McClintock found that never-ending puzzle compelling. Having provided the best evidence yet for what genes are—hereditary units aligned along the chromosome like pearls on a necklace—she kept going, building on her work to make new discoveries.
In 1944, McClintock was elected to the National Academy of Sciences, one of the highest honors a scientist can receive. That same year, she noticed that a single leaf on one of the many maize plants she was growing at Cold Spring Harbor Laboratory in Long Island had a white streak (Figure 3). That was odd; the leaf was on a side branch and it ought to have been genetically identical to the main stalk, and thus solid green. McClintock wanted to get a closer look at what made that happen, so she performed an experiment by self-fertilizing the plant: collecting fresh powdery pollen from the tassel and shaking it onto the sticky, newly emerged silks on the ear. This commonly-used procedure promotes the appearance of recessive traits in the offspring.
Figure 3: White streaking in maize leaf, from Barbara McClintock’s papers.
The resulting ear of corn grew four different types of kernels. The most common was plain white and non-waxy, a type that she knew ought to produce plants with no mottling or streaking on their leaves. McClintock planted all forty of these white, non-waxy kernels on a seedling bench in her greenhouse in late winter to get an early start on the growing season. “Now the little seedlings that came up were extraordinary,” she recalled, “About half of them seemed quite normal. And the other half were full of streaks” (Comfort, 2003). Some of the seedlings’ leaves had wide green and wide yellow streaks, some were yellow with tiny little green streaks, some were green with spots of white. McClintock knew that each spot or streak came from a “mutable gene”: a gene that mutated as the plant was developing. But only two mutable genes had ever been described in maize before; among the offspring of the white-streak plant, McClintock was surprised to find seven or eight. She discussed her findings with a fellow geneticist then at Columbia University, Marcus Rhoades. With him, she shared her idea that these mutable genes must be more common than previously thought, but “they just have been neglected because no particular thought has been given to the appearance of changed sectors” (Fedoroff, 1998), or those spots and streaks. In fact, she thought that many plants that had exhibited these mutations might have been discarded from previous experiments as accidents that were a result of contamination (Comfort, 2003).
McClintock gave their appearance a lot of thought, and she had many discussions with Rhoades. She knew the details of her corn plants and their inheritance patterns better than anyone, and she knew that her experiments were not accidents. As a result of her extensive experience and background knowledge, McClintock was able to explain most of the mutable genes as variations of mechanisms she had already come up with in her earlier work. But one of them didn’t make any sense. Usually, even though the gene mutated as cells divided and the plant grew, it mutated at a constant rate: a plant either had leaves with lots of streaks or leaves with just a few, but different leaves on the same plant shouldn’t have different amounts of streaks or spots (Keller, 1983).
Plants bearing this odd mutable gene, though, did exhibit a varying mutation rate. A zone within a leaf could have more, or fewer, than the number of “expected” streaks. McClintock started to notice a pattern: one zone’s mutation rate went up exactly as much as a neighbor’s rate went down. Because of the way corn grows, McClintock knew that the pair of zones descended from a pair of cells, which began with the division of a single cell into two. “I couldn’t get it out of my head that one cell gained what the other cell lost,” she said (Keller, 1983).
What was it, then, that one cell gained? McClintock dropped all her other scientific projects and for the next six years grew descendants of that single side branch with the white streak on its leaf. She planned crosses, studied patterns of color on the leaves and kernels, and examined chromosomes under the microscope. She attended to every spot—sometimes to the point of seeing patterns were there were none, and laughing at herself in the morning. She also deeply respected the mysterious nature of creativity, and felt that sometimes the best thing she could do for her work was to go for a walk or sit under a tree. “When you suddenly see the problem, something happens that you have the answer—before you are able to put it into words. It is all done subconsciously” (Keller, 1983).
Her diligence, walks in the woods, and perseverance paid off. Eventually, McClintock showed that what one cell gained (and another lost) was a gene – a gene that had moved from one cell to another. This was a radical conclusion that flew in the face of the theory that she had helped to establish, a theory that described genes and chromosomes as stable entities. Genes were not supposed to move between cells. But this gene jumped. During a cell division, it removed itself from one chromosome and inserted itself into another. McClintock called these jumping genes “transposons”.
McClintock knew that her ideas would challenge the traditional notion of a stable genome. Genes that weren’t just sitting inertly on a chromosome, but could move around, and didn’t fit easily into the brand-new construct of a stable genome aligned along chromosomes. She thus waited until she had amassed enough evidence to present her work publicly, unveiling her intricate and complex hypothesis about transposons at the Cold Spring Harbor symposium of 1951 (McClintock, 1953). By that time, her results had been confirmed by other researchers at the University of Wisconsin, and though few in the audience understood her complex explanations, no one could refute it.
Transposons turn out to be endlessly important. About half the human genome, in fact, is a graveyard of formerly jumping DNA (Mills et al., 2007). A little of it (<0.05%) still jumps, and these active transposons may be linked to genetic disorders such as hemophilia, leukemia, and breast cancer. The now inactive, repetitive sequences of old transposons are slightly different from person to person, and matching those sequences forms the basis of the use of DNA in forensics (Novick et al., 1996). The genome that was supposedly “mapped” in 2001 (Venter et al., 2001) is, in fact, a constantly evolving record, and scientists—everyone from molecular biologists to evolutionary geneticists to physicians—are still making progress in developing their understanding of the processes and consequences involved.
McClintock received the Nobel Prize in Physiology/Medicine in 1983 for her discovery of transposons. That discovery would not have been possible without her extremely detailed observations and well-planned experiments – she noticed even the smallest changes in individual kernels that she believed others had dismissed as contamination or error. She said that, “The important thing is to develop the capacity to see one kernel that is different, and make that understandable. If [something] doesn’t fit, there’s a reason, and you find out what it is” (Keller, 1983). In other words, a scientist should not automatically dismiss the unexpected or unusual, because that unusual thing might be the clue to a new discovery. McClintock enjoyed the puzzle that such unexpected observations presented, even though they challenged previously held notions (including her own). Over the course of her scientific career, McClintock’s creativity and diligence allowed her to define – and redefine – the genes that had been postulated by other scientists before her.hide
Coe, E., and Kass, L., 2005, Proof of physical exchange of genes on the chromosomes: Proceedings of the National Academy of Sciences of the United States of America, v. 102, p. 6641.
Comfort, N.C., 2003, The tangled field: Barbara McClintock's search for the patterns of genetic control, Harvard University Press.
Creighton, H.B., and McClintock, B., 1931, A correlation of cytological and genetic crossing over in Zea Mays: Proceedings of the National Academy of Sciences, v. 17, p. 492-497.
Fedoroff, N., 1998, Marcus Rhoades and Transposition: Genetics, v. 150, p. 957-961.
Keller, E.F., 1983, A feeling for the organism: The life and ^~work of Barbara McClintock: New York, W.H. Freeman, p. 235
McClintock, B., 1953, Induction of instability at selected loci in maize: Genetics, v. 38.
Mills, R., Bennett, E., Iskow, R., and Devine, S., 2007, Which transposable elements are active in the human genome?: Trends in Genetics, v. 23, p. 183-191.
Novick, G., Batzer, M., Deininger, P., and Herrera, R., 1996, The Mobile Genetic Element" Alu" in the Human Genome: BioScience, v. 46, p. 32-41.
Venter, J.C., Adams, M.D., Myers, E.W., Li, P.W., Mural, R.J., Sutton, G.G., Smith, H.O., Yandell, M., Evans, C.A., Holt, R.A., Gocayne, J.D., Amanatides, P., Ballew, R.M., Huson, D.H., Wortman, J.R., Zhang, Q., Kodira, C.D., Zheng, X.H., Chen, L., Skupski, M., Subramanian, G., Thomas, P.D., Zhang, J., Gabor Miklos, G.L., Nelson, C., Broder, S., Clark, A.G., Nadeau, J., McKusick, V.A., Zinder, N., Levine, A.J., Roberts, R.J., Simon, M., Slayman, C., Hunkapiller, M., Bolanos, R., Delcher, A., Dew, I., Fasulo, D., Flanigan, M., Florea, L., Halpern, A., Hannenhalli, S., Kravitz, S., Levy, S., Mobarry, C., Reinert, K., Remington, K., Abu-Threideh, J., Beasley, E., Biddick, K., Bonazzi, V., Brandon, R., Cargill, M., Chandramouliswaran, I., Charlab, R., Chaturvedi, K., Deng, Z., Francesco, V.D., Dunn, P., Eilbeck, K., Evangelista, C., Gabrielian, A.E., Gan, W., Ge, W., Gong, F., Gu, Z., Guan, P., Heiman, T.J., Higgins, M.E., Ji, R.-R., Ke, Z., Ketchum, K.A., Lai, Z., Lei, Y., Li, Z., Li, J., Liang, Y., Lin, X., Lu, F., Merkulov, G.V., Milshina, N., Moore, H.M., Naik, A.K., Narayan, V.A., Neelam, B., Nusskern, D., Rusch, D.B., Salzberg, S., Shao, W., Shue, B., Sun, J., Wang, Z.Y., Wang, A., Wang, X., Wang, J., Wei, M.-H., Wides, R., Xiao, C., Yan, C., et al., 2001, The Sequence of the Human Genome: Science, v. 291, p. 1304-1351.
Anne E. Egger, Ph.D., Jessica Ruvinsky, Ph.D. "From Stable Chromosomes to Jumping Genes: with Barbara McClintock," Visionlearning Vol. SCIRE-1 (5), 2011.