The Legacy
The foundation for modern genetic theory originated some 150 years ago with Gregor Mendel’s discovery of chromosomal inheritance in peas, gaining heightened interest with the discovery of DNA and its almost magical ability to transport hereditary information from one generation to the next by Watson and Crick in the mid-1900s, and culminating with our ability to change our genetic blueprint with tools like CRISPR, engineered by Doudna and Charpentier more recently. These are the best-known achievements leading to the current understanding of what makes us – us. But along the route of these famous discoveries, cytogeneticist [1] Barbara McClintock, pioneered understanding more esoteric mechanisms and components for transporting genetic information.
In the Beginning
Born in 1902, she attended Erasmus Hall High School in Brooklyn before matriculating in Cornell University’s School of Agriculture (my alma mater), majoring in biology (as did I), and from where she obtained her PhD in botany. Her penchant for isolation and a love of science first appeared as a youngster. However, even earlier, her parents recognized that her birth name, Eleanor, was too delicate to reflect their daughter’s strong persona, changing it to Barbara. (Hmm, that’s my name, too). In 1923, when Dr. McClintock enrolled in Cornell’s Ag School (now the School for Life Sciences and Agriculture), the male-to-female ratio was 4 to 1; a half-century later, when I enrolled, the disparity was even greater, 6 to 1. [2]
Comfortable in isolation and content that she was not considered suitable teaching talent, for most of her professional life, McClintock remained cloistered in her cornfields and laboratories as a lone researcher—first at Cornell and later at Cold Spring Harbor, investigating the genetic mechanisms of maize that expressed itself in the colors and mottling of its kernels.
Liz Taylor’s Eye Color and How the Kernels Got Their Colors
Most people with brown eyes have dark (generally brown) hair. Most people with blue eyes have blonde or red hair. That’s because hair and eye color are sex-linked characteristics; the genes for each usually ride on the same chromosome and are inherited as a unit. But sometimes, we see people with dark hair and blue or green eyes – even an occasional set of violet eyes. Understanding that mechanism went wanting until Barbara McClintock helped prove the intricacies of chromosomal recombination or gene cross-over in the 1930s. It turns out that our chromosomes, long-legged creatures that they are, can be twisted through recombination – crossing over, such that the genes for eye and hair color get separated and switched. The brown hair marker is now inherited with the green-eyed gene instead of its usual compatriot – the brown one. As for purple eyes, they come from mutations, inherited, spontaneous, or caused by external factors. These occur when the genetic units responsible for coding for a particular trait get messed up or an error occurs when turning them on or off. But what drives these mutation-causing events? It took Dr. McClintock another quarter of a century to work that out.
The multiple steps in the tango that determine the expression of our genes – defied explanation until McClintock began her love affair with corn. Where we once thought of chromosomal expression as a hereditary and immutable expression on the gene’s part, based on simple dominance or receptiveness (e.g., brown eyes over blue), McClintock asked deeper questions, looking at more complicated presentations such as variegation in corn, i.e., when two colors appear together on the same cob.
By investigating the mottling pattern of variegated kernels(corn’s embryos), she was able to choreograph the chromosomal dance, explaining the mechanism directing how the kernels got their colors, identifying where they store their enablers (in structures she called transposons), and when they use them. She found that mutations (or changes in the hereditable material) can switch on and off and that genes are controlled by other genes in a domino effect.
This pattern production relies on a cast of four:
- One gene determines whether the kernels have a background color or not
- One gene determines the mottling or variegation, either purple or blue, or none.
- Two “influencers” act sequentially, determining which color-producing messages are activated.
- Finally, there’s a director, an autonomous activator element residing outside the chromosome, dictating where and when chromosomal breakage occurs, initiating the pattern process.
- Together, they create corn’s appearance, its phenotype.
Those Influencers outside the chromosome can be affected by chemical or physical “stressors.” This feature explains epigenetic influences, which we are finally recognizing today, such as the recent work documenting epigenetic but heritable changes to sperm.
When McClintock published the results of her painstaking work in 1951 demonstrating that genetic expression relied on extra-chromosomal influences – some of which move (she called these transposons or ‘jumping genes’), ’ her colleagues were either so mystified or offended that she would question the conventional wisdom that all inherited traits are governed via chromosomal genes, that she and her work were rebuffed. This surely was painful, and after a second attempt at conveying her findings in 1956 with a similar reception, she simply stopped publishing!
‘Over the years I have found that it is difficult if not impossible to bring to [the] consciousness of another person the nature of his tacit assumptions….. One must await the right time for conceptual change.”
- Barbara McClintock in Letter to geneticist Oliver Nelson
Luckily for us, she persevered in her research, continuing her work after she retired in 1967 and until her death in 1992 [3]. By the 1960s and 1970s, the importance of her work was finally recognized and replicated by others – and in 1983, still a sole researcher holed up in her lab at Cold Spring Harbor, she was awarded an unshared Nobel prize in medicine and physiology (along with many other awards), to date the only woman to achieve that honor.
Einsteins’ Dreams and Barbara’s Visions: Obstacles of the Gods
It’s unclear what prevented the understandable exposition of her work (even her biographer, a molecular biologist, had problems making it accessible). Perhaps the passage of time allowed the science-literate to absorb the novel notions; maybe it was being a woman at a time when women’s voices were shut out. Perhaps it was due to her unorthodox approach to generating hypotheses.
Einstein supposedly arrived at his equations by imagining the visual experience of a traveler on a beam of light. Reading McClintock’s biography, I felt her experiences were even more intense; it was as if she envisioned herself transported into the seed of corn, riding atop the chromosomal structure as it passed through the rites of cell division, now on one gene, now another, participating in the dance of life as a partner in a polonaise [4]. To me, she had a mind like Einstein’s – but where his visions were embraced, hers were derided.
Without a husband or family to facilitate the networking or ease the professional-social milieu needed to obtain receptivity for groundbreakingly novel ideas (like Marie Curie, Irene Joliot Curie, Ellen Swallow Richards, or Caroline Hershel), not having Lise Meitner’s more easily tolerated female-meekness or devoted familial colleague, nephew Otto Frisch, and without the championship of an avatar such as Albert Einstein, like Emmy Noether, McClintock couldn’t break into the mainstream. Said to be shy, she was also pointedly outspoken and direct, an unusual trait for women of the day; by her own admission, she was too ‘anomalous” and too much of a maverick. Known as being an eccentric troublemaker, even as she was considered a genius with a unique style of research, she was isolated by her peers and then isolated herself, struggling to find professional acceptance and even employment until her work could no longer be ignored, even if she could be.
Epitaph
Perhaps McClintock’s contributions can best be summed up by geneticist James Shapiro of the University of Chicago:
“Barbara McClintock was “the most important figure there is in biology.”
[1] cytogenetics is the study of the structure and function of chromosomes
[2] Today, Cornell has more women than men (55% to 45%), including the School of Arts and Sciences and the three other state schools with more liberal arts majors. I can’t find the breakdown for the Ag school or the biology department.
[3] “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
[4] slow dance in triple time, consisting chiefly of an intricate march or procession
Source: A Feeling for the Organism – The Life and Work of Barbara McClintock by Evelyn Fox Keller
