The Monster in Dr. McClintock: The Twisted Tale of Jumping Genes
Isolation makes monsters, and none so monstrous as those who willingly seek it. It is hard to work up a great deal of sympathy for individuals who, under the banner of intellectual freedom, demand the resources to do whatever they want, however they want to do it, and then routinely bite the hands of those who make their ideal life possible. The heroism of hyper individualism runs hard against our human expectations of gratitude and social reciprocity, winning for the individualist at best a cold respect.
Barbara McClintock (1902-1992) is one of these figures, not exactly monstrous, but not quite human either. Undeniably a key figure in the history of genetics, her recasting of her role in that history was a bitter and deeply unfair accounting of a community which had, for decades, provided everything she wanted. In portraying herself as a misunderstood maverick, she had to paint her fellow scientists in the colors of the establishment villains, and for decades that is the monodimensional story which has remained in the popular fancy.
The truth is, McClintock was a natural genius at what she did, and was recognized as such throughout her long career. As a cytologist, she saw chromosomal patterns where others saw only chaos, allowing her to grasp at an instant the important differences between cells and solve genetic conundrums in days that had stumped more experienced colleagues for years. More than that, over decades of experience working through the mutations of her chosen benchmark organism, the maize plant, she developed an uncanny ability to infer from unique physical characteristics what the underlying explanatory genetic mechanisms might be. While other researchers sought the simplest organisms in order to plumb the genetic depths, McClintock sought complexity, wrestling with the thorniest of phenotypes to gain a deeper understanding of how genes might work to create individuals.
In the 1920s and 30s, she worked on the problem of variegation, in particular on how and why maize plants displayed streaks and flecks of color. How could Mendelian genetics account for the wild variations that she was uncovering, season after season, in her carefully cross-bred corn crops? She looked for mechanisms that might lose and regain genetic material, and found them in ring chromosomes – chromosomes that had attached their ends together and that were inconsistently passed on in cell divisions – and more importantly, in the Breakage-Fusion-Bridge cycle.
If she had done nothing else, the BFB cycle would have solidified McClintock’s reputation in the genetic pantheon. It works like this: Take a chromosome. At its tips it possesses sections called telomeres that ordinarily prevent adjacent chromosomes from sticking together. However, when struck by X-Rays, those telomeres can get blasted off, leaving behind ordinary chromosomal ends. So, when that chromosome replicates during mitosis, it will create another chromosome with a sticky end, and if those two free ends fuse, it will create a giant gene with two centromeres. During anaphase, when the sister chromatids are separated to opposite sides of the cell, the giant gene gets pulled in two directions, tearing it at a random location (think of two people pulling on a wishbone), giving the daughter cells a genetic makeup that is different from the parent cell. Each subsequent division of those daughter cells, then, can produce new BFB events, and therefore new genetic possibilities.
Not only was this a powerful tool for explaining variation among cells, but it allowed McClintock to elegantly produce new mutations of a given gene without having to use brute force X-Ray techniques. And that dizzying array of new mutations lead in turn to the discovery she won the Nobel Prize for: the translocation of genetic material.
Working with a particularly wild strain of mutant corn, she noted a location on maize’s 9th chromosome where breaks seemed to happen particularly often, what she would later call the Ds locus. Digging further, it seemed that the Ds was activated by yet another gene, Ac. Originally thought to sort independently, some mutants showed them to be linked, meaning that the genes must have somehow moved closer together. Years spent fine tuning the different configurations of Ds and Ac revealed a complicated picture that would rewrite the genetic playbook.
Firstly, chromosomes are made up of different types of locations – locations that code for products, like pigments, and locations that seem to have a regulatory role in determining the expression of the gene. As opposed to earlier views, that held that genes are making all of their possible products, all the time, McClintock’s work with Ds and Ac indicated that parts of the gene could be turned on and off, and that the agent responsible for that timing was part of the chromosome itself. This idea would be substantiated dramatically in the early Sixties.
Secondly, genes can move – they can cut themselves out of the chromosome and insert themselves at a different location, with often marked consequences for gene activity. This discovery was behind the resurrection of McClintock’s reputation in the late Seventies and early Eighties.
These discoveries were the culmination of decades of research. Having attempted to work as a regular university professor, she realized that she didn’t like having responsibilities not of her own choosing. She didn’t like teaching non-genius students, didn’t like sitting on committees, didn’t like having to justify her work, and generally speaking hated everything that most scientists put up with as part of the reality of working together in groups. She wanted to go somewhere with complete freedom, and obtained precisely that from the research labs at Cold Spring Harbor. There, she received funding to study whatever she wanted, freedom to publish or not, however she saw fit, and to visit genetics labs at other universities whenever she felt like it. Whenever she threatened to leave, she was granted unheard of levels of new autonomy from a bureaucracy that wanted to keep her at all costs, even as she wrote letters to her colleagues casting suspicious accusations against those who were fighting to give her what she desired.
The tendency to ungraciously lash out at her colleagues manifested in many ways, from the limited case of lying about her superiors’ intentions to give her tenure in the 1930s, to the more systemic attempts to cast the genetic community of the 1950s and 1960s as fundamentally hostile to her discoveries. Gene translocation and gene expression, she claimed in later life, were willfully ignored by a scientific community too set in its ways to recognize her brilliance. In fact, her work on translocation was almost instantly accepted as established fact, and confirmed by multiple sources. Her paper on the subject was repeatedly cited, and its implications were taken up in spirited debate. The charges that the scientific community ignored or did not understand translocation are false, a fabrication that, again, made McClintock look good retroactively, but that hurt many of her colleagues who, after decades of faithful support, woke up one morning to have their motives and histories rewritten on television.
What McClintock really objected to was that her idea, that these translocating genes represented the mechanism of gene expression, never caught on. She never forgave the scientific world for not taking her word for it, that her interpretation was correct. She had a habit of turning acridly against anybody who challenged her, and whereas in previous years she had been backed up by the meticulousness of her work, when it came to the role of translocation in gene expression, she was on more speculative ground, but expected her speculations to be accepted with the same unquestioning reverence that her previous work had enjoyed.
The scientific community, however, noticed the gaps between the data and the theory, and since McClintock refused to release a monograph detailing all of her data, there was nothing for it but to declare that her ideas, while tantalizing, were not yet irrefutably founded.
As it turned out, her account of translocation’s role in gene expression was wrong, and the scientific community’s caution justified. Her theories, which were based on very clever analogical reasoning, were outstripped by the molecular interpretations that rose to prominence in the 1960s. And while she appreciated the work of the molecular geneticists, she refused to modify her own decades-old techniques to incorporate their methods. Instead, like Newton after Hooke squashed his work on optics, she retreated into her own world, seeking to prove, once and for all, the role that translocation played in gene expression. She found a new jumping gene, one that was even more complex in its manifestations than Ds and Ac, and spent the rest of her career in an increasingly Baroque attempt to hitch its vagaries to her old theoretical apparatus, and to map out the complete genetic history of maize. While interesting work, it seemed quaint and old-fashioned against the backdrop of the molecular biological revolution.
McClintock threatened to fade into the darkness completely when a series of discoveries about translocation put her old work back into the collective scientific memory. While none of these discoveries had McClintock’s work as its starting point, there was enough of a family resemblance that various of McClintock’s supporters thought it was high time to stage a revival. She received a steady stream of professional honors and monetary rewards, including a $60,000 annual stipend for life, and finally, in a cunningly worded Nobel nomination that focused on translocation while leaving out gene expression, she was at last awarded the Nobel in 1983.
Of course, she fumed that it was for the wrong thing, that she should be honored for her work on gene expression, and not on translocation. And with the cameras turned her way, she became for a while the darling of popular science, the 80 year old woman who told charming and profoundly untrue stories about her daring individualism in the face of a cold and ignorant genetic establishment.
In the end, we must forgive genius much. If she distorted her past, trod on others to magnify her own accomplishments, and was driven by suspicion to see malice where there was only good will, and if we maintained that story because it made for good copy with a timely political element, there is no doubt that she was, heart and soul, a great scientist. She never married, never allowed anybody to form so much as a close friendship with her, in order to maintain her absolute freedom to do as she wished at all times. Human closeness was a tie, a limitation, and her life was a struggle against any non-self-imposed responsibility. She lived for her maize and the problems it posed, and in pursuing those problems with single-minded determination for sixty years, she gave us a new idea of the gene’s interaction with its environment, and itself, that transitioned genetics from the Mendelian to the Molecular Age. Her selective memory might wound, but her self-sacrifice in pursuit of a scientific mystery was unique and profound, and if it harmed those who came too close, at least it gave them stories to tell, of scientific devotion and its costs.
FURTHER READING: Nathaniel C. Comfort’s The Tangled Field: Barbara McClintock’s Search for the Patterns of Genetic Control (2001) was the first book to lift the veil on the inconsistencies in the classic McClintock story as laid down in Evelyn Fox Keller’s 1983 biography A Feeling for the Organism. It’s a great, psychologically astute and thorough account of McClintock’s work that doesn’t spare the scientific details, hampered only by a thoroughly unnecessary first chapter about the theory of myths that can be safely skipped.