Nathaniel Comfort

From controlling elements to transposons: Barbara McClintock and the Nobel Prize

McClintock to win the Nobel Prize? In the mid-1940s, McClintock discovered genetic transposition in maize. She published her results over several years and, in 1951, gave a famous presentation at the Cold Spring Harbor Symposium (Figs 1,2), yet it took until 1983 for her to win a Nobel Prize. The delay is widely attributed to a combination of gender bias and gendered science. McClintock’s results were not accepted, the story goes, because women in science are marginalized, because the idea of transposition was too far-fetched and because her scientific style was too intuitive, too holistic and too feminine to be believed. Most scientists I know detest this story. McClintock loathed it too. She was not scorned, biologists insist, because she was a woman nor for any other reason, she was misunderstood. The intricacy of her experiments, combined with her eccentric, elliptical style of presentation, made her science difficult to understand. Furthermore, her findings were limited to maize, and their significance was not clear until the late 1960s and early 1970s, when transposition was found to be widespread in Nature and of general importance. The Nobel Prize was not late; McClintock was early, ahead of her time. Both of these stories are myths. Both assume that, had things gone differently, the transposition prize might have been awarded sooner. Both neglect the fact that McClintock did not win the prize for what she thought was most important in her work. A closer look at how McClintock came to receive the Nobel Prize reveals that she won only after her major contribution to science was recast to fit better with the current understanding of the genome. The McClintock papers in the Nobel archive will not be accessible until 2033. However, nominators retain the rights to their nominations. Several scientists have generously made their nominations and stories of McClintock available to me; other evidence I have gleaned from interviews and archived correspondence. From these and other materials, we can reconstruct the events leading up to the 1983 prize†. What are known today as transposable elements, McClintock called ‘controlling elements’. During the years 1945–1946, at the Carnegie Dept of Genetics, Cold Spring Harbor, McClintock discovered a pair of genetic loci in maize that seemed to trigger spontaneous and reversible mutations in what had been ordinary, stable alleles. In the language of the day, they made stable alleles into ‘mutable’ ones. The resulting patterns in the maize leaves and kernels indicated systematic alterations in mutation rates. McClintock concluded that she had disrupted the cell’s mechanism for regulating gene activity. By early 1948, difficulties in mapping the loci led her to conclude that they were not, in fact, loci – sites on the chromosomes – but chromosomal elements that moved from place to place. It soon became clear that these new elements were capable of exerting a wide range of actions upon the genes. By 1950, McClintock had developed a theory about how controlling elements orchestrated development and differentiation of the organism. The key to her theory was coordinated transposition. In each nucleus, platoons of controlling elements would transpose in concert, inhibiting and modulating the effects of the genes to execute the developmental program of the cell. Transposition was never in doubt. Other geneticists quickly confirmed transposition in maize, but, at the time, few considered it McClintock’s major claim. Although McClintock was indeed difficult to understand, all her peers grasped that her real point was control. Yet, to most scientists, transposition seemed a random process. By ~1953, once McClintock had thoroughly documented the fact of transposition, she worked hard to prevent her controlling elements from moving because their effects were difficult to study when they jumped around. She never had any inclination to pursue the biochemistry of transposition. Current understanding of how gene activity is regulated, of course, springs from the operon, François Jacob and Jacques Monod’s 1960 model of a block of structural genes under the control of an adjacent set of regulatory genes (Fig. 3) TRENDS in Genetics Vol.17 No.8 August 2001

The Real Point is Control: The Reception of Barbara McClintock's Controlling Elements

In the standard narrative of her life, Barbara McClintock discovered genetic transposition in the 1940s but no one believed her. She was ignored until molecular biologists of the 1970s “rediscovered” transposition and vindicated her heretical discovery. New archival documents, as well as interviews and close reading of published papers, belie this narrative. Transposition was accepted immediately by both maize and bacterial geneticists. Maize geneticists confirmed it repeatedly in the early 1950s and by the late 1950s it was considered a classic discovery. But for McClintock, movable elements were part of an elaborate system of genetic control that she hypothesized to explain development and differentiation. This theory was highly speculative and was not widely accepted, even by those who had discovered transposition independently. When Jacob and Monod presented their alternative model for gene regulation, the operon, her controller argument was discarded as incorrect. Transposition, however, was soon discovered in microorganisms and by the late 1970s was recognized as a phenomenon of biomedical importance. For McClintock, the award of the 1983 Nobel Prize to her for the discovery of movable genetic elements, long treated as a legitimation, may well have been bittersweet. This new look at McClintocks experiments and theory has implications for the intellectual history of biology, the social history of American genetics, and McClintocks role in the historiography of women in science.

Genome editing: That's the way the CRISPR crumbles

Nathaniel Comfort finds heroism but little nuance in Jennifer Doudnas account of her co-discovery.

When Your Sources Talk Back: Toward a Multimodal Approach to Scientific Biography

Interviewing offers the biographer unique opportunities for gathering data. I offer three examples. The emphatic bacterial geneticist Norton Zinder confronted me with an interpretation of Barbara McClintock’s science that was as surprising as it proved to be robust. The relaxed setting of the human geneticist Walter Nance’s rural summer home contributed to an unusually improvisational oral history that produced insights into his experimental and thinking style. And “embedding” myself with the biochemical geneticist Charles Scriver in his home, workplace, and city enabled me to experience the social networks that drive the practical events of his career, which in turn helped me explain the theoretical basis of his science. Face-to-face interaction and multisensory experience will shape each biographer’s experience uniquely. Recent developments in sensory physiology suggest that the experience of integrating sense data encourages different patterns of observation and reflection. It is reasonable, then, to think that biography based on face-to-face interviews will, for a given author, have a different character than one based entirely on documents. I reflect on how interviewing shapes my own writing and I encourage the reader to do the same.

Zelig: Francis Galton's Reputation in Biography

Francis Galton (1822–1911) is the Zelig of biomedicine. Or rather, his reputation is. Like the title character in the Woody Allen movie, Galton—the father of eugenics, of biometry, of the nature–nurture debate, of twin studies and pedigree analysis, of fingerprinting, and of reading underwater—morphs with each scene. Although the real Galton was in fact an original thinker with real virtues and flaws, his reputation shifts kaleidoscopically, reflecting the predispositions, inclinations, and prejudices of his biographers. I mean more than that he receives different interpretations—that much is true of everyone honored with multiple biographies. But all of Darwin’s biographers, say, agree on some basics, despite their wide range of interpretation: his theory was clever; he was kind to those he cared about; many people, over many years, have thought him important. Galton has enjoyed no such consistency. Depending on whom one reads, he can appear a genius or a fool, a confident optimist or a bumbling neurotic, a towering scientific giant or a notorious intellectual dwarf.

Nature still battles nurture in the haunting world of social genomics

Nathaniel Comfort lauds a sociologist’s study of the problems built into genetic research. Nathaniel Comfort lauds a sociologist’s study of the problems built into genomics. Man kneels next to the Brooks Life Science Systems A3+ SmaRTStore, which stores and retrieves DNA samples.

Genetics: Dawkins, redux

Nathaniel Comfort takes issue with the second instalment of the evolutionary biologists autobiography.

Genetic determinism rides again

Nathaniel Comfort questions a psychologist’s troubling claims about genes and behaviour.Nathaniel Comfort questions a psychologist’s troubling claims about genes and behaviour.

Playing to win

PR O BA BL E BO O K S Science is a gamble. Publication, applying for grants, student admissions and corporate relationships all involve high-stakes bets, a mixture of skill and luck, and often a bit of bluffing. Which game is science most like? It’s not a slot machine, mindlessly addictive. In dark moments it may seem like roulette, with its powerful house advantage and long odds. Sometimes it’s a horse race, when one thoroughbred laboratory noses out another in isolating a long-sought gene or subatomic particle. For Albert Sjoerdsma, sometimes called the father of clinical pharmacology, science was most like craps. Craps, an intricate dice game that can involve many players and interweaving rounds of betting, is a thinking person’s pastime. Winning depends on an understanding of probability and being able to weigh complex constellations of risks and payouts. In Starting with Serotonin, Sjoerdsma’s biographer daughter Ann Sjoerdsma argues that craps was her father’s favourite game of chance — and the key theme in his scientific life. Albert Sjoerdsma came to the table with a modest stack of chips. Born in 1924 and raised near Chicago in Illinois, he grew up with little money or social sophistication, but with a first-class brain and a mountain of confidence. He was a rough-and-tumble child, more likely to be found playing sports or getting into mischief than curled up with his nose in a book. Yet his grades were nearly perfect, and he was accepted at the University of Chicago under president Robert Hutchins, whose innovative programmes helped to train some of the best minds of the late twentieth century. Sjoerdsma was cocky and sometimes disrespectful, especially when faced with arbitrary displays of power. His daughter describes him as a maverick, a clichéd but apt term. Starting With Serotonin: How a High-Rolling Father of Drug Discovery Repeatedly Beat the Odds by Ann G. Sjoerdsma Improbable Books: 2008. 640 pp.

The Birth of Modern Science: Rossi, Paolo: Oxford: Blackwell, 276 pp., Publication Date: May 2001

27.50 Rather than fold with a bachelor’s degree, Sjoerdsma stayed in the game, taking an MD and a PhD at Chicago. He then went east to Bethesda, Maryland, where he joined the National Institutes of Health (NIH) in 1951. After two years of residency at the Public Health Service’s Marine Hospital in Baltimore, Sjoerdsma landed a position at the National Heart Institute back in Bethesda. There, he formed a team that became known locally as the “wild bunch”, a group of brilliant, hardworking and hard-playing researchers. Sjoerdsma began exploring ways of reducing high blood pressure, leading to his investigation of the then recently discovered neurotransmitter serotonin. His analysis of its effects on different organ systems and metabolic pathways led him into a strongly applied style of pharmacology, in which he largely eschewed lab-based studies in favour of whole patients, and focused on bridging the gap between laboratory science and clinical medicine. He was a pioneer in the development of monoamine oxidase inhibitors as antidepressants, such as iproniazid, originally developed as an anti-tuberculosis drug. With colleague Sidney Udenfriend, he found that monoamine oxidase was a major pathway for serotonin in both mice and humans, and that inhibitors such as iproniazid raised blood serotonin levels. This established the physiological basis of the antidepressant action of these drugs. Sjoerdsma’s 20 years at NIH coincided with the ‘golden age’ of its intramural research, an era of Nobel prizes, headline-grabbing breakthroughs and major contributions to science. In 1972, he parlayed his successes as a bench scientist into a job as director of a new research centre in Strasbourg, France, set up by the pharmaceutical company Richardson– Merrell. His blunt, incisive intellectual and administrative style was polarizing in genteel Europe. He won many devoted friends and colleagues — and lost some, too. But there was no arguing with his successes. The biggest was terfenadine (Seldane), the first antihistamine that did not cause drowsiness. Developed in the 1970s, it was a blockbuster drug until heart arrhythmias surfaced in some users. Sjoerdsma remained with Richardson– Merrell through the 1980s, until a merger moved the company to Kansas City, Kansas, and gave the management over to a group of businessmen who knew everything about marketing and nothing about science. Sjoerdsma felt the house had changed the rules mid-game. Stripped of his title, and eventually even of his parking space, he felt as if he had lost the shirt off his back. Ann Sjoerdsma’s dual role, as daughter and as professional journalist, creates both windows and blind spots as she examines her father’s life. She explains the science and integrates it into Sjoerdsma’s career choices and decisions. She draws on interviews she conducted with her father and with his friends and colleagues. The numerous quotations from Sjoerdsma himself, set in italics and without attribution, make it seem as though he is looking over his daughter’s shoulder, adding a story or colourful detail, or murmuring assent. His assent is crucial, for her primary concern is to tell her father’s version of his story. In Sjoerdsma’s world, the US Food and Drug Administration is a stifling regulatory monster, and it is drugs, more than patients, that live or die. Sometimes he comes across as callous, whereas at other times he is a champion of humanitarian medicine, such as when he developed a therapy for African sleeping sickness. The author rarely questions such views or their motives. Also, she never inquires deeply into Sjoerdsma’s emotions. Particularly striking is the minor role of family in this life portrait. The other Sjoerdsmas feature from time to time, but we never get much sense of how Albert treated them or how the information necessary to decide whether an object should be taken into the body or expelled. Many years ago, when working with Gilbert at the Monell Chemical Senses Center in Philadelphia, I recognized his way with words as well as with scientific research. What the Nose Knows melds the academic and business worlds of smell into an entertaining and illuminating rumination on this almost magical sense that, even with a Nobel Prize to its credit, still holds many mysteries. ■ Gary Beauchamp is director of the Monell Chemical Senses Center, 3500 Market Street, Philadelphia 19104, Pennsylvania, USA. With Stuart Firestein and David V. Smith, he is co-editor of Olfaction and Taste. e-mail: beauchamp@monell.org