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DRIVE AND CURIOSITY What Fuels the Passion for Science
By ISTVAN HARGITTAI
Prometheus Books Copyright © 2011 Istvan Hargittai
All right reserved.
Chapter One "IGNORANT" GENIUS Double Helix
[On the human genome] A more important set of instruction books will never be found. James D. Watson
The discovery of the double-helix structure of DNA, the substance of heredity, has been likened in significance to that of Darwin's theory of evolution. The principal actors in this discovery were James D. Watson (1928–) and Francis Crick (1916–2004). Watson wanted to make a discovery; Crick wanted to understand what life was. Watson was a genius in bringing together the biological interest in DNA and the possibilities of structural chemistry. It helped that he was somewhat ignorant of the limitations of recent techniques. Had he been fully versed in them, he might not have dared to initiate the determination of the DNA structure. In hindsight, Watson realized that one could not be fully qualified in an area before embarking on a project that would culminate in a big leap in science. Some of Watson's traits were especially helpful in his achieving success in this discovery and in the rest of his career.
The last sentence of Watson and Crick's seminal paper about the double helix has become a celebrated quotation in the scientific literature: "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material." Today, this copying mechanism is commonly known, whereas at that time, in 1953, the thought was revolutionary. The double-helix structure of deoxyribonucleic acid (DNA) came within a decade after the discovery that DNA was the genetic material. When Oswald Avery and his two associates first pronounced in 1944 that the substance of heredity was DNA, few people noticed it and fewer yet were impacted by it. When, in 1952, the same pronouncement was made by Alfred Hershey and Martha Chase, and on the basis of less thorough experiments, it was enthusiastically accepted.
Watson and Crick's paper in the April 1953 issue of Nature was barely longer than one page, and it stressed that its authors merely suggested—rather than determined—a structure. However, the structure had important novel features. One was that DNA consisted of two helical chains, each coiling around the same axis but having opposite directions and thus complementing each other. The other novel feature was the manner in which the two helices were held together through hydrogen bonds between the purine and pyrimidine bases. The bases were joined in pairs, a single base from one helix paired with a single base from the other helix. The two bases in a pair lay side by side, and the complementary pair of a purine base was always a pyrimidine and vice versa.
The report in Nature was illustrated by a majestically simple sketch.
The structure was consistent with all the information available by then: X-ray crystallography, model building, and chemical analysis of DNA. The latter indicated equal amounts of the purine and pyrimidine bases, regardless of the organism for whose DNA the composition was determined.
The discovery of the double helix opened a new era in science with a direct route to the Human Genome Project four decades later, which mapped out the human genetic material. Its limitless benefits for medicine have not yet been fully fathomed. But in 1953, it was only a suggestion, and the painstaking work of many scientists was needed before the double helix became a certainty. For years, Watson had doubts about the structure, and it wasn't until the early 1970s that he had his first good night's sleep about the double helix. This was when he learned that reliable crystal structure determinations of DNA, finally, confirmed his and Crick's original suggestion.
Although there were uncertainties about the 1953 discovery, it catapulted the twenty-five-year-old Watson to a place at the top of twentieth-century science. He was an ambitious young man who himself wondered in retrospect about how he could "go beyond [his] ability and come out on top." He had had doubts all along as to whether he was bright enough, whether he would be able to solve a problem, and whether he would ever have original ideas. He was much sooner a genius than a great scientist. What happened to him was the fortunate confluence of many factors of being at the right place at the right time and, above all, being the right person for his self-ordained task. It certainly was not sheer luck, because it was his decision about what to do and where to continue his career when he faced competing options. But circumstances, too, favored what he decided doing. Peter Medawar, the Nobel laureate immunologist, remarked, "Lucky or not, Watson was a highly privileged young man." It was less through his background at home than the environments he eventually found himself in and utilized that made him privileged.
Watson came from a nonpracticing Christian family with mostly Irish and Scottish roots. His family lived on the south side of Chicago in a neighborhood that was not very well-to-do, but it was not impoverished either. His parents were determined to help their two children get a good education. Watson, in his blunt style, referred to this as having been brought up in a "quasi-Jewish" atmosphere in which books were more important than material goods.
He went to schools that were not especially remarkable, and he breezed through them at an accelerated pace. He was not a child prodigy, but he participated in quiz competitions with remarkable success. He left his mother's Catholic faith by the age of twelve and graduated from high school at the age of fifteen. He became a student of the University of Chicago under its maverick president, Robert Hutchins, who did not care much for specialized instruction and placed the Great Books as the focus of college instruction. This broad-based education proved beneficial to Watson. Already in his youth, he was more ambitious than most other students, and when he found a subject that interested him, he was keener to learn more about it than anybody else. He did not mind when he saw that others might be more talented than he was; on the contrary, he sought out their company. If he could learn from others, he did, and he did not find it beneath him to imitate others if he found them worthy of imitation.
It was during his undergraduate studies that Watson read Erwin Schrödinger's influential book What Is Life? It, more than anything, contributed to his transformation from a bird watcher/zoologist into a geneticist, which he remained for the rest of his life. By the age of nineteen, he had completed his college education and was considering graduate schools. The big-name schools were not kind to him, and perhaps there was nothing remarkable about him, except his eagerness, which may not have come through in his written application. He ended up at Indiana University in Bloomington in 1947, and as it turned out, Indiana was probably the best place for his further development. For a brief period, Bloomington offered top graduate education in modern biology. It had one Nobel laureate, Hermann J. Muller, and two future Nobel laureates—three, including Watson—in the same department at the same time.
Muller, who had been a professor at Indiana since 1945, was awarded the Nobel Prize for his studies of mutations by X-ray irradiation in 1946. His presence was a significant addition to the status of Indiana, but it impacted Watson less than the presence of Salvador Luria and others. Luria became Watson's doctoral mentor and would later win a Nobel Prize himself. Luria was a cofounder of Max Delbrück's school of phage study. The phage, short for bacteriophage, is the virus that attacks bacteria, and it was thought to be the best target for genetic research. Through Luria, Watson came under Delbrück's influence. He was not the only one, as Delbrück was a major influence on twentieth-century biology-not so much through his research or his ideas, which in most cases did not prove to be correct, but through his ability to challenge and inspire others. Schrödinger's What Is Life? was to a great extent an expression of Delbrück's views; Delbrück had transformed himself from a physicist into a biologist.
Despite being in the American Midwest, Indiana University provided Watson a diverse international environment with a strong European flavor. Muller was American with experience in Soviet Russia; Luria was a Jewish-Italian refugee who had escaped from fascist Italy; and another fellow student and future Nobel laureate, Renato Dulbecco, was a postwar immigrant from Italy.
Watson received a PhD degree at the age of twenty-two. His dissertation examined whether phages that had been inactivated by X-rays could be reactivated. His work was unremarkable, which was—paradoxically—a blessing in disguise, because he did not feel any pressure to continue his doctoral project. Nor did he feel pressure from others to achieve anything extraordinary—yet. This was a period for absorbing knowledge and information, which he did mainly from personal encounters. He had no inhibitions about walking up to anybody, even if that person was the greatest name in the field, if that person possessed the information he sought.
Upon earning his doctorate, Watson left for Denmark for postdoctoral studies. He was not happy with his first assignment, so he moved to another laboratory, but the project there did not satisfy him either. At that point, in the spring of 1951, he attended a meeting in Naples where he listened to Maurice Wilkins talk about the X-ray work on DNA at King's College in London. Watson glimpsed Wilkins's photograph of an X-ray diffraction pattern and decided "to move to an X-ray crystallographic lab devoted to macromolecules."
Watson's decision to switch to working on the structure of DNA was significant for at least two reasons. One was mundane: though the funding agency for his postdoctoral fellowship opposed his move, Watson disregarded its opposition and subsequently lost his fellowship. The other reason was that at this point he hardly knew anything about X-ray crystallography, let alone its application to biological macromolecules. This was the time when the giant of science, Linus Pauling, was struggling with his protein structure, ultimately leading to his discovery of alpha helix. This was also the time when the star-studded British team of W. Lawrence Bragg, Max Perutz, and John Kendrew had already published a plethora of erroneous models for protein structures (see chapter 4). Watson's ignorance must have contributed to his bold decision for his next career move, but it was also a sign of genius that he embarked on this route.
The use of the term ignorance here calls for a caveat. Watson was, of course, not ignorant in many aspects of the research skills needed to discover the structure of DNA. He was not ignorant in recognizing the importance of DNA and its structure. But he was not clear about the possibilities and limitations of structural chemistry and X-ray crystallography at the time. Even the experts found it very difficult to elucidate the structure of the supposedly easier target proteins (as is illustrated in chapter 4). There is nothing wrong in being ignorant in some aspects of the research one is about to conduct: if we were all well-versed in every aspect of our scientific research, it could hardly be called scientific research. Rita Levi-Montalcini might have had Jim Watson in mind and his initiating the work on the DNA structure when she stressed in her autobiography the importance of underestimating the "difficulties, which cause one to tackle problems that other, more critical and acute persons instead opt to avoid."
Once Watson had decided on his project, he had to choose the venue for it. There were not many places at the time where he could pursue his quest for the DNA structure. Pauling's laboratory at the California Institute of Technology (Caltech) was a possibility, and there were the British laboratories—King's College in London and the Cavendish Laboratory in Cambridge. Watson wanted to remain in Europe, and the next choice, between London and Cambridge, was not difficult, as both tradition and the name of W. Lawrence Bragg favored Cambridge. Wilkins, at King's College, may have lit the spark, but he did not attract Watson to join him. Looking back, the partnership with Francis Crick proved unsurpassable, but Watson could not have known that at the time.
The change from being on the periphery of science in Denmark (periphery, that is, in molecular biology, not, of course, in Niels Bohr's physics) to a world-class center in Cambridge was to Watson's liking. No sooner had he arrived than he teamed up with Francis Crick, his assigned roommate. Crick had a background in physics, was full of ideas, and had been engaged half-heartedly in an unexciting project. He was soon infected by Watson's vision, and they formed one of the most remarkable partnerships in science history.
It fell on Watson—as a proxy—to present the results from the experiments of Hershey and Chase in 1952, which reinforced Avery and his colleagues' findings that DNA was the substance of heredity. Also, in 1952, the biochemist Erwin Chargaff visited the Cavendish Laboratory and told Watson and Crick about his seminal experiments. Chargaff's discovery, which had direct relevance to Watson and Crick, was that the DNA bases adenine (a purine) and thymine (a pyrimidine) occurred in roughly equal amounts, and so did the bases guanine (a purine) and cytosine (a pyrimidine), regardless from which organism they had been extracted.
Scientists congregated in Cambridge and were anxious to share their latest findings with the researchers there, as if seeking their approval. Then yet another fortunate circumstance occurred: Linus Pauling had sent his son Peter to Cambridge, and Peter became friendly with Watson and Crick. The young Pauling was happy to carry the news from his father about progress at Caltech to his new friends. Also, Watson and Crick welcomed a new roommate at the Cavendish in the person of American chemist Jerry Donohue, who put them on the right track about the preferred chemical forms of the bases in DNA.
Watson knew hardly any chemistry at the time of the double-helix discovery, but he was always ready to learn what he needed to know. Much later, when he won the Nobel Prize and had to give a Nobel lecture, he chose an expressly chemical topic for his presentation, as if correcting the popular image about his ignorance of chemistry. Incidentally, Crick's Nobel lecture was not about the discovery of the double helix; it was about the genetic code. Only Wilkins spoke about the discovery of the double helix, in which he had the most minor role among the three in 1953.
Another scientist, Rosalind Franklin, had been more directly involved, but she had died by the time the Nobel award was granted for the double helix. Had she lived, she might or might not have been included. There is a three-person limit of awardees in any given category of the Nobel Prize, and in the early 1960s, Franklin's contribution had not been recognized to the extent it has since. Her negative portrayal in Watson's book The Double Helix a few years later would generate a large amount of research into her contributions, which has been followed by widespread appreciation for her work. She was a crystallographer at King's College, and a strong animosity developed between her and Wilkins. She and her student Raymond Gosling produced superb X-ray diffraction patterns of DNA samples. Wilkins showed the best of her diffraction plates to Watson without Franklin ever learning about this act of betrayal. Then, Max Perutz, while serving on a review committee evaluating the work at King's, informed Watson and Crick about the progress of Franklin's work, again without her knowledge. She was thirty-eight years old when she died of cancer in 1958. After Franklin's death, her former associate and future Nobel laureate Aaron Klug examined her lab journal and discovered that she was much closer to solving the DNA structure than had been believed. Her forced departure from King's College, however, terminated her work on the DNA structure before she could have completed it.
Excerpted from DRIVE AND CURIOSITY by ISTVAN HARGITTAI Copyright © 2011 by Istvan Hargittai. Excerpted by permission of Prometheus Books. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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