The following is reprinted, with the permission of Cold Spring Harbor Laboratory Press, from the book “Inspiring Science: Jim Watson and the Age of DNA.“
James Dewey Watson was admitted to the University of Chicago as a teenager, in 1943. Robert Hutchins, who had become President of the University in 1929, was an educational innovator who felt that the education provided by American high schools was inadequate or perhaps even worse. He developed a four-year program at Chicago that covered the last two years of high school and the first two years of college, thus bringing bright students into the university environment at the earliest possible age. It is not clear why Jim was among the chosen few. His performance at school was satisfactory but not stellar—he wrote later that his IQ was but a respectable 120. Jim had made his mark on a wider audience when he took part in the Quiz Kids radio show, but, as he tells it, he took part in the program primarily because the show’s producer lived next door. And it was not likely that his performance played a significant part in the University’s decision to accept him—he did not last long on the show, being beaten by a precocious nine-year-old girl. Perhaps those interviewing him caught some glimpse of his potential.
That potential was not altogether realized while he was at the University of Chicago. Rather like his high school days, Jim performed well, but he was not an outstanding student, getting mainly Bs. But it is clear that Jim’s experiences at Chicago shaped his general intellectual approach to the world. He wrote many years later that he learned to go to original sources, that theory was important, and that it was more important to know how to think than to memorize facts. Most striking to all who have come to know him in later years, one of his major personal traits appears to have developed in this period: “…crap was best called crap. Offending someone was always preferable to avoiding the truth… . But being honest about what is bad and false leads nowhere unless you hold equally strong values about what is right.”
Jim’s interests changed from bird watching to genetics while at Chicago. It was there that he read the newly published “What is Life?” (1945, The Macmillan Co.) by the theoretical physicist Erwin Schrödinger and decided that the gene was where the action was, or should be. His new-found enthusiasm for genetics was reinforced when he sat in on the course taught by Sewall Wright who, together with Ronald Fisher and J.B.S. Haldane, laid the foundations of population and evolutionary genetics.
So it was that when Jim, now 19 years old, graduated in the summer of 1947, his mind was on genes rather than birds. His first choice of graduate school was the Department of Biology at the California Institute of Technology, then a powerhouse of genetics. Thomas H. Morgan (Nobel Laureate, 1933) had been Professor of Biology from 1928 to 1945, and Morgan’s closest colleague, Alfred Sturtevant, was still active. George Beadle (Nobel Laureate, 1958) had taken over from Morgan, and Max Delbrück (Nobel Laureate, 1969) was carrying out phage research. But Caltech rejected Jim as did Harvard, so instead he followed the recommendation of his advisor and went to Indiana University at Bloomington.
As regards genetics, Indiana University might be thought of as the Caltech of the Midwest. The Department of Zoology had its genetics Nobel Laureate in Hermann Muller (1946) and the eminent protozoan geneticist Tracy Sonneborn, and Salvador Luria (Nobel Laureate, 1969) was in the Department of Bacteriology. Jim soon realized that Drosophila’s position as the genetic subject par excellence had faded and that Luria’s phages were much more promising for an ambitious young man seeking the gene. Luria accepted him as a graduate student and assigned a project examining the effects of mutation-inducing X-rays on phage. Renato Dulbecco (Nobel Laureate, 1975), a newly arrived postdoctoral fellow from Italy, was already carrying out similar work using ultraviolet light.
It was not long before Jim began moving in the highest circles of the newly emerging field of molecular genetics. Soon after Jim’s arrival, Max Delbrück visited Bloomington and Jim was thrilled to meet a legendary figure and was entranced by Delbrück’s personality. (Erwin Schrödinger had made Delbrück’s work on the gene the core of What Is Life?) In the summer of 1948, Luria took Jim and Dulbecco to Cold Spring Harbor where he met two other young men, Gunther Stent and Seymour Benzer. It was a formative experience for them all—Seymour Benzer wrote later that he changed from a solid-state physicist to a geneticist in the course of one morning.
By the summer of 1949, Jim had done sufficient work for his Ph.D. thesis, but he did not write it up until early in 1950. It was not, he felt, a particularly exciting piece of work, which Delbrück thought was just as well. As Jim describes it, Delbrück told him “…that I was lucky that I had not found anything as exciting as Dulbecco had, thereby being trapped in a rat race where people wanted you to solve everything immediately.” (Dulbecco had discovered photoreactivation of phage that had been inactivated by irradiation with ultraviolet light.) Jim defended his thesis—The Biological Properties of X-ray-inactivated Bacteriophage—on May 26, 1950; his examiners included Muller, Sonneborn, Luria, and the biochemist Irwin C. Gunsalus. The defense was successful and the examiners wrote to Dean Stith Thompson of the Indiana University Graduate School that Jim had passed his final exam. The degree was conferred officially on October 15, 1950, but by then Jim had moved to new pastures, far from the plains of Indiana.
Talking and Thinking
After a month of writing which he described as “torture,” Jim successfully defended his Ph.D thesis on “The Biological Properties of X-ray-inactivated Bacteriophage,” in late May, 1950. What to do next had been under discussion since the previous summer, which Jim had spent under the vigilant authority of Max Delbrück in Pasadena. From reading Erwin Schrödinger’s “What Is Life” (1945, The Macmillan Co.) as an undergraduate in Chicago, Jim had learned that genes were the keys to life, but his years in Indiana had convinced him that phage genetics could not provide a clarifying and elucidative physical description of genes. By 1950, then, Jim was convinced that his goal of understanding how genes function could not be achieved without knowing what genes are; i.e., what chemicals they are made of. Salvador Luria recognized this but disliked—Jim uses “abhorred”—chemists, and it was clear that Jim was not going to learn what genes were made of by staying any longer in Indiana. Jim had also acquired a taste for European manners from Luria and Delbrück and from the Europeans whom he had met at meetings and during the summers at Cold Spring Harbor:
“"Europe seemed the natural place since, in the Luria-Delbrück circle, the constant reference to their early lives left me with the unmistakable feeling that Europe’s slower paced traditions were more conducive to the production of first-rate ideas."”
Jim writes in the “The Double Helix” (1968, Atheneum) that there was the issue of what sort of chemistry he should learn. For most biologists who thought about these things, proteins were the strongest candidates for the material of heredity; their 20 amino acids led to a complexity of molecular structure that nucleic acids with a mere four nucleotides could not match. However, Luria and Delbrück believed that Oswald Avery’s work demonstrated that genes were made of nucleic acids and so it was to a nucleic acid chemist that Jim should go. There was one European biochemist who, in Luria’s eyes, was not entirely beyond the pale. Herman Kalckar from Copenhagen had first made a name working on oxidative phosphorylation, but when in New York in the 1940s, he became interested in nucleoside and nucleotide metabolism. Before returning to Copenhagen in 1946, Kalckar had been a student in the first Cold Spring Harbor Phage Course, taught by Delbrück and Luria in 1945. That Kalckar was a biochemist and showed some interest in biology was hopeful; perhaps, Jim thought, learning some biochemistry from Kalckar would not be so bad. Jim applied for a Merck Fellowship, worth $3000 per year, from the National Research Council.
Jim was not the only phage researcher to go to Kalckar’s laboratory. Gunther Stent who was a postdoctoral fellow with Delbrück was also going there to learn nucleic acid biochemistry. Unfortunately, things did not go well. Jim had met Kalckar in Chicago in November 1949 when it appeared that Kalckar was keen to study phage replication using isotopes and wanted phage researchers to bring a biological and genetical slant to his laboratory. However, any hope that Luria and Delbrück might have had that their protégé would advance an understanding of genetics through chemistry was, as Jim put it “…a complete flop. Herman [Kalckar] did not stimulate me in the slightest.”
Fortunately for Jim and Stent, Kalckar’s friend, Ole Maaløe, had just returned from Caltech where he had become a passionate convert to phage research. Maaløe worked at the State Serum Institute, and the two Americans began experiments there, Jim making his way by bicycle. The experiments with Maaløe were successful, and they produced a respectable, if not earth-shattering, paper. This success notwithstanding, the fact remained that Jim was not doing what he was supposed to be doing—learning biochemistry with Kalckar. He was forced to face this uncomfortable fact when the National Research Council asked him to outline his plans for the coming year. Not prepared to risk losing the Fellowship through confessing to a boredom with biochemistry, Jim asked to stay in the “stimulating” environment of Copenhagen for another year, thinking that he would ask permission to move after the renewal had been granted.
Kalckar was to spend April and May, 1950, at the Stazione Zoologica in Naples and suggested that Jim accompany him. This was an opportunity not to be missed—the experiments with Maaløe were complete and the prospect of sunshine of Naples was attractive after the long winter in Copenhagen.
Unfortunately, the weather was not what Jim expected, and biochemistry in Naples was no more exciting than in Copenhagen. “Sometimes,” Jim “daydreamed about discovering the secret of the gene…,” but not once did he have “…the faintest trace of a respectable idea.” The only thing to look forward to was a meeting on the structures of biological macromolecules that was to include some papers on nucleic acids. But most of these were “hot air,” except that of Maurice Wilkins, who was substituting for his boss, J.T. Randall, Director of the Biophysics Unit at King’s College, London. In his talk, Wilkins said that when living matter is prepared in crystal form, the arrangement of its molecules can be seen and may lead to an understanding of the gene, and then he showed an X-ray diffraction picture of DNA, recently taken by Raymond Gosling.
“"...Maurice’s X-ray diffraction picture of DNA...was flicked on the screen near the end of his talk. Maurice’s dry English form did not permit enthusiasm as he stated that the picture showed much more detail than previous pictures and could, in fact, be considered as arising from a crystalline substance. And when the structure of DNA was known, we might be in a better position to understand how genes work. Suddenly I was excited about chemistry."”
That the three-dimensional structure of any biologically interesting macromolecule had not yet been solved did not dampen Jim’s excitement. Jim engaged Wilkins in conversation but failed, even with the added attraction of Elizabeth, his sister, to arouse much enthusiasm in Wilkins for the idea that Jim should be his colleague in London.
But Jim was now a convert to X-ray crystallography, a transformation made stronger by the revelatory derivation of the á-helix motif in proteins by Linus Pauling. What attracted Jim was that Pauling had relied on model building, constrained by bond angles and other parameters of the atoms. Jim was convinced he could use the same method to solve the structure of DNA if only he could have access to X-ray crystallographic data. Three laboratories were possibilities. He quickly whittled these down to one by reasoning that Pauling at Caltech would not be interested in a “mathematically deficient biologist,” and as his interaction with Wilkins in Naples had been less than dazzling, it left only Max Perutz at the Cavendish Laboratory in Cambridge. Jim wrote to Luria who, by chance, met John Kendrew, also of the Cavendish and reported back to Jim that Kendrew was “…quite anxious to have somebody like you.” The Cambridge group was, Luria thought, “…sounder than Astbury and Bernal,” who were the other world leaders in X-ray crystallography.
Jim’s intended move into X-ray crystallography at Cambridge did not sit well with Paul Weiss, Chairman of the Merck Fellowship of the National Research Council. To add to the complications, Jim took up residence in Cambridge before contacting the NRC. Weiss was not pleased that Jim was changing both fields and countries, and perhaps in the back of his mind were his ambivalent memories of Jim as a student in his zoology course at Chicago. Weiss recollected many years later that Jim “was (or appeared to be) completely indifferent to anything that went on in class; he never took any notes and yet at the end of the course he came [out] on top of the class.” In January 1952, it seemed that Jim’s Fellowship was to be treated as a new application and would be granted, but by March, it was clear that this was not going to happen. It took hard work and string-pulling on Luria’s part to finesse the change. “As for Paul Weiss,” wrote Luria to Jim, “I incline to agree with your definition, although being less British than you are, I would call him a ‘damn son-of-a-bitch’ rather than a ‘bloody bastard’.”
It took only some six months for Jim to develop his life-long Anglophilia, for he rapidly fell under the spell of Cambridge, the most beautiful place he had ever seen: “From my first day in the lab I knew I would not leave Cambridge for a long time…” But it was not the beauty of the place that kept him “…for I had immediately discovered the fun of talking to Francis Crick.” The two of them, according to Crick, “…hit it off immediately…” and so the most famous partnership in biology—perhaps in all of science—was under way.
A Day in June
Jim Watson presented a paper on the double-helical structure of DNA at the 18th Cold Spring Harbor Symposium on “Viruses” in early June, 1953, six weeks after the publication of the Watson-Crick paper in Nature. In the days when journals were transported by sea, many at the meeting had not yet heard of the discovery; others knew the basic facts but little more; and a select few, particularly the members of the Phage Group, were well aware of the structure and had already partly embraced its biological implications. For all, however, the 1953 Cold Spring Harbor Symposium was the first opportunity to see the model.
Jim was potentially facing a fairly sceptical audience. Even as late as 1953, a good many people, in particular the biochemists, remained unconvinced that DNA was the genetic material. They were unwilling to acknowledge the importance of the key experiments preceding the Watson-Crick model, in particular the transformation experiments of Oswald Avery and his Rockefeller colleagues. The Waring blender experiment of Al Hershey and Martha Chase, much more to the liking of the biochemists and immediately convincing to the Phage Group, was in fact far from conclusive since the phage DNA associated with the infected cell was accompanied by 20% protein.
Max Delbrück, who had a major hand in the organization of the Symposium, had invited Jim to speak at the meeting soon after receiving Jim’s letter of March 12 containing a hand-drawn sketch of a base pair (see page 117). Max was excited by, and immediately accepting of, the model, although he could not see how bases located internally to the phosphate-sugar backbone could carry information; nor could he see how the two strands could unwind during replication. Nevertheless, with great enthusiasm, he set about proselytizing the Watson-Crick structure, both at Caltech and elsewhere.
So the members of Phage Group arrived at the Cold Spring Harbor Symposium fully primed to accept the model. But how would it be received by others?
In 1993, people who had attended the 1953 Symposium were asked to record their memories of the occasion and their impressions of Jim. A few people left the meeting unaware of the significance of what they had heard; others had vague recollections of Jim’s talk but could not recall details. Others had clear and crisp memories. Extracts from some of their letters are printed on the following pages, together with photographs of the Symposium participants.
Caltech, Cambridge and Harvard
In May, 1953, exactly three years after completing his lackluster Ph.D, Jim boarded a BOAC Constellation bound for New York, to tell the world about the structural basis of heredity. That year, the topic of the Cold Spring Harbor Symposium was “Viruses” and almost all of the phage group had assembled on the bucolic North Shore of Long Island. Milislav Demerec, the Director of the Biological Laboratory at Cold Spring Harbor, was the chief organizer of the Symposium. However, Jim’s invitation came from Max Delbrück, to whom Jim had written regularly during his time in Cambridge. His letter first describing the discovery of the double helix, complete with a sketch of the base pairs, had been sent to Delbrück on March 12, just three weeks after the model of DNA had been completed and a few days before the final version of the Watson and Crick paper was typed. Delbrück was convinced by the model and distributed copies to the participants at the Symposium of the three structural papers published in the April 25th issue of Nature (Watson and Crick, Nature 171: 737 ; Wilkins et al., Nature 171: 738 ; Franklin and Gosling, Nature 171: 740 ).
Although Jim’s presentation at the Symposium went well, there is a photograph of a rather pensive Watson sitting with Max Delbrück, Aaron Novick, and Leo Szilard (see page 115) on the porch of Blackford Hall. Jim was right to be thinking about his future; his time at Cambridge was coming to a close and he was due to continue research on phage with Delbrück at Caltech. But Cambridge had changed his scientific interests and he had achieved his goal of determining the structure of the genetic material. His next goal was to understand the process by which DNA directed protein synthesis, and this meant understanding the role of RNA. The strategy Jim intended to follow was the same as with DNA, that is, he expected that the function of RNA would be revealed by its structure.
Jim arrived in Pasadena in September, 1953. It was not an auspicious start as “the acrid stench” which greeted him when he left the plane “…grew even viler as the taxi ascended the Pasadena Freeway.” Things did not improve and by the end of September “…the full horror of being in Pasadena hit me.” Jim found himself at odds with the society and with the political outlook of the Caltech faculty, and at odds with the scientific interests of Delbrück’s group. Even as Jim and Francis were working away in Cambridge, Delbrück had abandoned phage genetics. His new love was the mold Phycomyces and his new hope was that an analysis of its phototropic responses would lead to insights into the interactions of organisms with their environment. Jim had lost his interest in phage in Kalckar’s laboratory, and his new way of thinking was much more appropriate for Linus Pauling’s empire. Not surprisingly, he did not want to be under the authority of the autocratic Pauling and, instead, remained in Delbrück’s group and formed a collaboration with Alex Rich in Pauling’s laboratory. Together they began X-ray diffraction studies of RNA.
Unfortunately, their pictures of RNA were at best fuzzy, and while different from those of DNA, the diffraction images of RNA had no clearly defined pattern that would lend itself to structural analysis. Although Rich and Watson published a couple of papers on their findings (Rich and Watson, Nature 173: 995–996 ; Rich and Watson, Proc. Natl. Acad. Sci. 40: 759–764 ), and Leslie Orgel, a British chemist, joined in modeling possible DNA-RNA interactions, it was a depressing time scientifically. Even entertaining discussions with George Gamow, a rather manic Russian-American physicist, about the genetic code and the formation of an organization called the RNA Tie Club were not enough to compensate for the lack of attractive young women on the Caltech campus. But a visit to Paul Doty in July, 1954, had already implanted in Jim’s mind the thought that Harvard might be the place to be, and not only for the girls he saw in Harvard Yard. Doty had high hopes that changes were on their way which would transform the old-fashioned Harvard Biology Department into something far more exciting. Further conversations with Doty and the evolutionary biologist Ernst Mayr led to a job seminar at Harvard in January, 1955, which was well-received. Two months later, Jim was offered an Assistant Professorship to begin on July 1, 1955. But, with a panache that many will recognize, Jim persuaded the Chairman of the Harvard Biology Department to grant him a one year leave of absence, so that he would spend the first year of his appointment in Cambridge on the other side of the Atlantic!
The year in Cambridge was devoted to ridding himself of the Los Angeles smog, if Jim’s account in “Genes, Girls, and Gamow” (2002, Knopf) is to be taken at face value. He seems to have spent much time on the continent and at college dinners in Cambridge, not to mention a visit to Naomi Mitchison’s grand house in Scotland, where Christa Mayr, Ernst Mayr’s daughter, revealed that their long-standing friendship could not be more than that. But it was not all play and Jim did two important pieces of work, often overlooked, in his premature sabbatical year. The first was an X-ray structural study of tobacco mosaic virus in which he showed that the arrangement of protein subunits on TMV was helical (Watson, Biochim. Biophys. Acta 13: 10–19 ). However, he was unable to calculate the number of subunits per turn of the helix—a problem that was eventually solved by Rosalind Franklin. The second study, a theoretical one with Crick, was on the assembly of small viruses (Crick and Watson, Nature 177: 473–475 ).
So it was, with his intellectual batteries recharged, that Jim left Cambridge, England, for Cambridge in the United States. He was now determined to work out the steps by which the information in DNA is turned into the order of amino acids along a protein, and he recognized that this had to be done experimentally—his laboratory was going to have to do biochemistry. Fortunately, while in Cambridge, Jim had met, and become friendly with, Alfred Tissières, a Swiss biochemist working on the constituents of the bacterial cell-free extracts used to study protein synthesis. Jim invited him to Harvard and so the Watson laboratory’s first projects dealt with the ribosome.
It is notable that Jim’s publication record was not stellar, averaging two papers per year while at Harvard. This did not reflect the output of the laboratory, nor Jim’s intellectual contributions to the work published by his graduate students and postdoctoral fellows. Rather, his name was included with the authors only when he felt that his contributions were substantive. (Later, some of his graduate students felt deprived of the honor of appearing on the same paper as a discoverer of the double helix.) But the publications that did bear his name were important and included papers on the ribosome and the discovery of messenger RNA.
It was in his Harvard period that Watson emerged as a writer in two quite distinct areas and made unique contributions in both. The first was in scientific autobiography, with the publication of “The Double Helix” in 1968 (Atheneum). It was highly controversial, with threats of law suits from Francis Crick and Maurice Wilkins, and Harvard University Press reneging on its commitment to publish the book. It was published and evoked responses ranging from outright condemnation to acclamation as a new and honest form of scientific autobiography (see “The Reviews” section of the Norton Critical edition of The Double Helix [1980; ed. Gunther S. Stent]). It became a best seller and was translated into many languages. The second was in textbook publishing. Jim found that there was no textbook that covered the topics in molecular biology and genetics that he was teaching to the Harvard undergraduates. He set out to correct this deficiency and with “Molecular Biology of the Gene” (1965, W.A. Benjamin) created a new style of textbook with declamatory subheadings and stylized diagrams (drawn by Keith Roberts). This felicitous style was rapidly adopted by textbooks of all genres and is Jim Watson’s enduring contribution to education.
Jim’s legacy to Harvard was equally great, although it was not appreciated as such by the Biology Department. Paul Doty, John Edsall, Konrad Bloch, and George Wald were leaders in a push to revitalize the Department and, as a first step, formed the Committee on Higher Degrees in Biochemistry. Watson was openly contemptuous of the fuddy-duddy Biology faculty and fought savagely for every new faculty position that came open. The dedicated myrmecologist E.O. Wilson found him “the most unpleasant human being I ever met,” and called him the “Caligula of Biology.” Nevertheless, Jim helped to attract a remarkable set of scientists—Matt Meselson, Wally Gilbert, Mark Ptashne, Guido Guidotti—to the Committee and eventually, in 1967 just before Jim became Director of Cold Spring Harbor Laboratory, the Committee was transformed into the Department of Biochemistry and Molecular Biology.
An Emotional Attachment
Bungtown Road, the main thoroughfare of Cold Spring Harbor Laboratory, runs from Route 25A through the Laboratory before making a sharp left-hand bend by Airslie, the Director’s house. It is a road walked each year by thousands of meetings participants as they make their way to the wine and cheese parties, held on Airslie’s lawn. Very few of the scientists can imagine, as they walk along the broad black-topped road with its tidy borders, mowed grass, and manicured trees, what a wild, unkempt, but still beautiful place it was when Jim Watson first came to Cold Spring Harbor in 1947. Twenty years later, the grounds were still “…disorderly and delightful with cover, vibrant with birds and animals. Bungtown Road…in early spring…[became] a narrow culvert whose flowered walls were a mass of head-high brambles and rhododendrons.” It is not surprising, then, that Jim fell immediately under the spell of the beautiful location. He found equal satisfaction in the reductionist style of doing science proselytized by Max Delbrück, Salvador Luria, Al Hershey, and the Phage Group. However, he had to wait 20 years for an opportunity to join these esthetic satisfactions together by promoting beautiful science in an even more beautiful place.
In 1947, two separate institutions shared the southwest shore of Cold Spring Harbor: the Biological Laboratory and the Department of Genetics of the Carnegie Institution of Washington. The former had been founded in 1890 as a summer school for biology teachers while the latter was established in 1904 and was originally called the Station for Experimental Evolution. It was the Biological Laboratory that was host to the annual Symposia on Quantitative Biology and to the summer courses, of which the Phage Course was one. The two institutions were independent of each other, although for much of the period between 1904 and 1964, they had the same Directors. Even so, the two institutions were careful to remain financially independent of each other. The result was predictable; while the Department of Genetics flourished under the wing of the Carnegie Institution, the Biological Laboratory led a hand-to-mouth existence and for many years existed on the charity of a local group, the Long Island Biological Association.
At the time of Jim’s first visit, Milislav Demerec, originally a Drosophila geneticist who had moved to bacterial genetics, was the Director of both institutions. On Demerec’s retirement in 1960, separate Directors were appointed, but a crisis soon arose. Through the latter part of Demerec’s tenure, the finances of the Biological Laboratory had worsened, and in 1962, there was a potential catastrophe when the Carnegie Institution declared that it was withdrawing its support for the Department of Genetics, then housing Barbara McClintock and Al Hershey. On hearing that the proposed solution was to amalgamate the two institutions to create the Cold Spring Harbor Laboratory, the two Directors promptly decided to resign or retire. John Cairns stepped into the breach, and over the next five years, against great odds and at great personal cost, he brought the new Laboratory on to a more even keel. In 1966, he had done all he could and tendered his resignation.
Jim had visited Cold Spring Harbor almost every year since 1947 and joined the Board of Trustees in 1965. The full story of how he came to be Director is told in the first two contributions to this section, although these accounts differ markedly from each other. Certainly Jim’s love of the place was a key factor, but so was his desire to start a major new project focusing on cancer research. The key to unlocking the cellular mechanisms underlying cancer was, he thought, to be found in tumor viruses. These viruses had very small numbers of genes—an important fact in the days before gene cloning and DNA sequencing—yet could convert normal cells into cancer cells. Joe Sambrook was recruited from Renato Dulbecco’s laboratory and he formed the nucleus of the Tumor Virus Group working on viruses such as SV40, polyomavirus, and adenovirus, while other groups, for example, in cell biology, studied the cellular process of transformation. This was a very vigorous area of research that sparked the development of methods to map the patterns of gene expression of DNA tumor viruses, to construct genetic and physical maps of the viruses, and, in 1977, to the Nobel Prize-winning discovery of RNA splicing.
By then, Jim had already set his sights on other areas of research. By the late 1960s, he was seeking funds to promote a Cold Spring Harbor program in neuroscience, and in 1970, the Alfred P. Sloan Foundation made a substantial grant to support summer courses in neurobiology. Year-round neuroscience research began in 1978 with a project to develop monoclonal antibodies against neurons in the leech brain. However, the neurobiology group broke up in 1984, and there was a hiatus of some seven years until the Beckman Neuroscience Center opened and a new era of research began, focusing on the genetic underpinnings of learning and memory.
Jim expanded science at Cold Spring Harbor in other directions too. He enthusiastically adopted Ira Herskowitz’s suggestion that yeast genetics become part of the Laboratory’s research portfolio. Herskowitz had phoned Jim to tell him of the exciting work being done on the cassette model for mating-type interconversion and urged him to make use of the empty space in Davenport (later Delbrück) laboratory. That the space was used for courses during the summer months was not a deterrent, and within a short while, the first mating-type gene was cloned. Delbrück laboratory was home also to a fledgling Plant Molecular Biology Group which, working on the molecular analysis of transposable elements in maize, had close intellectual ties to the yeast research. Jim pursued funding for plant research and was eventually successful in attracting a large grant from Pioneer Hi-Bred International to use recombinant DNA techniques to modify maize.
If Jim’s intellectual acumen was rapidly expanding and diversifying science at the Laboratory, nowhere was his hand more physically evident than in the buildings and grounds. While some, including Barbara McClintock, bemoaned the loss of the overgrown shrubbery and the appearance of well-kept lawns that attracted Canadian geese, Jim argued that a physically attractive institute was essential to maintain the sanity of the scientists and to stimulate the generosity of potential benefactors. The former would enjoy the beauty while the latter would feel that here was a well-established, prosperous institute that would do a good job with their money. Liz, Jim’s wife, played a key role in ensuring that the older buildings were restored authentically and elegantly and painted in the colors appropriate for their period. The campus changed even more drastically through an extraordinary building program that began with an addition to James laboratory and continued with Grace Auditorium (1986) and the Dolan Hall and Beckman Neuroscience buildings (1989).
Between 1968 and 1993, when Watson stepped down as Director and became President of the Laboratory, the annual income rose from $633,000 to $44,800,000, and by all measures, the Laboratory had become one of the world’s great research institutions.
Managing the Genome
The 1986 Cold Spring Harbor Symposium was titled, with true Watsonian flourish, “The Molecular Biology of Homo sapiens” at a time when many would have thought that the subject hardly existed, let alone there being enough hard facts to sustain a five-day meeting. However, Jim was certainly correct when he wrote of “…our newfound ability to study ourselves at the molecular level,” and much of the meeting was occupied with the molecular studies of human DNA through mapping, cloning, and sequencing of genes.
None of these were easy to do at that time. Finding human disease genes by using restriction-fragment-length polymorphisms as genetic markers had had its first successes only two years earlier and required heroic efforts in both finding families and carrying out the subsequent linkage analyses. Moving from a mapped position to a cloned gene was no less heroic, and no one had yet succeeded, although hunters of the genes for cystic fibrosis, Huntington’s disease, and Duchenne muscular dystrophy were fast closing in on their targets. And DNA sequencing, although routinely using Sanger or Maxam-Gilbert methods, was limited to fairly short tracts. It still required a major commitment of resources and chutzpah on the part of an investigator to tackle sequences longer than a few kilobases. To think of tackling something of the size and complexity of the human genome seemed both foolhardy and harebrained. By the end of the Symposium, this had changed. Jim had organized a “consciousness-raising” discussion about what large-scale DNA sequencing might achieve, and participants left the meeting with the idea that sequencing of genomes might be possible and that there were some people who planned to do it!
Jim was not the first or even an early proponent of sequencing the human genome. The first discussions had taken place at the University of Santa Cruz at a time when Robert Sinsheimer had hoped that a Human Genome Project could capture funding intended originally for a new telescope in Hawaii. He convened a small meeting attended by Wally Gilbert, David Botstein, Lee Hood, Sydney Brenner, John Sulston, Bob Waterston, and Ron Davis—people whose names were to reappear frequently throughout the long saga of establishing the Human Genome Project. The meeting concluded that a Human Genome Project was not only desirable, but doable. Sinsheimer’s estimate of the cost was $5 million (1984 dollars) per year for up to 20 years. But, even at this bargain price, a Human Genome Project proved unattractive to the donor who was interested in stars rather than genes. However, in the nick of time, an unlikely angel appeared on the scene—the United States Department of Energy (DOE).
The DOE had a long-standing interest in human genetics because of its need to determine the mutagenic effects of radiation on humans. Believing that sequencing genomic DNA might be a way to do this, Charles DeLisi, then head of the Office of Health and Environmental Research at DOE, convened a series of meetings in 1986 that led the DOE to reassign some 1987 funding to a genome project.
Meanwhile, the National Institutes of Health (NIH), the federal institute that would have seemed the natural home for a Human Genome Project, seemed oblivious to the discussions at Santa Cruz and DOE, in part because these early meetings had been restricted to a small coterie of scientists. In September, 1985, Renato Dulbecco was the keynote speaker at the dedication of a new laboratory at Cold Spring Harbor and used the occasion to argue that the best approach to cancer was to determine all the genes involved by sequencing the human genome. His address reached a far greater audience when it was published as a perspective in Science in March, 1986.
At the last moment, Jim inserted a discussion on sequencing the human genome, led by Paul Berg and Walter Gilbert, into the 1986 Symposium program on Saturday, June 3. The auditorium was packed as Berg outlined what was meant by a Human Genome Project, and it was filled with drama as Gilbert began to write numbers on the board, showing that such a project would cost $3.5 billion. There was a heated exchange as the discussion was opened to the audience. Many argued that the money could come only by cutting investigator-initiated grants, that the work was too boring, that it wasn’t science, and that no one would want the results. There were other, less-emotive arguments advanced in the following months. Bob Weinberg, for example, wanted to know how the sequence was to be interpreted. If he were to be offered the 200,000-base sequence of the retinoblastoma gene, he could not imagine “…what help this would prove in solving the important problems surrounding the function of this gene and its encoded protein.”
Despite the largely negative response, the idea of a Human Genome Project had taken hold and Jim, Berg, and Gilbert soon began to urge Jim Wyngaarden, the Director of NIH, to take up the cause. As Wyngaarden describes in his contribution to this book, he needed little encouragement and soon arranged for a series of reports that recommended setting up a Human Genome Project under the NIH. By the summer of 1988, all that was needed was to find a project director. The issue came up during a meeting held by the Office of Technology Assessment when Watson commented that “I instinctively believe that one person should be in charge of it who understands the scientific issues and who is not chosen purely to be an administrator.” A little later, Watson asked John Sulston whether, from his experience mapping C. elegans, he believed that the Genome Project required one person in charge, who would “…live and die for the thing.”
Sulston: “It seems to me rather appalling…He’s [the director of the project] adminsitrating (sic) this huge empire. Do you really want to see that?”
Watson: “I think someone has got to do it.”
Sulston: “You would like to do it.”
Watson: “Well, I couldn’t think of a job I’d like less (laughter)….But I just have a feeling that someone has to keep track of the whole thing over a long period of time with a certain degree of intensity…”
These early protests not withstanding, Jim’s strong statements that the project had to be run by a scientist and not a bureaucrat left him with few options when Wyngaarden offered him the job. The doubts expressed by E.O. Wilson when Watson became Director of Cold Spring Harbor Laboratory had long been laid to rest by Watson’s subsequent success, but becoming a federal official was rather different. It was immediately clear that NIH had never had a Director like Watson, who, used to being a benevolent autocrat in his own domain, insisted on impressing his goals and ethos on the Human Genome Project. His declarations on the societal implications of the Human Genome Project, his extension of the project to include other organisms, and his stipulation that the sequencing data be freely available irrevocably determined the style of the project.
Jim continued to deploy that “certain degree of intensity” whenever he felt that the project was under attack. At one meeting where two critics—Bernard Davies and Don Brown—spoke, Watson told Brown to stop being “mystical” about traditional investigator-initiated projects funded by RO1 grants. When Brown responded that it wasn’t appropriate for “…someone in the Genome Project to demean RO1s,” Jim replied in characteristic fashion: “That is pure crap.”
It was, perhaps, inevitable that Jim’s determination to call a spade a spade eventually led to him falling afoul of bureaucratic conventions. His insistence that the human genome should be in the public domain, coupled with his determination that the project should go ahead with the best people, led to a confrontation with an entrepreneur, Fred Bourke, and Bernadine Healy, director of NIH and Jim’s boss. Jim Wyngaarden and Robert Cook-Deegan describe the episode more fully in their contributions to this book, but the end result was that Jim resigned in April, 1992.
Although Jim’s tenure ended in acrimony, there is no doubt that Wyngaarden made exactly the right choice in taking him on. Although there were many other scientists who could have taken on the task, none had the panache, political clout, and commitment to see the job through without the reward of personal aggrandizement. Jim had always believed that structure was the best and perhaps only key to understanding how things work. He saw that the Human Genome Project would enlighten the entire sweep of human biology and behavior in the same way that his discovery of the DNA structure had illuminated the inner workings of single cells. As Jim put it in 1989 “How can we not do it? We used to think our fate was in our stars. Now we know, in large measure, our fate is in our genes.”
Communicating the Science
It is unlikely that those who listened to Jim’s first student lecture—given at Caltech where he moved after Cambridge—would have held out much hope that he would become a great educator. By his own admission, it was “dreadful,” but he used its failure to think of ways to improve the “coherence if not actual zing” of the remaining lectures in the series. Nevertheless, Jim’s style of presentation does not seem to have been any better by the time he had his job seminar at Harvard in January, 1955. It cannot have been an easy talk, reporting as he was on the highly speculative scheme, devised by Leslie Orgel and himself, in which a single-stranded RNA molecule was synthesized on a double-stranded DNA template. This involved some rather improbable chemistry, with RNA being synthesized in an anhydride form. Fortunately, the Biology Department had few chemists to pose awkward questions. However, Jim spoke in a “…low voice that only occasionally made it to the back of the lecture hall.” The chairman of the search committee, John R. Raper, an authority on sexuality in fungi, was sufficiently concerned to write to several scientists asking what they thought of Jim’s lecturing skills. Fritz Lipmann’s response was succinct and to the effect that if Jim had interesting things to say, the students would come to hear him.
This was indeed the case. The Harvard student body published an annual review of lecturers and, despite repeated references to the need for Harvard to provide him with a microphone, Jim’s lectures were highly rated, even before the added luster of his 1962 Nobel Prize. Lecturing was made more difficult because there was no textbook covering a young field that had not yet moved beyond the research laboratory. Jim resolved to write the textbook he wanted and in the style he believed was needed. As Keith Roberts describes in his essay in this section, the book, “Molecular Biology of the Gene,” was unlike any previous textbook in biology in its style of writing and design. Not content with giving “facts,” Jim conveyed the excitement of the new field, intent on converting students to think about biology in molecular terms. It was a sensation, leading to a major revision of the style of science textbooks.
The science textbook was not the only genre that Jim revolutionized. The phrase “scientific autobiography” on a dust jacket has been known to put readers to sleep even before opening the book; the autobiographies were often self-congratulatory and written to portray the scientist-author in the manner of Arrowsmith or Gottlieb, seekers of natural truths, untainted by the whims and wiles of ordinary people. The Double Helix changed that view of scientists forever. It covered just the period of the discovery, and Jim wrote as though he was living the experience and not in the manner expected of a Harvard professor. Controversial even before publication — the principal players in the story threatened to sue and Harvard’s President Nathan Pusey forced Harvard Press to drop the book — “The Double Helix” is a fast-moving, opinionated memoir in a style more to be expected of a roman-à-clef than an autobiography. Hugely successful, never out of print and translated into 22 languages, it continues to arouse strong passions, especially for Jim’s characterization of Rosalind Franklin. Brenda Maddox’s recent biography of Franklin gives a comprehensive, balanced, and readable account of Franklin’s life and work.
Jim’s enthusiasm for books continued and has been a major part of his intellectual life. He went on to co-author two more very successful textbooks, Molecular Biology of the Cell and Recombinant DNA, the latter opening with the undeniable statement that “There is no substance as important as DNA.” And in The DNA Story, he and John Tooze collected materials relating to the recombinant DNA debates of the 1970s that showed with devastating clarity how much the debate was driven by hysteria and politics.
Jim’s move to Cold Spring Harbor provided him with new opportunities, for now he had his own meetings program and publishing house. He soon expanded the number of meetings and courses held each year. This was regarded as a mixed blessing by the year-round staff who, for many years, had to relinquish their laboratories for three months to accommodate the summer courses. Charles Robertson’s gift of his Banbury estate in 1976 enabled Jim to develop it as a conference center for small discussion meetings. And Jim provided the means and support for David Micklos to create the DNA Learning Center, where students as young as eighth graders (14 years of age) learn genetics and carry out laboratory experiments.
Just as Jim built upon the existing meetings program at Cold Spring Harbor, so he developed a vigorous publication program on the financial base provided by the sale of the annual Symposium volumes. Jim used the meetings as the sources for books, often on topics that no commercial publisher would consider but for which there was a scientific need. Many were published in the Cold Spring Harbor Monograph series as definitive accounts of the current state of an area of research. In large part, the financial freedom to cover recondite topics came from sales of laboratory manuals, the first of which was Jeffrey Miller’s Experiments in Molecular Genetics. Its successors have become the most respected and widely used source of technical information in molecular biology.
The Laboratory was slow to join the rush to publish new scientific journals, chiefly because of possible conflicts of interest and accusations of favoritism. But after much debate, Genes & Development was launched in 1987. By any objective criteria, G&D has been a success. It attracts a steady flow of good papers, ranks among the most highly cited journals in biology, has a reputation for editorial probity, and, to everyone’s relief, has made a return on its investment in the past few years. Other journals have followed.
In 1995, Jim articulated his vision of a graduate school for the Laboratory. It would be highly selective, offer a unique curriculum designed to train communicators of science not just investigators, and graduate its students in four years rather than the average seven. The Watson School of Biological Sciences enrolled its first class in October 1999 and awarded its first Ph.D. in May, 2003.
Many think that Jim’s Cold Spring Harbor has made as great a world-wide impact through its education programs as through its science.
© 2003 Cold Spring Harbor Laboratory Press. Reprinted with permission.