THE

    DOUBLE HELIX

    A Personal Account of the Discovery

    of the Structure of DNA

    by James D. Watson

    Foreword by Sir Lawrence Bragg

    THIS ACCOUNT of the events which led to the solution of the structure of DNA, the fundamental

    genetical material, is unique in several ways. I was much pleased when Watson asked me to write

    the foreword.

    There is in the first place its scientific interest. The discovery of the structure by Crick and

    Watson, with all its biological implications, has been one of the major scientific events of this

    century. The number of researches which it has inspired is amazing; it has caused an explosion in

    biochemistry which has transformed the science. I have been amongst those who have pressed the

    author to write his recollections while they are still fresh in his mind, knowing how important they

    would be as a contribution to the history of science. The result has exceeded expectation. The latter

    chapters, in which the birth of the new idea is described so vividly, are drama of the highest order;

    the tension mounts and mounts towards the final climax. I do not know of any other instance where

    one is able to share so intimately in the researcher's struggles and doubts and final triumph.

    Then again, the story is a poignant example of a dilemma which may confront an

    investigator. He knows that a colleague has been working for years on a problem and has

    accumulated a mass of hard-won evidence, which has not yet been published because it is

    anticipated that success is just around the comer. He has seen this evidence and has good reason to

    believe that a method of attack which he can envisage, perhaps merely a new point of view, will

    lead straight to the solution. An offer of collaboration at such a stage might well be regarded as a

    trespass. Should he go ahead on his own It is not easy to be sure whether the crucial new idea is

    really one's own or has been unconsciously assimilated in talks with others. The realization of this

    difficulty has led to the establishment of a some what vague code amongst scientists which

    recognizes a claim in a line of research staked out by a colleague up to a certain point. When

    competition comes from more than one quarter, there is no need to hold back. This dilemma comes

    out clearly in the DNA story. It is a source of deep satisfaction to all intimately concerned that, in

    the award of the Nobel Prize in 1962, due recognition was given to the long, patient investigation

    by Wilkins at King's College (London) as well as to the brilliant and rapid final solution by Crick

    and Watson at Cambridge.

    Finally, there is the human interest of the story the impression made by Europe and by

    England in particular upon a young man from the States. He writes with a Pepys like frankness.

    Those who figure in the book must read it in a very forgiving spirit. One must remember that his

    book is not a history, but an autobiographical contribution to the history which will some day be

    written. As the author himself says, the book is a record of impressions rather than historical facts.

    The issues were often more complex, and the motives of those who had to deal with them were less

    tortuous, than he realized at the time. On the other hand, one must admit that his intuitive

    understanding of human frailty often strikes home.

    The author has shown the manuscript to some of us who were involved in the story, and we

    have suggested corrections of historical fact here and there, but personally

    I have felt reluctant to alter too much because the fresh ness and directness with which impressions

    have been recorded is an essential part of the interest of this book.

    W. L. B. Preface

    HERE I relate my version of how the structure of DNA was discovered. In doing so I have tried to

    catch the atmosphere of the early postwar years in England, where most of the important events

    occurred. As I hope this book will show, science seldom proceeds in the straightforward logical

    manner imagined by outsiders. Instead, its steps forward (and sometimes backward) are often very

    human events in which personalities and cultura1 traditions play major roles. To this end I have

    attempted to recreate my first impressions of the relevant events and personalities rather than

    present an assessment which takes into account the many facts I have learned since the structure

    was found. Although the latter approach might be more objective, it would fail to convey the spirit

    of an adventure characterized both by youthful arrogance and by the belief that the truth, once

    found, would be simple as well as pretty. Thus many of the comments may seem one-sided and

    unfair, but this is often the case in the incomplete and hurried way in which human beings

    frequently decide to like or dislike a new idea or acquaintance. In any event, this account represents

    the way I saw things then, in 1951-1953: the ideas, the people, and myself.

    I am aware that the other participants in this story would tell parts of it in other ways,sometimes because their memory of what happened differs from mine and, perhaps in even more

    cases, because no two people ever see the same events in exactly the same light. In this sense, no

    one will ever be able to write a definitive history of how the structure was established. Nonetheless,I feel the story should be told, partly because many of my scientific friends have expressed

    curiosity about how the double helix was found, and to them an incomplete version is better than

    none. But even more important, I believe, there remains general ignorance about how science is

    done. That is not to say that all science is done in the manner described here. This is far from the

    case, for styles of scientific research vary almost as much as human personalities. On the other

    hand, I do not believe that the way DNA came out constitutes an odd exception to a scientific world

    complicated by the contradictory pulls of ambition and the sense of fair play. The thought that I

    should write this book has been with me almost from the moment the double helix was found. Thus

    my memory of many of the significant events is much more complete than that of most other

    episodes in my life. I also have made extensive use of letters Written at virtually weekly intervals to

    my parents. These were especially helpful in exactly dating a number of the incidents. Equally

    important have been the valuable comments by various friends who kindly read earlier versions

    and gave in some instances quite detailed accounts of incidents that I had referred to in less

    complete form. To be sure, there are cases where my recollections differ from theirs, and so this

    book must be regarded as my view of the matter.

    Some of the earlier chapters were written in the homes of Albert Szent-Gy?rgyi, John A.

    Wheeler, and John Cairns, and I wish to thank them for quiet rooms with tables overlooking the

    ocean. The later chapters were written with the help of a Guggenheim Fellowship, which allowed

    me hospitality of the Provost and Fellows of King’s College.

    As far as possible I have included photographs taken at the time the story occurred, and in

    particular I want to thank Herbert Gutfreund, Peter Pauling, Hugh Huxley, and Gunther Stent for

    sending me some of their snapshots. For editorial assistance I'm much indebted to Libby Aldrich

    for the quick, perceptive remarks expected from our best Radcliffe students and to Joyce Lebowitz

    both for keeping me from completely misusing the English language and for Innumerable

    comments about what a good book must do. Finally, I wish to express thanks for the immense help

    Thomas J. Wilson has given me from the time he saw the first draft. Without his wise, warm, and

    sensible advice, the appearance of this book, in what I hope is the right form, might never have

    occurred.

    J. D.W.

    Harvard University

    Cambridge, Massachusetts

    November 1967 Diagrams

    1. Short section of DNA, 1951..............................................................................20

    2. Chemical structures of the DNA bases, 1952...................................................21

    3. Covalent bonds of the sugar-phosphate backbone .........................................30

    4. Schematic view of a nucleotide........................................................................31

    5. Mg++ ions binding phosphate groups ............................................................32

    6. Schematic view of DNA, like-with-like base pairs ...........................................65

    7. Base pairs for the like-with-like structure .......................................................66

    8. Tautomeric forms of guanine and thymine ......................................................68

    9. Base pairs for the double helix ........................................................................70

    10. Schematic illustration of the double helix ....................................................74

    11. DNA replication .............................................................................................77 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

    IN THE summer of 1955, I arranged to join some friends who were going into the Alps. Alfred

    Tissieres, then a Fellow at King's, had said he would get me to the top of the Rothorn, and even

    though I panic at voids this did not seem to be the time to be a coward. So after getting in shape by

    letting a guide lead me up the Allinin, I took the two-hour postal bus trip to Zinal, hoping that the

    driver was not carsick as he lurched the bus around the narrow road twisting above the falling rock

    slopes. Then I saw Alfred standing in front of the hotel, talking with a long-mustached Trinity don

    who had been in India during the war. Since Alfred was still out of training, we decided to spend

    the afternoon walking up to a small restaurant which lay at the base of the huge glacier falling

    down off the Obergabelhorn and over which we were to walk the next day. We were only a few

    minutes out of sight of the hotel when we saw a party coming down upon us, and I quickly

    recognized one of the climbers. He was Willy Seeds, a scientist who several years before had

    worked at King's College, London, with Maurice Wilkins on the optical properties of DNA fibers.

    Willy soon spotted me, slowed down, and momentarily gave the impression that he might remove

    his rucksack and chat for a while. But all he said was, How's Honest Jim? and quickly increasing

    his pace was soon below me on the path.

    Later as I trudged upward, I thought again about our earlier meetings in London. Then DNA

    was still a mystery, up for grabs, and no one was sure who would get it and whether he would

    deserve it if it proved as exciting as we semisecretly believed. But now the race was over and, as

    one of the winners, I knew the tale was not simple and certainly not as the newspapers reported.

    Chiefly it was a matter of five people: Maurice Wilkins, Rosalind Franklin, Linus Pauling, Francis

    Crick, and me. And as Francis was the dominant force in shaping my part, I will start the story with

    him. ~~1~~

    I HAVE never seen Francis Crick in a modest mood. Perhaps in other company he is that way, but I

    have never had reason so to judge him. It has nothing to do with his present fame. Already he is

    much talked about, usually with reverence, and someday he may be considered in the category of

    Rutherford or Bohr. But this was not true when, in the fall of 1951, I came to the Cavendish

    Laboratory of Cambridge University to join a small group of physicists and chemists working on

    the three-dimensional structures of proteins. At that time he was thirty-five, yet almost totally

    unknown. Although some of his closest colleagues realized the value of his quick, penetrating mind

    and frequently sought his advice, he was often not appreciated, and most people thought he talked

    too much.

    Leading the unit to which Francis belonged was Max Perutz, an Austrian-born chemist who came

    to England in 1936. He had been collecting X-ray diffraction data from hemoglobin crystals for

    over ten years and was just beginning to get somewhere. Helping him was Sir Lawrence Bragg, the

    director of the Cavendish. For almost forty years Bragg, a Nobel Prize winner and one of the

    founders of crystallography, had been watching X-ray diffraction methods solve structures of ever-

    increasing difficulty. The more complex the molecule, the happier Bragg became when a new

    method allowed its elucidation.

    Thus in the immediate postwar years he was especially keen about the possibility of solving the

    structures of proteins, the most complicated of all molecules. Often, when administrative duties

    permitted, he visited Perutz' office to discuss recently accumulated X-ray data. Then he would

    return home to see if he could interpret them.

    Somewhere between Bragg the theorist and Perutz the experimentalist was Francis, who

    occasionally did experiments but more often was immersed in the theories for solving protein

    structures. Often he came up with something novel, would become enormously excited, and

    immediately tell it to anyone who would listen. A day or so later he would often realize that his

    theory did not work and return to experiments, until boredom generated a new attack on theory.

    There was much drama connected with these ideas. They did a great deal to liven up the

    atmosphere of the lab, where experiments usually lasted several months to years. This came partly

    from the volume of Crick's voice he talked louder and faster than anyone else and, when he

    laughed, his location within the Cavendish was obvious. Almost everyone enjoyed these manic

    moments, especially when we had the time to listen attentively and to tell him bluntly when we lost

    the train of his argument. But there was one notable exception. Conversations with Crick frequently

    upset Sir Lawrence Bragg, and the h sound of his voice was often sufficient to make Bragg move to

    a safer room. Only infrequently would he come to tea in the Cavendish, since it meant enduring

    Crick's booming over the tea room. Even then Bragg was not completely safe. On two occasions

    the corridor outside his office was flooded with water pouring out of a laboratory in which Crick

    was working. Francis, with his interest in theory, had neglected to fasten securely the rubber tubing

    around his suction pump.

    At the time of my arrival, Francis' theories spread far, beyond the confines of protein

    crystallography. Anything important would attract him, and. he frequently visited other labs to see

    which new experiments had been done. Though he was generally polite and considerate of

    colleagues who did not realize the real meaning of their latest experiments, he would never hide

    this fact from them. Almost immediately he would suggest a rash of new experiments that should

    confirm his interpretation. Moreover, he would not refrain from subsequently telling all who would

    listen how his clever new idea might set science ahead.

    As a result, there existed an unspoken yet real fear of Crick, especially among his

    contemporaries who had yet to establish their reputations. The quick manner in which he seized

    their facts and tried to reduce them to coherent patterns frequently made his friends' stomachs sink

    with the apprehension that, all too often in the near future, he would succeed, and expose to the world the fuzziness of minds hidden from direct view by the considerate, well-spoken manners of

    the Cambridge colleges.

    Though he had dining rights for one meal a week at Caius College, he was not yet a fellow

    of any college. Partly this was his own choice. Clearly he did not want to be burdened by the

    unnecessary sight of undergraduate tutees. Also a factor was his laugh, against which many dons

    would most certainly rebel if subjected to its shattering bang more than once a week. I am sure this

    occasionally bothered Francis, even though he obviously knew that most High Table life is

    dominated by pedantic, middle aged men incapable of either amusing or educating him in anything

    worthwhile. There always existed King's College, opulently nonconformist and clearly capable of

    absorbing him without any loss of his or its character. But despite much effort on the part of his

    friends, who knew he was a delightful dinner companion, they were never able to hide the fact that

    a stray remark over sherry might bring Francis smack into your life. ~~2~~

    BEFORE my arrival in Cambridge, Francis only occasionally thought about deoxyribonucleic acid

    (DNA) and its role in heredity. This was not because he thought it uninteresting. Quite the contrary.

    A major factor in his leaving physics and developing an interest in biology had been the reading in

    1946 of What Is Life? by the noted theoretical physicist Erwin Schrodinger. This book very

    elegantly propounded the belief that genes were the key components of living cells and that, to

    understand what life is, we must know how genes act. When Schrodinger wrote his book (1944)

    there was general acceptance that genes were special types of protein molecules. But almost at this

    same time the bacteriologist 0. T. Avery was carrying out experiments at the Rockefeller Institute

    in New York which showed that hereditary traits could be transmitted from one bacterial cell to

    another by purified DNA molecules.

    Given the fact that DNA was known to occur in the chromosomes of all cells, Avery's

    experiments strongly suggested that future experiments would show that all genes were composed

    of DNA. If true, this meant to Francis that proteins would not be the Rosetta Stone for unravelling

    the true secret of life. Instead, DNA would have to provide the key to enable us to find out how the

    genes determined, among other characteristics, the color of our hair, our eyes, most likely our

    comparative intelligence, and maybe even our potential to amuse others.

    Of course there were scientists who thought the evidence favoring DNA was inconclusive

    and preferred to believe that genes were protein molecules. Francis, however, did not worry about

    these skeptics. Many were cantankerous fools who unfailingly backed the wrong horses. One could

    not be a successful scientist without realizing that, in contrast to the popular conception supported

    by newspapers and mothers of scientists, a goodly number of. scientists are not only narrow-

    minded and dull, but also just stupid.

    Francis, nonetheless, was not then prepared to jump into the DNA world. Its basic

    importance did not seem sufficient cause by itself to lead him out of the protein field which he had

    worked in only two years and was just beginning to master intellectually. In addition, his

    colleagues at the Cavendish were only marginally interested in the nucleic acids, and even in the

    best of financial circumstances it would take two or three years to set up a new research group

    primarily devoted to using X rays to look at the DNA structure.

    Moreover, such a decision would create an awkward personal situation. At this time

    molecular work on DNA in England was, for all practical purposes, the personal property of

    Maurice Wilkins, a bachelor who worked in London at King's College

    Like Francis, Maurice had

    been a physicist and also used X-ray diffraction as his principal tool of research. It would have

    looked very bad if Francis had jumped in on a problem that Maurice had worked over for several

    years. The matter was even worse because the two, almost equal in age, knew each other and,before Francis remarried, had frequently met for lunch or dinner to talk about science.

    It would have been much easier if they had been living in different countries. The

    combination of England's coziness – all the important people, if not related by marriage, seemed to

    know one another plus the English I sense of fair play would not allow Francis to move in on

    Maurice's problem. In France, where fair play obviously did not exist, these problems would not

    have arisen. The States also would not have permitted such a situation to develop. One would not

    expect someone at Berkeley to ignore first-rate problem merely because someone at Cal Tech had

    started first. In England, however, it simply l would not look right.

    Even worse, Maurice continually frustrated Francis by never seeming enthusiastic enough

    about DNA. He appeared to enjoy slowly understating important arguments. It was not a question

    of intelligence or common sense Maurice clearly had both; witness his seizing DNA before almost

    A.division of the University of London, not to be confused

    the Kings College, Cambridge everyone else. It was that Francis felt he could never get the message over to Maurice that you did

    not move cautiously when you were holding dynamite like DNA. Moreover, it was increasingly

    difficult to take Maurice's mind off his assistant, Rosalind Franklin.

    Not that he was at all in love with Rosy, as we called her from a distance. Just the

    oppositea1most from the moment she arrived in Maurice's lab, they began to upset each other.

    Maurice, a beginner in X-ray diffraction work, wanted some professional help and hoped that Rosy,a trained crystallographer, could speed up his research. Rosy, however, did not see the situation this

    way. She claimed that she had been given DNA for her own problem and would not think of herself

    as Maurice's assistant.

    I suspect that in the beginning Maurice hoped that Rosy would calm down. Yet mere

    inspection suggested that she would not easily bend. By choice she did not emphasize her feminine

    qualities. Though her features were strong, she was not unattractive and might have been quite

    stunning had she taken even a mild interest in clothes. This she did not. There was never lipstick to

    contrast with her straight black hair, while at the age of thirty-one her dresses showed all the

    imagination of English bluestocking adolescents. So it was quite easy to imagine her the product of

    an unsatisfied mother who unduly stressed the desirability of professional careers that it could save

    bright girls from marriages to dull men. But this was not the case. Her dedicated, austere life could

    not be thus explained she was the daughter of a solidly comfortable, erudite banking family.

    Clearly Rosy had to go or be put in her place. The former was obviously preferable

    because, given her belligerent moods, it would be very difficult for Maurice to maintain a dominant

    position that would allow him to think unhindered about DNA. Not that at times he didn't see, some

    reason for her complaints – King's had two combination rooms, one for men, the other for women,certainly a thing of the past. But he was not responsible, and it was no pleasure to bear the cross for

    the added barb that the women's combination room remained dingily pokey whereas money had

    been spent to make life agreeable for him and his friends when they had their morning coffee.

    Unfortunately, Maurice could not see any decent way to give Rosy the boot. To start with,she had been given to think that she had a position for several years. Also, there was no denying

    she had a good brain. If she could only keep her emotions under control, there would be a good

    chance that she could really help him. But merely wishing for relations to improve was taking

    something of a gamble, for Cal Tech's fabulous chemist Linus Pauling was not subject to the

    confines of British fair play. Sooner or later Linus, who had just turned fifty, was bound to try for

    the most important of an scientific prizes. There was no doubt that he was interested. Our first

    principles told us that Pauling could not be the greatest of all chemists without realizing that DNA

    was the most golden of all molecules. Moreover, there was definite proof. Maurice had received a

    letter from Linus asking for a copy of the crystalline DNA X-ray photographs. After some

    hesitation he wrote back saying that he wanted to look more closely at the data before releasing the

    pictures. All this was most unsettling to Maurice. He had notes carped into biology only to find it

    personally as objection able as physics with its atomic consequences. The combination of both

    Linus and Francis breathing down his neck often made it very difficult to sleep. But at least Pauling

    was six thousand miles away, and even Francis was separated by a two-hour rail journey. The real

    problem, then, was Rosy. The thought could not be avoided that the best home for a feminist was in

    another person's. ~~3~~

    IT WAS Wilkins who had first excited me about X-ray work on DNA. This happened at Naples

    when a small scientific meeting was held on the structures of the large molecules found in living

    cells. Then it was the spring of 1951, before I knew of Francis Crick's existence. Already I was

    much involved with DNA, since I was in Europe on a postdoctoral fellowship to learn its

    biochemistry. My interest in DNA had grown out of a desire, first picked up while a senior in

    college, to learn what the gene was. Later, in graduate school at Indiana University, it was my hope

    that the gene might be solved without my learning any chemistry. This wish partially arose from

    laziness since, as an undergraduate at the University of Chicago, I was principally interested in

    birds and managed to avoid taking any chemistry or physics courses which looked of even medium

    difficulty. Briefly the Indiana biochemists encouraged me to learn organic chemistry, but after I

    used a bunsen burner to warm up some benzene, I was relieved from further true chemistry. It was

    safer to turn out an uneducated Ph.D. than to risk another explosion.

    So I was not faced with the prospect of absorbing chemistry until I went to Copenhagen to

    do my postdoctoral research with the biochemist Herman Kalckar. Journeying abroad initially

    appeared the perfect solution to the complete lack of chemical facts in my head, a condition at

    times encouraged by my Ph.D. supervisor, the Italian trained microbiologist Salvador Luria. He

    positively abhorred most chemists, especially the competitive variety out of the jungles of New

    York City. Kalckar, however, was obviously cultivated, and Luria hoped that in his civilized,continental company I would learn the necessary tools to do chemical research, without needing to

    react against the profit-oriented organic chemists.

    Then Luria's experiments largely dealt with the multiplication of bacterial viruses

    (bacteriophages, or phages for short). For some years the suspicion had existed among the more

    inspired geneticists that viruses were a form of naked genes. If so, the best way to find out what a

    gene was and how it duplicated was to study the properties of viruses. Thus, as the simplest viruses

    were the phages, there had sprung up between 1940 and 1950 a growing number of scientists (the

    phage group) who studied phages with the hope that they would eventually learn how the genes

    controlled cellular heredity. Leading this group were Luria and his German-born friend, the

    theoretical physicist Max Delbrück, then a professor at Cal Tech. While Delbrück kept hoping that

    purely genetic tricks could solve the problem, Luria more often wondered whether the real answer

    would come only after the chemical structure of a virus(gene) had been cracked open. Deep down

    he knew that it is impossible to describe the behavior of something when you don't know what it is.

    Thus, knowing he could never bring himself to learn chemistry, Luria felt the wisest course was to

    send me, his first serious student, to a chemist.

    He had no difficulty deciding between a protein chemist and a nucleic acid chemist.

    Though only about one half the mass of a bacterial virus was DNA (the other half being protein),Avery's experiment made it smell like the essential genetic material. So working out DNA's

    chemical structure might be the essential step in learning how genes duplicated. Nonetheless, in

    contrast to the proteins, the solid chemical facts known about DNA were meager. Only a few

    chemists worked with it and, except for the fact that nucleic acids were very large molecule built up

    from smaller building blocks, the nucleotides, there was almost nothing chemical that the geneticist

    could grasp at. Moreover, the chemists who did work on DNA were almost always organic

    chemists with no interest in genetics. Kalckar was a bright exception. In the summer of 1945 he had

    come to the lab at Cold Spring, Harbor, New York, to take Delbrück's course on bacterial viruses.

    Thus both Luria and Delbrück hoped the Copenhagen lab would be the place where the combined

    techniques of chemistry and genetics might eventually yield real biological dividends.

    Their plan, however, was a complete flop. Herman did not stimulate me in the slightest. I

    found myself just as indifferent to nucleic acid chemistry in his lab as I had been in the States. This

    was partly because I could not see how the type of problem on which he was then working ( the metabolism of nucleotides) would lead to anything of immediate interest to genetics. There was

    also the fact that, though Herman was obviously civilized, it was impossible to understand him.

    I was able, however, to follow the English of Herman's close friend Ole Maal?e. Ole had

    just returned from the States (Cal Tech), where he had become very excited about the same phages

    on which I had worked for my degree. Upon his return he gave up his previous research problem

    and was devoting full time to phage. Then he was the only Dane working with phage and so was

    quite :pleased that I and Gunther Stent, a phage worker from Delbrück's lab, had come to do

    research with Herman. Soon Gunther and I found ourselves going regularly to visit Ole's lab,located several miles from Herman's, and within several weeks we were both actively doing

    experiments with Ole.

    At first I occasionally felt ill at ease doing conventional phage work with Ole, since my

    fellowship was explicitly awarded to enable me to learn biochemistry with Herman; in a strictly

    literal sense I was violating its terms. Moreover, less than three months after my arrival in

    Copenhagen I was asked to propose plans for the following year. This was no simple matter, for I

    had no plans. The only safe course was to ask for funds to spend another year with Herman. It

    would have been risky to say that I could not make myself enjoy biochemistry. Furthermore, I

    could see no reason why they should not permit me to change my plans after the renewal was

    granted. I thus wrote to Washington saying that I wished to remain in the stimulating environment

    of Copenhagen. As expected, my fellowship was then renewed. It made sense to let Kalckar (whom

    several of the fellowship electors knew personally) train another biochemist.

    There was also the question of Herman's feelings. Perhaps he minded the fact that I was

    only seldom around. True, he appeared very vague about most things and might not yet have really

    noticed. Fortunately, however, these fears never had time to develop seriously. Through a

    completely unanticipated event my moral conscience became clear. One day early in December, I

    cycled over to Herman's lab expecting another charming yet totally incomprehensible conversation.

    This time, however, I found Herman could be understood. He had something important to let out:

    his marriage was over, and he hoped to obtain a divorce. This fact was soon no secret everyone else

    in the lab was also told. Within a few days it became apparent that Herman's mind was not going to

    concentrate on science for some time, for perhaps as long as I would remain in Copenhagen. So the

    fact that he did not have to teach me nucleic-acid biochemistry was obviously a godsend. I could

    cycle each day over to Ole's lab, knowing it was clearly better to deceive the fellowship electors

    about where I was working than to force Herman.to talk about biochemistry.

    At times, moreover, I was quite pleased with my current experiments on bacterial viruses.

    Within three months Ole and I had finished a set of experiments on the fate of a bacterial-virus

    particle when it multiplies inside a bacterium to form several hundred new virus particles. There

    were enough data for a respectable publication and, using ordinary standards, I knew I could stop

    work for the rest of the year without being judged unproductive. On the other hand, it was equally

    obvious that I had not done anything which was going to tell us what a gene was or how it

    reproduced. And unless I became a chemist, I could not see how I would.

    I thus welcomed Herman's suggestion that I go that spring to the Zoological Station at

    Naples, where he had decided to spend the months of April and May. A trip to Naples made great

    sense. There was no point in doing nothing in Copenhagen, where spring does not exist. On the

    other hand, the sun of Naples might be conducive to learning something about the biochemistry of

    the embryonic development of marine animals. It might also be a place where I could quietly read

    genetics. And when I was tired of it, I might conceivably pick up a biochemistry text. Without any

    hesitation I wrote to the States requesting permission to accompany Herman to Naples. A cheerful

    affirmative letter wishing me a pleasant journey came by return post from Washington. Moreover,it enclosed a 200 check for travel expenses. It made me feel slightly dishonest as I set off for the

    sun. ~~4~~

    MAURICE WILKINS also had not come to Naples for serious science. The trip from London was

    an unexpected gift from his boss, Professor J.T.Randall. Originally Randall had been scheduled to

    come to the meeting on macromolecules and give a paper about the work going on in his new

    biophysics lab. Finding himself overcommitted, he had decided to send Maurice instead. If no one

    went, it would look bad for his King's College lab. Lots of scarce Treasury money had to be

    committed to set up his biophysics show, and suspicions existed that this was money down the

    drain.

    No one was expected to prepare an elaborate talk for Italian meetings like this one. Such

    gatherings routinely brought together a small number of invited guests who did not understand

    Italian and a large number of Italians almost none of whom understood rapidly spoken English, the

    only language common to the visitors. The high point of each meeting was the day-long excursion

    to some scenic house or temple. Thus there was seldom chance for anything but banal remarks.

    By the time Maurice arrived I was noticeably restless and impatient to return north. Herman

    had completely misled me. For the first six weeks in Naples I was constantly cold. The official

    temperature is often much less relevant than the absence of central heating. Neither the Zoological

    Station nor my decaying room atop a six-story nineteenth-century house had any heat. H I had even

    the slightest interest in marine animals, I would have done experiments. Moving about doing

    experiments is much warmer than sitting in the library with one's feet on a table. At times I stood

    about nervously while Herman went through the motions of a biochemist, and on several days I

    even understood what he said. It made no difference, however, whether or not I followed the

    argument Genes were never at the center, or even at the periphery, of his thoughts.

    Most of my time I spent walking the streets or reading journal articles from the early days of

    genetics. Sometimes I daydreamed about discovering the secret of the gene, but not once did I have

    the faintest trace of a respectable idea. It was thus difficult to avoid the disquieting thought that I

    was not accomplishing anything. Knowing that I had not come to Naples for work did not make me

    feel better.

    I retained a slight hope that I might profit from the meeting on the structures of biological

    macromolecules. Though I knew nothing about the X ray diffraction techniques that dominated

    structural analysis, I was optimistic that the spoken arguments would be more comprehensible than

    the journal articles, which passed over my head. I was specially interested to hear the ta1k on

    nucleic acids to be given by Randall. At that time almost nothing was published about the possible

    three-dimensional configurations of a nucleic acid molecule. Conceivably this fact affected my

    casual pursuit of chemistry. For why should I get excited learning boring chemical facts as long as

    the chemists never provided anything incisive about the nucleic acids?

    The odds, however, were against any real revelation, then. Much of the ta1k about the three

    dimensional structure of proteins and nucleic acids was hot air. Though this work had been going

    on for over fifteen years, most if not all of the facts were soft. Ideas put forward with conviction

    were likely to be the products of wild crystallographers who delighted in being in a field where

    their ideas could not be easily disproved. Thus, although virtually all biochemists, including

    Herman, were unable to understand the arguments of the X ray people, there was little uneasiness.

    It made no sense to learn complicated mathematical methods in order to follow baloney. As a

    result, none of my teachers had ever considered the possibility that I might do postdoctoral research

    with an X ray crystallographer.

    Maurice, however, did not disappoint me. The fact that he was a substitute for Randall made

    no difference: I had not known about either. His talk was far from vacuous and stood out sharply

    from the rest, several of which bore no connection to the purpose of the meeting. Fortunately these

    were in Italian, and so the obvious boredom of the foreign guests did not need to be construed as

    impoliteness. Several other speakers were continental biologists, at that time guests at the Zoological Station, who only briefly alluded to macromolecular structure. In contrast, Maurice's X-

    ray diffraction picture of DNA was to the point. It 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. Before Maurice's ta1k I had worried about the

    possibility that the gene might be fantastically irregu1ar. Now, however, I knew that genes could

    crystallize; hence they must have a regular structure that could be solved in a straightforward

    fashion. Immediately I began to wonder whether it would be possible for me to join Wilkins in

    working on DNA. After the lecture I tried to seek him out. Perhaps he a1ready knew more than his

    talk had indicated often if a scientist is not absolutely sure he is correct, he is hesitant to speak in

    public. But there was no opportunity to talk to him; Maurice had vanished.

    Not until the next day, when all the participants took an excursion to the Greek temples at

    Paestu, did I get an opportunity to introduce myse1f. While waiting for the bus I started a

    conversation and explained how interested I was in DNA. But before I could pump Maurice we had

    to board, and I joined my sister, Elizabeth, who had just come in from the States. At the temples we

    all scattered, and before I could comer Maurice again I realized that I might have had a tremendous

    stroke of good luck. Maurice had noticed that my sister was very pretty, and soon they were eating

    lunch together. I was immensely pleased. For years I had sullenly watched Elizabeth being pursued

    by a series of dull nitwits. Suddenly the possibility opened up that her way of life could be changed.

    No longer did I have to face the certainty that she would end up with a mental defective.

    Furthermore, if Maurice really liked my sister, it was inevitable that I would become closely

    associated with his X ray work on DNA. The fact that Maurice excused himself to go and sit alone

    did not upset me. He obviously had good manners and assumed that I wished to converse with

    Elizabeth.

    As soon as we reached Naples, however, my day: dreams of glory by association ended.

    Maurice moved off to his hotel with only a casual nod. Neither the beauty of my sister nor my

    intense interest in the DNA structure had snared him. Our futures did not seem to be in London.

    Thus I set off to Copenhagen and the prospect of more biochemistry to avoid ~~5~~

    I PROCEEDED to forget Maurice, but not this DNA photograph. A potential key to the secret of

    life was impossible to push out of my mind. The fact that I was unable to interpret it did not bother

    me. It was certainly better to imagine myself becoming famous than maturing into a stifled

    academic who had never risked a thought. I was also encouraged by the very exciting rumor that

    Linus Pauling had partly solved the structure of proteins. The news hit me in Geneva, where I had

    stopped for several days to talk with the Swiss phage worker Jean Weigle, who was just back from

    a winter of work at Cal Tech. Before leaving, Jean had gone to the lecture where Linus had made

    the announcement.

    Pauling's talk was made with his usual dramatic flair. The words came out as if he had been

    in show business all his life. A curtain kept his model hidden until near the end of his lecture, when

    he proudly unveiled his latest creation. Then, with his eyes twinkling, Linus explained the specific

    characteristics that made his model the α-helix uniquely beautiful. This show, like all of his

    dazzling performances, delighted the younger students in attendance. There was no one like Linus

    in all the world. The combination of his prodigious mind and his infectious grin was unbeatable.

    Several fellow professors, however, watched this performance with mixed feelings. Seeing Linus

    jumping up and down on the demonstration table and moving his arms like a magician about to pull

    a rabbit out of his shoe made them feel inadequate. If only he had shown a little humility, it would

    have been so much easier to take Even if he were to say nonsense, his mesmerized students would

    never know because of his unquenchable self-confidence. A number of his colleagues quietly

    waited for the day when he would fall flat on his face by botching something important.

    But Jean cou1d not tell me whether was right. He was not an X ray crystallographer and

    could not judge the model professionally. Several of his younger friends, however, trained in

    structural chemistry, thought the a helix looked very pretty. The best guess of Jean's acquaintances,therefore, was that Linus was right. If so, he had again accomplished a feat of extraordinary

    significance. He would be the first person to propose something solidly correct about the structure

    of a biologically important macromolecule. Conceivably, in doing so, he might have come up with

    a sensational new method which could be extended to the nucleic acids. Jean, however, did not

    remember any special tricks. The most he could tell me was that a description of the α-helix would

    soon be published.

    By the time I was back to Copenhagen, the journal containing Linus' article had arrived

    from the States. I quickly read it and immediately reread it. Most of the language was above me,and so I could only get a general impression of his argument. I had no way of judging whether it

    made sense. The only thing I was sure of was that it was written with style. A few days later the

    next issue of the journal arrived, this time containing seven more Pauling articles. Again the

    language was dazzling and full of rhetorical tricks. One article started with the phrase, Collagen is

    a very interesting protein. It inspired me to compose opening lines of the paper I would write

    about DNA, if I solved its structure. A sentence like Genes are interesting to geneticists would

    distinguish my way of thought from Pauling's.

    So I began worrying about where I could learn how to solve X-ray diffraction pictures. Cal

    Tech was not the place Linus was too great a man to waste his time teaching a mathematically

    deficient biologist. Neither did I wish to be further put off by Wilkins. This left Cambridge,England, where I knew that someone named Max Perutz was interested in the structure of the large

    biological molecules, in particular, the protein hemoglobin. I thus wrote to Luria about my newly

    found passion, asking whether he knew how to arrange my acceptance into the Cambridge lab.

    Unexpectedly, this was no problem at all. Soon after receiving my letter, Luria went to a small

    meeting at Ann Arbor, where he met Perutz' coworker, Jobn Kendrew, then on an extended trip to

    the States. Most fortunately, Kendrew made a favorable impression on Luria; like Kalckar, he was

    civilized and in addition supported the Labor Party. Furthermore, the Cambridge lab was understaffed and Kendrew was looking for someone to join him in his study of the protein

    myoglobin. Luria assured him that I would fit the bill and immediately wrote me the good news.

    It was then early August, just a month before my original fellowship would expire. This

    meant that I could not long delay writing to Washington about my change of plans. I decided to

    wait until I was admitted officially into the Cambridge lab. There was always the possibility that

    something would go wrong. It seemed prudent to put off the awkward letter until I could talk

    personally with Perutz. Then I could state in much greater detail what I might hope to accomplish

    in England. I did not, however, leave at once. Again I was back in the lab, and the experiments I

    was doing were fun, in a second-class fashion. Even more important, I did not want to be away

    during the forthcoming International Poliomyelitis Conference, which was to bring several phage

    workers to Copenhagen. Max Delbrück was in the expected group, and since he was a professor at

    Cal Tech he might have further news about Pauling's latest trick.

    Delbrück, however, did not enlighten me further. The α-helix, even if correct, had not

    provided any biological i insights; he seemed bored speaking about it. Even my in I.formation that

    a pretty X ray photograph of DNA existed elicited no real response. But I had no opportunity to be

    depressed by Delbrück's characteristic bluntness, for the poliomyelitis congress was an unparalleled

    success. From the moment the several hundred delegates arrived, a profusion of free champagne,partly provided by American dollars, was available to loosen international barriers. Each night for a

    week there were receptions, dinners, and midnight trips to waterfront bars. It was my first

    experience with the high life, associated in my mind with decaying European aristocracy. An

    important truth was slowly entering my head: a scientist's life might be interesting socially as well

    as intellectually. I went off to England in excellent spirits. ~~6~~

    MAX PERUTZ was in his office when I showed up just after lunch. John Kendrew was still in the

    States, but my arrival was not unexpected. A brief letter from John said that an American biologist

    might work with him during the following year. I explained that I was ignorant of how X rays

    diffract, but Max immediately put me at ease. I was assured that no high-powered mathematics

    would be required: both he and John had studied chemistry as undergraduates. All I need do was

    read a crystallographic text; this would enable me to understand enough theory to begin to take X

    ray photographs. As an example, Max told me about his simple idea for testing Pauling's α he1ix.

    Only a day had been required to get the crucial photograph confirming Pauling's prediction. I did

    not follow Max at all. I was even ignorant of Bragg's Law, the most basic of all crystallographic

    ideas.

    W e then went for a walk to look over possible digs for the coming year. When Max

    realized that I had come directly to the lab from the station and had not yet seen any of the colleges,he altered our course to take me through King's, along the backs, and through to the Great Court of

    Trinity. I had never seen such beautiful buildings in all my life, and any hesitation I might have had

    about leaving my safe life as a biologist vanished. Thus I was only nominally depressed when I

    peered inside several damp houses known to contain student rooms. I knew from the novels of

    Dickens that I would not suffer a fate the English denied themselves. In fact, I thought myself t

    very lucky when I found a room in a two-story house on Jesus Green, a superb location less than

    ten minutes', walk from the lab.

    The following morning I went back to the Cavendish, since Max wanted me to meet Sir

    Lawrence Bragg. When Max telephoned upstairs that I was here, Sir Lawrence f came down from

    his office, let me say a few words, and then retired for a private conversation with Max. A few

    minutes later they emerged to allow Bragg to give me his formal permission to work under his

    direction. The performance was uncompromisingly British, and I quietly concluded that the white

    mustached figure of Bragg now spent most of its days sitting in London clubs like the Athenaeum.

    The thought never occurred to me then that later on I would have contact with this apparent

    curiosity out of the past. Despite his indisputable reputation, Bragg had worked out his Law just

    before World War I, so I assumed he must be in effective retirement and would never care about

    genes. I politely thanked Sir Lawrence for accepting me and told Max I would be back in three

    weeks for the start of the Michaelmas term. I then returned to Copenhagen to collect my few

    clothes and to tell Herman about my good luck in being able to become a crystallographer.

    Herman was splendidly cooperative. A letter was dispatched telling the Fellowship Office in

    Washington that he enthusiastically endorsed my change in plans. At the same time I wrote a letter

    to Washington, breaking the news that my current experiments on the biochemistry of virus

    reproduction were at best interesting in a nonprofound way. I wanted to give up conventional

    biochemistry, which I believed incapable of telling us how genes work. Instead I told them that I

    now knew that X ray crystallography was the key to genetics. I requested the r approval of my

    plans to transfer to Cambridge so that I might work at Perutz' lab and learn how to do

    crystallographic research.

    I saw no point in remaining in Copenhagen until permission came. It would have been

    absurd to stay there wasting my time. The week before, Maal?e had departed for a year at Cal

    Tech, and my interest in Herman's type of biochemistry remained zero. Leaving Copenhagen was

    of course illegal in the formal sense. On the other hand, my request could not be refused. Everyone

    knew of Herman's unsettled state, and the Washington office must have been wondering how long I

    would care to remain in Copenhagen. Writing directly about Herman's absence from his lab would

    have been not only ungentlemanly, but unnecessary.

    Naturally I was not at all prepared to receive a letter refusing permission. Ten days after my

    return to Cambridge, Herman forwarded the depressing news, which had been sent to my Copenhagen address. The Fellowship Board would not approve my transfer to a lab from which I

    was totally unprepared to profit. I was told to reconsider my plans, since I was unqualified to do

    crystallographic work. The Fellowship Board would, however, look favorably on a proposal that I

    transfer to the cellphysiology laboratory of Caspersson in Stockholm.

    The source of the trouble was all too apparent. The head of the Fellowship Board no longer

    was Hans Clarke, a kindly biochemist friend of Herman's, then about to retire from Columbia. My

    letter had gone in~ stead to a new chairman, who took a more active interest in directing young

    people. He was put out that I had overstepped myself in denying that I would profit from

    biochemistry. I wrote to Luria to save me. He and the new man were casual acquaintances, and so

    when my decision was set in proper perspective, he might reverse his decision.

    At first there were hints that Luria's interjection might cause a change back to reason. I was

    cheered up when a letter arrived from Luria that the situation might be, smoothed over if we

    appeared to eat crow. I was to write Washington that a major inducement in my wanting to be in

    Cambridge was the presence of Roy Markham, an English biochemist who worked with plant

    viruses. Markham took the news quite casually when I walked into his office and told him that he

    might acquire a model student who would never bother him by cluttering up his lab with

    experimental apparatus. He regarded the scheme as a perfect example of the inability of Americans

    to know how to behave. Nonetheless, he promised to go along with this nonsense.

    Armed with the assurance that Markham would not squeal, I humbly wrote a long letter to

    Washington, outlining how I might profit from being in the joint presence of Perutz and Markham.

    At the end of the letter I thought it honest to break the news officially that I was in Cambridge and

    would remain there until a decision was made. The new man in Washington, however, did not play

    ball. The clue came when the return letter was addressed to Herman's lab. The Fellowship Board

    was considering my case. I would be informed when a decision had been made. Thus it did not

    seem prudent to cash my checks, which were still sent to Copenhagen at the beginning of each

    month.

    Fortunately, the possibility of my not being paid in the forthcoming year for working on

    DNA was only annoying and not fatal. The 3000 fellowship stipend that I had received for being

    in Copenhagen was three times that required to live like a well-off Danish student. Even if I had to

    cover my sister's recent purchase of two fashionable Paris suits, I would have 1000 left, enough

    for a year's stay in Cambridge. My landlady was also helpful. She threw me out after less than a

    month's residence. My main crime was not removing my shoes when I entered the house after 9:00

    P.M., the hour at which her husband went to sleep. Also I occasionally forgot the injunction not to

    flush the toilet at similar hours and, even worse, I went out after 10:00 P.M. Nothing in Cambridge

    was then open, and my motives were suspect. John and Elizabeth Kendrew rescued me with the

    offer, at almost no rent, of a tiny room in their house on Tennis Court Road. It was unbelievably

    damp and heated only by an aged electric heater. Nonetheless, I eagerly accepted the offer. Though

    it looked like an open invitation to tuberculosis, living with friends was infinitely preferable to any

    other digs I might find at this late moment so without any reluctance I decided to stay at Tennis

    Court Road until my financial picture improved. ~~7~~

    FROM my first day in the lab I knew I would not leave Cambridge for a long time, Departing

    would be idiocy, for I had immediately discovered the fun of talking to Francis Crick. Finding

    someone in Max's lab who knew that DNA was more important than proteins was real luck.

    Moreover, it was a great relief for me not to spend full time learning X ray analysis of proteins. Our

    lunch conversations quickly centered on how genes were put together. Within a few days after my

    arrival, we knew what to do: imitate Linus Pauling and beat him at his own game.

    Pauling's success with the polypeptide chain had naturally suggested to Francis that the

    same tricks might also work for DNA. But as long as no one nearby thought DNA was at the heart

    of everything, the potential personal difficulties with the King's lab kept him from moving into

    action with DNA. Moreover, even though hemoglobin was not the center of the universe, Francis'

    previous two years at the Cavendish certainly had not been dull. More than enough protein

    problems kept popping up that required someone with a bent toward theory. But now, with me

    around the lab always wanting to talk about genes, Francis no longer kept his thoughts about DNA

    in a back recess of his brain. Even so, he had no intention of abandoning his interest in the other

    laboratory problems. No one should mind if, by spending only a few hours a week thinking about

    DNA, he helped me solve a smashingly important problem.

    As a consequence, John Kendrew soon realized that I was unlikely to help him solve the

    myoglobin structure. Since he was unable to grow large crystals of horse myoglobin, he initially

    hoped I might have a greener thumb. No effort, however, was required to see that my laboratory

    manipulations were less skillful than those of a Swiss chemist. About a fortnight after my arrival in

    Cambridge, 37 we went out to the local slaughterhouse to get a horse heart for a new myoglobin

    preparation. If we were lucky, the damage to the myoglobin molecules which prevented

    crystallization would be averted by immediately freezing the ex racehorse's heart. But my

    subsequent attempts at crystallization were no more successful than John's. In a sense I was almost

    relieved. If they had succeeded, John might have put me onto taking X ray photographs.

    No obstacle thus prevented me from talking at least several hours each day to Francis.

    Thinking all the time was too much even for Francis, and often when he was stumped by his

    equations he used to pump my reservoir of phage lore. At other moments Francis would endeavor

    to fill my brain With cyrstallographic facts, ordinarily available only through the painful reading of

    professional journals. Particularly important were the exact arguments needed to understand how

    Linus Pauling had discovered the α-helix.

    I soon was taught that Pauling's accomplishment was a product of common sense, not the

    result of complicated mathematical reasoning. Equations occasionally crept into r his argument, but

    in most cases words would have sufficed. The key to Linus' success was his reliance on the simple

    Laws of structural chemistry. The α-helix had not been found by only staring at X ray pictures; the

    essential trick, instead, was to ask which atoms like to sit next to each other. In place of pencil and

    paper, the main working tools were a set of molecular models superficially resembling the toys of

    preschool children.

    We could thus see no reason why we should not solve DNA in the same way. All we had to

    do was to construct a set of molecular models and begin to play with luck, the structure would be a

    helix. Any other type of configuration would be much more complicated. Worrying about

    complications before ruling out the possibility that the answer was simple would have been damned

    foolishness. Pauling never got anywhere by seeking out messes.

    From our first conversations we assumed that the DNA molecule contained a very large

    number of nucleotides linear~ linked together in a regular way~ Again our reasoning was partially

    based upon simplicity. Although organic chemists in Alexander Todd's nearby lab thought this the

    basic arrangement, they were still a long way from chemically establishing that all the

    internucleotide bonds were identical. If this was not the case, however, we could not see how the DNA molecules packed together to form the crystalline aggregates studied by Maurice Wilkins and

    Rosalind Franklin. Thus, unless we found all future progress blocked, the best course was to regard

    the sugar phosphate backbone as extremely regular and to search for a helical three-dimensional

    configuration in which all the backbone groups had identical chemical environments.

    Immediately we could see that the solution to DNA might be more tricky than that of the α-

    helix. In the α-helix, a single polypeptide ( a collection of amino acids) chain folds up into a helical

    arrangement held together by hydrogen bonds between groups on the same chain. Maurice had told

    Francis, however, that the diameter of the DNA molecule was thicker than would be the case of

    only one polynucleotide ( a collection of nucleotides ) chain were present. This made him think that

    the DNA molecule was a compound helix composed of several polynucleotide chains twisted about

    each other. If true, then before serious model building began, a decision would have to be made

    whether the chains would be held together by hydrogen bonds or by salt linkages involving the

    negatively charged phosphate groups.

    A further complication arose from the fact that four types of nucleotides were found in

    DNA. In this sense, DNA was not a regular molecule but a highly irregular one. The four

    nucleotides were not, however, completely different, for each contained the same sugar and

    phosphate components. Their uniqueness lay in their nitrogenous bases, which were either a purine

    ( adenine and guanine ) or a pyrimidine ( cytosine and thymine ).But since the linkages between the

    nucleotides involved only the phosphate and sugar groups, our assumption that the same type of

    chemical bond linked all the nucleotides together was not affected. So in building models we would

    postu1ate that the sugar phosphate backbone was very regular, and the order of bases of necessity

    very irregular. If he base sequences were always the same, all DNA molecules would be identical

    and there would not exist the variability that must distinguish one gene from another. (Fig. 1)

    Though Pauling had got the α-helix almost without the X ray evidence, he knew of its

    existence and to a certain extent had taken it into account. Given the X ray data, a large variety of

    possible three-dimensional configurations for the polypeptide chain were quickly discarded. The

    exact X ray data should help us go ahead much faster with the more subtly constructed DNA

    molecule. Mere inspection of the DNA X-ray picture should prevent a number of false starts.

    Fortunately, there already existed one ha1f good photograph in the published literature. It was taken

    five years previously by the English crystallographer W.T. Astbury, and could be used to start us

    off. Y et possession of Maurice's much better crystalline photograph's might save us from six

    months' to a year's work. The painful fact that the pictures belonged to Maurice could not be

    avoided.

    There was nothing else to do but talk to him. To our surprise, Francis had no problem in

    persuading Maurice to come up to Cambridge for a weekend. And there was no need to force

    Maurice to the conclusion that the structure was a helix. Not only was it the obvious guess, but

    Maurice already had ......