Dna: The Secret of Life

by Watson, James

  We thank the many people who contributed generously to this project in one way or another in the acknowledgments at the back of the book. Four individuals, however, deserve special mention. George Andreou, our preternaturally patient editor at Knopf, wrote much more of this book – the good bits – than either of us would ever let on. Kiryn Haslinger, our superbly efficient assistant at Cold Spring Harbor Lab, cajoled, bullied, edited, researched, nit-picked, mediated, wrote – all in approximately equal measure. The book simply would not have happened without her. Jan Witkowski, also of Cold Spring Harbor Lab, did a marvelous job of pulling together chapters 10, 11, and 12 in record time and provided indispensable guidance throughout the project. Maureen Berejka, JDW's assistant, rendered sterling service as usual in her capacity as the sole inhabitant of Planet Earth capable of interpreting JDW's handwriting.

  James D. Watson

  Cold Spring Harbor, New York

  Andrew Berry

  Cambridge, Massachusetts

  INTRODUCTION

  THE SECRET OF LIFE

  As was normal for a Saturday morning, I got to work at Cambridge University's Cavendish Laboratory earlier than Francis Crick on February 28, 1953. I had good reason for being up early. I knew that we were close – though I had no idea just how close – to figuring out the structure of a then little-known molecule called deoxyribonucleic acid: DNA. This was not any old molecule: DNA, as Crick and I appreciated, holds the very key to the nature of living things. It stores the hereditary information that is passed on from one generation to the next, and it orchestrates the incredibly complex world of the cell. Figuring out its 3-D structure – the molecule's architecture – would, we hoped, provide a glimpse of what Crick referred to only half-jokingly as "the secret of life."

  We already knew that DNA molecules consist of multiple copies of a single basic unit, the nucleotide, which comes in four forms: adenine (A), thymine (T), guanine (G), and cytosine (C). I had spent the previous afternoon making cardboard cutouts of these various components, and now, undisturbed on a quiet Saturday morning, I could shuffle around the pieces of the 3-D jigsaw puzzle. How did they all fit together? Soon I realized that a simple pairing scheme worked exquisitely well: A fitted neatly with T, and G with C. Was this it? Did the molecule consist of two chains linked together by A-T and G-C pairs? It was so simple, so elegant, that it almost had to be right. But I had made mistakes in the past, and before I could get too excited, my pairing scheme would have to survive the scrutiny of Crick's critical eye. It was an anxious wait. But I need not have worried: Crick realized straightaway that my pairing idea implied a double-helix structure with the two molecular chains running in opposite directions (see Plate 1). Everything known about DNA and its properties – the facts we had been wrestling with as we tried to solve the problem – made sense in light of those gentle complementary twists. Most important, the way the molecule was organized immediately suggested solutions to two of biology's oldest mysteries: how hereditary information is stored, and how it is replicated. Despite this, Crick's brag in the Eagle, the pub where we habitually ate lunch, that we had indeed discovered that "secret of life," struck me as somewhat immodest, especially in England, where understatement is a way of life.

  Crick, however, was right. Our discovery put an end to a debate as old as the human species: Does life have some magical, mystical essence, or is it, like any chemical reaction carried out in a science class, the product of normal physical and chemical processes? Is there something divine at the heart of a cell that brings it to life? The double helix answered that question with a definitive No.

  Charles Darwin's theory of evolution, which showed how all of life is interrelated, was a major advance in our understanding of the world in materialistic – physicochemical – terms. The breakthroughs of biologists Theodor Schwann and Louis Pasteur during the second half of the nineteenth century were also an important step forward. Rotting meat did not spontaneously yield maggots; rather, familiar biological agents and processes were responsible – in this case egg – laying flies. The idea of spontaneous generation had been discredited.

  Despite these advances, various forms of vitalism – the belief that physicochemical processes cannot explain life and its processes – lingered on. Many biologists, reluctant to accept natural selection as the sole determinant of the fate of evolutionary lineages, invoked a poorly defined overseeing spiritual force to account for adaptation. Physicists, accustomed to dealing with a simple, pared-down world – a few particles, a few forces – found the messy complexity of biology bewildering. Maybe, they suggested, the processes at the heart of the cell, the ones governing the basics of life, go beyond the familiar laws of physics and chemistry.

  That is why the double helix was so important. It brought the Enlightenment's revolution in materialistic thinking into the cell. The intellectual journey that had begun with Copernicus displacing humans from the center of the universe and continued with Darwin's insistence that humans are merely modified monkeys had finally focused in on the very essence of life. And there was nothing special about it. The double helix is an elegant structure, but its message is downright prosaic: life is simply a matter of chemistry.

  Crick and I were quick to grasp the intellectual significance of our discovery, but there was no way we could have foreseen the explosive impact of the double helix on science and society. Contained in the molecule's graceful curves was the key to molecular biology, a new science whose progress over the subsequent fifty years has been astounding. Not only has it yielded a stunning array of insights into fundamental biological processes, but it is now having an ever more profound impact on medicine, on agriculture, and on the law. DNA is no longer a matter of interest only to white-coated scientists in obscure university laboratories; it affects us all.

  By the mid-sixties, we had worked out the basic mechanics of the cell, and we knew how, via the "genetic code," the four-letter alphabet of DNA sequence is translated into the twenty-letter alphabet of the proteins. The next explosive spurt in the new science's growth came in the 1970s with the introduction of techniques for manipulating DNA and reading its sequence of base pairs. We were no longer condemned to watch nature from the sidelines but could actually tinker with the DNA of living organisms, and we could actually read life's basic script. Extraordinary new scientific vistas opened up: we would at last come to grips with genetic diseases from cystic fibrosis to cancer; we would revolutionize criminal justice through genetic fingerprinting methods; we would profoundly revise ideas about human origins – about who we are and where we came from – by using DNA-based approaches to prehistory; and we would improve agriculturally important species with an effectiveness we had previously only dreamed of.

  But the climax of the first fifty years of the DNA revolution came on Monday, June 26, 2000, with the announcement by U.S. president Bill Clinton of the completion of the rough draft sequence of the human genome: "Today, we are learning the language in which God created life. With this profound new knowledge, humankind is on the verge of gaining immense, new power to heal." The genome project was a coming-of-age for molecular biology: it had become "big science," with big money and big results. Not only was it an extraordinary technological achievement – the amount of information mined from the human complement of twenty-three pairs of chromosomes is staggering – but it was also a landmark in terms of our idea of what it is to be human. It is our DNA that distinguishes us from all other species, and that makes us the creative, conscious, dominant, destructive creatures that we are. And here, in its entirety, was that set of DNA – the human instruction book.

  DNA has come a long way from that Saturday morning in Cambridge. However, it is also clear that the science of molecular biology – what DNA can do for us – still has a long way to go. Cancer still has to be cured; effective gene therapies for genetic diseases still have to be developed; genetic engineering still has to realize its phenomenal potential for improving our food. But all these things will come. Th
e first fifty years of the DNA revolution witnessed a great deal of remarkable scientific progress as well as the initial application of that progress to human problems. The future will see many more scientific advances, but increasingly the focus will be on DNA's ever greater impact on the way we live.

  CHAPTER ONE

  BEGINNINGS OF GENETICS:

  FROM MENDEL TO HITLER

  My mother, Bonnie Jean, believed in genes. She was proud of her father's Scottish origins, and saw in him the traditional Scottish virtues of honesty, hard work, and thriftiness. She, too, possessed these qualities and felt that they must have been passed down to her from him. His tragic early death meant that her only nongenetic legacy was a set of tiny little girl's kilts he had ordered for her from Glasgow. Perhaps therefore it is not surprising that she valued her father's biological legacy over his material one.

  Growing up, I had endless arguments with Mother about the relative roles played by nature and nurture in shaping us. By choosing nurture over nature, I was effectively subscribing to the belief that I could make myself into whatever I wanted to be. I did not want to accept that my genes mattered that much, preferring to attribute my Watson grandmother's extreme fatness to her having overeaten. If her shape was the product of her genes, then I too might have a hefty future. However, even as a teenager, I would not have disputed the evident basics of inheritance, that like begets like. My arguments with my mother concerned complex characteristics like aspects of personality, not the simple attributes that, even as an obstinate adolescent, I could see were passed down over the generations, resulting in "family likeness." My nose is my mother's and now belongs to my son Duncan.

  Sometimes characteristics come and go within a few generations, but sometimes they persist over many. One of the most famous examples of a long-lived trait is known as the "Hapsburg Lip." This distinctive elongation of the jaw and droopiness to the lower lip – which made the Hapsburg rulers of Europe such a nightmare assignment for generations of court portrait painters – was passed down intact over at least twenty-three generations.

  The Hapsburgs added to their genetic woes by intermarrying. Arranging marriages between different branches of the Hapsburg clan and often among close relatives may have made political sense as a way of building alliances and ensuring dynastic succession, but it was anything but astute in genetic terms. Inbreeding of this kind can result in genetic disease, as the Hapsburgs found out to their cost. Charles II, the last of the Hapsburg monarchs in Spain, not only boasted a prize-worthy example of the family lip – he could not even chew his own food – but was also a complete invalid, and incapable, despite two marriages, of producing children.

  Genetic disease has long stalked humanity. In some cases, such as Charles II's, it has had a direct impact on history. Retrospective diagnosis has suggested that George III, the English king whose principal claim to fame is to have lost the American colonies in the Revolutionary War, suffered from an inherited disease, porphyria, which causes periodic bouts of madness. Some historians – mainly British ones – have argued that it was the distraction caused by George's illness that permitted the Americans' against-the-odds military success. While most hereditary diseases have no such geopolitical impact, they nevertheless have brutal and often tragic consequences for the afflicted families, sometimes for many generations. Understanding genetics is not just about understanding why we look like our parents. It is also about coming to grips with some of humankind's oldest enemies: the flaws in our genes that cause genetic disease.

  Our ancestors must have wondered about the workings of heredity as soon as evolution endowed them with brains capable of formulating the right kind of question. And the readily observable principle that close relatives tend to be similar can carry you a long way if, like our ancestors, your concern with the application of genetics is limited to practical matters like improving domesticated animals (for, say, milk yield in cattle) and plants (for, say, the size of fruit). Generations of careful selection – breeding initially to domesticate appropriate species, and then breeding only from the most productive cows and from the trees with the largest fruit – resulted in animals and plants tailor-made for human purposes. Underlying this enormous unrecorded effort is that simple rule of thumb: that the most productive cows will produce highly productive offspring and from the seeds of trees with large fruit large-fruited trees will grow. Thus, despite the extraordinary advances of the past hundred years or so, the twentieth and twenty-first centuries by no means have a monopoly on genetic insight. Although it wasn't until 1909 that the British biologist William Bateson gave the science of inheritance a name, genetics, and although the DNA revolution has opened up new and extraordinary vistas of potential progress, in fact the single greatest application of genetics to human well-being was carried out eons ago by anonymous ancient farmers. Almost everything we eat – cereals, fruit, meat, dairy products – is the legacy of that earliest and most far-reaching application of genetic manipulations to human problems.

  An understanding of the actual mechanics of genetics proved a tougher nut to crack. Gregor Mendel (1822-1884) published his famous paper on the subject in 1866 (and it was ignored by the scientific community for another thirty-four years). Why did it take so long? After all, heredity is a major aspect of the natural world, and, more important, it is readily, and universally, observable: a dog owner sees how a cross between a brown and black dog turns out, and all parents consciously or subconsciously track the appearance of their own characteristics in their children. One simple reason is that genetic mechanisms turn out to be complicated. Mendel's solution to the problem is not intuitively obvious: children are not, after all, simply a blend of their parents' characteristics. Perhaps most important was the failure by early biologists to distinguish between two fundamentally different processes, heredity and development. Today we understand that a fertilized egg contains the genetic information, contributed by both parents, that determines whether someone will be afflicted with, say, porphyria. That is heredity. The subsequent process, the development of a new individual from that humble starting point of a single cell, the fertilized egg, involves implementing that information. Broken down in terms of academic disciplines, genetics focuses on the information and developmental biology focuses on the use of that information. Lumping heredity and development together into a single phenomenon, early scientists never asked the questions that might have steered them toward the secret of heredity. Nevertheless, the effort had been under way in some form since the dawn of Western history.

  The Greeks, including Hippocrates, pondered heredity. They devised a theory of "pangenesis," which claimed that sex involved the transfer of miniaturized body parts: "Hairs, nails, veins, arteries, tendons and their bones, albeit invisible as their particles are so small. While growing, they gradually separate from each other." This idea enjoyed a brief renaissance when Charles Darwin, desperate to support his theory of evolution by natural selection with a viable hypothesis of inheritance, put forward a modified version of pangenesis in the second half of the nineteenth century. In Darwin's scheme, each organ – eyes, kidneys, bones – contributed circulating "gemmules" that accumulated in the sex organs, and were ultimately exchanged in the course of sexual reproduction. Because these gemmules were produced throughout an organism's lifetime, Darwin argued any change that occurred in the individual after birth, like the stretch of a giraffe's neck imparted by craning for the highest foliage, could be passed on to the next generation. Ironically, then, to buttress his theory of natural selection Darwin came to champion aspects of Jean-Baptiste Lamarck's theory of inheritance of acquired characteristics – the very theory that his evolutionary ideas did so much to discredit. Darwin was invoking only Lamarck's theory of inheritance; he continued to believe that natural selection was the driving force behind evolution, but supposed that natural selection operated on the variation produced by pangenesis. Had Darwin known about Mendel's work (although Mendel published his results shortly after The Origin
of Species appeared, Darwin was never aware of them), he might have been spared the embarrassment of this late-career endorsement of some of Lamarck's ideas.

  Whereas pangenesis supposed that embryos were assembled from a set of minuscule components, another approach, "preformationism," avoided the assembly step altogether: either the egg or the sperm (exactly which was a contentious issue) contained a complete preformed individual called a homunculus. Development was therefore merely a matter of enlarging this into a fully formed being. In the days of preformationism, what we now recognize as genetic disease was variously interpreted: sometimes as a manifestation of the wrath of God or the mischief of demons and devils; sometimes as evidence of either an excess of or a deficit of the father's "seed"; sometimes as the result of "wicked thoughts" on the part of the mother during pregnancy. On the premise that fetal malformation can result when a pregnant mother's desires are thwarted, leaving her feeling stressed and frustrated, Napoleon passed a law permitting expectant mothers to shoplift. None of these notions, needless to say, did much to advance our understanding of genetic disease.