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Chapter One

THE IMPORTANCE

OF BEING DOLLY

* * *

IAN WILMUT

Dolly seems a very ordinary sheep--just an amiable Finn-Dorset ewe--yet as all the world has acknowledged, if not entirely for the right reasons, she might reasonably claim to be the most extraordinary creature ever to be born. Mammals are normally produced by the sexual route: an egg joins with a sperm to form a new embryo. But in 1996 Keith Campbell and I, with our colleagues at Roslin Institute and PPL, cloned Dolly from a cell that had been taken from the mammary gland of an old ewe and then grown in culture. The ewe, as it happened, was long since dead. We fused that cultured cell with an egg from yet another ewe to "reconstruct" an embryo that we transferred into the womb of a surrogate mother, where it developed to become a lamb. This was the lamb we called Dolly: not quite the first mammal ever to be cloned, but certainly the first to be cloned from an adult body cell. Her birth overturns one of the deepest dogmas in all of biology, for until the moment in February 1997 when we made her existence known through a brief letter in the scientific journal Nature , most scientists simply did not believe that cloning in such a way, and from such a cell, was possible. Even afterward, some doubted that we had done what we claimed.

Dolly's impact was extraordinary. We expected a heavy response--the birth of Megan and Morag in 1995 had provided some warning of what might follow--but nothing could have prepared us for the thousands of telephone calls (literally), the scores of interviews, the offers of tours and contracts, and in some cases the opprobrium, though much less of that than we might have feared. Everyone, worldwide, knew that Dolly was important. Even if they did not grasp her full significance (and the full significance, while not obvious, is far more profound than is generally appreciated), people felt that life would never be quite the same again. And in this they are quite right.

Most obviously--and unfortunately, because it is certainly not the most important aspect--commentators the world over immediately perceived that if a sheep can be cloned from a body cell, then so can people. Many hated the idea, including President Clinton of the United States, who called for a worldwide moratorium on all cloning research. But others welcomed human cloning, and some--like Dr. Richard Seed--who is in fact a physicist, not a physician--even offered to set up cloning clinics, surely jumping the gun by several decades since very few scientists have the necessary expertise, and even in the best hands, human cloning at this stage would be absurdly risky. I fielded many of the telephone calls that flooded into Roslin Institute in the days after we went public with Dolly, and quickly came to dread the pleas from bereaved families, asking if we could clone their lost loved ones. I have two daughters and a son of my own and know that every parent's nightmare is to lose a child, and what parents would give to have them back, but I had and have no power to help. I suppose this was my first, sharp intimation of the effect that Dolly could have on people's lives and perceptions. Such pleas are based on a misconception: that cloning of the kind that produced Dolly confers an instant, exact replication--a virtual resurrection. This simply is not the case. But the idea is pervasive and was reflected in articles and cartoons around the world. Der Spiegel's cover showed a regiment of Einsteins, Claudia Schiffers, and Hitlers--the clever, the beautiful, and the not very nice.

Yet human cloning is very far from Keith's and my own thoughts and ambitions, and we would rather that no one ever attempted it. If it is attempted--and it surely will be by somebody sometime--it would be cruel not to wish good luck to everyone involved. But the prospect of human cloning causes us grave misgivings. It is physically too risky, it could have untoward effects on the psychology of the cloned child, and in the end we see no medical justification for it. For us, the technology that produced Dolly has far wider significance. As the decades and centuries pass, the science of cloning and the technologies that may flow from it will affect all aspects of human life--the things that people can do, the way we live, even, if we choose, the kinds of people we are. Those future technologies will offer our successors a degree of control over life's processes that will come effectively to seem absolute. Until the birth of Dolly, scientists were apt to declare that this or that procedure would be "biologically impossible"--but now that expression, biologically impossible, seems to have lost all meaning. In the twenty-first century and beyond, human ambition will be bound only by the laws of physics, the rules of logic, and our descendants' own sense of right and wrong. Truly, Dolly has taken us into the age of biological control.

Dolly is not our only cloned sheep. Megan and Morag were our first outstanding successes--Welsh Mountain ewes cloned from cultured embryo cells. Taffy and Tweed, two Welsh Black rams, were cloned from cultured fetal cells at the same time as Dolly and are at least as important as she is, since fetal cells may well be the best kind to work with. If it hadn't been for Dolly, Taffy and Tweed would now be the most famous sheep in the world. At the same time as Dolly, too, we cloned Cedric, Cecil, Cyril, and Tuppence from cultured embryo cells--four young Dorset rams who are genetically identical to one another and yet are very different in size and temperament, showing emphatically that an animal's genes do not "determine" every detail of its physique and personality. This is one of several reasons "resurrection" of lost loved ones, human or otherwise, is not feasible.

But Keith and I did not set out simply to produce genetic replicas of existing animals. Some other biologists who have contributed enormously to the science and technology of cloning have indeed been motivated largely by the desire to replicate outstanding--"elite"--livestock. Our broader and longer-term ambitions at Roslin, together with our collaborating biotech company PPL, lie in genetic engineering: the genetic "transformation" of animals and of isolated animal and human tissues and cells, for a myriad of purposes in medicine, agriculture, conservation, and pure science. Future possibilities will in principle be limited only by human imagination. A hint of what might come is provided not so much by Megan and Morag or by Dolly and her contemporaries, who have all been cloned but have not been genetically altered, but by Polly, born the year after Dolly, in 1997. Polly is both cloned and genetically transformed.

Indeed, we should not see cloning as an isolated technology, single-mindedly directed at replication of livestock or of people. It is the third player in a trio of modern biotechnologies that have arisen since the early 1970s. Each of the three, taken alone, is striking; but taken together, they propel humanity into a new age--as significant, as time will tell, as our forebears' transition into the age of steam, or of radio, or of nuclear power.

The chief of these three biotechnologies is genetic engineering, which first began to be developed in the early 1970s. "Genetic engineers" transfer genes from one organism to another--and, which is truly miraculous, the transferred genes may function perfectly in the new organism. The genetically engineered organism is then said to be "transformed," or to be "transgenic"; the transferred gene is called a transgene. Some scientists and politicians in recent years have tried to underplay the significance of such gene transfer--suggesting that all it does is accelerate the techniques of crop and livestock improvement that farmers and breeders have practiced for thousands of years. Not so. Traditional breeders must operate within the reproductive boundaries that define species. If they want to improve sheep, then they have to crossbreed the animals with other sheep. Potatoes can be improved only by crossing them with other potatoes. The modern genetic engineer, however, can in principle take genes from any organism and put them into any other: fungal genes into plants; mouse genes into bacteria; human genes into sheep. Again, we see that traditional breeders were bound by the restraints of biology, while modern genetic engineers are in theory bound only by the laws of physics, by their imagination, and by the laws and ethics of their society. Genetic engineers have a precision, too, that traditional breeders lack; they can add just one gene at a time, or they can take out individual genes, or take them out and alter them and put them back, or indeed (in principle) create genes, artificially, that have never existed before in nature. In evil hands, such power could be ghoulish. Ethically directed, the potential for doing good is immense.

Genetic engineering, however, has been severely limited by the simple fact that most of the genes in most creatures remain unidentified. Human beings have about 80,000 functional genes each, but of these, only a few thousand are known--that is, what they look like, what they do. While genetic engineers are developing the power to transfer genes from one organism to another, for the most part, they do not know which genes to transfer.

Over the past few decades, the science and technology of genomics has developed: the attempt to map all the genes in an organism and eventually to unravel their individual structures and find out what each of them does. The genes of some simple organisms--yeasts, the cresslike Arabidopsis , and the roundworm Caenorhabditis --have already been mapped in their entirety. Biologists throughout the world are now cooperating to identify all the genes in the human being--this is the Human Genome Project, or HUGO. The first phase should be completed within another decade or so. Our colleagues at Roslin are cooperating with other laboratories to identify and map all the genes in each of the common livestock species--poultry, sheep, cattle, pigs. When the knowledge gained by genomics comes on line, the power of genetic engineering will truly become evident.

Yet one player is missing. It is easy (relatively speaking!) to transform bacteria genetically. Put crudely (although in truth the procedures are immensely complicated) you just have to grow the bacteria in a dish and add DNA--DNA being the stuff of which genes are made--and then pick out the individual bacteria that have taken up the added genes most satisfactorily. The same, broadly speaking, can be done with plants. Plant tissue can be grown in a dish, which is what "culturing" means; once the new DNA is added, a whole new plant is regenerated from the cells that have taken up the added gene most effectively.

But with animals up until now--until Polly, in fact--this just has not been possible. Genetic engineering of animals was first achieved in the 1980s, and many animals have been genetically transformed since then--mostly laboratory mice but also more commercial species, such as cattle. But the only way to do this was to inject a gene (that is, a piece of DNA) into the young, one-celled embryo (otherwise known as a zygote) that is first formed by the fusion of egg and sperm. Then--with luck--all the cells of the animal that develops from that zygote will contain the new gene.

This procedure has produced some remarkable results; notably, before Keith joined us at Roslin, my colleagues and I spent much of the 1980s putting human genes into the sheep so that they would produce valuable therapeutic proteins in their milk. As described in the next chapter, this became a serious commercial proposition with huge medical implications, as PPL is demonstrating. Nevertheless, injection of DNA into zygotes is inefficient. How much better it would be to grow animal cells in a dish, as if they were bacteria or cultured plant cells, transform them en masse, and then--as is already carried out with bacteria and plants--grow whole new animals from the cells that had taken up the new genes most efficiently! Indeed, with the cells already in culture, genetic engineers are not confined simply to the addition of genes; they can subtract genes or alter them, or add artificial genes, just as is now possible in principle in bacteria and plants.

But until we started cloning sheep at Roslin, it simply was not possible to re-create whole animals from cultured cells. Keith came to Roslin in 1991, and he and I first achieved this in 1995 with Megan and Morag, who really should be seen as the most important of all our clones. They were the ones who first showed that cloning from cultured cells is possible. Dolly, born in 1996, might be seen as the gilt on the lily--although she had the added and stunning refinement that she was grown from an adult cell. Polly, born in 1997, shows the promise of times to come. She was cloned from cultured cells that were transformed genetically--a human gene was added to them--as they were cultured.

The point is that the three technologies together--genetic engineering, genomics, and our method of cloning from cultured cells--are a very powerful combination. Genetic engineering is the conceptual leader: transfer of genes from organism to organism, and the creation of quite new genes, makes it possible in principle to build new organisms at will. Genomics provides the necessary data: knowledge of what genes to transfer--where to find them, and what they do. Cloning of the kind that we have developed at Roslin and PPL makes it possible in principle to apply all the immense power of genetic engineering and genomics to animals. Animals are the creatures human beings identify with most closely: Livestock form one of the most important components of the world's economy and indeed of its ecology, and human beings, of course, are animals too. Commentators at large were right to observe that, in principle, whatever can be done in sheep might also be done in people, but they did not for the most part perceive that cloning per se--mere replication--is only a fraction of what might be done.

These technologies, powerful as they may seem, are still not the end of the matter. Beyond technology, and in harness with it, is science. People conflate the two: Most of what is reported on television by "science" correspondents is in fact technology. Technology is about changing things, providing machines and medicines, altering our surroundings to make our lives more comfortable and to create wealth. Science is about understanding, how the universe works and all the creatures in it. The two pursuits are different, and not necessarily linked. Technology is as old as humankind: Stone tools are technology. People may produce fine instruments and weapons, cathedrals, windmills, and aqueducts, without having any formal knowledge of underlying science--metallurgy, mechanics, aerodynamics, and hydrodynamics. In contrast, science at its purest is nothing more nor less than "natural philosophy," as it was originally known, and needs produce no technologies at all.

Our method of cloning--transferring a nucleus from a body cell into an egg--is a powerful technology, but it also provides wonderful opportunities for scientific insight. For example, biologists already have a good idea of how genes work, but they would deafly like to know more. We know, for instance, that genes make all creatures the way they are; they provide the proteins that form much of our body structure and catalyze the reactions of the cell's metabolism. But we also know that the genes do not operate in isolation. They are in constant dialogue with the rest of the cell, which in turn responds to signals from the other cells of the body, which in the end are in touch with the world at large. The influence of factors outside the genes, which act on them throughout life, is clearly seen in Cyril, Cedric, Cecil, and Tuppence: four very different though genetically identical individuals.

The dialogue between the genes and their surroundings is understood to some extent, but we need to know far more. This dialogue controls the development of an organism from a single cell into a sheep--or indeed into a human being or an oak tree. It determines that some cells within an animal form brains, while others form liver or lung or a hundred other tissues; in other words, the dialogue shapes the processes of differentiation . Birth defects are sometimes caused by flaws in the genes themselves--harmful mutations--but they also result from interruptions in the dialogue between the genes and their surroundings. They can be caused, for example, by toxins or infections. The dialogue between genes and their surroundings continues after the animal is born and throughout life, and if it goes awry, the genes go out of control; the cells grow wildly and the result is cancer. In short, once we understand how the genes interact with their surroundings--the nature of the dialogue--then we will truly begin to appreciate how bodies really work and develop, and what goes wrong in disease. That understanding is science.

Although science and technology are different pursuits with different histories, they work in concert. Technology without science is, well, technology: stone tools, windmills, mud huts. Technology with science is "high technology"; "high tech" is the technology that emerges from science. "Biotechnology" is high tech of a biological nature: Genetic engineering and cloning are the prime examples. Biotechnology is rapidly becoming one of the world's great industries. In truth, ideas do not flow simply from science into technology. They run in both directions--for without technology, science would grind to a halt. We shall see throughout this book how the science and craft of cloning depends on technological input: extraordinary microscopes of wonderful optical purity, high-precision instruments for microdissection, preparations of purified hormones to control the reproductive cycles of our experimental animals, methods of genetic analysis, and so on.

In our pursuit of cloning, Keith and I have been engrossed by the science and the technology that make cloning possible, and that which will develop from it in the future. I once wanted to be a farmer and am very happy with the idea that scientific research should have practical results--that it should lead to useful high technologies. My current interest in medical biotechnology was fired by the suffering of my own father, who was diabetic. He was blinded by the disease in the 1960s and lost part of a leg and much of the use of his hands before his death in 1994. As we will see later, we intend to adapt aspects of the technology that produced Dolly to provide a cure for diabetes: It will be possible one day to replicate and restore the islet cells that produce insulin, the hormone diabetics lack. The same principle can be applied to many other diseases. Keith perhaps is more of a pure scientist--"I just want to know how everything works," he says. His curiosity started young. As a boy, he filled his mother's kitchen with frogs, But he has also been a medical technician, and has worked on cancer. After Dolly was born, he moved from Roslin, the scientific research laboratory, to PPL, the commercial biotech company, and on to Nottingham (my old university) to be a professor. In reality, scientific research and biotechnological development feed into each other.

This is why Dolly matters--and why Megan and Morag, Taffy and Tweed, and Polly matter perhaps even more. Human cloning has grabbed people's imagination, but that is merely a diversion--and one we personally regret and find distasteful. We did not make Dolly for that. Still less did we ever intend to produce vast flocks of identical sheep. If all you want to do is multiply sheep, then good old-fashioned sex is the way to do it. Our work completes the biotechnological trio: genetic engineering, genomics, cloning. It also provides an extraordinarily powerful scientific model for studying the interactions of the genes and their surroundings--interactions that account for so much of development and disease. Taken together, the new biotechnologies and the pending scientific insights will be immensely powerful. Truly they will take humanity into the age of biological control.

So how did we come to do all this? If we simply wanted a good story, we could tell it as if Dolly was our destiny. The research that produced Megan and Morag, and then Dolly and the rest, requires two main kinds of expertise: embryology, or developmental biology, on the one hand (the science that describes how sperm and eggs normally combine to make single-celled embryos, which multiply and grow to form entire organisms, like us and sheep, with billions of cells of many different types), and cell biology on the other--a knowledge of the workings of individual cells, how they grow and divide, and how they can be manipulated.

I set out from the start of my scientific career to be an embryologist, and Keith was always a cell biologist; both of us were interested in cloning at least from the 1980s. I first came to Roslin as a Senior Scientific Officer in 1973 (when it was called ABRO) and after 1986, began the program that eventually led to Dolly; Keith joined us with just the expertise we required, and some revolutionary ideas, in 1991. I suppose there is a hint of destiny about all this. In truth, though, the outcome of science is not predestined. Luck plays a large part, and so does serendipity, which is something more than luck: unexpected and unlooked-for happiness. To a large extent, luck and serendipity made us the kinds of scientists we are, and brought us together. The cliché has it that if we had not done this work, then somebody else would soon have done so. But this common presumption comes with no guarantees. You can judge for yourself, as the story of Dolly unfolds, whether others would have gone down the same path--and if so, how quickly. History can only tell us what happened; it cannot tell us what might have been.

We are very different people, Keith and I. We have gotten along well this past decade; but although we have had many an amicable and intense conversation in our offices at Roslin, we very rarely meet outside work, even though we live within a few miles of each other. We both have families to get home to. I am now in my fifties, Keith in his forties. We have both worked in Scotland for some time--I since the early seventies, while Keith had research fellowships at Edinburgh and Dundee universities before he joined Roslin (then called IAPGR) in 1991. We almost qualify as honorary Scots, but we both came originally from the Midlands of England. My father was a math teacher, a man of immense presence (though not physically large), and I greatly admired him. He became diabetic at an early age, and later--in the 1960s--the disease made him blind. He bore his suffering patiently and became a computer programmer after the blindness made it impossible to teach. Perhaps I resemble him a bit in character; I would like to think so. People often seem to think I'm a schoolteacher. Perhaps it's the beard and the bald head, and the fact that I do like to be in charge. Or at least, I don't like other people telling me what to do. I suppose it goes with the job.

Keith and I differ outside the laboratory as well. I live with my wife, Vivienne, in a village some way to the south of Roslin--our children are well into their twenties and have fled the nest--while Keith lives even farther away with his partner. Ange, and their two small daughters. So we commute. Science can be an extraordinary job with extraordinary outcomes, but for the most part, daily life is as routine as any other. We have to clock in these days. We spend much of our time applying for grants. For relaxation I used to jog. Now I am content to walk over the hills. I like belonging to the local community--I have been president of the farmers' club, for instance--and have become reasonably adept at curling, the peculiarly Scottish game (though it is now an Olympic sport much favored by the Japanese) that resembles bowls, or lawn bowling, on ice. The "bowls" in fact are stones, big and flat like old-fashioned kettles, though a lot heavier, sent skittering over the ice. I don't like to compete, though. I get too nervous. Keith has a more artistic look. He plays the drums and races at high speed over the hills on a mountain bike. His daughters are still young, too, and take up much of his time.

I did not exactly shine at school--though I did meet Vivienne at that time. Her grammar school was next to mine, although the authorities had thoughtfully positioned the gates as far apart as possible to reduce contact to a minimum, and it was a long walk from one to the other. I seemed to work reasonably hard, but I left school with too few passes at A level* and had to make up a year before I joined the Agricultural College at Nottingham University. Farming was my first love--but to be a successful farmer you have to be good at business; I soon realized that I was not.

So I shuffled sideways into scientific research. In my last year as an undergraduate, in the long summer vacation of 1966, I won a scholarship from the Pig Industry Development Authority (PIDA) to work for eight weeks under E. J. C. (Chris) Polge at the ARC's Unit of Reproductive Physiology and Biochemistry at Cambridge (usually just called the Animal Research Station). Chris is a wonderful man--an excellent scientist (he is a Fellow of the Royal Society), but also kind and jovial. My job was to assist generally with the experiments, and there I learned to work with embryos. I found them very beautiful. Those weeks with Chris set the cast of my life. Chris later became one of the pioneer scientist-entrepreneurs of the 1980s, when he established a company called Animal Biotechnology Cambridge.

When I graduated from Nottingham in 1967 (with an Upper Second; not bad, not brilliant), I went back to work with Chris at the Animal Research Station. He supervised me through my Ph.D.--on the freezing of boar semen--which was awarded by Darwin College, Cambridge, in 1971. I stayed on with Chris, continuing the freezing research, after I got my doctorate. In 1973, I became the first scientist to freeze a calf embryo successfully, thaw it again, and transfer it to a surrogate mother--who went on to give birth to the world's first "frozen calf," a red-and-white Hereford x Friesian whom I called Frostie. The Veterinary Record published the news in June 1973, within weeks of his birth, which was one of the fastest scientific publications ever. Frostie gave me my first taste of the media. Newspapers as far away as New Zealand picked up the story, while Britain's Daily Mail won the perennial headline competition with ICE-AGE CALF WEIGHS IN. I did my first TV interview, with the BBC at Norwich, relayed to London. Frozen calf embryos have since played a significant part in agriculture and even in conservation. Frozen embryos of kudu antelope have been transferred into the wombs of the more common eland and have been born successfully.

In short, with Chris Polge in the 1960s and 1970s, I learned many of the basic techniques of reproductive physiology that later fed in to our cloning work at Roslin. As we will see, another key figure in the history of cloning is the Danish veterinarian Steen Willadsen, who, among other things, gave me some vital tips in the mid-1980s. He, too, worked for Chris Polge--in fact, he took over my job when I left. Willadsen began cloning at the Animal Research Station, initially just by dividing embryos. But more of this later. I left Chris's laboratory in 1973--to join ABRO, which became IAPGR, which became Roslin Institute.

Keith is the son of a seedsman, and was brought up in part on the farm where his grandfather worked. He did not exactly shine at his grammar school either. He was a scholarship boy, but he left without any A levels at all to work as a medical technician while studying in night school and day-release* for the applied equivalents of A levels--an ONC (Ordinary National Certificate) and then an HNC (Higher National Certificate), which he was awarded in 1975. But, he says, "I resigned my job the day I qualified to do it"--and went on to read microbiology at Queen Elizabeth College, London. He says he was lazy at university, but every undergraduate claims as much, and in fact, he attended all the lectures and wrote up the notes conscientiously. He, too, got an Upper Second.

By training and inclination, Keith is a cell biologist. By the standards of most scientists, his career (as is often noted) is unusual. After he graduated from Queen Elizabeth, he helped control Dutch elm disease in Sussex; then he worked as a medical technician in Saudi Arabia before going to the Marie Curie Memorial Foundation in London. There he saw how cancer cells change their character--from specialized differentiated cells into less differentiated cells that then could differentiate again in new ways. This insight later deeply affected his approach to cloning. He completed his doctorate at Sussex University in 1987 with "Aspects of cell cycle regulation in Yeast and Xenopus"--Xenopus being the African clawed frog featured in some of the earliest cloning experiments in the 1960s. This experience profoundly influenced his approach to cloning because "I realized that when you look closely at cells, they are all much the same. If yeasts can clone--which they do--I didn't see any absolute reason mammals couldn't be cloned too."

As a postdoc, Keith first spent two years at the University of Edinburgh, then another eighteen months at the University of Dundee before seeing the advertisement that I had placed in Nature , in February 1991, which lured him to Roslin. By then, I was already several years into the cloning project, and I knew I needed a cell biologist who understood cell cycles. Keith seemed tailor-made for the task.

Science is a human pursuit. Style matters. Keith and I have different backgrounds as well as styles, both of which I believe are complementary; it has been a fruitful alliance. It is vital, in science, to be sure of your ground; if you once start assuming things that are not clearly established, then you may follow a false trail that could take the rest of your career. There are many examples of this. You cannot be certain of everything in science, but you have to be as certain as you can of the things that are knowable. My own philosophy, and modus operandi, has been to identify the broad nature of the problem in hand, for as long ahead as possible, then to identify step-by-step the things we need to know to provide a solution, and then to move methodically through the steps, leaving as little as possible to chance. Such was the route I planned from the late 1980s to take us into cloning.

Keith is more adventurous. It was only when he joined the group and brought in his different experience that I fully understood the significance of the cell cycle in the development of cloned embryos. If our different experiences had not blended so well, we certainly would not have produced Megan and Morag, and then Dolly, by the middle of the 1990s. The science needed a change of direction, a new focus.

The science and technology of cloning, at least by our method, take us into some of the most esoteric reaches of biology: the details of reproductive physiology, the intricacies of gene behavior. As the great Russian-American biologist Theodosius Dobzhansky once commented, "Nothing makes sense in biology except in the light of evolution," so we should look at the broad philosophical background as well. We have made the explanations as simple as we can without fudging, but as Einstein said, "Everything should be made as simple as possible, but not simpler." We have not ducked the technical language. Technical terms describe entities and phenomena that simply do not exist in everyday life, and unless we employ those terms we cannot refer, clearly, to the essential elements of the story. So we will explain what the terms mean and then use them. "Karyoplast," "cytoplast," "Maturation Promoting Factor," and the various components of the cell and the cell cycle are a few (actually the most important) of the terms that appear throughout this book. We also believe that one of the main purposes of "popular" accounts such as this is to introduce nonspecialists to the real thing--so that with luck, when you have finished reading this book, you will be able to read the original, specialist accounts with understanding and even with pleasure. To see whether we have succeeded in this, we present the key paper describing the creation of Dolly at the end of the book.

Although the story is complicated, it is biology, and biology is not physics: that is to say, it is not weird . It does not ask you to believe that time passes at different rates in different circumstances, or that a photon can be in two places at once, and it is not so rooted in math, which in general the human brain does not do well. There is nothing in it, in other words, that anyone who picks up this book cannot understand. We think the research is worth understanding for a cultural reason: the science is interesting; and for a practical reason: the technology that emerges from the science affects all of us, in a hundred different ways.

A complicated narrative, however, needs a preview, to give it shape. So in the rest of this introductory chapter I will give a rough outline of all that we did, and why.

When I came to Roslin (ABRO) in 1973, it was not to do cloning, or anything like it. Robert Briggs and Thomas King in America, and John Gurdon in Cambridge, had carried out the first cloning studies in frogs at that time, but the cloning of mammals was not properly on the agenda until the 1980s. Even if it had been, I had no reason to become involved in it at the start of my career. At first, I worked on a variety of developmental problems, and by the start of the 1980s I was carrying out research into embryo death. In farm animals, about 25 percent of eggs that are fertilized fail to produce live births. Yet other animals do better: mice, for example, generally lose 20 percent of their babies in utero, but strains can be bred that lose only about 10 percent; animals such as red deer, which have only a very short breeding season, and in effect cannot afford to lose embryos, have adapted accordingly and lose far fewer than cattle do. It was, and is, a fascinating problem and an important one.

But in 1982, just as I was coming seriously to terms with embryo death, I was obliged to change course. The Agricultural Research Council, which was then the government agency in charge of ABRO, decided that government-supported research in general needed to change its philosophy; most of the research stations had to trim their sails. The fashionable science at that time was molecular biology, and John King, who was then ABRO's director, wanted to introduce more molecular biology--which required more funds, not less. King was shortly succeeded as director by Roger Land, who brought in John Bishop from the Department of Genetics at Edinburgh as a special consultant. ABRO then appointed its first full-time molecular biologist, Rick Lathe, who worked at the biotechnology laboratory Transgene in Strasbourg, France.

Bishop and Lathe came up with the idea that transformed much of the research at Roslin, gave rise to PPL, and brought me into the line of research that led to Dolly. Again, however, on the face of things, their idea seemed to have nothing directly to do with cloning. They wanted to carry out genetic engineering in sheep. Specifically, they wanted to see whether it would be possible to transfer human genes into sheep that would make proteins that would be of therapeutic value. Among many they had in mind were proteins involved in blood clotting, notably Factor VIII and Factor IX, a lack of which leads to hemophilia, and the enzyme alpha-1-antitrypsin, or AAT, used to treat sufferers of emphysema and cystic fibrosis.

Again, this work seemed to have nothing much to do with me or my line of interest, but Roger Land decided to bring my work on embryo death to a close and offered me instead the chance to work on the genetic engineering project. As we have seen, genetic engineering in those days (and for the most part, even in these days) was carried out by injecting DNA into one-celled embryos, otherwise known as zygotes; my job would be to supply the zygotes, and indeed to inject the DNA provided by the molecular biologists. Supply of zygotes certainly called upon my skills as a developmental biologist, but injection of DNA did not. For one thing, I have a problem with very small-scale manipulations because I have a hand tremor. For another, this work seemed tediously routine. It did not present the kind of intellectual challenges that had attracted me to science. So at that time I thought long and hard about leaving ABRO. But 1982 was a hard year for British agricultural science. Many of my colleagues had simply lost their jobs. I discussed the whole issue at length with Vivienne and decided I should tough it out. We had been in Scotland for nearly ten years, we liked the area and the people, the children were at school, and life is rarely perfect; sometimes you just have to put up with it. From the start, though, I agreed with Roger Land that as soon as I had developed a routine for genetic transformation of zygotes, I should seek more efficient methods.

This early research on genetic transformation of sheep at Roslin--without cloning--is described in Chapter 2. Out of that work came Tracy, born in 1990, who expressed large amounts of AAT in her milk. PPL took over this work and now has flocks of sheep similar to Tracy that produce commercial quantities of AAT. If all goes well, sheep-produced AAT will be commercially available within a few years.

Where does cloning come into this? As we will see in the next chapter, the standard way of making genetic transformations is unsatisfactory in several ways. One obvious drawback was (and is) that there is only one zygote per animal, so you get only one attempt per animal; if that fails, you waste a whole zygote. It soon occurred to me that it would be better if we could first allow the zygote to multiply, to produce several or many cells, then add new DNA to several or many of those cells, and then produce new embryos from each of the transformed cells. Such multiplication is cloning.

Research elsewhere in the early 1980s suggested a possible route. Biologists working on mice had cultures of embryo stems that retained embryonic qualities. These were called embryo stem cells, or ES cells. ES cells could be taken out of culture and put back into more mouse embryos; they were then able to develop into any of the tissues of the host embryo--muscle, brain, gut, or indeed eggs or sperm. Biologists were able to carry out genetic engineering with ES cells: They could transform the cells in culture, return them to mouse embryos, and then hope that some of the transformed cells would form eggs or sperm so that when the embryos grew into adult mice, they would produce genetically transformed offspring.

Note, however, that biologists of the early 1980s were never able to create entirely new mice directly from ES cells, transformed or otherwise; indeed, this has never been done. But they were able to add transformed cells to existing embryos. I felt that if only we could create ES cells from sheep, then we could do the same thing. But a few years later--after a meeting with Steen Willadsen in 1986--I realized that in sheep we should be able to go one better than the biologists; we should, in fact, be able to create embryos directly from transformed ES cells. In other words, we should be able to clone sheep from ES cells--and if we transformed the ES cells first, we would thereby produce genetically transformed sheep.

So I first moved into the genetic engineering of sheep and then sought to apply the technology of cloning to this endeavor by creating, and then cloning, ES cells. This ambition set the tone of my research from the late 1980s to the early 1990s. The complexities will unfold in the following chapters. But we will also see that the method that eventually led to success, with Megan and Morag and then with Dolly, did not involve ES cells; there is a huge twist in the story. Science is a logical pursuit, but progress in science does not necessarily, or even usually, proceed along a straight path. You just have to follow your nose--and sometimes you have to put treasured ideas aside and go down a different route. The different route, in this case, was opened up by Keith.

But I am running ahead. We should take the story step-by-step. It is appropriate to begin with the line of work that first got me involved in genetic engineering and then led, by a circuitous route, into cloning. We should begin, in short, with Roslin's (then IAPGR's) first great success in this field: Tracy.

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The Second Creation

0374141231

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