Ian Wilmut, Keith Campbell, and Colin Tudge
The Second Creation: Dolly and the Age of Biological Control

The notion that science proceeds by a series of "eureka moments"--dramatic insights that seem to come from nowhere--is not necessarily the case. (p. 152)
The Second Creation is an excellent place to start if you know little or nothing about cloning. If you are already an expert on the subject then you will find the contents rather dull I suppose. Not only does the book cover the basics in how cloning is done, why it is done, and reasons why we may or may not want to continue to exploit the practice, but the reader is also treated to a behind the scenes look of how the most famous clone to date came about. For two of the authors were the "gods" of Dolly.

I suppose you could say this is four books in one. It is an autobiography of sorts for Wilmut and Campbell. It is a history of cloning (which is much longer than I previously was aware). It is a "how to" book for those interested in how cloning is done. And it poses the ethical questions (with Wilmut's answers) when it comes to (human) cloning.

Clones have been produced by nuclear transfer since 1951 and before that by means of embryo splitting. Beginning in the late 1950s John Gurdon even "produced fully functional adult frogs from specialist tadpole cells, but he never managed to produce adult frogs from nuclei transferred from adult cells." (p. 79) Steen Willadsen was the first to clone mammals by nuclear transfer. He didn't multiply the donor cells in culture before transfer however. Nor did he pay attention to cell cycles--a topic which Campbell spends much time going over.

So why was Dolly so important and why did she receive so much attention when there are many other animals that have been "cloned"? Dolly was the first animal to be cloned from an adult cell. The other animals that had been cloned before had come from embryonic (or tadpole) cells. However, Dolly was not the end of the line or even the ultimate goal of the research that was being carried on and continues to this day. Polly, born a year after Dolly, is closer to the objective. She was a manipulated clone who has different DNA than the animal she was cloned from. She was genetically transformed along the way. These kinds of results can potentially produce sheep (or other animals) capable of secreting enormous quantities of rare enzymes like AAT in their milk that can be used to treat lung disorders or other ailments.

In some ways..., Dolly is not quite as interesting scientifically as Megan and Morag. They, after all, were the very first mammals to be grown from cultured, differentiated cells. Dolly may not have as much practical significance as Taffy and Tweed, who were also born in the summer of 1996 but developed from fetal fibroblast cells, which for general purposes are probably the best bet. She has been superseded by Polly, who was born in 1997 and developed from fetal fibroblast cells that had been genetically transformed. But Dolly has one startling attribute that is forever unassailable: she was the first animal of any kind to be created from cultured, differentiated cells taken from an adult. Thus she confutes once and for all the notion--virtual dogma for 100 years--that once cells are committed to the tasks of adulthood, they cannot again be totipotent. (p. 209)
How is cloning done? That's too large a question for my review, but the book covers the complications in significant detail. DNA from cells that have totipotency (the ability to differentiate into all the various kinds of cells) is usually required. Hence, embryonic cells, that haven't begun to differentiate yet, were initially necessary. Wilmut and Campbell found ways to restore totipotency to adult cells that had already differentiated.

The topic, which is frequently in the news these days, of embryo stem cells is also covered. But of most interest, to some, will be the final section of the book which asks where we may be going from here and why. From the reasons to why cloning may wish to be continued and expanded upon (like for identical populations in the laboratory, replication of elite livestock, conservation efforts, and others) to why it will probably never make sense to use it as a human fertility device Wilmut and Campbell cover more areas than I had previously heard about or thought of. Wilmut devotes over 30 pages to why cloning people is a risky, repugnant, and poor idea. He also covers the frequently asked question of "are clones identical?" with a firm "no" on many grounds.

He ends with some good (and practical) advice:

what is "natural" is not necessarily right, and what is "unnatural" is not necessarily wrong. (p. 298)
What is important is to think about, study, and become knowledgeable of the subject rather than to form a knee-jerk reaction/opinion/conclusion based to some degree on ignorance. The ethical issues aren't going to easily go away, but better decisions can only be made through education. The Second Creation: Dolly and the Age of Biological Control offers this and more.

from the publisher:
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 ... 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.

The cloning of Dolly in 1996 from the cell of an adult sheep was a pivotal moment in history. For the first time, a team of scientists, led by Ian Wilmut and Keith Campbell at the Roslin Institute near Edinburgh, was able to clone a whole mammal using a single cultured adult body cell, a breakthrough that revolutionized three technologies and brought science ever closer to the possibility of human cloning.

In this definitive account, the scientists who accomplished this stunning feat explain their hypotheses and experiments, their conclusions, and the implications of their work. Researchers have already incorporated into sheep the gene for human factor IX, a blood-clotting protein used to treat hemophilia. In the future, cultures of mammary cells may prove to be valuable donor material, and genetically modified animal organs may be transplanted into humans. Normal pig organs, for example, are rapidly destroyed by the human immune system, but if altered genetically, they could alleviate the serious shortage of available organs. Genetically engineered sheep are also expected to be valuable as models for genetic defects that mimic human disorders such as cystic fibrosis, and for cell-based therapies for diseases--such as Parkinsonís, diabetes, and muscular dystrophy--that lack universally dependable treatments.

But what are the ethical issues raised by this pioneering research, and how are we to reconcile them with the enormous possibilities? Written with award-winning science writer Colin Tudge, The Second Creation is a Landmark work that details the most exciting and challenging scientific discovery of the twentieth century--with the furthest-reaching ramifications for the twenty-first.

Ian Wilmut studied embryology at Nottingham University and received his doctoral degree at Cambridge University before joining the Animal Breeding Research Station, an independent research institution that eventually became the Roslin Institute. He was the leader of the team that cloned Dolly.

Keith Campbell studied microbiology at Queen Elizabeth College, London, and obtained a D.Phil. from the University of Sussex. A cell biologist and embryologist now working at the University of Nottingham, he joined the Roslin Institute in 1991 to work on the project that resulted in Dolly.

Colin Tudge was educated at Cambridge University, where he majored in zoology. A writer and broadcaster, he is also a Research Fellow at the Centre for Philosophy at the London School of Economics. Tudge is the author of more than a dozen books, including, most recently, The Variety of Life: A Survey and a Celebration of All the Creatures That Have Ever Lived, published by Oxford University Press.

 "Fascinating and comprehensive...very readable...Not many books describe how science is actually done...Non-scientists will not only learn a lot of biology, but they will also get a good idea of what make scientists tick." --Anne McLaren, Nature

"An exciting story, well told, about an important piece of science.  Colin Tudge deserves our thanks." --Steven Rose, The Lancet

"An admirable chronicle of the birth of the world's first fatherless mammal, describing the science involved in intricate, but never baffling detail.  The Second Creation is, if nothing else, commendably readable." --Robin McKie, The Observer (London)

"Fascinating...A thoughtful and engaging account of a wonderful chapter in modern biology." --Harold T. Shapiro, chairman of the U.S. National Bioethics Advisory Commission and president of Princeton University, in The New Scientist

"Readable, admirably clear and informative." --Maggie Gee, The Daily Telegraph

"An honourable attempt to explain without oversimplifying or sensationalizing...Its subject matter is the most urgent imaginable." --Bryan Abbleyard, The Sunday Times (London)

The following is an excerpt:

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 Caenorbabditis--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 "acculturing" 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 dearly 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.

Copyright © 2000 Ian Wilmut, 
Keith Campbell, and Colin Tudge