Clone: The road to Dolly, and the path ahead
Remaking Eden: Cloning and beyond in a brave new world
The New England Journal of Medicine
Vol. 339:134-135, July 9, 1998
On February 27, 1997, Ian Wilmut and his colleagues at an animal-husbandry research center near Edinburgh, Scotland, announced in Nature the birth of Dolly. This was no mere birth notice: Dolly was produced by fusing the nucleus of a cell from the udder of a six-year-old sheep with an unfertilized, nucleus-free egg from another sheep. For the first time, the restricted genetic information in the nucleus of a differentiated mammalian cell was reprogrammed to reveal everything it knew about forming all the other cells of the body. In effect, cellular time was reversed a terminally differentiated cell reverted to its primordial ancestor. Moreover, Dolly also showed that chemical messages in the cytoplasm of an unfertilized egg can awaken the genes that differentiation puts to sleep. The identification of the ovular messages that repeal the genetic injunctions imposed by differentiation could yield immense benefits to medicine.
Dolly is an identical twin of the anonymous animal that donated the nucleus, but at her birth she was six years younger than her sister. Therein lies the rub. Dolly is a clone, and because, imprisoned in her surrogate womb, Dolly nevertheless had escaped the iron grip of sexual reproduction, she ignited an immediate worldwide reaction. Within weeks of the publication of the paper by Wilmut and his colleagues, politicians in Washington began drawing up prohibitive legislation, and in some European countries and China the cloning of humans was declared illegal. Well-known ethicists decried the experiment on talk shows Dolly reminded several commentators of Aldous Huxley's Brave New World, The Boys from Brazil, which involved a plot to produce clones of Adolf Hitler, or Woody Allen's Sleeper, in which the cloning of a dictator was attempted from his nose. Meanwhile, Clonaid, a company based in the Bahamas, was proposing to clone humans for a mere $200,000 a copy.
Through all the uproar and self-righteous posturing, the science that created Dolly and the potential benefits of cloning mammals were neglected or seriously misunderstood. Few who spoke out publicly recognized the possible practical applications of the technique and how cloning from an adult nucleus could advance our understanding of normal and abnormal differentiation, aging, and cancer. Wilmut's motivation had nothing to do with cloning humans. He wanted to improve livestock and make genetically engineered animal factories that would produce medically useful proteins, such as clotting factors. Indeed, 10 months after Wilmut's paper was published, Schnieke et al. (Science 1997;278:2130-3) reported that they had fused enucleated ovine oocytes with fetal fibroblasts not with adult cells, as Wilmut had done that had been transfected with the gene for factor IX linked to the promoter for the alpha-lactoglobulin gene for the purpose of producing sheep that would secrete the scarce human clotting factor in their milk.
The two books under review deal with these fascinating matters in different ways. In Clone, Gina Kolata, a well-known science writer for the New York Times, takes us on a breezy, journalistic tour of cloning. The writing is vivid and clear. Anyone who reads her book will come away with an appreciation of the main scientific and ethical issues. She will engage you with the historical background and sharply etched portraits of the leading figures in the drama. As a journalist, Kolata has an ear for chitchat and scandal. For example, she gives us an extended account of David Rorvik's book In His Image: The Cloning of a Man (Philadelphia: J.P. Lippincott, 1978), which was advertised as a true chronicle of the cloning of a mysterious, unnamed millionaire; the publisher ultimately admitted that it was a hoax. And she tells in detail the story of Karl Illmensee, who fooled the scientific community for years with his claim to have cloned mice by nuclear transfer. The relevance of these lengthy asides to the main issues is dubious, but Clone is worthwhile as an entertaining summary of the biology of the new millennium.
In Remaking Eden Lee Silver, a professor in the Department of Molecular Biology at Princeton University, gives us a panoramic view of molecular genetics, sexual reproduction, in vitro fertilization, and cloning. His book is an outstanding achievement. Silver addresses the uninitiated with clear writing and straightforward explanations of complex phenomena, but experts, especially ethicists and policy makers, will also profit from reading this book. Any physician should find this book remarkable. Silver analyzes the issues soberly, often with provocative examples. Some of his cases are hypothetical; others are drawn from real life.
A high point of the book is Silver's analysis of the treatment of Anissa Ayala, a girl with acute myelogenous leukemia who received a bone marrow transplant from her sister; the sister had been deliberately conceived in the hope that her marrow would be histocompatible with Anissa's. The new sister's marrow was indeed a match, and five years later Anissa, now a hematopoietic chimera, appeared to be cured. Silver's answer to prominent ethicists who strongly objected to this procedure is simple: what's wrong with it when the motive is love and affection? Who had the right to say that Marissa, the new sister, would not be loved for herself as much as Anissa? Silver's approach to ethical issues related to cloning and in vitro fertilization is refreshing: no nonsense, no pontificating, just the facts, just common sense. He makes his position clear with the question, "Why is it that so many politicians seem to care so much about cloning but so little about the welfare of children in general?"
According to legend, 1000 years ago King Canute tried to hold back the tides. Those who believe that they can limit the progress of science or any other branch of human knowledge will repeat Canute's error. Barbara Tuchman's classic A Distant Mirror (New York: Alfred A. Knopf, 1978) and a recent translation of Johan Huizinga's magisterial The Autumn of the Middle Ages (Chicago: University of Chicago Press, 1996) give us an extraordinary picture of the superstition, ignorance, folly, and pestilence that ruled Western Europe 500 years ago. Five hundred years later we have arrived at Dolly, and there is no way of turning back. Instead, the imperative is to use our knowledge with the compassion advocated by Lee Silver. Gina Kolata is wrong when she emphasizes that by producing Dolly, Wilmut was "breaking the laws of nature." Nature's laws cannot be broken. What we must understand is that Wilmut's feat revealed, rather than broke, the laws of nature. The remarkable potential of this revelation is a cause for hope, not despair.
Robert S. Schwartz, M.D.