Goodbye Dolly … and friends?

Abstract

In the past few weeks two notable sheep have died. Dolly, the first mammal cloned from an adult cell, was put down aged 6 years, on February 14; a little earlier Matilda, the first Australian sheep produced by the same technology, died aged 3 years in more mysterious circumstances. Necropsies failed to show any association of their death with the manner of their birth. Matilda was described as “particularly sprightly”; by contrast Dolly was overweight, with arthritis—possibly the result of her celebrity lifestyle. The report of Dolly's birth by researchers from the Roslin Institute, Edinburgh, UK, was in many ways a model of how such advances should be handled. They published the news of Dolly's birth in Nature (385; 810–13); when her identity as a clone was questioned an independent expert checked it and this report was also published. These descriptions allowed researchers to reproduce the work; scientists have now cloned mice, cows, pigs, rabbits, goats, and cats using similar technology—nuclear transfer. However, the controversies sparked by Dolly's birth will long survive her. The stories of Dolly and other cloned mammals reveal not only the developmental complexity of higher organisms but also how scientific issues can inform debate on the ethics of such procedures. Many researchers are concerned whether any clone is normal. Although Dolly's creators have said that there is no evidence for her health problems and premature death being related to the cloning, the Roslin Institute has stated that “Many of the cloned cattle and sheep that are born are much larger than normal and apparently normal clones may have some unrecognised abnormalities. The high incidence of abnormalities is not surprising”. The mechanism underlying these abnormalities is intimately related to the cloning procedure. During normal gametogenesis DNA is epigenetically marked by a wave of global demethylation followed by selective remethylation which establishes, among other things, the parental origin (imprint) of each allele. Failure of correct imprinting causes several disorders, such as Prader-Willi and Angelman syndromes. Animals cloned by nuclear transfer do not go through this remethylation process, and hence any of the thousands of mammalian genes could be reprogrammed incorrectly during cloning. However, if a clone has offspring they will probably be normal, but only if they themselves are not clones. One of the foremost researchers in this area, Rudolf Jaenisch of the Massachusetts Institute of Technology, has used these potential problems in clones to argue repeatedly against human reproductive cloning. In a statement to the Science, Technology and Space Subcommittee of the US Senate in 2001, he stated, “Our experience with animal cloning allows us to predict with a high degree of confidence that few cloned humans will survive to birth and of those the majority will be abnormal”. Is there a place for reproductive cloning in any species, particularly primates? To produce a clone involves, at the very least, discomfort for many other animals; currently many oocytes must be harvested from donors, and then many pregnancies induced before one clone is born. Such difficulties are used to argue against cloning pets—raised as a possibility by the birth of a cloned cat in 2002. Some researchers say that cloning primates might reduce the need for large numbers of animals in experiments, although so far the nearest that researchers have come to achieving this goal is embryo splitting to induce monozygotic twin embryos. By having identical animals (as in colonies of mice) experiments could be done without the possibility of genetic confounders. But who knows which confounders to eliminate? Without many generations of experience it seems unlikely that such colonies would be sufficiently useful to justify producing clones. A more rational use of cloning might be to preserve endangered species. But it is not clear that colonies derived from these animals will have sufficient long-term fitness to survive—it can take populations thousands of years to recover from genetic bottlenecks. Even cloning of animals for agriculture might not be scientifically useful—in the words of Harry Griffin of the Roslin Institute they are “yesterday's best animals”. So although reproductive cloning was a technological breakthrough it seems to be of use only to a species on the edge of extinction, and it is hard to view it as anything more than a technological game. By contrast, therapeutic cloning offers a real chance for good, and governments should ensure that scientists are encouraged to pursue this research.