Sheep cloning a success

(February 1997)

February brought us news of the world's first cloned sheep. Workers at the Roslin Institute in Edinburgh have succeeded in a task which, up until now, has only worked with mice. The implication appears to be that what can be done with sheep can probably be done with humans, opening up a whole range of "Brave New World" scenarios, and jokes about Elvis have been resurrected as well - unlike Mr Presley, so far.

Credit is shared between the Roslin Institute, part of Britain's Biotechnology and Biological Sciences Research Council, and PPL Therapeutics, an Edinburgh biotechnology company, whose shares rose in value after the announcement.

Dr Ian Wilmut announced on February 22 that he had taken the DNA from a sheep's ovum, replaced it with the DNA from an adult sheep, and grew it into a living lamb. The DNA was taken from the udder of the "donor" sheep, but the major breakthrough was in getting the DNA to become inactive, or quiescent, to use the geneticists' term. He then took an ovum from another sheep, and removed all of the DNA from it.

The next step was to fuse the ovum with an adult udder cell, after which the udder cell DNA took over the ovum, and controlled its growth and division. Wilmut then implanted the embryo in yet a third sheep, who gave birth to a lamb which is genetically identical to the original DNA donor. Dolly was born in July last year, and during the last week of February, was responsible for more headlines bearing the phrases "Hello Dolly" and "Send in the Clones", than Hollywood and Broadway ever inspired.

The next few months should see a flurry of bio-ethicists straining to make themselves heard about what the implications of this are, but the guidelines are already in place to deal with issues which surround human clones, so problems are unlikely, at least in the short term. In the longer term, the costs of breeding a master race are likely to be so large that no "secret program" will be possible, but a number of television script writers were probably reading the scientific press as February ended.

Scientific background

No less than three sheep were produced by much the same cloning method, but only Dolly was able to command serious scientific attention, as the other two sheep had been developed from cells taken respectively from a fetus and from an embryo. Given the existence of Dolly, the other sheep were of limited interest.

The genes in a cell become committed at an early stage of development, and while you can take a nucleus from one egg and put it in another egg, with some hope of achieving a result, the standard view has been that you could not take an adult cell and expect the genes to develop in any sort of normal way to grow an individual. When a cell has differentiated, specialised to form some kind of tissue, that should be enough to block it ever growing to a whole individual.

Against this, single plant cells can be taken and cultured to produce a whole plant, but somehow, plants all seemed to be a whole lot less complicated. Even when Wilmut's group succeeded in establishing clones from cell lines taken from early embryos (blastocysts), the standard barriers to successful cloning seemed still to be in place. Mouse embryos could be cloned if you took nuclei from the eight-cell stage, but no later, because the genetic material had been switched to a pathway of development, and could not be switched back.

Another problem was getting the cell division cycles of the donor cell and the host cell lined up-remember that a key feature is putting the donor nucleus into a cell where the surroundings are egg-like-so that later cell divisions do not produce cells with non-standard numbers of chromosomes. Wilmut's team managed to hold the donor cells in an arrested division state called the diploid G0 phase of the cell cycle by serum starvation.

The effect of this was to get a better synchronisation between the host cell and the new nucleus, but Wilmut's group may also have been fortunate in another respect-the sheep embryo does not begin committing cells (called transcription of the genome) until the 8-16 cell stage, against the 2 cell stage in mice, so there is more time for synchronisation to develop.

If this factor is important, then it casts doubt over whether or not other mammal species can be cloned in the same way, as the start of transcription of the genome varies between species. In the first few days of March, a monkey cloning breakthrough was reported which may or may not prove significant in the longer run.

The best analysis suggests that the cloning of human beings by this method would be possible in somewhere from one to ten years from now. The first calls for banning actually went out before the story broke in Nature, with an email from an unnamed "Harvard academic" who urged that Nature not publish details of the procedures until more thought had been given to questions of bio-ethics. Soon after the publication, President Clinton urged a moratorium on all such experiments. In Washington, Jeremy Rifkin demanded that the attempt to clone humans be placed on a par with rape, child abuse and murder.

On the other hand, Axel Kahn, a French geneticist (also in the news this month over transgenic corn) has suggested that side-issue of the technique might help a woman who had a serious mitochondrial disease to have a healthy child by inserting a nucleus into a donor cell. While this is not cloning, it may still be more acceptable than some of the other scenarios which are floating around.