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Dr Ryuzo Yanagimachi, first master of the young science of cloning mice, has produced 200 of the little creatures in his laboratory in the idyllic setting of the University of Hawaii in Honolulu. Now he would like to try his hand at something larger. It's warm in Hawaii. But not too warm, perhaps, for a mammoth.
Yanagimachi and his colleague Teruhiko Wakayama belong to one of several research teams around the world that have applied to the academic guardians of a frozen mammoth carcass, recently sawn out of the Siberian permafrost, for a sample of the extinct creature's cells. They want to examine the cells' core of genes to see if they have survived intact after tens of thousands of years in deep freeze. If the DNA looks OK, well, why not acquire elephant eggs, hollow them out, put the ancient genes inside, insert the fertilised egg into an elephant and wait 22 months for the birth of a cloned mammoth? "Why do it? Scientific curiosity," says Yanagimachi. "Also, if you can do it with a mammoth, maybe you can save many extinct species. It's a challenge for me."
On the face of it, to jump from cloning mice to mammoths in such a short time shows how far and how fast the field of cloning has moved since February 1997 when the birth of Dolly the sheep, the first mammal cloned from an adult cell, was announced to the world.
The truth is that the pace of change has been dictated by the shock of the revolution Dolly represented. Reproductive biologists had been convinced that cloning could not be done. Now they are racing to make up for lost time. "What we really believed, deep in our hearts, was that this was one biological feat we could never master," confessed the Princeton biologist Lee Silver in his book, Remaking Eden. "It was impossible, we thought, for a cell from an adult mammal to become reprogrammed."
So many different species have now been successfully cloned, with new ones reported almost every quarter - rabbits are rumoured to be next - that society, at first stunned then dismayed by the concept of cloning, seems to have become almost blasi at the notion of identical animals conceived without sex. The public uproar over genetically modified foods and irradiated foods has masked the fact that we are capable of shrugging our shoulders over equally radical interventions in nature, such as the international frozen bull semen trade or the extreme breeding techniques which have given us giant, flavourless Californian strawberries.
Yet the greatest cause of unease, the idea of cloning human beings, while it may have receded, remains to be rekindled. Cloning researchers - many of whom have had to turn away grieving relatives seeking the rebirth of a dead child or dying partner - have made strenuous efforts to reassure the world that human cloning is neither necessary, easy nor right.
The fourth truth they are reluctant to add is that the breadth of cloning experience acquired in other animals in the three years since Dolly was born, and the relative simplicity of the equipment required, makes human cloning more feasible today than ever. "Things are calmer now," says Dr Harry Griffin, assistant director at the Roslin Institute in Edinburgh where Dolly was born and still thrives. "You can't maintain a heightened sense of fear about human cloning indefinitely. Scientists around the world who are involved in cloning have been uniformly outgoing in explaining the limitations of the technology, that success rates are very low, that there are differences in all species and that in no circumstances should people be experimenting on young women.
"I think that message has got through to some of those enthusiasts who think human cloning is just like in-vitro fertilisation and to those who don't understand that if you clone an adult human being you get a child.
"We have very low success rates, like one in 100. A woman going through IVF would generally provide 10 eggs. There's a bit of a shortfall there. Cloning is never going to be as effective as IVF. I'm sure none of the men who have shown an interest in human cloning have ever discussed it with their wives."
Everyone knows Neil Armstrong. Few remember the second man on the moon. Soon after Dolly appeared, she was joined by Noto and Kaga, two calves cloned in Japan. They will be two in July; about 100 calves have been cloned since they were born.
While much of the British research into cloning has focused on replicating transgenic animals - livestock genetically tweaked to produce vital human proteins in milk, or provide organs for human transplantation - Japanese researchers have been most aggressive in trying to get clones from the laboratory to the dinner plate. There was some consumer angst in Japan last year when it emerged that beef produced using an earlier, limited cloning technique - a bit like artificially provoking identical twins or triplets - had been on sale, unlabelled, since the mid-90s. The beef is now labelled, but the government argues that there is nothing to distinguish it from any other meat. It is not genetically modified; factually, if not philosophically, it is no more peculiar than a plant grown from a cutting, which is also a clone.
The Roslin Institute reckons that if the international price of a cloned cow embryo could be brought down to around the $100 mark, 85% of herds could be clones eventually: identical copies of the best milkers, the best breeders and the meatiest beef cows. Researchers are now looking at the minimum number of "originals" required as sources for the clones in order to preserve a vestige of diversification in farm animals.
In Hawaii, Yanagimachi's first cloned mouse, Cumulina, is two and a half years old - pensionable age. "She's in pretty good shape," he says. Biotechnology researchers use mice by the truckload in experiments, and exact multiple copies of the same mouse would enable them to make precise comparisons of the effects of drugs and disease. The Honolulu team has improved the success rate of cloning: now one in 10, instead of the original one in 100, of its cloned embryos survives to birth.
In early March, in a Virginia research centre run by the Scottish firm PPL Therapeutics, the first cloned pigs, Millie, Christa, Alexis, Carrel and Dotcom, were born. This major achievement paved the way to the start of organ farming for transplant into humans; the next step is to clone "knockout" pigs, which have a gene knocked out that would otherwise cause a human body to reject transplanted organs.
Goats have been cloned in the US; horses, cats and dogs have yet to be cloned, but it seems only a matter of time. In Texas, an anonymous wealthy couple have invested $2.3 m (#1.37m) in a research centre to clone their beloved dog, Missy. The project, Missyplicity, has a commercial offshoot, Genetic Savings and Clone, which offers to freeze and store genetic samples of any favourite animal against the day when they can be reliably and economically cloned.
"Regardless of whether the animal in your care is a champion bull, a rare white tiger, or a beloved mutt," announces the Missyplicity website, "Genetic Savings and Clone is the safest place to store its DNA."
Advances in cloning are not straightforward. The Dolly breakthrough was one of those moments in science which creates a mystery rather than solving one. Before Dolly, it was known that the genetic core of an embryonic cell - a cell from the first tiny cluster of cells which grows after conception - could be detached, inserted into a donor egg and used to create another embryo. Ian Wilmut and his Roslin team shattered biology dogma when they showed that the genetic material from a non-embryonic cell- a cell which had already settled into its specialised lifetime role, in the case of Dolly, forming part of an adult ewe's udder - could be inserted into a donor egg and reprogrammed by the egg to become an embryonic cell. How strange is this? As much as waking up to find find that your hand is turning into a foot or a tongue.
The trouble is, nobody yet knows why the egg is capable of doing this. And while the technology for cloning may be relatively simple, the technique remains fiendishly hard, with a low success rate. At the Regional Primate Centre in Oregon, Don Wolf and his colleagues achieved early success four years ago with a simpler form of cloning than the Dolly method when they produced twin rhesus monkeys, Netti and Ditto. But they have not been able to repeat the feat. "It's one step forward and two steps back," said Wolf. "We still have the same set of goals, to produce animals for biomedical research and vaccine development, but it's slow."
Yanagimachi agrees. "The success rate is low. Most cloned embryos die. We need another breakthrough."
Yet even the gloomiest cloners have moved far away from the doubts which lingered for months after Dolly was born, when some biologists refused to believe she really was a clone; perhaps they had simply stumbled on an embryonic cell, known as a stem cell, by mistake.
Hawaii and Japan have routed the sceptics. "Now it's simply a matter of working out the challenges of each species," says Wolf.
"Eventually it will be proven that you can clone each of the million or so species on the planet."
Including, presumably, ourselves. The early flirters with human cloning have gone to ground: Richard Seed, the American who announced plans to set up a human cloning clinic in Japan, has not been heard of since that country followed the lead of most of the big western states by banning the practice. There is no suggestion that Clonaid, the company set up by the Raelians, the religious cult which believes the resurrected Christ was a man cloned by aliens, has managed to emulate its extraterrestrial patrons. Like Missiplicity, Clonaid is offering to freeze-store cell samples for future cloning - but of humans, not animals.
A more serious human cloning effort was carried out in August 1998 at a fertility clinic in South Korea, where doctors obtained six eggs from two women undergoing fertility treatment, implanted them with cell nucleii from the same women, and managed to grow one to the four-cell stage before deliberately destroying it - the stage at which it could have been implanted in the womb. If true, this was the first recorded case of a human clone. And with hundreds of fertility clinics with similar levels of expertise around the world, all poring over the technical details in scientific journals and patent applications, no-one can be sure that a wealthy individual, able to buy the large number of human eggs which would need to be sacrificed for human cloning to succeed, has not already been cloned, and that his or her infant twin is not already growing.
Not only are there powerful incentives, selfish or altruistic, for individuals to seek cloning - infertility, same-sex couples, single men or women who wish to have children without a partner, early loss of a loved one, need for compatible transplant tissue - but some of the ethical issues have already been confronted. In 1990, a young Californian leukaemia patient's life was saved by a bone marrow transplant from her baby sister. Their parents had the second child - the mother was 42, the father needed a reverse vasectomy - only because they needed a source of marrow. Ethicists were dismayed, yet both children went on to grow up healthy in a loving family.
The transplant issue - and, indeed, the South Korean furore - highlight why cloning researchers dislike the terms of the human cloning debate. For many animal cloners do want to carry out what is, effectively, human cloning but not to create human replicas. They call it "therapeutic cloning" - using the egg's ability to reprogramme cells to manufacture replacement human tissue. Growing replacement brain cells for victims of Parkinson's disease is one of the areas that excites the Roslin researchers.
There was disappointment among medical scientists in Britain last year when the government rejected recommendations to ban whole human cloning but permit experiments into cloning human tissue. The government temporarily banned both: it is due to announce within the next few weeks whether it will lift the ban on the second type of cloning. This would allow scientists to experiment with cloning human cells without actually allowing them to clone people.
Researchers' enthusiasm to differentiate between the two types of human cloning has made them great promoters of the virtues of old-fashioned sex as the best procreation method. After all, as Yanagimachi points out, a human child is a half-clone of each parent. "Few species reproduce by cloning. Sexual reproduction produces diversity. Mother Nature somehow chose this method. There must be a reason for that. No one is perfect and they look in their mate for something missing in themselves so that their children are better."
Griffin agrees. "I would very much regret this technique being used to clone a human being, but I don't think cloning is going to be popular. Sex is always going to be viewed as cheaper and more enjoyable."
-- Risteard Mac Thomais (firstname.lastname@example.org), March 31, 2000
I guess no one ever told them: Leave well enough alone.
-- Mara (MW@aol.com), March 31, 2000.