Cloning around (The Economist)
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Cloning around Mar 15th 2001

Human cloning is the stuff of fantasy, but a group of maverick scientists wants to make it real

SCIENCE fiction has not, on the whole, been kind to those at the cutting edge of human reproduction. From “The Boys from Brazil” to “The 6th Day”, Arnold Schwarzenegger’s latest oeuvre, people in the awkward business of human cloning appear as crazed, power-hungry, profit-seeking individuals on the fringes of society.

On March 9th, life took a turn towards art as a band of controversial scientists gathered before a mob of journalists in Rome to launch a project to produce a human by cloning. The protagonists—led by Severino Antinori, an Italian infertility specialist, Panos Zavos, an American researcher in the same area, and Avi Ben Abraham, an Israeli biotechnologist—plan to start tinkering with cells in the laboratory by the end of this month and to have a human clone alive and kicking by 2003. They claim their aim is to tackle male infertility by allowing those not up to the job of old-fashioned or even test-tube fertilisation, to have children who share their genes.

The team’s flamboyant scheme, which is long on secrecy but short on substance, has been condemned from all quarters and on a variety of counts. Many oppose the whole notion of cloning humans as an affront to human dignity. Bioethicists are troubled by concerns for the clone’s welfare, the viability of his or her family and the implications for wider society. Lawyers fret about the legality of such science, given regulations governing human cloning and embryo research in various countries. More surprisingly, strong arguments against the initiative come not just from those opposed to the principle of reproductive cloning, but also from researchers at the forefront of the technology.

Veterans, such as Alan Trounson at Monash University in Melbourne, Australia, have succeeded in cloning several species of mammal. But they are appalled at the prospect of trying the technique in humans when its problems have yet to be worked out in experimental animals. Dr Trounson, like many leading practitioners, is certain that human cloning can and will be done. Some of his colleagues, indeed, look forward to that day. What worries them is not the end, a cloned baby. Rather, they have serious doubts about the means, which will involve stillbirths and sudden deaths for as long as cloning remains a mysterious process.

Conventional fertilisation, in which sperm meets egg, is a complex event that brings together two half-sets of genetic material—one from each parent—to provide the resulting individual with a full complement of chromosomes. Cloning bypasses this by putting the genetic material from a pre-existing adult cell (which already carries a full complement of chromosomes) into an egg that has had its half-set of chromosomes removed. If all goes well, the egg will then develop into a normal, healthy individual.

Baby steps Unfortunately, all seldom goes well. Naturally formed embryonic nuclei have the advantage of being new to the world. They are therefore adapted to the task of turning on the genes necessary for development. The nuclei of adult cells, in contrast, have settled into a quiet middle age. In them, most of the genes for early development have been turned off and are difficult to reinvigorate. The great leap forward in cloning came when Ian Wilmut and his colleagues at the Roslin Institute, near Edinburgh, found a way to awaken these sluggish nuclei. They produced a lively and, to all intents and purposes, normal sheep, known as Dolly, from the nucleus of a mammary-gland cell.

Even so, according to Alan Colman, a nuclear transfer expert at PPL Therapeutics, a British biotechnology firm, cloning is still a crude process. For every 100 eggs used, a researcher is lucky to end up with a single cloned calf or a solitary pig in a poke. By comparison, in vitro fertilisation (IVF) has a success rate of roughly 25%.

The difference lies in the large number of individuals that fall by the wayside at every step of the cloning process. This begins with a stimulus, such as an electric shock, that promotes the fusion of an egg cell that has had its nucleus removed with a donor cell whose nucleus it will assume. Roughly four-fifths of fusions succeed, but only two-thirds start down the path of development that leads to a new individual.

After a couple of days, the newly nucleated cell should have divided to form a ball of cells called a blastocyst. Here again, losses occur, and only 10% of the original egg cells used in nuclear transfer make it this far. Once the blastocyst is implanted in the womb, at most 20% of pregnancies are carried to term, compared with three-fifths in IVF. The fetuses that are spontaneously aborted are often abnormally large. They also tend to have severe deformities, and their placentas are distorted. Finally, and most disturbingly to Dr Colman, half the cloned (and seemingly normal) cows and sheep that make it through to birth drop dead within three weeks. Post-mortem examination often reveals subtle, but nonetheless fatal, flaws in the heart muscle or kidneys of these animals—the sorts of changes that are hard to predict and therefore almost impossible to prevent.

Researchers are only beginning to get a sense of the range of things that can go awry in cloning. Certainly, something unusual is happening in the process by which the egg cell sends out signals to reprogram its new nucleus and put the developmental genes back into action. There appears, in particular, to be a problem with a phenomenon known as genetic imprinting.

Most genes in a cell are present as two copies, one from the mother and one from the father. Imprinting is the process by which one of those copies is silenced so as not to overdose a cell with whatever that gene provides. Although the transplanted nucleus enters the egg properly imprinted, reprogramming messes this up. As a result, some genes become too active and others fail to work at all. By studying the expression patterns of individual genes, cloners have found that certain genes which should be turned on in early development, such as those that control the implantation of the embryo into the uterus, are activated much later in cloned embryos.

Unfortunately, they have little idea why this is the case. Nor do they know the full set of genes that go awry, which makes foolproof screening of faulty embryos impossible. Without such safeguards in place, there is no reason to assume that human cloning will not repeat the messy trial and error of current animal research. Not surprisingly, those who know reproductive cloning best are urging others to refrain from trying it on people until the bugs have been worked out on hundreds more animals.

Means, motive, opportunity Such uncertainties do not deter Dr Antinori and his crew. They believe the technical problems associated with animal cloning have been greatly exaggerated, and may not be relevant to humans. In any case, they reckon that their experience with IVF gives them “enough knowledge and sophistication and technology to break the rules of nature, and now is the time.”

Dr Antinori is certainly well known in IVF circles, but more for such stunts as impregnating a 62-year-old woman using IVF than for his scientific prowess. In any case, success at IVF—which was thoroughly tested on animals before moving into humans and was never plagued by the sorts of trouble seen in nuclear transfer—is no guide to success in cloning. As yet, the team has little expertise in nuclear transfer, and although its members say they will try to bring the right people on board, the best in the business are unlikely to be drawn in while human reproductive cloning remains at the margins of scientific and social respectability.

As to cost, Dr Trounson estimates that it will take at least $1m to clone a human, given the equipment, labour and hundreds of human eggs that will be required to get a single, live birth. There are enough infertile couples desperate to reproduce, enough small sects eager to keep their numbers up and their gene pools pure, and enough megalomaniacs intent on replicating themselves, to make money the least of would-be cloners’ problems. Indeed, Dr Zavos claims the consortium has more than enough cash to do its work, and up to 700 volunteers ready to take part. Few scientists believe that the group will reach its goal within the next two years, but many acknowledge that the technology will one day permit human reproductive cloning. Whether society will condone it is an entirely different matter.