Cloned Sheep Raises Ethical Issues

She does not look like a circus freak or a monster or an omen of evil. Her eyes and ears have a pinkish hue - just like they are supposed to.

Cloned Sheep Raises Ethical Issues

She does not look like a circus freak or a monster or an omen of evil. Her eyes and ears have a pinkish hue - just like they are supposed to. She is seven months old and coated with fistfuls of woollen curls, a natural sweater against Scottish air so cold on this winter morning that her breath rises in puffs every time she bleats. Her white eyelashes blink sleepily despite the mania around her: the staccato popping of strobe lights and whirring of cameras as photographers elbow closer to her pen, whistling to get her attention and calling out "Dolly, Dolly, over here Dolly," as if she were someone's pet dog instead of a sheep. "Who's the freak here?" Dolly might well have wondered, gazing back at the pack of one-eyed humans.

As you can see, she is a normal sheep," says Dr. Alan Colman, a redheaded 48-year-old scientist watching with a bemused smile from a few feet away. "She looks like a sheep, behaves like a sheep." But that does not mean Dolly is just any old Finn Dorset from down on the farm. She was created by what Colman's research partners at the Roslin Institute just south of Edinburgh were calling - with some understatement - "an unusual method." For Colman is also a businessman and his business is BIOTECHNOLOGY, an industry where the maxim is build a better mouse and the world will beat a path to your door. Judging by the worldwide interest in Dolly's coming out last week, he and his Roslin partners have done it.

In the scientific language of the landmark paper Roslin's researchers published in the British science journal Nature, Dolly "was born after nuclear transfer from a mammary gland cell, the first mammal to develop from a cell derived from adult tissue." In everyday language, they did something that most people considered to be purely in the realm of pulp science fiction. Taking a cell containing 98 per cent of the DNA, or its genetic blueprint, from the udder of a six-year-old adult sheep, they fused it to the egg of another sheep to produce a lamb that is virtually an exact copy - an identical twin, six years younger - of the original animal. (Two per cent of DNA is transmitted only through a mother's egg.) The lamb, Dolly, has the same hereditary characteristics as her genetic mother. And if they can do it with a cell from an adult animal, the researchers acknowledge it is "probable" that the same technique could be used to copy humans. "What Dolly shows, in principle, is that we can start again," says Ian Wilmut, the embryologist who headed the Roslin team.

Whether the discovery was of atom-splitting significance for science or just another step along the biogenetic road was debatable. But there was a convulsive popular reaction to breaking the barrier between the realms of science and fantasy. While many scientists welcomed any new understanding of biology's mysteries, religious leaders and many ethicists shuddered at this latest method by which science can now tamper with the fundamentals of life. The Vatican condemned it. The German media, hearing ugly echoes of Nazi eugenics experiments, brooded about it. And the British government, with an eye on the storm, announced an end to Roslin's funding.

Many people shared the unease of British Nobel Peace Prize winner Joseph Rotblat, who called for international ethical safeguards against abuses of biotechnology. Genetic engineering, said Rotblat, "was a threat to humankind." One set of humans clearly in danger: the Roslin researchers themselves, who were openly nervous that their discovery would prompt animal rights activists to seek revenge for their experiments with sheep. The scientists would not divulge where they lived, and camera crews were told not to take pictures of the staff. Animal rights activists vowed to take revenge anyway.

While Dolly allowed late-night-show gag writers to breathe easier for a week, she also spawned widespread speculation about how the technique might be used - and abused. The institute was quickly swamped with appeals from the wacky and the sad, people from around the world desperately begging the researchers to regenerate dead husbands and children. Talk shows touched on outlandish scenarios. Was it now possible for people ill with terminal diseases to produce a twin they could tap for "spare parts"? Could musicians clone themselves to continue creating for eternity, or supermodels provide designers with an endless supply of bony look-alikes? And would megalomaniac dictators be tempted to populate the world with copied versions of their evil selves?

The reality, of course, is that even if human cloning took the enormous leap from the theoretical to the practical, personalities are shaped by an array of factors beyond genetics. But that vision of multiple Hitlers troubled even Colman's wife, who asked her husband at home one night whether "some tin-pot dictator somewhere in the world could use unscrupulous means to clone himself." Colman told her it would be exceedingly difficult but technically possible. "I'm not absolutely sure that reassured her," he said dryly last week. His 14-year-old son also questioned what his dad was unleashing on the world. "I knew then," said Colman, squirming slightly as he reluctantly divulged his own family's misgivings, "that we were going to have a problem with the general public."

The twin burden of scientific hero and ethical villain rests mainly on the shoulders of Wilmut. A balding, bearded 52-year-old who cites walking, curling and sipping single-malt scotch as his hobbies, he is an unlikely candidate for cinematic casting in either role. Wilmut began working on his thesis that it was possible to clone one mammal from another adult 10 years ago, distracted only by the frequent need to beat the bushes for more research funds. He says he "never came close to giving up." When asked what kept him plugging away for so long on a theory that most biologists ruled out as preposterous, he allows only a self-deprecating smile and says: "I guess I lacked of imagination to go away and do something else."

Wilmut was born near Warwick, England, the son of a math teacher, "a very clever man." But he describes himself as an average student, who went to university to study farming simply because he wanted to work outdoors. Discovering that he had "no commercial instincts whatsoever," he fell instead under the spell of researcher Chris Porge at Cambridge. Porge had discovered how to freeze cells in 1949, and Wilmut went on to do a doctorate in freezing pig semen. "He taught me a lot about cells," recalls Wilmut. In 1973, Wilmut produced his first calf from a frozen embryo.

Wilmut answers a curt "No" when asked if he is religious. To him, embryos are "still a bunch of undifferentiated cells, about one-twenty-fifth of an inch in size." Like others in the field of biotechnology, he has made his personal peace with the ethics of manipulating the early stages of life, as well as with the need to induce genetic defects - and therefore some degree of suffering - into animals in the search to unravel the puzzle of diseases. But he has had to get used to jibes since a year ago, when his team used a revolutionary technique to produce two sheep from embryo cells. People attacked him in public and asked how he could sleep at night. They called him Dr. Frankenstein.

"It doesn't hurt my feelings; I have no sleepless nights," he says slowly when asked about those incidents. "I fully understand that there are people who find this all deeply offensive." Wilmut does complain, however, about the "breed of people in Britain who make a living by generating anxiety." He blames misguided academics and animal rights activists for the alarmist reaction last week to Dolly's conception. "This isn't making a human," he says forcefully. "There isn't any practical use for this technology with humans. If people would realize that, then we could take the emotion out of the debate."

So Wilmut says he had no soul-searching moment when Dolly was born, no crushing epiphany like the one that struck J. Robert Oppenheimer on watching the atomic weapon he designed explode over the New Mexican desert in 1945. "It worked," was all Oppenheimer said after the first atomic flash, but he later recalled a line from Hindu scriptures to describe his emotion: "Now I have become Death, the destroyer of worlds." "Nothing like that," snaps Wilmut, almost disdainful at any suggestion that his emotions might have gone beyond a biologist's simple excitement at seeing something happen for the first time. "I think we all went out for dinner." He is not buying into any Oppenheimer analogies. "Nuclear weapons are much more dangerous than this," he says.

But Wilmut has also taken his critics head on. He sits on a Church of Scotland committee that meets monthly to examine ethical issues raised by advances in science and technology. "We have our disagreements," says Michael Appleby, a university lecturer in animal welfare who is also a member. "I am religious and Ian is an avowed non-believer. But he wanted to address the ethical issues, and ethics are by no means the sole prerogative of the church." Wilmut says he and the others on the committee have had some convergence of opinion on the issue. If so, that was not evident in the newspaper article that Donald Bruce, who chairs the committee, wrote last week, attacking Wilmut's cloning research. "To produce replica animals on demand would be to go against something basic and God-given about the nature of life," wrote Bruce. And, he added, "history suggests we could never rest assured that no human being would dream of exploiting genetics or embryology to evil ends."

Wilmut was also attacked earlier this month when he spoke at Glasgow's Centre for Contemporary Art as part of a panel during an exhibition on science and animals. "It's hard to find people who will publicly defend animal experimentation because there's such fanaticism out there," said Francis McKee, the show's curator. "Ian is on the front lines of genetics, and I was worried for him when he agreed to appear." McKee, who is also a medical historian, says he is not sure he agrees with cloning, "but I know you can't stop that kind of curiosity or drive in a scientist."

Wilmut's colleagues say he shares that purist's thirst for knowledge. But as the front man for Roslin's cloning project, he parries attacks on the research by stressing its possible medical benefits to humans. At every opportunity last week, he turned the discussion of his discovery back to its potential for producing herds of so-called transgenic animals - essentially animals that are living drug factories because their milk produces the therapeutic proteins that make up some medicines. Making transgenic drugs is already a multibillion-dollar industry, but the current method of producing transgenic animals is an inefficient, hit-and-miss process. Wilmut's procedure should guarantee that every animal in the herd is transgenic, secreting enough protein-laced milk to speed up clinical trials of new drugs and get them to market faster.

Over and over, Wilmut and Colman emphasized the therapeutic possibilities of their cloning technique. Allergic properties could be removed from cow's milk to make it digestible to more people, they said. Pig organs could be genetically modified for transplanting into humans without the risk of passing viruses across the species barrier. And the technique would allow certain genes to be more easily isolated and modified. For example, they proposed that genes that might make cattle susceptible to the so-called mad-cow disease that has devastated British herds could be altered or removed. "When we start to put what we've done into life and death situations, then it suddenly becomes more acceptable," insists Wilmut. "And as it becomes more acceptable, people will lose their fears." Then he took another question from a reporter, one about what would prevent some egotistical billionaire from secretly hiring a scientist to clone him a twin.

The breakthrough that allowed Roslin to stun the world was no new high-tech gizmo, but an idea. Several researchers around the world were trying to do the same thing: fuse DNA from donor cells to unfertilized egg cells by passing an electric current through them. But the process they used tended to damage the DNA. Roslin researchers overcame that problem by doing the fusing when the donor cell was in a dormant state, somewhat like an animal in hibernation. The stage is called G-zero or "quiescence," and the Roslin team calls it the key to their success.

Keith Campbell is the researcher who had the moment of eureka two years ago to use G-zero. "I don't think in a straight line; there are all sorts of things flying around up here," explains the engaging 42-year-old frog biologist, pointing to his curly-haired head. Unlike Wilmut, whose PR responsibilities required him to restrain his enthusiasm in front of the world's cameras, Campbell was openly exuberant about the project in an interview. "I'm just fascinated by the biology of it all," he said as he drew a sorry doodle of a sheep on the corner of a newspaper to illustrate how Dolly was produced.

Campbell has had several different scientific careers, from running tests in a medical lab to studying Dutch elm disease. But his doctorate is in frog biology, and scientists in that field were demonstrating that they could clone amphibians as far back as the early 1970s. "I thought my background could help this research," he says about the decision that took him to Roslin five years ago. "If we could do it in frogs, I didn't see why we couldn't do it in mammals. Don't get me wrong," he continues. "There are a lot of differences between frogs and humans. It's significantly easier to do in frogs."

"But as a frog biologist, I think nothing is impossible, just slightly improbable," he explains. "Now, we've proved a point that's been debated for a long time. But I have always believed." He pauses for a second, for the obviousness of it all to sink in on his visitor. "Because we could do it in frogs," he implores.

But the move from frogs to so-close-to-humans in a generation conjures images of men in lab coats messing with life-forms. "Serious science-fiction writers avoided the subject of cloning - they wanted realism," says Robert Sims, president of the University of Edinburgh Science Fiction Society. "Cloning was only for scare stories. It was used as an example of bad science, of science gone wrong." Bill Bell, a University of Edinburgh English professor who specializes in science fiction, agrees that cloning is one of those subjects that has darkened science for the layman. "There is a deeply ingrained popular suspicion that the roots of science are in the occult," he says. "There is always this fear that science is asking questions it shouldn't, that it is seeking forbidden knowledge. That's why there is such a negative reaction to cloning."

And it manifests itself in more than polite literary debate. In Europe, protesters have periodically demonstrated over the past year to try to block shipments of genetically modified foods, such as corn and soybeans. Animal rights demonstrators in Britain have campaigned against genetic engineering for years. In 1989, arsonists tried to burn the Roslin facility down, and succeeded in razing another biotech lab in the neighboring town of Bush. "The spotlight will be falling on Roslin pretty brightly now," warns Robin Webb, spokesman for Britain's Animal Liberation Front, which uses "economic sabotage" to battle researchers who experiment on animals. The group considers the property of any employee at Roslin, or of any company that services the institute, to be fair game.

And it is not even the most radical group. Others calling themselves the Animal Rights Militia and the Justice Department have sent mail bombs to their targets. So Roslin's security is tight. There is a lot of electronic surveillance, and two German shepherds, Buster and Prince, conduct night patrols. Staff members say the dogs know where their loyalties lie.

The dogs at Walter Brown's farm a few kilometres down the road from the institute also know their job. The three border collies rolling in the mud and then jumping up on Brown's clean pants are there to round up his 800 or so sheep, scattered across the surrounding moors. Walter has heard about Dolly on television, and he pauses when asked how scientists might modify the genes to produce a better sheep. He offers something about the need for newborn lambs to be woollier, to keep them from dying of exposure during the cold April lambing season. But as the collies keep pawing him, he has a better idea. "They could give the sheep better brains, make 'em smarter." It makes him laugh. "Then we wouldn't need the dogs."

Another Ewe

To create Dolly, the Roslin Institute researchers:

1. Extracted mammary (udder) cells from an adult ewe.

2. Removed the nucleus containing the genetic material from another sheep's unfertilized egg.

3. Fused a mammary cell, with its own DNA, to that egg with electricity to make it start to grow into an embryo.

4. Transplanted the growing embryo into the uterus of another ewe that served as surrogate mother.

Born in July, Dolly contains the same genetic information as the ewe that provided the mammary cells.

Body Doubles

Now that science has figured out how to Xerox sheep, fears are running rampant that a brave new breed of human replicants is just around the corner. Big deal. Hollywood, where they have been treating people like sheep for ages, has already perfected the cloning business. Take, for example, the movie about the mad scientist who fabricates his offspring in the laboratory. Which movie? Take your pick. Ever since the early Frankenstein flicks, the premise itself has been cloned over and over and over again.

The classic example of a gene-cloning movie is the 1978 thriller The Boys from Brazil, in which Gregory Peck is ludicrously miscast as Dr. Josef Mengele, a Nazi psychopath who incubates a brood of spoiled teenage boys with blue eyes and shocks of straight black hair from samples of skin and blood donated by Adolf Hitler before his death. Mengele's goal is to resurrect the Third Reich with a Hitler clone. Laurence Oliver plays Lieberman, the Nazi hunter who tracks down the bad doctor. In a scene designed to lend the premise some plausibility, he listens to a scientist - a sane one - explain how he has cloned rabbits by injecting donor cells into eggs stripped of their genetic nucleus.

"And this can be done with humans?" asks the incredulous Lieberman. "It's monstrous!" The scientist gives him a blank look. "Why?" he asks. "Wouldn't you want to live in a world of Mozarts and Picassos? Of course it's only a dream. Not only would you have to reproduce the genetic code of the donor, but the environmental background as well."

Good thinking. Not every cloning flick is so fastidious - certainly not Woody Allen's Sleeper (1973), in which a dictator's disembodied nose held the blueprint for cloning a new world order. But most movies do portray ovum engineering as an evil business, leading to the propagation of a runaway species that could consume the planet. In the Frankenstein tradition, however, the scientists can have benign intentions. The Nobel laureate played by Peter O'Toole in Creator (1985) was just trying to make a facsimile of his dead wife to keep him company in his old age. And the dinosaur-incubating eggheads in Jurassic Park - which will be cloned in a blockbuster sequel this summer - just wanted to build a zoo.

There is, of course, an entire genre of sci-fi movies populated by cybernetic clones - ranging from the replicants in Blade Runner to the Arnold Schwarzenegger gladiator in Terminator 2. They are, basically, disposable people. Their flesh can be graphically gored, squished, punctured, cut and ripped, and for some reason the violence is supposed to seem less offensive because it is just machine flesh. Aliens, meanwhile, are old hands at cloning people as hosts. Movies ranging from Invasion of the Body Snatchers (1956) to Species (1995) have taught us that soulless mutants may be lurking under the skin of even the most regular-looking folks.

Finally, there is the clone as household drone. In last year's comedy Multiplicity, Michael Keaton played an overworked construction foreman who replicates himself with the help of a local geneticist. The first clone is a macho overachiever, the second an effeminate New Man, and the third (a clone of a clone) a blithering idiot. The film fared poorly at the box office, putting a damper on future projects in the same vein. But Dolly's fame has changed all that - at the studios, cloning scripts are suddenly in demand.

But then cloning is what Hollywood is all about - call it the dubbing-down of mass culture. The movie industry thrives on duplicating the same formulas again and again, turning out sequels, remakes and knock-offs from an ever-shrinking gene pool of creativity. It also clones its stars, replicating a single personality into common currency. Andy Warhol, pop art's genius freak, figured it out in the 1960s with his serial silk screens of such icons as Marilyn Monroe, Elvis Presley and the Mona Lisa. Duplicating both the living and the dead, Warhol cloned the very tissue of celebrity, printing it up like sheets of counterfeit money. He was both mocking and minting Hollywood culture, and in case anyone missed the point, he also ran off silk-screened images of dollar bills.

In a globalized culture where a face can become an instant franchise - witness the proliferation of merchandise emblazoned with the Edvard Munch painting The Scream - cloning is a metaphor that has come full circle. In the typical horror fantasy, what draws the laboratory scientist to play God is a lust for immortality. In their own way, artists have always hoped to leave a mark that lasts beyond their death. But Hollywood has industrialized that desire. And if special-effects wizards have their way, the stars of the future could actually be clones - the digital kind. Director Robert Zemeckis, who brought John F. Kennedy back to life in Forrest Gump, has predicted that actors may soon be able to extend their careers indefinitely by banking computer clones of themselves in their prime. They could co-star with their younger selves in flashbacks, and be cast in movies long after their death.

But some stars might prefer to replicate themselves in the flesh. Madonna, for instance, could sidestep that whole messy business of finding a mate. She could conceive her own immaculate bundle of blond ambition - just like a virgin.

Maclean'sMarch 10, 1997