DCSIMG

A breed apart

NOVEMBER 2000: IAN WILMUT & DOLLY

DOWN a storm-lashed country road, past the security guard, to a farmyard, where my escort keys a secret code into an electronic panel at the entrance to an anonymous whitewashed building. The metal doors slide open and I step into what looks like a stage set for Sydney Devine: all scrubbed stone floors and neatly stacked hay bales. This is what is known as 'the celebrity sheep shed'.

Nearby, in the rolling countryside south of Edinburgh, rain-sodden flocks of Scottish Blackfaces are being buffeted across the hillsides. But here - in the smartest ovine residence in the country - the nation's favourite fleece-wearer is sitting warm and pretty in her own stone-built corner stall.

Or rather, she is standing, front hoofs on metal gate, the opposite of sheepish, batting her long, white eyelashes, ready for her close-up. As I dip my hand into a sack of feed pellets, I note her scent is lanolin (naturally) and her decor cream and vanilla (very Hello! magazine). She is on the plump side (the result of too many high-protein snacks from members of the media) and her wool is longer than average (for the same reason). As her visitor book reveals, her entire life so far, four years and four months, has been lived in front of the camera lens - her latest photo session was two hours with a fashion photographer from the New York Times.

But now her creators, the researchers at Roslin Institute, say that science has moved on. It is time to say, "Goodbye, Dolly!" and turn the spotlight on to new developments. As with the Hollywood A list, this final audience with her is being granted for promotional purposes: to put the case for a controversial change in the law which will make a dramatic difference to humankind. The proposed legislation will be voted on in Parliament within the next few weeks.

As she eagerly nibbles a fistful of feed, I'm thrilled to be touching the most famous quadruped in the world - better known than Lassie, Skippy and Trigger put together; right up there with two-legged 20th-century icons Lenin, Elvis and Mandela. In terms of the future of homo sapiens, she is even more significant. One biologist reckoned the year of her birth should be declared AD 1 - After Dolly.

She is not the first mammal to be cloned by nuclear transfer. That honour goes to a lamb created in 1985 by Scandinavian biologist Steen Willadsen. But he worked with embryo cells. Dolly's distinction is that she is the first known mammal to be cloned from a fully developed adult cell, thus ushering in a brave new world of scientific possibility. When she was born, sci-fi film fantasy like The Boys from Brazil(mad scientist creates Nazi clones deep in South American jungle) suddenly looked frighteningly close to becoming reality. More immediately, for Dolly and those closest to her, her overnight transformation from anonymous lab lamb 6LL3 to ovine superstar drove her into the full glare of the media spotlight.

"Coming up with a photogenic animal was quite important. You get some sheep with huge ears and big Roman noses," says Dr Harry Griffin, the institute's bearded, amiable assistant director, who also acts as Dolly's very own Max Clifford. From the beginning, he says, "Dolly has charmed reporters", and the resultant 'Dollymania' has won the kind of publicity press agents dream of.

Named Science Breakthrough of the Year in 1997 by the prestigious US journal Science - ahead of NASA's Mars Pathfinder mission - Dolly has brought the institute kudos and funding: for instance, the 2.5 million they now receive from the American company Geron to investigate cell reprogramming. Today, her scientific purpose has been fulfilled. She has proved it is possible to clone an animal from an adult cell, and that such an animal can conceive and give birth normally.

But partly because of her PR value, and partly because none of the institute's 350 staff could bear to send her to the slaughterhouse, she is one of the few sheep to have the privilege of being allowed to die of natural causes. When this happens - she is expected to live to about 12 years of age - her carcass will be stuffed and put on display at the National Museum of Scotland in Edinburgh.

She already has her own authorised biography, The Second Creation: The Age of Biological Control by the Scientists Who Cloned Dolly. This fascinating and readable book contains snapshots from a sheep's life: proud Dolly with her first lamb, Bonnie; trimmed Dolly after her first shearing; relaxed Dolly at home in her pen with researcher friends. Despite being a serious book, the introduction - by highly respected science writer Colin Tudge - reads like a celebrity profile: "I first met Dolly in March 1997... She was a sweet creature, much cosseted since birth and extraordinarily tame. She danced round her pen at Roslin Institute as eagerly and vociferously as a spaniel, leaping into her feed trough for a better view, sociable even by the standards of sheep."

Professor Ian Wilmut, leader of the team who created her, describes her as "the very model of ovine affability... probably the tamest and most trusting sheep in the world". No wonder. Even before she was born she was receiving the kind of pampering normally reserved for the royal corgis.

For weeks prior to her birth, researchers camped out in the sheep shed. Since her arrival in the world, kicking and bleating, she has been treated to a high-protein diet and the best veterinary care. If the weather is fine, she goes out to graze, but otherwise she stays indoors in the warmth. To help her through the trauma of her first shearing (a difficult rite of passage for any sheep), a world champion sheep-shearer was flown in and a vet was kept on standby. The wool from her first fleece was featured on the BBC's The Clothes Show and a competition was held to design a jumper, now on display at London's Science Museum.

When Dolly met David, a Welsh Mountain ram, for her first mating (the natural, old-fashioned way), her pregnancy was confirmed by ultrasound scan. To protect her from the intense media interest surrounding the birth of Bonnie (because she is "a bonnie wee lamb") - born on Easter Monday 1998 - a private TV and stills shoot was held in her pen, and the images beamed around the world. After giving birth to three more lambs last year, and two this year, it has now been decided to spare Dolly the upheaval of any more pregnancies.

Despite her worldwide fame, she has never once left the farm where she was born, although it is not for lack of invitations. She has been invited on countless chat shows and even requested to make a personal appearance at 'Dollywood', the Tennessee theme park celebrating country and western star Dolly Parton. (As almost every school child now knows, the reason for Dolly being named after the Mae West-shaped singer is that she was cloned from mammary cells.) Griffin did give permission, however, for Dolly's nose print (as individual to animals as fingerprints are to humans) to be recorded for posterity by the Mississippi Crime Lab and for a Japanese wedding couple to fulfil their dream of posing for photographs with her. "A one-off," insists Griffin. "Dolly is still an experimental animal and is not available for opening fetes or attending agricultural shows."

As with so many famous figures, Dolly's beginnings are humble. Roslin Institute in unglamorous Midlothian is a government laboratory and the first piece of paperwork to relate to her is, prosaically enough, an application for 484,519 in funding from the Ministry of Agriculture. The request was made in October 1995, two months after the birth of Roslin clones Megan and Morag, lambs made from cells taken from nine-day-old embryos. At that time, the scientific world was convinced it would be impossible to clone animals from adult cells. Despite that, Dr Ian Wilmut and Dr Keith Campbell - as they then were - decided to make the attempt.

Intriguingly, the two men who came up with the scientific achievement of the decade did not do particularly well at their grammar schools. Wilmut did not pass enough A-levels to start a degree course and had to do a catch-up year before getting into Nottingham University to study embryology. Graduating with an upper second ("not bad, not brilliant"), he initially wanted to be a farmer. It was only because he didn't like the business-side of agriculture that he did a PhD and moved into scientific research at the laboratories now known as Roslin Institute. His first big success was creating Frostie, the world's first 'frozen calf', made by freezing a calf embryo, thawing it and then transferring it to a surrogate mother to give birth to it.

Critics of such work have tried to portray Wilmut and Campbell as crazed Dr Frankensteins, but in reality they are two ordinary blokes who have carried out extraordinary science. A bearded, bespectacled family-man with a wife, three grown-up children and a penchant for curling, 55-year-old Wilmut is often mistaken for a school teacher. In contrast, Campbell, ten years younger, with shoulder-length hair and a passion for playing the drums, looks more like a folk singer. He and his partner have two small daughters.

The first sign of Campbell's enquiring mind was in boyhood when he used to fill his mother's kitchen with frogs. Despite that, he left school without any A-levels to become a medical technician. "In other words, I trained initially not to be a research scientist but. the kind of person who helps the researchers to do their work," he recalls.

Eventually though, boredom with his job motivated him to get into Queen Elizabeth College, London, to study microbiology. He went on to do a DPhil at Sussex University, then worked in research to do with Dutch elm disease and cancer, before finally, in 1991, responding to a job advert Wilmut had placed in scientific journal Nature for a cell biologist to join him at Roslin.

Much of the work they did was top secret. Even the colleagues lunching with them in the canteen didn't know that Wilmut and Campbell were pursuing pioneering cloning experiments until their first creations, Megan and Morag, were born. The reason they chose to experiment on sheep rather than mice (the traditional laboratory animal) is the latter proved poor candidates for cloning. Sheep and cattle are more suitable, and of the two, sheep are cheaper and easier to handle.

The science behind cloning is extremely complex, but given the accompanying controversy, Dolly's creators have been on a mission to explain ever since she was born. They seem to have succeeded: there is now even a children's book called How to Clone a Sheep.

In Dolly's case, the procedure began with mammary gland cells from a Finn-Dorset ewe; Finn-Dorsets being a cross between Finnish rams and Dorset ewes. The cells came from PPL, a commercial bio-tech company on the same campus as Roslin Institute, which also provided some funding for a project most scientists would have dismissed as a waste of time. When Wilmut's team set to work in the winter of 1995/96, it was thought that while embryo cells could be reprogrammed to create any of the types of tissue typical of the organism, adult cells were irrevocably 'fixed'. The ewe that provided the cells to clone Dolly was six years old, elderly by ovine standards.

First, the genes of this unnamed Finn-Dorset were put into eggs taken from Scottish Blackface ewes to create 277 embryos. Then, in a series of operations Wilmut describes as "farmyard meets hospital meets laboratory", these embryos were transferred temporarily into a completely different group of ewes, and then removed. Only 29 of the embryos developed sufficiently to be used for the next stage, which was to transfer them into yet another group of 13 ewes. Of these sheep, only one became pregnant. This Scottish Blackface surrogate mother was kept in ovine luxury in the 'celebrity sheep shed', until - on July 5, 1996 - she gave birth to a 6.6kg lamb.

Out of the 277 embryos created from the adult mammary cells, this was the only one that had stayed the full course and become a live lamb - the one and only Dolly. "It remains astonishing that the experiment worked at all. But even so, this was a skin-of-the-teeth success," recalls Wilmut. "If none of the 277 had succeeded, then sensible biologists everywhere would have been confirmed in their belief that this could not be done. We probably would not have tried again."

Even before Dolly's official birth announcement in Nature, newshounds got hold of the story and within hours Roslin Institute was besieged by reporters and TV crews from around the world. Headline writers had a field day: 'We're All Flock Tamson's bairns'; 'Ewe Must Remember This'; 'Clone on the Range'; 'Will There Ever Be Another Ewe?'

Meanwhile, Dolly Parton declared herself "honoured" to be the inspiration behind the lamb's name and said there was no such thing as "baaaaad publicity".

Reaction ranged from the measured - 'Good or Bad, Dolly Has a Role to Play' in Scotland on Sunday - to the ridiculous (and wildly inaccurate) 'Dolly the Cloned Sheep Kills a Lamb and EATS it!' in the Weekly World News. Later, a story in the Sunday Times suggested headless human clones might be used to meet the shortage of organs for transplantation. "Perhaps the prime example of a story where everyone concerned seemed to lose their sense of perspective," notes Griffin.

On the political front, questions were asked in the Commons and President Clinton called on experts to report on the ethical implications. In the scientific world, opinion divided between doubters, who demanded more proof (they got it), and copycats, who rushed off to do their own cloning (there are now cloned mice, cows, goats and pigs).

Poignantly, the institute was also deluged with enquiries from grieving relatives asking whether lost loved ones could be cloned. And overnight, a company called Clonaid was set up in Canada, offering to replicate human beings for $200,000. Its founder was a cult leader called Claude Vorilhon, whose followers believe Christ's resurrection was the result of cloning by aliens.

Technically, cloning humans is now possible. But the idea of being able to replicate the dearly departed is a false one. At the same time as making Dolly, Wilmut's team also produced four young Dorset ram clones called Cedric, Cecil, Cyril and Tuppence from cultured embryo cells. Although genetically identical, they are very different in size and temperament, showing that an animal's genes do not determine every detail of its physique and personality. Or, as one Italian ethicist put it: "If you cloned Mother Teresa, you've got as much chance of getting a serial killer as a saint."

This knowledge has not prevented an anonymous millionaire, desperate to clone his pet dog Missy, donating $2.3 million to an animal scientist at Texas A&M University to develop the necessary techniques. Three years on, there is no puppy clone. Other animal lovers are already paying between $300 and $2,000 to have tissue removed from living or recently departed pets to be cultured, frozen and stored in liquid nitrogen until science is advanced enough for Fido or Kitty to be cloned.

Meanwhile, visitors have continued to flock to Dolly's pen. "Dolly, admirable creature that she is, responded splendidly and became even more tame and spoiled than she was already," observes Wilmut, now Professor Wilmut OBE but still working at Roslin. Campbell is now a Professor of Animal Physiology at Nottingham University. Their final joint creation was Polly, a sheep that was cloned and genetically transformed. Born a year after Dolly, the existence of Polly shows that 'pharming' (the genetic transformation of farm animals) could become routine - if public opinion allows it. (Already the huge outcry over genetically modified crops - 'Frankenstein food' - indicates that pharming may not be politically acceptable.) Dolly's creators are wholly opposed to cloning humans. As their co-author Tudge explains in Second Creation: "Keith suggests that human cloning may already be possible technically, in the sense that somebody who is prepared to take enormous risks might just get away with it. But he stresses that the present obvious dangers - the high rate of late abortions and perinatal deaths, and the attendant deformities - will surely prevent anyone who is not actually deranged from making such an attempt in the immediate future. I suppose it will happen eventually, though."

The main concern at Roslin Institute now, though, is whether they will be allowed to apply aspects of the technology used in producing Dolly to provide cures for a wide range of medical conditions. "Dolly's main contribution was to open our eyes to the possibility that we can reprogramme cells," says Griffin. He compares genes to an orchestra in which many of the musicians are asleep: wake them up and you can get them to play an entire symphony.

Researchers, including Wilmut, are now working on cell therapy which eventually could result in radical new treatments for leukaemia, diabetes, Parkinson's disease, strokes, heart attacks and a wide range of degenerative diseases, including osteoarthritis and muscular dystrophy.

"My current interest in medical biotechnology was fired by the suffering of my own father, who was diabetic, was blinded by the disease in the 1960s, and lost part of a leg and much of the use of his hands before his death in 1994," says Wilmut.

The problem is that while much of this research can be done on sheep and mice, at some point it will be necessary to use cells from human embryos to check the results. At present, the Human Fertilisation and Embryology Act only allows research on human embryos up to 14 days of development (when they are smaller than a full stop) for five specific purposes connected with fertility, contraception and genetic disorders. Two proposed amendments will be put to a free vote in both Houses of Parliament within the next few weeks.

If approved, they will permit research on finding therapies for a range of rare but devastating genetic diseases, as well as for more common conditions such as Parkinson's, which currently affects 120,000 people in the UK alone. Also possible will be further investigation into tissue engineering to create, for instance, artificial skin for burns victims, cartilage, blood vessels and even artificial bladders. While scientists and organisations like the Parkinson's Disease Society are lobbying hard for the amendments to be made law, pro-life groups are vehemently opposed.

However, as the ethical debate continues to rage fiercely, the sheep with the starring role in this scientific drama tamely accepts her daily diet of human attention. As long as I remain with her, she stays as close to me as she can, her big, liquid-brown eyes watching my every move. Only when I leave does she retreat, with two of her newest lambs, to a far corner of her pen. On the way out of the sheep shed, I sign her visitors' book. Although I'm out of her sight I shout: "Goodbye, Dolly."

From behind the cream-painted wall of her private stall comes a loud response: "Baaaaaaaa."

 
 
 

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