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Ten years on, has the cloning dream died?The
birth of Dolly the sheep heralded a biological revolution.
But her legacy is not what we imagined. Were she still with us, the most famous sheep in history would doubtless celebrate her 10th birthday on 5 July by posing for the world's media and gobbling down a celebratory cake of barley and molasses. Dolly the cloned sheep seemed to know she was special and, unlike her creators, loved being centre stage. "It was fortunate for us that Dolly was such a media star," says Ian Wilmut, who headed the group at the Roslin Institute in Midlothian, UK, that created her. "In a biological sense we realised the enormity of what we achieved. What I didn't anticipate was the enormous interest that followed:" Dolly died in February 2003, but her iconic status as the first mammal cloned from a specialised adult cell lives on. Yet 10 years after her euphoric birth, the hopes, and fears, that cloning would spark a revolution in biotechnology, animal breeding and human medicine have so far proved wide of the mark. Dolly was created by reprogramming an adult cell - in her case a sheep's udder cell. At the time, the received biological wisdom was that a mammalian cell's developmental clock could never be turned back in this way. "There was massive relief and surprise when it worked," says Alan Colman, former head of PPL Therapeutics, the company collaborating with Roslin to exploit cloning technology. From the beginning, though, politics began to cloud the issue. Headlines often concentrated not on the Roslin team's scientific achievement, nor on the wider possible applications of cloning technology, but on concerns about cloning humans. In response, some scientists focused on the potential benefits of "therapeutic cloning' - deriving embryonic stem cells genetically matched to individual patients, which might be used to grow tissues to replace those lost to disease or injury. In fact, the Roslin team had pursued cloning primarily to improve livestock, hoping to create hordes of identical animals from one elite individual. For cloning offered a unique means of creating genetically modified animals, to produce drugs in milk, or to provide organs for transplantation into people. Fast forward, and few of the predictions have come to pass. Humans have not been cloned despite claims by maverick scientists. "There are no cloned Hitlers marching around," Colman observes. Therapeutic cloning has yet to live up to its billing, and may even have muddied the debate over stem cell research, while there have been mixed successes with applications in animal breeding. Several of the companies formed to exploit cloning technology have, like Dolly, met their demise, and only now is cloning starting to pay its way in a few select areas. The main problem is that creating healthy embryos by cloning has proved much harder than anticipated. To make Dolly, Wilmut, Keith Campbell and their colleagues started by fusing nuclei from 277 cells of an adult ewe's udder with "enucleated" sheep egg cells-those stripped of their own chromosomes. Somehow the eggs seemed to re-programme the genomes of the adult cells, allowing some to start developing into embryos. But only 29 grew to the point at which they could be transferred into the uterus of a surrogate mother, and only one live lamb-Dolly-was born. When these results appeared in Nature in February 1997, they were seen as a proof of principle, so no one dwelled on the numbers. Researchers assumed it would quickly be possible to boost the efficiency of cloning, by refining techniques used to manipulate and culture the cells and embryos. Some progress has been made: by tinkering with their methods, researchers have managed to clone about a dozen mammalian species. And those cloning livestock now lose fewer fetuses during gestation than they used to. But there has been no leap forward to transform the dismal numbers game. "Essentially, the efficiencies are not much different than in the early days," says Bob Lanza of cloning company Advanced Cell Technology (ACT) in Worcester, Massachusetts. "We really don't know what's going on:" Normal genes? One major problem is that cloning causes abnormalities in "epigenetic" modifications to DNA, such as the addition of methyl groups, which alter the activity of critical genes. The failure to reset the epigenetic changes present in the adult cell used for cloning may undermine the survival of the resulting cloned embryo. So researchers are still looking for the magic recipe to turn cloning into a routine procedure. Last December, for instance, a team led by Teruhiko Wakayama of the RIKEN Center for Developmental Biology in Kobe, Japan, announced that it could boost the number of implantable mouse embryos up to fivefold by treating them with a drug called trichostatin A, which wipes clean many epigenetic changes to DNA. Other researchers doubt whether such simple treatments will solve the problems with efficiency. "They can never ensure that a nucleus is completely reprogrammed into a normal embryonic state," says Konrad Hochedlinger, a cloning specialist at the Massachusetts General Hospital in Boston. Then there is the related question of whether clones can ever be "normal". The large numbers of cloned animals that die during gestation or around birth bear testament to serious problems, and whether those that survive into adulthood are truly healthy is still a matter of debate. In the early days, cloning specialists worried that cloned animals would age prematurely due to shortened telomeres - caps on the ends of mammalian chromosomes that protect genes but erode as cells divide. Today, this is not thought to be a major problem, and ACT and other firms have found no obvious clinical abnormalities in their cloned animals. But it may be a different story at the cellular level, because of the epigenetic abnormalities. At the Massachusetts Institute of Technology, researchers led by Rudolf Jaenisch have compared the epigenetic profiles of cloned and normal mice, and found massive differences that affect the activity of a wide variety of genes. "I don't think that cloned animals will ever be completely normal," says Hochedlinger, who worked on the experiments with Jaenisch. Pharming dreams Dolly's legacy is not completely dominated by disappointment, however. PPL hoped cloning would usher in the era of "pharming" - genetically modifying animals to produce useful proteins in their milk. The company also hoped to help many people waiting for organ transplants by engineering pigs whose organs would not immediately be rejected by the human immune system. PPL went bust in 2004. Its plans to market alpha-1-antitrypsin, an enzyme to treat the lung disease emphysema, sank due to inconclusive results and a lack of money. Rather than embracing the idea of making proteins in animals, the biotech industry has concentrated on other methods, such as cultures of genetically modified mammalian cells, which pose fewer regulatory hurdles. But cloning is finally starting to be accepted as a way to deliver some pharmed products, because it offers a much more precise way of making genetically engineered animals. Traditionally, transgenic animals were made by injecting gene copies into a new embryo - an inefficient and chaotic process. Genes can land anywhere in the genome, disrupting other genes. Now researchers can insert DNA at a precise position into a single adult cell, and then clone it to create the desired animals. GTC Biotherapeutics in Framingham, Massachusetts, is now using cloning to make animals that produce novel proteins, and cloning is starting to make its mark for application: such as gene "knockouts", where it is the only option. For example, Hematech, a company in Sioux Falls, South Dakota, has created cows that can make human antibodies, by knocking out the animals' own antibody genes and adding the human equivalents. Company president Jim Robl says that cloning was necessary both for the knockouts and also to "rejuvenate" the cells between rounds of genetic engineering. And the dream of creating pigs that can serve as organ donors is still alive, with a descendant of PPL called Revivicor in Blacksburg Virginia. It has made "double knockout" pigs in which both copies of a gene for the enzyme alpha 1,3 galactosyl transferase a disabled. This enzyme adorns pig cells with a sugar against which the human immune system mounts a massive attack, causing rapid "hyperacute" rejection. Kidneys and hearts from the knockout pigs transplanted into baboons lasted up to four months. The organs were still rejected, so Revivicor has added two other genes to its knockout pigs: one to prevent blood clots in the transplanted organs; the other to mop up antibodies against the organs. The next step is to transplant organs from these animals into primates. Finally, cloning can be used to create knockout animals in which to study human disease. For instance, Randall Prather of the University of Missouri-Columbia is trying to clone pigs missing the CFTR gene, which causes cystic fibrosis when faulty. Some of these applications would not immediately have sprung to mind with the birth of Dolly exactly 10 years ago. Dolly remains an icon, and one whose legacy remains to be fully written She may yet turn out to be the trigger for many ground-breaking innovations -which isn't at all bad for a rather ordinary-looking sheep that just happened to love the limelight. Peter Aldhous and Andy
Coghlan
See also The Roslin Institute and Dolly the Sheep One of a kind Therapeutic cloning set back by hype and fraud Cloning - use and misuse Stem Cell Biodiversity Cod, DNA and code Cloned babies New class of technology pioneers First embryonic stem cell trial on the cards The Demise of Homo sapiens |
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