WHEN the birth of the first cloned animal, Dolly the sheep, was announced in 1997, the question in many people鈥檚 minds was: can we clone people too? 鈥淲e鈥檝e no idea if it would work,鈥� Dolly鈥檚 creator, Ian Wilmut, told 快猫短视频 at the time.
Seven years later, Wilmut himself is planning to attempt human cloning. He argues in this issue (鈥淭he moral imperative for human cloning鈥�) that stem cells taken from cloned human embryos could be of enormous benefit for medical research, as well as providing a means of treating disease. Most controversially, he argues that cloning techniques could be combined with genetic engineering to cure hereditary diseases. The potential benefits are so great, Wilmut says, that 鈥渋t would be immoral not to do it鈥�.
The first step towards realising his vision has been taken by a team in South Korea. In a paper published in Science last week, they described how they managed to derive stem cells from a cloned human embryo.
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Before this, only one group had published details of attempts to clone human embryos, in 2001. The team, at biotech company Advanced Cell Technology of Massachusetts, did not manage to get any embryos to grow beyond the six-cell stage. And all attempts to clone monkeys from adult cells have also failed. Last year, cloning expert Gerald Schatten of the University of Pittsburgh in Pennsylvania published a paper suggesting that reproductive cloning would never work in primates.
So how has a team at Seoul National University in South Korea managed to achieve what some said was impossible? And just how much of a breakthrough is their achievement?
A few commentators have implied their success was due to the fact that they were unhampered by the regulations researchers in the west have to deal with. While the team did not have to go through the lengthy application process that Wilmut faces in the UK, South Korea has clear laws on cloning, banning it for reproductive purposes while sanctioning research. The US, by contrast, has no national laws. The Korean experiments were carried out under strict guidance from a review board, and with the consent of health agencies.
One reason for the Korean team鈥檚 success is the calibre of its members, led by Woo Suk Hwang. Embryonic stems cells (ESCs) derived by team member Shin Yong Moon are included in the American stem cell registry, the list of 72 human ESC lines to which federally funded research is restricted. The researchers are also highly experienced cloners. A little-noted paper by Hwang published last year, for instance, describes a series of interspecies cloning experiments involving no fewer than 1700 cow eggs (Fertility and Sterility, vol 80, p 1380).
Hwang and his colleagues also have the support of their government, which 鈥� together with an unnamed private source 鈥� funded their work. 鈥淭hese people are a national resource in South Korea,鈥� says Schatten.
But perhaps their biggest advantage was a plentiful supply of eggs: 16 unpaid volunteers donated 242 healthy eggs. It is a gargantuan quantity compared with those available to western scientists so far. 鈥淲e paid several hundred thousand dollars for a few dozen eggs,鈥� says Robert Lanza of Advanced Cell Technology, referring to the company鈥檚 failed attempt in 2001.
Hwang鈥檚 team used all the eggs in a clever way, trying out several different approaches to find out what works. In the largest experiment, using all they had learned, the team obtained 19 blastocysts 鈥� the stage at which ESCs can be derived 鈥� from 66 eggs, a success rate of 29 per cent.
This figure is comparable to success rates in cows and pigs. While the culture conditions may have made the difference, the team also introduced a new method of squeezing the nucleus out of the egg, which might be less damaging than sucking it out with a micropipette.
From one of the blastocysts, the researchers managed to derive stem cells. This ESC line appears to have the same characteristics as those derived from normal embryos. After years of discussion and hype, we finally have proof that therapeutic cloning is possible in humans.
What this means is that tissue for treating a sick individual could be obtained by taking a cell from that person鈥檚 body, cloning it and then extracting stem cells from the resulting embryo. The stem cells could be used for everything from repairing damaged hearts to tissue-engineering replacement organs. The great advantage of therapeutic cloning is that cells with a patient鈥檚 own DNA would be given to them, so immune rejection would not be a problem.
Animal experiments back the idea that stem cells derived via therapeutic cloning can be used to treat disease. In the February issue of Circulation Research, for instance, Lanza鈥檚 team describes injecting stem cells derived from cloned embryos into mice that had suffered a heart attack. After a month, the stem cells had replaced nearly half the damaged tissue and improved function.
But similar trials have already been carried out in humans, using adult stem cells derived from each patient鈥檚 bone marrow. And this is just one way of obtaining matching cells without resorting to therapeutic cloning. Several groups are working on the idea of developing an ESC bank with a large enough number of cell lines to guarantee that a good enough match can be found for any patient. Other approaches include modifying ESCs so they do not trigger an immune response in an unmatched recipient, and turning adult cells directly into stem cell-like cells or even other adult types.
If anything, the Korean work emphasises the enormous practical difficulties that still remain to be overcome before therapeutic cloning could be used to treat people. Despite their success in getting cloned embryos to grow into blastocysts, the Korean researchers managed to derive stem cells from just one of the 30 blastocysts they created.
What鈥檚 more, this success was achieved during one of their early rounds of experiments, in which they fused one of the cumulus cells found around eggs with an empty egg taken from the same woman. When they tried using cells from other women, they got blastocysts but no stem cells, Hwang told reporters in Seattle last Friday. And with male cells they did not even get good blastocysts.
If both the eggs and cells have to come from the same person, then therapeutic cloning will obviously be of limited use. Only further experiments will tell.
Now that the optimal set of conditions for cloning humans is available, however, research should move forward at a much faster rate. 鈥淗ere you have the cookbook, the recipe,鈥� says Lanza.
This research is most likely to happen in countries such as South Korea, Singapore and the UK, where governments have decided to allow research into therapeutic cloning. In the US, normally the powerhouse of scientific research, scientists, and the companies that fund them (as government funds cannot be used for such research) fear such work will soon become a crime. 鈥淲e鈥檙e going into the battle with both hands tied behind our backs,鈥� says Lanza.
Do we now have a recipe for creating cloned babies?
THERE can be no doubt that the rogue scientists who want to create cloned babies despite the high risk of abnormalities are poring over all the details published in Science last week. But there is a big difference between getting stem cells from a cloned human embryo and creating a cloned baby.
Experiments by Gerald Schatten鈥檚 group at the University of Pittsburgh in Pennsylvania show that cloned monkey embryos, while healthy in appearance, have many genetic abnormalities. He thinks this is because the first step in cloning, removing the nucleus of an egg, also removes the spindle proteins cells need to divide properly, producing chromosomal abnormalities in the developing embryo. This could be why attempts at cloning monkeys have failed, though not all researchers agree.
The fact that stem cells could be derived from only one of the 30 blastocysts created by the Korean team points to similar problems, says Tanja Dominko, now at biotech company CellThera of Massachusetts, who did the monkey cloning experiments with Schatten. There might have been genetic abnormalities in all the blastocysts that did not yield ESCs. 鈥淒id they look normal? I would have liked to have seen a little more analysis,鈥� says Dominko.
Even the blastocyst that yielded the ESC line might have been defective. It has been shown that stem cells can be derived from poor-quality embryos discarded by IVF clinics. And seemingly normal stem cells have also been derived via parthenogenesis, in which an unfertilised egg is 鈥渢ricked鈥� into developing as if fertilised (快猫短视频, 26 April 2003, p 17). But parthenogenic embryos cannot develop to term.
Suppose this one blastocyst was healthy. Even then, rogue cloners would either have to implant dozens of cloned embryos in women in the hope that one or two are healthy, or find some way of identifying healthy embryos before implantation. No reliable method exists.
Then there is the fact that the cloning technique worked best when an adult cell was fused with an egg donated by the same woman, and did not yield good quality blastocysts when male cells were used. That would place a severe limitation on who could be cloned. 鈥淭his is a recipe for human cloning only in the sense that 鈥榗atch a turtle鈥� is a recipe for turtle soup,鈥� the editor of Science, Donald Kennedy, told reporters in Seattle.