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Cloning for Kicks

by Pete ShanksGeneWatch (Sep-Oct 2009)

Hwang and Snuppy

Pet cloning is a terrible idea -  and, we now know, an extremely unpopular one. Cloning endangered species is equally foolish. Re-creating extinct species is an absurd concept, whose worst extreme is the proposal to re-make a Neanderthal. Taken together, they represent a triumph of reckless technological tinkering, and of adolescent curiosity over meaningful ethics.

The idea of cloning pets immediately followed the 1997 announcement of the first mammal cloned from a somatic cell. John Sperling, a multi-billionaire, was reading about Dolly the sheep when he whimsically wondered if it would be possible to clone his girlfriend's dog, Missy. He delegated the project to his girlfriend's son, Lou Hawthorne, who ran with it for the next decade.

A dozen laboratories are said to have been interested, but the initial contract went to Texas A&M. They estimated that the project might cost a million a year and take five years. Sperling could afford it - and the A&M team got an entree to the intriguing world of mammalian cloning.

That was a hot new field in the late 1990s, and a lot of scientists wanted to dive in. By July 2002, 50 papers had been published in peer-reviewed scientific journals, describing 68 experiments involving about 45,000 eggs, 552 "live births" that did not live long and 386 surviving clones, of 7 different species. Cattle accounted for almost half of the survivors, and mice for most of the rest, followed by goats, pigs, sheep, a few rabbits and one cat (a side experiment by the A&M team).

Endangered Species

Some of these attempts involved endangered, or at least vulnerable, species. The first publicity went to Advanced Cell Technology (ACT), which took time out from cows to clone a gaur (Bos gaurus, a species of wild cattle), which unfortunately died two days after its birth. One of the sheep was of a wild, endangered variety (Ovis orientalis musimon, a European mouflon), which was cloned using a surrogate from a closely related domestic sheep, Ovis aries. In 2003, a threatened African wildcat was cloned, using a domestic cat surrogate; in the same year, a banteng (another cow) was born. More recently, there have been a couple of gray wolves, and that seems to be the sum total of 'success' so far.

There are a few legitimate environmentalists who think that cloning could be one of the tools used to assist endangered species. But the problems are substantial. Cloning does nothing to improve their environment; it adds no genetic diversity; it requires many surrogates and egg donors, who may be harmed; and it may distract from lower-tech but more practical conservation measures.

Some of  the people involved in endangered species cloning may have been well-meaning, but publicity was always part of the point. (ACT in particular was chronically short of capital, and developed a reputation for stunts.) Just look at the names given to these clones: Ditteaux for the Louisiana-based wildcat, CC for the domestic cat, Noah for the gaur, and so on. The master of this was Hawthorne, who first dubbed the dog-cloning effort the Missyplicity Project and then set up a company called Genetic Savings and Clone (GSC), to do gene-banking for pets and eventually to sell pet clones at a profit.

Except that the technology did not work very well. The A&M team never did clone a dog, though there was one stillbirth. And the cat was, to Hawthorne, "a disaster" in terms of  public relations: she did not look like the genetic donor. In retrospect, the choice of donor was a mistake, since she was calico. This multi-color pattern is caused by the random silencing, in early development, of one of the two X-chromosomes in each cell. The result is that a clone might be black and white (like CC), or orange and white, but never a combination of the three, as the donor was.

Enter Hwang Woo-Suk

GSC eventually stopped funding Texas A&M's efforts, and began their own, without much success, though they did beyond selling a couple of cats. Meanwhile a team at Seoul National University (SNU) led by the soon-to-be-notorious Hwang Woo-Suk was working intensively on the dog problem. They had the advantage of access to animals bred for food and the preparation of a local tonic; reportedly they used 5,000 dogs in their experiments. Finally, in 2005, they succeeded in cloning an Afghan hound - after creating 1,095 embryos and transferring them, over the course of two years, into 123 surrogates, which resulted in three pregnancies, one miscarriage, one puppy that died after 22 days, and one success. (Their cute name: Snuppy, for SNU-puppy.)

This triumph of persistence was rapidly overshadowed by the discovery that Hwang had faked some of his work on human embryonic stem cells, embezzled millions of dollars in government funds, and violated laws and ethical guidelines about acquiring women's eggs. He left SNU in disgrace; at the time of writing, he is still awaiting sentencing. In the meantime, he set up his own research establishment, and Hawthorne hired him. GSC had gone bust, but Hawthorne now headed two other companies: BioArts and Encore Pet Services. And eventually, five clones of the original Missy were born - after a decade of work, millions of dollars and who knows how many surrogates and egg donors.

The one peer-reviewed paper to emerge from all this only covers the work of Hwang's team, and is largely devoted to comparing two different embryo activation methods. In the best case, 14 dogs were needed to produce one live clone. That's with essentially unlimited funds and animals, and some of the most skilled technicians aroundavailable. A 2008 survey article estimated that only 1%-5% of all cloned embryos transferred into surrogates develop into viable offspring. A 2007 paper by mouflon-cloner Pasqualino Loi et al. described the production of living offspring as "phenomenological," which in this context seems to be a high-falutin'grandiose way of saying that the process is "trial and mostly error."

"Error" is in fact too bland a word. Some animals grow too large in the womb, sometimes to the point of killing their surrogate mothers. Some seem to be developing normally but then are miscarried or still-born. Some are born unable to breathe, or with skeletal malformations. Some seem healthy at first but rapidly show such signs of discomfort that they have to be killed before they die in agony.

Extinct Species

Despite this, and despite the overall lack of success in cloning endangered species, there has been at least one serious attempt to re-create an extinct one. This was a Pyrenean goat called a bucardo. The last bucardo died in 2000, but tissue samples were saved. In January, 2009, there were actually headlines claiming success, even though the kid was unable to breathe and died within minutes.

Several other species have been discussed for re-creation, including the saber-toothed tiger, the short-faced bear, the giant ground sloth, the moa, the Irish elk and the giant beaver. The one that has attracted most attention is the wooly mammoth. Both Hwang and a Japanese team tried and completely failed, because the frozen tissues were too degraded, but now hopeful scientists are estimating that it could be done for $10 million or so.

Here's the plan. First scientists must finish sequencing mammoth DNA, which seems to be less than 1% different from an elephant's (about 400,000 gene variants). Then they take an elephant cell, reprogram it to an embryonic state, and modify it to match the mammoth's sequence. This could then be the basis of a mammoth clone in an elephant's egg, which would be brought to term in an elephant surrogate. That is, if they can find one. Elephants are themselves threatened, but this does not seem to stop the speculation.

Even if all this is possible, which is not certain, it is not entirely clear what the result would be. Genetically, it would be a mammoth, at least essentially. (It would presumably include a tiny bit of elephant mitochondrial DNA, and it seems inevitable that there will be gaps in the code, bridged with stretches of elephant DNA.) But it would surely be one disturbed beast, even if it were physically healthy. There would be no herd, so the social aspect would be lacking, or severely distorted; the vegetation, climate and entire ecological surroundings would be quite different from that of 5-30,000 years ago; it would be a mammoth-like simulacrum.

An even more disturbing prospect has been mooted: cloning a Neanderthal through a similar process. The obvious surrogate would be human, but that's off the table. Instead, the idea would be to modify a chimpanzee, which is genomically very similar to both humans and Neanderthals. Then a chimpanzee surrogate would bring the near-Neanderthal to term. "The big issue," George Church of Harvard has said, "would be whether enough people felt that a chimp-Neanderthal hybrid would be acceptable, and that would be broadly discussed before anyone started to work on it."

The Dog Business

The nascent dog cloning business was rocked by two announcements in the late summer of 2009. First, a Korean company, RNL Bio announced a major investment in it, with the expressed intention of dropping the price to $30,000. Second, Hawthorne quit. His company, BioArts, had been trying to sell the service at $138,500, and the price-cutting announcement seems to have been the last straw.

Hawthorne seems to think that RNL just wanted to drive him out of business, perhaps because they were involved in litigation over cloning patents. His envoi was a 3200-word statement that revealed, among other things, just how few people want cloned pets. BioArts ran a well-publicized essay competition in 2008 to give away a clone. They expected hundred of thousands of applications, and received 237.

Opinion polls always suggest animal cloning was unpopular, and this confirms it. Evidently people understand the absurdity of trying to clone a once-beloved pet. Clones are not copies, and the attempt to make them causes obvious harm to animals. Hawthorne has now admitted that not only did some cloned dogs have unexpected coloration, some had skeletal malformations, and (weirdest of all) one clone of a male was actually born female, presumably because something very strange happened in early development.

Quite Exactly what RNL Bio expects from the market is not clear. Until now, they have been using the SNU team, now led by Hwang's former colleague Lee Byeong-chun, who cloned a "drug-sniffing" dog that works for Korean Customs for them; the seven puppies cost over $700,000, which may be too much for the government. (When announced, they all had the same cute name: Toppy, for Tomorrow's Puppy.) There has been discussion of cloning endangered wolves and "a new breed of dogs known for their talent at detecting cancer cells."

None of these seem like much more than publicity stunts. RNL is an ambitious multi-national with a major focus on human stem-cell treatments. Their president has talked about making human-dog hybrids for medical research, which might give them a reason to develop cloning technologies. The pets, however, seem like a side-show.

Conclusion

In 1997, it was surprising that somatic cloning worked at all. A decade on, it seems that there has been more to learn from its failures than its successes. In any case, the basic science of developmental biology should not be driven by technological whim.

The very idea of cloning seems to fascinate some scientists, however, and to drive them to find excuses to pursue it. Consider the work on endangered species: What is the question here that researchers are trying to answer? From the outside, it appears to be not so much "How can we help endangered species?" as "How can we use cloning?"

This enthusiasm has survived the failure of the technique to develop as once expected. Efficiency has improved a little, but not much. Every failure involves living, breathing and too often suffering animals. And for what? To replace a pet? To add an attraction to a zoo? Animal -welfare arguments are tricky enough in medical research, where the justification is human benefit. When the benefits are so trivial, the harm to animals clearly outweighs them.

A deeper - probably unconscious - motivation may be one of control, a desire to mold the natural world into shapes we ourselves imagined. Let's see what a Neanderthal looks like! Wouldn't that be neat? No, it would not. The result would either be a failure or, in the unlikely and unprovable event that it succeeded, an ethical monstrosity - a near-human created for pure curiosity.

Cloning for fun is simply a bad idea.

Pete Shanks is an author and commentator who writes on the eugenic possibilities of biotechnology for the Center for Genetics and Society. He is the author of Human Genetic Engineering: A Guide for Activists, Skeptics, and the Very Perplexed.



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