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Stem-cell research

Crunch time for Korea's cloners

A team in Seoul has stolen a march with its work towards human therapeutic cloning. The researchers have been fêted, but an ethical controversy may threaten their work. David Cyranoski investigates.

Copy shop: members of the Seoul team extract cow eggs from ovaries for use in cloning experiments. Credit: D. CYRANOSKI

Woo Suk Hwang's laboratory, set in the hilly campus of Seoul National University, is a cloning factory. In one room, a gaggle of blue-coated researchers sits around a table plucking egg cells from cows' ovaries. Next door, other members of the team dart around the lab's 12 micromanipulators. At one of these workstations, researchers punch holes in the cow eggs and squeeze out their nuclei. At the next, colleagues take the stripped-down eggs and fuse them with cells from adult cows.

This production line underpins a project to create genetically modified cows that should be resistant to mad cow disease1. It is just one of several cloning projects that require Hwang's army of researchers, students and technicians to handle up to 600 pig, cow and dog eggs every day. Hwang, a veterinary scientist, moved into cloning research in the late 1990s because of its promise in producing livestock with precisely defined genetic characteristics.

But it was a cloning experiment involving human eggs and cells that catapulted Hwang to fame this February. His team, together with researchers led by his Seoul National University colleague Shin Yong Moon, announced that they had obtained embryonic stem cells from a cloned human embryo2. This provided a proof of principle for therapeutic cloning — the idea of repairing damaged or diseased tissues using cells derived from the patient, which shouldn't be rejected by the immune system.

Therapeutic cloning is a controversial technique, opposed by anti-abortion activists because it involves the destruction of several-day-old human embryos. But additional ethical questions are swirling around Hwang's work, relating to the recruitment of the women who donated eggs for the project, and whether guidelines designed to protect their rights were correctly applied (see News, page 3).

A-list celebrity

When Nature visited Hwang's lab last month, however, he was riding high. Hwang has been a celebrity in South Korea since 1999, when he unveiled the country's first cloned cow. Since his February paper, he has been fêted both at home and abroad. On 20 April, Hwang received the South Korean government's ‘best scientist' award, worth US$260,000. Days later, he and Moon were listed in Time magazine's “A-list of the world's most influential people”.

Interviewed in his office, Hwang sat on the arm of a sofa, seeming flustered but apparently enjoying the attention. He had just received a delegation from the European Union; later, guests from Germany were due. “Everyone wants to know why we did the experiment or if they can collaborate,” he told Nature. In demand to give lectures worldwide, Hwang's itinerary for this year includes visits to Britain, Germany, Italy and Spain.

His research schedule is similarly busy. Hwang wants to clone animals for various agricultural applications. He is working on a project to clone the endangered Siberian tiger (Panthera tigris altaica), long extinct in the wild in South Korea, by fusing cells from captive adults with cow, pig, and dog eggs. And he plans to clone pigs to provide organs for transplants to humans. These will be genetically engineered to minimize the chances of the rejection by the human immune system.

The human therapeutic cloning project also needs much work. “It's the very beginning,” says Moon. “Please don't talk about clinical applications.” Before therapeutic cloning becomes a reality, the production of cloned embryonic stem cells must be made more efficient, as must the techniques of growing them into specific cell types to treat conditions such as Parkinson's disease, diabetes, or spinal cord injury.

Hwang and Moon made their cloned embryos by fusing eggs that had been stripped of their nuclei with cumulus cells. These cells, which surround and nurture developing eggs, came from the same individuals who donated the eggs. Attempts to clone embryos by fusing cumulus cells from one woman with eggs from another have so far failed. For therapeutic cloning to reach the clinic, it will be necessary to obtain viable embryonic stem cells using various types of cells from both men and women.

The researchers also want to see whether it will be possible to avoid the need for human egg donors by using cow eggs instead. Other groups are working along similar lines. Last year, for instance, Huizhen Sheng of Shanghai Second Medical University in China reported that her team had obtained embryonic stem cells from cloned embryos created by fusing human cells with rabbit eggs3. So far, Hwang says that his most successful experiment has brought 9% of the human-cow hybrid embryos to the stage at which embryonic stem cells can be harvested. But they have not yet been able to derive a stem-cell line.

Magic touch

Cell mates: their creation of cloned human embryos (below) has made Hwang Woo Suk (left) and Shin Young Moon famous in Korea and beyond. Credit: G. G. YOUNG/JOONGANGILBO/EPN/AP/T. S. WARREN UPI/W. S. HWANG/SNU

Hwang attributes the Korean team's progress to its members' “magic hands”. Experts who have visited the Seoul campus also point to the sheer scale of its cloning facilities. “I've never seen anything like it,” says Jose Cibelli of Michigan State University in East Lansing, who worked briefly with Hwang's group on its landmark human cloning paper. Cibelli was also struck by the Korean researchers' dedication and industry. Hwang says that members of his group commonly work from six in the morning until ten at night. “It is tiring, but they do not refuse,” he says.

Hwang has some 40 researchers in his team at Seoul National University's College of Veterinary Medicine; their equipment, provided through generous government support, is state-of-the-art. The human cloning work, meanwhile, was conducted in a separate facility, which Hwang says was funded through private donations. Because some Koreans oppose the creation of human embryos to obtain stem cells on moral grounds, Hwang says he kept his therapeutic cloning work separate from his state-funded projects on cloning animals.

At the nearby College of Medicine, Moon has 30 more researchers working on the establishment and characterization of stem-cell lines. Elsewhere on the Seoul National University campus, affiliated groups are working on every step of the process of creating cell-based therapies that might one day be used to repair faulty organs or tissues. In total, the university hosts some 180 researchers working on cloning and related aspects of regenerative medicine.

But perhaps the biggest factor underlying Hwang and Moon's success in their human cloning experiments was the recruitment of 16 women who were prepared to have hormone injections to make them superovulate. These donors provided the 242 egg cells that were required to obtain the single line of cloned human embryonic stem cells described in their paper, published in Science.

The resulting cell cultures are so precious that they are held in three separate, secure locations that are closed to visitors. “Even some of our research staff are not allowed to go in there,” says Hwang.

Keeping the embryonic stem cells themselves under wraps is understandable. But when Nature visited Seoul, citizens' rights activists and bioethicists were starting to complain about a lack of transparency surrounding the recruitment of the egg donors, and raising questions about how rigorously Hwang and his colleagues followed the ethical guidelines laid down for their research.

Egg collecting

These concerns will be heightened by an interview that Nature conducted with one of Hwang's PhD students, who was also a co-author on the paper, in which she said that she and one other member of the lab had donated eggs. The student later changed her story, denying she had donated eggs and blaming her poor English for a misunderstanding.

Bioethicists argue that such a donation would be a breach of good practice, which should keep donors and researchers at arm's length, so that principal investigators cannot influence donors directly. It would also apparently breach the guidelines adopted for the experiment, which should have excluded donors who might benefit from the research.

No other cloning research group has recruited so many egg donors. Women usually have the procedure either to conceive through in vitro fertilization, or in rare cases to donate eggs to other women. In the United States, women who donate eggs can be paid several thousand dollars for expenses and as compensation for the inconvenience of the invasive medical procedures. When Cibelli experimented with human cloning in 2001, while employed by the company Advanced Cell Technology in Worcester, Massachusetts, he used less than 20 eggs4, obtained from donors who were paid in this way.

By contrast, Hwang says that the Korean egg donors were not paid, and were motivated by a desire to help sick people, and through national pride. Cultural differences may also partly explain the Korean team's success in recruiting willing volunteers: in Asian societies a greater stress is placed on serving the common good.

Hwang has worked hard to engage the Korean public with his research, giving several public lectures each week. He wants to promote South Korea's economic development, borne in part from his memories of a childhood marked by poverty. “I want to make Korea a more well-equipped country, especially in science and technology,” says Hwang.

Public spirit

A herd of clones? One aim of Hwang Woo Suk's cow-cloning programme is to create genetically modified cattle that are resistant to mad cow disease. Credit: C. S. SIK/JOONGANGILBO/EPN

The motivations of the PhD student who initially told Nature that she was among the donors fit with this picture of altruism and intense patriotism. In her original interview, she mentioned a desire to help sick children, and her love for Korea.

Challenged about his PhD student's initial statement, Hwang said he checked the informed-consent forms signed by all 16 women and could not find her name. Some students did offer to donate eggs, Hwang added, but he “strongly refused”.

Even before Nature's enquiries, questions were being raised about the recruitment of egg donors for Hwang and Moon's research. Experts expressed suprise that the team had been able to recruit so many women prepared to donate their eggs for free. In late March, the Korean Bioethics Association convened a committee to consider the issue. “It is all speculation now, but we want to investigate whether there were any vulnerable donors involved, maybe some young female researchers or women with a conflict of interest,” says the association's secretary, Young-Mo Koo, a medical ethicist at the University of Ulsan College of Medicine.

The Korean Bioethics Association is pushing the National Human Rights Commission to investigate several aspects of Hwang and Moon's research, including the recruitment of egg donors, and whether the local Institutional Review Board that gave ethical approval for the project did an adequate job. The government-funded commission is expected to decide whether to investigate by 21 May. “It is a very delicate matter. Dr Hwang's experiment is a very big issue in Korean society,” says Young Jun Choi, an expert adviser to the commission.

This sensitivity is underlined by the reactions of some Korean scientists who admit to concerns about the ethical questions surrounding the research. “No one wants to debate the ethics because the government is so excited about it,” says one senior biologist at Seoul National University. “Most scientists are also worried about a lack of students in science, so they don't want to break the excitement either. We need a hero.”

Under pressure

For now, Hwang's work on human cloning is on hold. A national law was approved last December that would require a government committee to provide a license before any research using human eggs can be done. While the law does not come into effect until January 2005, Hwang says he wants to wait until the licensing system is in place. “If we can reach a consensus, we can continue our research with the support of the whole society,” he says.

But Hwang's critics argue that the research reported in his Science paper has already moved beyond the national consensus. “He did not have the social acceptance of the people,” claims Jae-kak Han, who heads the scientific division of People's Solidarity for Participatory Democracy, one of South Korea's leading citzens' rights groups.

Given the questions that are now being raised, the pressure is on Hwang to demonstrate that his work followed appropriate ethical guidelines. Any suggestion that it did not could undermine both Hwang's own plans to press ahead with therapeutic cloning research, and provide ammunition for critics of the technique worldwide.

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Cyranoski, D. Crunch time for Korea's cloners. Nature 429, 12–14 (2004). https://doi.org/10.1038/429012a

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