Verdict: Hwang’s human stem cells were all fakes: Landmark papers shown to be fraudulent, but Snuppy turns out to be a real cloned dog.

Hwang’s home university announced damning results in a press conference today.

SEOUL The results are in. The university committee looking into scientific misconduct in the laboratory of South Korean cloner Woo Suk Hwang announced on 10 January that his 2004 claim to have cloned a human embryo was fake. But his Afghan hound Snuppy is a real clone.

The announcement finally confirms the gravest suspicions of Hwang’s work with humans. There are two papers in which Hwang’s group claimed to clone human cells - a 2004 article that describes the first cloned embryo and derivation of a stem-cell line from it (W. S. Hwang et al. Science 303, 1669-1674; 2004), and a 2005 article that claims the establishment of eleven ‘patient-specific’ stem-cell lines (W. S. Hwang et al. Science 308, 1777-1783; 2005). Both have turned out to be complete and deliberate fakes.

“Such an act is nothing other than deception of the scientific community and the public at large,” concludes Myung Hee Chung of Seoul National University (SNU), who headed the committee.

With the 2005 paper already discredited in the panel’s interim report (see Nature 439, 8; 2005), Chung’s statement focused on the 2004 paper. DNA fingerprinting tests carried out by three laboratories found that the genetic material of the supposedly cloned human cell line, NT-1, did not match that of the donor. Nor did it match any of the stem-cell lines from the in vitro fertilization (IVF) embryos of MizMedi Hospital, which were the source for the faked data in the 2005 paper.

Further investigation revealed that mitochondrial DNA from the cell line matched one of the egg donors, but the DNA inside the cells’ nuclei varied at several locations. The committee concluded that the line was derived by parthenogenesis - where the single set of chromosomes in an egg develop as if it were fertilized. The images and data in the paper that showed perfect matches were fabricated.

The committee also found that Hwang worked with a staggering number of eggs - 2,061 from 129 women - despite claiming to have used only 242 eggs for the 2004 study and 185 for the 2005 study.

The findings are a huge setback for therapeutic cloning - the idea that cloned embryos could be used as a source of patient-matched stem cells to replace damaged tissues in a range of diseases. Even using numbers of human eggs of which other researchers can only dream, Hwang’s team was unable to derive such stem cells, and the field is now left with no evidence that it is possible in humans at all (see Nature, 438, 1056-1059; 2005).

The committee did find that Hwang succeeded in cloning human embryos to the blastocyst stage, from which stem cells can be derived. But the success rate was just 10%, and they were “in poor condition”. The only other group to have some success, Alison Murdoch’s team at the University of Newcastle upon Tyne, UK, has cloned just a single blastocyst (M. Stojkovic et al. Reprod. BioMed. Online 11, 226-231; 2005).

It is possible to create embryonic stem-cell lines, insists Kevin Eggan, a researcher in the field at Harvard University, Massachusetts. But no one will venture a guess as to when it might be accomplished. “There are many unknowns,” says Eggan. “We don’t know how many eggs will be needed and we don’t know how many women will step forward to contribute.”

Ethical transgressions in the way Hwang got his eggs - he seems to have coerced junior researchers into donating - have stimulated an international debate over how eggs should be obtained. Eggan expects to gain approval this spring to begin human stem-cell cloning research, and he says his group will follow the US National Academies’ guidelines. These stipulate that egg donors should receive no payment.

Even when admitting faked data, Hwang has maintained that his human cloning techniques are valid. But most experts say they merely involve tweaks to previously known methods, such as squeezing the nucleus out of cells rather than sucking them out with a needle. “Besides some slight adjustments, there was really nothing new,” says Teruhiko Wakayama of the Center for Developmental Biology in Kobe, Japan, who created the first mouse clones in 1998.

Many experts conclude that Hwang’s greatest achievement was Snuppy, the first cloned dog (B. C. Lee et al. Nature 436, 641; 2005). The SNU investigators verified Snuppy’s identity as a clone by proving that he had the same nuclear DNA as the skin-cell donor and the same mitochondrial DNA as the egg donor - a conclusion that was confirmed on 10 January by Nature’s own investigation.

Dog ovulation produces very immature eggs, so culturing them is difficult, even for basic IVF, says Wakayama. “If it’s real, this is their greatest accomplishment,” he says. The SNU committee also noted that Hwang - originally trained as a veterinarian - showed greatest skill when it came to cloning animals, notably pigs and cows.

As Nature went to press, however, the Munhwa Broadcasting Corporation, which originally accused Hwang of faking his data, was about to air a television programme questioning Hwang’s claim to have cloned a cow - the work that first shot him to fame in South Korea. The SNU committee said it was unable to confirm whether the cow was a clone because Hwang did not cooperate with them.

The committee, which issued a 50-page report covering the investigation, stopped short of accusing Hwang or other individuals on the team of deliberate fabrication. It deferred to national prosecutors who will now look into legal aspects of the case and the possibility of fraud. Hwang received huge funding from the Korean government for his work, including an annual stipend of US$3 million, which he started receiving this year as the country’s “supreme scientist”.

The New York Times December 16, 2005: News Analysis

Scandal for Cloning Embryos: 'A Tragic Turn' for Science

By GINA KOLATA

Last May, a stunning research paper in Science, one of the world's most respected scientific journals, instantly changed the tenor of the debate over cloning human embryos and extracting their stem cells. A team of South Korean scientists reported in the paper that they had figured out how to do this work so efficiently that the great hope of researchers and patients - to obtain stem cells that were an exact match of a patient's - seemed easily within sight.

But that rosy future has been cast into doubt with the statement last month by Dr. Hwang Woo Suk, who led the team that wrote the paper, that it contained fabricated evidence. Questions have also been raised about earlier research and a new debate has begun.

Scientists and ethicists caution that the full story is not in, but they are staggered by how the research has unraveled so far.

"This is a tragic turn," said Laurie Zoloth, director of the Center for Bioethics, Science and Society at Northwestern University. Stressing that she considers Dr. Hwang innocent until proven guilty, she asked, however, whether the edifice of stem cell research was built on sand.

"We depend entirely on the truthfulness of the scientific community," Dr. Zoloth said. "We must believe that what they are showing us and what they say has been demonstrated is worthy of our concern and attention."

The South Korean story, Dr. Zoloth added, raises questions about whether the science is good. "Good as in true and real and morally worthy of our funding," she explained. "That is so most especially in this twilight sort of terrain with a lot of open questions that people disagree about. At least we thought that the step-by-step slow technical achievements had placed the science on a trajectory."

"Is this our version of W.M.D.?" Dr. Zoloth said.

A vocal opponent of cloning human embryos voiced a similar concern. "Certainly, if these reports are true, it's a tragedy for science," said Nigel Cameron, president of the Institute on Biotechnology and the Human Future at the Illinois Institute of Technology.

He said the episode showed that stem cell research and cloning to create human embryonic stem cells, "is a hype balloon and it's been pricked." Not so, said the ethicist Arthur Caplan, an outspoken supporter of stem cell research. "We know that in science, speed kills if you go fast, and that's what the South Koreans did," he said. "It's also clear that they will do whatever it takes to right this ship. At the end of the day, critics of stem cell research will try to use this, but they won't get very far. People bending the rules in other countries doesn't reflect badly on us."

The promise of cloned human embryonic stem cells remains, said Dr. George Daley, a stem cell researcher at Children's Hospital in Boston.

"The goal is still there and the medical value is still largely theoretical but no less than before."

Dr. Cameron, however, said the political implications of the South Korean scandal are huge.

When it seemed that the South Koreans had taken a giant leap forward in stem cell research, he noted, "we panicked into thinking that we have to join in." Politicians and patient groups argued that cures were around the corner if scientists could get the needed support. States poured money into stem cell programs.

The collapsing South Korean claims, Dr. Cameron added, made him ask: "Where's the beef? Where are those cures? Why is it that there is no private money going into this research? The business community values it at zero."

Richard Doerflinger, deputy director of anti-abortion activities at the United States Conference of Catholic Bishops, said that he has argued for some time that the stem cell proponents were exaggerating the state of the science and misleading the public about scientific accomplishments. They promised cures that, if they ever came, would not come any time soon. But Mr. Doerflinger said that when he tried to point out what he saw as misleading claims, " no one would listen."

Now, he said, with the collapse of some of the South Korean scientists' research, the situation may change.

"In one sense, this puts us back to where we were before May of 2005, when there still was some uncertainty about whether this would work at all," Mr. Doerflinger said. "In another sense it does illustrate in my mind how hype and ambition have gotten ahead of the science."

"How am I going to exploit it?" he said. "You don't have to. It's just speaking for itself."

Then the rumors surfaced that the data in the paper itself were suspicious. Several of the published micrographs, which were presented as showing different sets of cells, upon closer examination turned out to be different views of the same cells. This, at least, seemed to have an innocent explanation: Hwang said the duplicates had been sent and published by mistake, and Science acknowledged that the duplicate images were not part of Hwang's original submission. But then researchers began to question why some of the DNA profiles of the clones of cells were so very similar--they looked like the same data because they lacked the expected level of experimentally induced variation. Then coauthor Gerald Schatten of the University of Pittsburgh, who had previously broken off his collaboration with Hwang in a very public split, asked Science if his name could be retracted from the paper because he had doubts about the paper's accuracy, and said cryptically that he had heard "allegations from someone involved with the experiments that certain elements of the report may be fabricated," to quote the New York Times.

How much of a colossal black eye will this scandal give to embryonic stem cell work in general? I commented on that point previously, back when it looked like Hwang's headaches all centered on the research ethics. But outright fraud carries this to a whole new level. Frankly, I've been surprised that some of the usually vociferous opponents of embryonic stem cell research haven't been making more of a fuss about the Hwang affair all along. I kept waiting to hear them argue that the ethical laxity of the Korean lab only proved that the moral of judgment of stem cell researchers couldn't be trusted--that no matter what promises the scientists made to uphold human dignity in their work, they would surely start committing atrocities once they were allowed to operate freely. (My hunch is that the clear willingness of so many in the stem cell community to push for strong codes of scientific ethics has blunted this attack so far.) Something tells me that those kinds of criticisms will become much more common shortly.
How does all this affect the international competition for stem cell dominance? American researchers like Robert Lanza of ACT have been complaining that the successes of Hwang's lab underscored how the U.S. had squandered its initial lead in this area of science. Korea might not have had the largest set of resources thrown against the problem, but Hwang's stardom certainly made it a frontrunner. If Hwang's work is illusory, though, the center of power would seem to have swung back over to the U.S.--that is to say, California.
How will Korea respond? Hwang has been a national hero over the past couple of years. The country had designed a stamp to celebrate stem cell research, for pete's sake! This may be a crushing blow for many Korean nationals.
Might this scandal end up helping the cause of good stem cell science? Many scientists and ethicists have been arguing for some time that some international code of responsible stem cell research needs to be accepted by the global scientific community. Some of them have further argued that it behooves the U.S. to spearhead this movement. Perhaps the Hwang affair will give that issue some traction.
If the Korean lab can't clone embryonic stem cells from adults, can anybody? How close are we to achieving that goal in reality? How much of a real setback is it for stem cell science if we can't, given that the application of embryonic stem cells to therapies was probably some way off anyway?
Who knew what when? That June 17 Science paper has 25 coauthors. It's easy right now to focus all the attention on Hwang because he was the principal investigator and rightly did have ultimate responsibility for the project. For example, Hwang said that some of the enthusiastic female researchers in his lab had gone behind his back to donate their own eggs even though he had counseled them not to. Still, as the principal investigator in the lab, he should have known where all the materials came from, so that's not much of an excuse. But surely at least some of those other coauthors had to have known that something fishy was going on if indeed so much of the data was falsified. If they didn't know, why not? Not to pick on Gerald Schatten, but what exactly was his role in this research supposed to be and, in retrospect, did he discharge those responsibilities as well as he should? In short, how many of the names on that author list are at least as guilty as Hwang seems to be in having perpetrated and covered up a scientific fraud? (And again, not to make excuses for him, but is it conceivable that Hwang supervised all those coworkers so loosely that he didn't know the extent of the fabrication until too late?)
And the obvious question: what were Hwang and company thinking? What made them think that they could fabricate results for a study that would inevitably receive almost unlimited scholarly attention? How did they think they could keep the evidence of their fabrication under wraps indefinitely? What were they going to do when the rest of the scientific world started asking them to produce more cloned cells under more supervised conditions?
There's an old wry observation that if you look back at disastrously bad decisions made throughout history, you could probably find someone connected to each who would have said, "Well, it seemed like a good idea at the time." But I can't see how anyone in the Hwang lab could have ever even thought that.