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Photos cast new doubt on cloning

Questions envelop S. Korean team

A landmark 2004 paper in which South Korean scientists claimed to have cloned human stem cells for the first time contains photos that appeared in an unrelated paper, calling their claim into question and increasing the controversy that surrounds the team.

Two photos in the 2004 paper, published to great fanfare in the journal Science, claim to show batches of the world's first cloned human embryonic stem cells. Yet the same photos appear in the journal Molecules and Cells, in a research article by another Korean team, submitted before the Science paper, and in that paper both photos are labeled as cells created without cloning.

The Globe showed the photos to four stem cell experts, and all said they appeared to be identical, down to the smallest detail. The two photos were used in the Science paper as evidence that the cells were cloned embryonic stem cells. The duplication, the scientists said, raised doubts about two of seven tests done to prove the cells were legitimate, but also raises serious questions about the legitimacy of the overall paper, especially after the questions raised about other work done by the team.

Last week, Hwang Woo Suk, leader of the Korean cloning team, said that he intended to retract a 2005 Science paper, in which he claimed to have improved his cloning method, after concerns were raised about that paper. The duplicate photos in the 2004 article now call into question his original claim. Hwang is the only scientist to claim to have cloned human stem cells; if his 2004 paper is discredited, it would mean that the daunting hurdles to human cloning, which Hwang had claimed to overcome, remain.

The photos appear to be copied, ''and that calls the entire paper into question," said Dr. Robert Lanza, a scientist at Advanced Cell Technology, a Worcester-based biotech that has worked on cloning human cells, and is a competitor of Hwang's. ''There seems to be a pattern here."

By yesterday, all three of Hwang's seminal papers -- two on cloning human cells, and one on cloning a dog -- were under investigation. The journal Nature is launching an investigation of the dog cloning paper, which it published in August, a spokesperson said yesterday. And a spokeswoman for Science, Barbara Rice, said yesterday that the journal's editors were now examining ''every aspect of papers from the Hwang lab, in light of the questions that have been raised, both about the 2004 and 2005 papers."

Hwang could not be reached by e-mail last night.

The investigations mark a setback for stem cell research. Hwang's two papers on cloning human cells electrified the scientific community, because many researchers believe that the technology will be a powerful tool for studying a wide range of diseases, and perhaps for generating new treatments. But, before Hwang, nobody had been able to overcome the numerous technical problems involved in cloning human cells. His papers seemed to have solved the technical problems, ushering in a new era of medical research. Instead, as the questions mount, scientists say that they cannot have confidence in any of the work the team did.

The two photos duplicated in the 2004 cloning paper come from a paper in the journal Molecules and Cells, by a group of scientists based at the MizMedi Hospital in Seoul. Two of the scientists listed as coauthors of this paper were also listed as coauthors of Hwang's 2004 cloning paper. In the Molecules paper, the scientists support some of their findings, about a type of cell called a ''human embryonic germ cell" with photos of embryonic stem cells created at the hospital, without cloning. Typically, human embryonic stem cells are taken from frozen embryos, left over from fertility treatments.

Two of these photos -- figures 3B and 3E -- are identical to two photos in the 2004 Science paper, figures 2B and 2D.

''The finding of duplicated photos in two papers make the [Hwang] results questionable," said Dr. Leonard Zon, a stem cell scientist at Children's Hospital Boston.

The Molecules paper was submitted Nov. 25, 2003, and published April 30, 2004. The Science paper was submitted Dec. 9, 2003, and published March 12, 2004.

Lanza raised questions about two other papers published by members of Hwang's team. In one paper, published last year in the Federation of European Biochemical Societies Letters, the results of a test done on two different groups of cells is presented, to compare how they respond to a growth factor. The test generates dark blobs, but two of these blobs seem to look precisely the same, except flipped, which would be very unlikely to happen by chance, Lanza said. This would imply that the test was not actually done, or that a serious mistake was made in preparing the paper. Hwang is not listed as an author on this paper, but two of the authors -- Kim Sun Jong and Park Jong Hyuk -- are listed on the 2004 cloning paper, as well as on the Molecules paper. The senior author of this paper could not be reached by e-mail last night.

In another paper, published in Molecular Reproduction and Development, there are several examples where blobs look exactly the same, even though they are supposed to be generated by different tests. Again, this implies that key tests were not done, or that the authors made errors in preparing their manuscript, Lanza said. Hwang is listed as the senior author.

Scientists said yesterday they are also concerned about Hwang's claim to have cloned a dog. Lanza, who has no evidence that there are problems with the paper, speculated that it would have been possible to create two identical dogs without cloning them. For example, he said, a scientist could split an early embryo in half, and both halves would be viable embryos. Then, the scientist could bring one embryo to term and freeze the other. After the first dog had grown, the second embryo could be brought to term -- effectively creating a twin that is younger.

However, Lanza said, scientists could verify whether the dog was actually cloned with a simple genetic test that looks at the mitochondrial DNA, a small amount of DNA outside the nucleus of every cell. If the dog is truly a clone, then it should have different mitochondrial DNA from the other dog.

Gareth Cook can be reached at cook@globe.com

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