Scientists Cast Doubts on Dolly

by Nicholas Wade
Copyright 1998 The New York Times
(February 28, 1998)

A year after the announcement that Dr. Ian Wilmut had cloned Dolly the sheep from the adult cell of another sheep, no other scientist has succeeded in repeating the experiment, despite several efforts, Wilmut is in a defensive posture, undertaking new tests to confirm that his claim was correct, and critics are asking why these tests were not required before publication by the scientific journal in which his report appeared.

In an e-mail note on Thursday, Wilmut said that he would test whether fetal cells could be found in the circulation of pregnant sheep, even though "it is extraordinarily unlikely that Dolly is from a fetal cell." Since the ewe from which Dolly was cloned was pregnant, critics have suggested Wilmut might by unlucky chance have selected a fetal cell, not an adult cell, from which to clone Dolly.

The turn of events is unexpected because Wilmut's claim generated sustained public debate about the possible cloning of humans, culminating in bills to ban research on human cloning that reached the floor of the Senate this month.

The assumption that human cloning is an imminent prospect was based on Wilmut's report that he had cloned one sheep from the adult cell of another, the first time that had been done in mammals.

Wilmut's experiment, long accepted without demur, came under criticism last month from Dr. Norton Zinder, a distinguished microbiologist at Rockefeller University. In a letter to the journal Science, Zinder said Wilmut's success rate, one in about 400 tries, was scientifically meaningless, because any number of possible errors could yield a false result.

Wilmut's critics come principally from the ranks of molecular biologists, who pride themselves on the rigor of their experiments. Researchers who work in embryology have been generally more supportive of his work.

"Replication of an experiment is important," said Dr. Randall Prather, an animal-cloning expert at the University of Missouri, "but I think we shouldn't be surprised that we haven't seen it a year later -- doing these experiments is not a trivial matter."

Wilmut has said he expects other laboratories to repeat his results in the near future, and said he may repeat the experiment himself, a shift from his previous position that repetition was unnecessary.

But the steps he is now taking to bolster his original claim have disturbed some scientists.

"It is kind of shocking that only a year later are we getting the tests done to see if Dolly's origins are as presented," said Dr. David Housman, a biologist at the Massachusetts Institute of Technology.

Zinder said he welcomed the new tests that Wilmut was undertaking but that they should have been done before the original report was accepted for publication.

The same point was made by Dr. Walter Gilbert, a Nobel laureate at Harvard University. The paper should not have been published in the form in which it appeared, Gilbert told The Sunday Times of London recently.

"There is almost no evidence offered in the paper that the cells were from the mammary gland of an adult sheep," he said, referring to the donor cells from which Dolly was said to be derived.

Nature, the journal that published Wilmut's report, has not taken a neutral part in the controversy. It has used Dolly in its advertising, and an editorial in the current issue described Zinder's letter as representing "an extreme position in its demands for proof."

It would be premature, the editorial said, "to draw any conclusions from the absence so far of a second mammal cloned from adult cells."

The editor of Nature, Dr. Philip Campbell, defended the decision to publish Wilmut's paper, saying it had received appropriate review and that important scientific findings, like the possible discovery of life in a Martian meteorite, often cannot be repeated to the extent desired.

But he said that the "extraordinary spotlight on this work wasn't anticipated and it may be that if everyone had thought it would be subjected to such scrutiny, they would have gone to greater lengths."

The dispute over Wilmut's claim raises the issue of how thoroughly a researcher should replicate an important result before publishing it, and the related question of what standards of proof a journal editor should demand before accepting a paper for publication.

Neophyte researchers are taught to be their own fiercest critics because the only thing worse than finding an error in one's favorite theory is to have one's helpful colleagues do so. Test tubes can get mixed up, cell cultures can be contaminated by different types of cells, and any number of other things regularly go wrong in even the best of laboratories.

So the golden rule is that before a scientist thinks of publishing a result he or she should replicate it several times to make sure it was not an error.

This caution was not observed in the case of Dolly, Wilmut's only success in 434 efforts. Because of factors having to do with the breeding season of sheep, it would have taken a long time to repeat the experiment with a new donor sheep, Wilmut has said.

Scientific journals like Nature ask experts to review the manuscripts submitted for publication and require authors to address reviewers' questions before publication. Several of the questions raised by Zinder are of the type a reviewer would usually ask.

Dr. Benjamin Lewin, editor of Cell, a leading journal of molecular biology, said he would probably have published Wilmut's paper, but would have insisted that the authors point out they could not prove that Dolly was derived from an adult sheep cell.

Experiments with a low success rate always raise questions of reproducibility, Lewin said, but it might have been unreasonable to ask for a repetition of the Dolly experiment if it required a year to do.

Also, Lewin said, "there is competition between journals, and if you get a paper that is very newsworthy, the editor has in the back of his mind that if he imposes unreasonably demanding standards the author may go to another journal."

Noting that his own journal and Nature are rivals, Lewin said that editors should publish only papers they believe are valid but that it is not their role to defend a paper from subsequent criticism.

"Nature has always had a tradition of backing horses," he said, "and it is an incautious thing for a journal to do."

Campbell said that he and his editors were aware that certain papers were likely to receive media attention, but he added: "It is not Nature's policy to lower our standards to prevent a paper going to another journal. I am absolutely sure that that was not a factor in our decision on the Dolly paper."

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