Where's the Beef?

by Elizabeth Pennisi
Science 1998;279:647
Copyright 1998 American Association for the Advancement of Science

In a perfect world, important scientific discoveries are impeccably documented and quickly replicated. But on page 635, two prominent biologists say that was not the case for Dolly, arguably the most famous lamb in history because she was reportedly cloned from adult cells. In a letter to the editor, Vittorio Sgaramella from the University of Calabria in Cosenza, Italy, and Norton Zinder of Rockefeller University in New York City ask for more convincing evidence that the experiment that produced Dolly worked as claimed. If in fact it hasn't, it would mean that human cloning, which for most conceivable purposes would start with adult cells, is not the immediate threat some worry about.

Because the mammary cells used to produce Dolly came from a pregnant ewe, Zinder and Sgaramella question whether she might have been cloned not from an adult mammary cell but from a contaminating fetal cell. And while Ian Wilmut, the embryologist at the Roslin Institute in Roslin, Scotland, where Dolly was cloned, and his colleagues cite evidence that that could not have happened, they may never be able to prove their assertion conclusively. Because "none of us expected to get Dolly," says embryologist Alan Colman of PPL Therapeutics in Roslin, which collaborated in the work, "we didn't do what we should have done" to document the genetic composition of either the ram that impregnated the ewe or the fetus she carried. Consequently, Dolly's DNA can't be compared with theirs. But the Roslin group also says that some of the other data Zinder and Sgaramella want, concerning whether Dolly's DNA has the mutations and other changes expected in an adult, will be available as soon as the analyses are completed.

Still, even if Dolly is an adult clone, no one has yet exactly replicated the experiment that produced her. Few laboratories, Wilmut's included, have even tried, mainly because the emphasis now is on using DNA from fetal cells, rather than adult cells, to commercialize the nuclear transfer technology used to create Dolly (see main text). Others, including Neal First's team at the University of Wisconsin, Madison, and Mark Westhusian's group at Texas A&M University in College Station, have tried to clone cows from adult cells but failed. None of the embryos survived to birth, they note. Similarly, in Boston last week at the annual meeting of the International Embryo Transfer Society, a team of researchers from Germany and Austria reported it had tried to use heifer udder cells as nuclei donors, but no embryo lived past 40 days of gestation.

Two other teams, one led by James Robl and Steven Stice, developmental biologists at the University of Massachusetts, Amherst, and the other at the biotech firm Infigen in DeForest, Wisconsin, say they have calves in utero that were cloned from adult cells. However, neither team is confident enough that these calves will make it through the final months of their 9-month gestation to reveal the tentative due dates.

But other results from the First team support the Roslin group's finding that adult DNA can be induced to support embryonic development. They used cow oocytes as universal recipients for nuclei obtained from the ear cells of adults from four other species: rats, sheep, pigs, and monkeys. Although only about 34% of eggs receiving rat nuclei began dividing, almost 86% of those with monkey DNA and 52% with pig DNA were activated, Wisconsin's Maissam Mitalipova reported at the embryo transfer meeting.

Dividing eggs continued to develop, with many expanding to 130 cells and reaching the stage where they needed to be implanted in a womb. These developing embryos also contained a protein, not found in the ear cells themselves, that is usually produced only in cells capable of developing into whole new organisms. "It means that if you can do [nuclear transfer] with fetal fibroblasts, you can do it with adult cells," says First. Robl agrees. Getting another clone from an adult cell is "a matter of time," he says. "If you do enough [transfers] and get lucky, you can do it."

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