Obesity in mice offers proof of cloning's unpredictability By Gareth Cook, Globe Staff, 1 March 2002 (Boston Globe) Raising new concerns about the technology used to copy life, scientists said yesterday that cloned mice are prone to striking cases of obesity. Numerous researchers have reported cases of abnormally large cloned animals, but the new work is the first systematic examination of a large number of animals to encounter the problem. One group of cloned mice, described in today's issue of the journal Nature Medicine, had insulin abnormalities, higher levels of body fat, and weighed an average 72 percent more than normal. Coming weeks after a report that cloned mice die young, scientists said the experiment showed how dangerous it would be to attempt to clone a human being. It is also a reminder, they said, that while cloning techniques have achieved some high-profile successes - most recently in a cat - they are fundamentally unpredictable. ''Cloning by the present methods is a lottery,'' said Ian Wilmut, the scientist who cloned Dolly the sheep, in commentary published with the finding. ''Several coins are thrown and must all come up as heads if life is to be normal.'' Scientists have seen a range of strange problems in cloned animals, including sudden unexplained deaths, signs of premature aging, abnormal immune systems and, in Dolly, a suspicious case of early arthritis. But the results vary widely from team to team, and researchers have been slow to do the broader experiments needed to determine the cause of the problems. ''This study underscores the need for long-term follow-up of cloned animals,'' said Robert Lanza, a scientist at Worcester-based Advanced Cell Technology Inc. who has conducted a similar study. ''Despite the fact that hundreds of animals have been cloned worldwide, this is the only study other than our own which has examined a large number of adult cloned animals.'' Problems can occur at any point in the life cycle of a clone. Even the most adept cloners find that the vast majority of the embryos die before they develop fully. In the latest experiment, conducted at the Obesity Research Center of the University of Cincinnati Medical Center, the cloned mice seemed to be growing just like normal mice for 8 to 10 weeks. The cloned mice then ballooned into larger animals, despite being fed the same diet, according to Kellie L. K. Tamashiro, a graduate student at the Medical Center who is the study's lead author. But, in another intriguing twist, the experiment also showed that there is something in the process of moving and handling the delicate egg cells - even if they are not cloned - which causes problems in the resulting animals. The Cincinnati team followed a group of mice which had not been cloned, but which had gone through similar manipulations while in the embryonic stage. The team found these animals were also larger. The scientists found all the altered mice were not just big, but clinically obese, according to Randall R. Sakai, an associate professor at the Medical Center who runs the lab where the work was done. In one experiment, for example, the normal mice averaged 14.4 percent fat tissue, while the clones averaged 25.2 percent. The embryos which had been manipulated but not cloned resulted in mice which averaged 19.5 percent fat tissue. When the researchers mated the cloned animals, the offspring appeared normal. Although the cause of the abnormalities is not known, many scientists suspect that the problem lies at the heart of the cloning process. Every cell in an animal contains the entire DNA rulebook, or genome, needed to run every function of every cell in the animal, from bone marrow to brain. What distinguishes one type of cell from another is that different patterns of genes, which are sections of DNA, are turned on. These crucial differences - the differing patterns of genes that are switched on - are referred to as ''epigenetic'' differences. To clone an animal, scientists take a cell from its skin, for example, and then coax the DNA back to its most primitive epigenetic setting, so that it will behave like a fertilized egg. From there, it can be implanted into a female and grow into a duplicate of the donor. Scientists suspect that the DNA is not entirely reset during cloning, or that the process of handling the cells causes other epigenetic changes, eventually leading to developmental problems such as obesity. Other cloned animals appear to be entirely normal. But scientists have not developed tests which would allow them to definitively say that any clone actually is normal. Gareth Cook can be reached at cook@globe.com. This story ran on page A3 of the Boston Globe on 3/1/2002. © Copyright 2002 Globe Newspaper Company. 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