February 11, 2002

BOSTON (The Boston Globe) - In the first birth-to-death study of cloned animals, Japanese scientists report that cloned mice die significantly earlier than their naturally born counterparts, the first clear evidence that cloning causes life-shortening biological abnormalities.

Researchers at Japan's National Institute of Infectious Diseases found that 10 out of 12 cloned mice died within 800 days, while only one of seven naturally born mice died that quickly. Scientists called the result the starkest argument to date against human reproductive cloning, which a few rogue scientists around the world reportedly are attempting.

"In the current cloning frenzy, (this paper) may serve as a deterrent, if one is needed, for some idiot who will start cloning people," said Dr. Davor Solter, a biologist at the Max Planck Institute for Immunobiology in Freiburg, Germany, who reviewed the paper.

Cloning science remains in its infancy, with researchers still unsure exactly how the process works or how it affects the long-term health of cloned animals. Researchers have cloned mice, pigs, cattle, and sheep, with mixed and confusing results: In many cases, clones have developed chronic health problems, while in a few other cases they appear healthy. The first cloned animal, Dolly the sheep, is 5 years old and developed early-onset arthritis late last year - the first warning that even apparently healthy clones might have subtle abnormalities that emerge over time. The new study is the first to systematically demonstrate this dismal prognosis for clones. The Japanese team, reporting in the journal Nature Genetics, found that their first cloned mouse died after 311 days. Three hundred days later, six more had died. All of the regular mice were still alive.

Dissections of six of the cloned mice showed that all had severe pneumonia arising from depleted immune systems. In addition, one had liver failure, one leukemia, and one lung cancer. The varied causes of death suggested deep flaws within the cloned mice genomes, said the researchers, who interpreted the results as holding dire consequences for human clones.

"The possible negative long-term effects of cloning, as well as the high incidence of spontaneous abortion and abnormal birth of cloned animals, give cause for concern about attempts to clone humans for reproductive purposes," wrote the team, led by Dr. Atsuo Ogura, among the world's foremost specialists in mouse cloning.

But another mouse-cloning pioneer, Dr. Teruhiko Wakayama of Worcester-based Advanced Cell Technology Inc., said the results actually provide hope that cloning could be perfected.

"It's too early to reach any conclusions about cloning," said Wakayama, one of the few scientists in the world who can efficiently clone mice.

ACT opposes cloning humans for reproductive purposes but is working on cloning human embryos to extract their stem cells. The company also makes money cloning farm animals.

"The big question is: What is the cause of death?" said Dr. Tony Perry, a molecular embryologist at ACT who, with Wakayama, published an editorial alongside the study. "It would give us an insight into where we should look for improvements." Perry and Wakayama argue in the editorial that, by presenting signs of numerous and deep problems with cloning, the study implied that fixes could be found as well. "I have every confidence that one day these technical problems will be solved," said Perry.

But one local researcher thought that view unrealistic.

"I think it's a little too optimistic. I mean, those guys are working for a company" with financial interests in cloning, said Konrad Hochedlinger, a cloning researcher at MIT-affiliated Whitehead Institute.

"At this point of research, you can't tell whether those problems can ever be solved. It will be hard to ever discover what the problem is," he said. The Japanese team wrote that it was uncertain what aspect of the cloning process led to the fatal midlife complications for their test mice. Numerous factors might play a role. Scientists clone by taking an unfertilized egg, replacing its DNA with DNA from another adult cell, then coaxing the egg to develop.

When scientists coax the development, the adult DNA has to genetically reprogram itself to behave as if it were young again in just hours. Scientists believe genetic mistakes occur during this process, including some that cause long-term damage but are not apparent at birth.

"Apparently normal animals can still develop tumor and immune defects later in life," said Hochedlinger, who works under Dr. Rudolf Jaenisch, the Whitehead Institute's cloning authority, who has spoken before Congress and on Beacon Hill about these midlife cloning dangers.

Several groups have said they are attempting to clone humans, most notably maverick Italian scientist Severino Antinori and Clonaid, a Bahamas-based project established by the Raelians, a Canadian cult that believes aliens created humanity through cloning. None have reported success.

To make sure the surgical procedure behind cloning was not responsible for the health damage, the Japanese team devised a control experiment: They created a third set of mice by transferring a sperm nucleus into an egg, thereby replicating cloning surgery but starting natural embryonic development. Only two out of six of those mice died before 800 days, indicating the surgery itself was not to blame. Some scientists said this was ample proof that human cloning, regardless of future advances in technology, should never be attempted.

"I would argue that defects in cloned animals are maybe not inevitable but so likely that it makes no difference," said Solter of the Max Planck Institute. "One can presume that one lucky clone will by accident have all its genes correctly reprogammed but, after all, some people win the lottery but you would not base your life on expecting it."