Editor's Note: This is part two of a two-part series on the issues surrounding animal cloning. Part one ran in Thursday's issue.

As the range of species that can be cloned has expanded, the ethics of such cloning have become more multifaceted. That's a hornet's nest of its own, but cloned animals also might have health problems that restrict their usefulness as research or performance animals.

Research has shown that cloned mice have a significantly shorter average lifespan than mice conceived either naturally or by fertility treatments.

Rudolf Jaenisch, a founding member of Whitehead Institute for Biomedical Research and professor of biology at the Massachusetts Institute of Technology, has published research showing that cloned mice, even those that appear normal upon cursory inspection, often have subtle abnormalities in gene expression.

Such dysregulation is due to epigenetic changes in cloned animals; though the DNA sequence of clones is a faithful reproduction of that of the parent, the methylation patterns of that DNA, which strongly influence gene expression, are not.

Asked whether his findings would apply to larger mammals, as well, Jaenisch told BioWorld Today: "Absolutely. There is no reason in the world why farm animals should be better off than mice or humans."

Looking A Cloned Horse In The Mouth

Jaenisch is skeptical of the idea that cloning animals is a scientifically sound way of reproducing them.

"I'm sort of extreme," he said, "but I believe that a normal clone has yet to be made." Furthermore, he believes the technology and "our present knowledge" are not advanced enough yet to make a normal clone.

Not surprisingly, those involved in the commercial cloning of animals disagree. Scott Davis is the founder and former head of ViaGen Inc. and current president of stART Licensing Inc. stART "manages and licenses a broad portfolio of intellectual property rights related to animal reproductive technologies," Davis said, including the nuclear transfer cloning technology that was developed for cloning Dolly. (See BioWorld Today, April 7, 2005.)

Davis noted that cloning success varies by species, but "in the hands of skilled practitioners," it now approaches the success rates of in vitro fertilization. He told BioWorld Today that "as efficiencies have improved remarkably, a lot of the clone health issues have fallen away."

As for the ethics of cloning, Davis said "the real issue has to do with discomfort to the animal. If cloning techniques had not improved [from the early stages], then I think a lot of people would have ethical issues with it. But they have."

Davis believes that the reason academic research shows more problems with cloning than industry data is that "the people doing the cloning in academia" - in many cases, graduate students who do not have a lot of experience or who clone at high volume - "are not the most technically skilled."

When hearing that suggestion, Jaenisch derided it as "utter nonsense," adding that "we are probably better than most, but technique is not the problem. The problem with cloning is not a technical one but a principal biological one." He added that "one often sees the problems in clones only at older ages, and the farm animals are just not at the comparable age when mice develop the typical problems."

Improvements in efficiency, in his opinion, do not address that issue. Instead, what you essentially have is "making abnormal clones more efficiently." Jaenisch pointed out that most clones die very early in development, and said, "You can't tell me that 95 percent [of clones] die before birth and the other 5 percent are normal.

"It's a continuum, and even the few that make it are abnormal."

Clone Might Be Abnormal, But Offspring Fine

Dolly was euthanized at the age of 6 due to lung disease; she had reached just half the maximal life span of a sheep. However, one short-lived sheep does not statistical significance make. Davis said that ViaGen purchased about 80 cloned sheep from PPL Therapeutics when PPL went out of business in 2004, and are keeping them to see how their average life span compares to that of normal sheep.

It will be a few years yet before the data come in. So far, the results are encouraging for cloners. In the past three years, only one sheep has died, and that was the kind of data-skewing death that make scientists groan in sympathy: Overly excited at feeding time, it choked to death on its dinner grain.

"That was annoying because, of course, it didn't have anything to do with cloning," Davis said. But, he added, "the fact that we are still waiting gives you an indication that they are not just dropping prematurely."

Whether a horse that, despite being genetically identical to a "high-performance horse," could be prone to lung and liver failure and an early demise is worth the cost of cloning is something the market will have to decide.

Jaenisch and Davis agreed that the offspring of cloned animals, which are produced by sexual reproduction and thus have normal methylation patterns, do not show epigenetic dysregulation, so cloning is a sound technique for bringing, for example, gelded or old animals back into the gene pool.

The disagreement is about the clone itself. Jaenisch called the approach "deeply flawed" and said that "you are not going to recreate the same horse." Davis said that most cloning is done for the purpose of reproduction, so the primary interest is in the offspring of the clone. But, he added, people who buy cloned animals also are interested in the clone itself. "They are quite proud of these animals and tend to want to show them off," he said.

As for cloned pets, consider this: Cc, the first cloned cat, neither looked nor acted like its genetic mother. It was produced by Genetic Savings and Clone, of South San Francisco, and the company has since improved its methods so that their cloned cats at least look like their single parent. However, given the strong environmental influences on animal behavior, whether they act like that parent enough to warrant their price tag again will be in the eye of the beholder.