A mix of mice and men

Injecting animals with human genes raises huge ethical questions - not to mention the 'yuck factor.'

In Greek mythology, they were monsters - with the head of a lion, the body of a goat, and the tail of a serpent. But today's chimeras (pronounced ky-MIR-uhs) are being crafted for a far different purpose. Scientists hope that by mixing genes of different animals they can better understand human biology and eventually test new drugs more safely and accurately, harvest organs for transplant into humans, and find new cures for human diseases.

There's just one twist: the genes being mixed are animal and human. Already in Israel, researchers have put human embryonic stem cells into chick embryos. In Switzerland, they've created mice with human immune systems; in Minnesota, pigs with humanlike blood; in Nevada, sheep with near-human livers.

Many people find the whole idea morally repugnant, even if they have a hard time articulating just why this "yuck factor" bothers them. Bioethicists and others are also struggling to reason their way through the issue, weighing possible benefits and risks. The President's Council on Bioethics is studying human-animal chimeras. Next month, the National Academies of Sciences will release guidelines on whether they're ethical to make. Congressional aides are investigating them, too, with thoughts of drafting legislation.

Inevitably, ethicists are led to debate several questions. Just what makes humans unique? When would a chimera become too human? And, if it did show human physical or behavioral traits, why would that be wrong?

After all, pig heart valves have been used to replace human ones for years. But experiments involving brains, which seem to come much closer to affecting the identity of a man or beast, bring deeper discomfort and more troubling discussions.

Irving Weissman, a researcher at Stanford University, for example, has proposed creating mice with brains containing 100 percent human neurons. By studying such mice, researchers might find cures for diseases such as Parkinson's and Alzheimer's, he reasons.

"Scientists are under a lot of pressure to be creative," adds Jason Robert, a bioethicist at Arizona State University in Tempe, "to come up with solutions that will help lessen the lag time between basic research and [medical cures]. But it's not clear that building chimeras is going to solve the problem."

Another complicating factor: The research involves the use of human stem cells, already a hot-button issue. "We've focused so much on the moral status of the [human] embryo that we've forgotten that there are other [ethical] issues coming to the fore," says Cynthia Cohen, a senior research fellow at the Kennedy Institute of Ethics at Georgetown University in Washington and an adviser to the Canadian government on stem-cell research.

"What we're really worried about is creating some sort of creature that would be functioning like a human being and yet having very strong animal-like features," Dr. Cohen says.

What, then, makes humans distinctive? Cohen argues that there are "a cluster of characteristics" either that are unique to humans or that humans express to a greater degree than animals, including the ability to distinguish right from wrong, make decisions and act on them, do complex thinking, and develop empathy. To keep these qualities distinct in humans preserves human dignity, she says.

But the proposed Stanford experiment would have had little likelihood of producing mice with any human behavioral characteristics, says Henry Greely, a professor of law at Stanford and the chairman of an ad hoc university committee that two years ago informally advised Weissman on the ethical implications of his venture. "Certainly if the mouse stood on its hind legs and said, 'Hi, I'm Mickey!' we'd be worried," says Professor Greely, who is also director of the Stanford Center for Law and the Biosciences. "We'd be more than worried."

But, he says, "we concluded that, if done properly, it could be done ethically." A mouse brain is 1/1,000th the size of the human brain and organized much differently, making the possibility of human behaviors or thinking remote. The committee advised Weissman to examine the mice at every stage of development and if he found any signs of humanlike qualities to "stop and discuss" how and whether to proceed.

The group didn't take a final position on whether it would necessarily be wrong to confer some human attributes on the mouse. Greely calls it "an interesting, hard question."

But some researchers say they would prefer that the Weissman experiment weren't carried out. "I'm a scientist, and I like to see scientific freedom," says Stuart Newman, a professor of cell biology at New York Medical College in Valhalla, N.Y. "It's scientific curiosity that drives it, but it really becomes something quite strange. It takes an approach toward living organisms that's really disturbing to many people."

Last month, Dr. Newman and a partner, antibiotechnology activist Jeremy Rifkin, learned that their seven-year effort to patent a process for making human-animal chimeras had been turned down by the United States Patent and Trademark Office. The two would not have used the patent to conduct chimera research. On the contrary, they would have held it to restrict others from doing so for the 20-year life of the patent. By having their patent turned down, the pair hope to make such patents more difficult for others.

The patent office seemed overwhelmed by the issue, Newman says. Its rejection "was accompanied by a statement from the patent office that they had no guidance from Congress as to what to do about these things."

For Greely, many of these ethical issues are best worked out when a specific case can be addressed, such as with the mouse-brain proposal at Stanford. More are on the way.

"There is a working group that I've been part of headed by Ruth Faden at Johns Hopkins [University] that's been specifically looking at this issue of transplanting human brain stem cells into nonhuman primates," he says. The group expects to report on the subject in the next few months. The issues there could be even more controversial, since the brain size and genetic makeup of apes and monkeys are closer to those of humans than are those of mice, increasing the possibility of behavioral transfers.

Biotechnology's ability to blur the lines between species should produce the opposite of a "yuck factor," something more akin to a "wow," suggests noted physicist Freeman Dyson in a commentary published in the March issue of Technology Review magazine.

"We are moving rapidly into the post-Darwinian era, when species will no longer exist," he writes. "Genetic engineering, once it gets into the hands of the general public, will give us an explosion of biodiversity. Designing genomes will be a new art form, as creative as painting or sculpture. Few of the new creations will be masterpieces, but all will bring joy to their creators and diversity to our fauna and flora."

Though Dr. Robert says he leans toward permitting chimera research, he's been struck by how "even secular people, people who aren't of faith, nonetheless see the wisdom of the 'playing God' objection" to creating chimeras.

Is a world with a looser definition of species "a great new world or a 'Brave New World?' " Robert asks. "I can't tell you." And he's skeptical of anyone who offers quick and easy answers. "I've been thinking about this stuff nonstop for the last three years," he says, "and I don't have any answers yet."

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