Mixing species--and crossing a line?
Israeli scientist Ronald Goldstein wasn't all that surprised when TV comedians started making fun of his work implanting cells from human embryos into chicken eggs. He had suspected the public would find the work bizarre--"people have a visceral reaction to this experiment," he says. But he did not expect it to pose problems for his fellow scientists.
Goldstein wanted to trace how well human embryonic stem cells turn into specific tissues and organs--the very shape-shifting quality that could make these cells an endless source of transplant tissues to treat diseases like Parkinson's and diabetes. He did not let the eggs hatch, and he made sure the human cells could not mingle with all of the developing chicks' tissues to create true chimeras. But even some of his scientific colleagues expressed disapproval recently when he presented his work, saying he had crossed a contentious ethical line. "This is a very, very gray area right now," Goldstein says.
Man or mouse? Yet other researchers are pursuing far more intimate marriages of human and animal tissue. South Korean scientists say they've created early mouse embryos marbled with human embryo cells--the very outcome Goldstein set out to avoid with his chicks. And U.S. researchers have proposed slipping another kind of stem cell into a mouse fetus to make an animal with a brain formed entirely of human neurons. Crossing species barriers in the lab is nothing new--scientists have created mice with human immune-system cells and organ-donor pigs with human genes. To many people, though, implanting stem cells in an animal is a different matter because these cells are the clay from which human beings are made.
Such concerns have transformed the debate over stem cells, which once focused on whether it's ethical to harvest stem cells from embryos. Now that scientists have the cells to work with--albeit a smaller, less varied supply than many would like--the arguments have shifted to how scientists should study these versatile cells in lab animals. An article about the "moral confusion regarding social and ethical obligations to novel interspecies beings" in the current American Journal of Bioethics is drawing unprecedented response. And a project to look at the ethics of stem cells has formed a special panel on chimeric brains, which will hold its first meeting next month.
"We are very confused about how we understand ourselves as human beings in contradiction to nonhuman species," says Ruth Faden, a bioethicist at Johns Hopkins University, who has teamed up with stem-cell expert John Gearhart to create the panel. The threshold of unease about cross-species research seems to vary depending on the kind of stem cell being studied, the kind of animal, and the age of the embryo or fetus in which the cells are implanted. And where one expert sees a routine study, another might see a risky bid to endow an animal with a touch of humanity.
Late last year at a stem-cell conference in New York, researchers pondered adding human embryonic cells to early mouse embryos to create chimeric animals. "It was pretty hotly debated, even among the scientists," recalls Fred Gage, a biologist at the Salk Institute for Biological Studies in La Jolla, Calif. To some, the scientific payoff seemed appealing. Putting human embryonic stem cells in these early embryos, called blastocysts, might prove better than any other lab test how well these cells produce all cell types.
Parent trap. Yet human stem cells added to a mouse blastocyst could even turn into sperm and eggs, producing an altered mouse with human gametes. Suppose it mated with another animal also carrying human germ cells, ethicists asked. "You're putting the possibility of creating future human beings into the animals," notes Cynthia Cohen, a bioethicist at Georgetown University.
U.S. stem-cell research guidelines forbid federally funded scientists from pursuing this kind of experiment, but researchers overseas don't face the same restrictions. Se-Pill Park, director of the South Korean firm Maria Biotech, says a team at the company did the very experiment discussed at the stem-cell conference. They injected human embryonic stem cells labeled with a fluorescent protein into 11 mouse blastocysts. Foster mouse mothers carried the embryos, and five babies were born with fluorescence in tissues including the heart, bones, kidney, and liver. But Park says the team shut down the project after the company "coped with severe protests" from the public.
Some of the worries fade when the implanted stem cells come from adult tissues instead of from embryos. Adult stem cells are thought not to have the same versatility as embryonic stem cells. Adult blood stem cells, for example, specialize in producing blood components; adult neural stem cells make neurons; and neither should give rise to sperm or eggs. One group has already implanted human blood stem cells in mouse blastocysts, resulting in animals with small numbers of human cells in their blood.
But others see even this kind of work as problematic, pointing to recent findings that suggest some adult stem cells retain a surprising ability to form many tissue types. Canadian researchers who would like someday to treat blindness with adult retinal stem cells recently decided to hold off on a test that required injecting these cells into a mouse blastocyst. Canada's stem-cell research guidelines forbid putting stem cells of any kind into an animal embryo if they might form many tissue types, explains Phillip Karpowicz, a researcher in Derek Van Der Kooy's lab at the University of Toronto.
The team has also postponed putting human retinal stem cells into a monkey fetus. This test could show how well these cells generate eye tissue. But because the retina emerges from the same cell reservoir as the nervous system, adding these human cells might alter the developing monkey's brain.
"What would happen to the structure or function of the brain that would be created?" asks Faden. Two years ago, some U.S. scientists did put human neural stem cells into the brains of fetal monkeys, to see how well these cells formed brain tissue. The cells thrived and migrated through the brain, but the experiment drew little notice at the time. Today it would spark more debate. "The brain is certainly the highest stakes in this kind of research," notes Karpowicz.
Still, Karpowicz adds, there are good reasons to study stem cells in animal brains. "The research is being done with an eye towards therapy." Any treatment for Parkinson's or stroke that's derived from stem cells, for example, might need safety testing in a nonhuman primate before going into humans.
The upcoming workshops on chimeric brains will bring together experts on primatology, neurology, ethics, and stem cells to assess whether such experiments might create monkeys capable of humanlike thought or experiences. If so, the panels will need to ponder whether scientists can ethically create such beings, and how researchers might recognize that their monkeys had become something more than lab animals.
It's familiar ground for Stanford University bioethicist Henry Greely. A few years ago, his Stanford colleague Irving Weissman, a stem-cell researcher, began thinking about experiments in fetal mice that would replace part or all of their brains with human neural stem cells. A living mouse with a brain made entirely of human neurons could be a boon for scientists trying to test drugs aimed at the nervous system, but Weissman knew his proposal would generate controversy. So he consulted with Greely, who put together a team of experts to consider it.
"We ultimately concluded that it should be taken slowly and carefully," says Greely. For example, scientists could monitor the brains to ensure they retained normal mouse structures, like a smooth surface. Any change that made the mouse brain look more like the wrinkly human organ would require a pause and reconsideration. But Greely thinks real problems seem unlikely, as mice have tiny brains.
Primates, he says, are a different story. "Nobody expects a mouse to stand up on its hind legs and say, `Hi, I'm Mickey,' " Greely says. "If you proposed doing this experiment on fetal chimps, I would be a lot more leery."
This story appears in the October 27, 2003 print edition of U.S. News & World Report.