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Creating 'human-animals' for research
Ethics report endorses mingling human cells with lesser beings
RENO, Nevada (AP) -- On a farm about six miles outside this gambling town, Jason Chamberlain looks over a flock of about 50 smelly sheep, many of them possessing partially human livers, hearts, brains and other organs.
The University of Nevada-Reno researcher talks matter-of-factly about his plans to euthanize one of the pregnant sheep in a nearby lab.
He can't wait to examine the effects of the human cells he had injected into the fetus' brain about two months ago.
"It's mice on a large scale," Chamberlain says with a shrug.
As strange as his work may sound, it falls firmly within the new ethics guidelines the influential National Academies issued this past week for stem cell research.
In fact, the Academies' report endorses research that co-mingles human and animal tissue as vital to ensuring that experimental drugs and new tissue replacement therapies are safe for people.
The National Academies -- private, nonprofit agencies chartered by Congress to provide public advice on science and technology -- consist of the National Academy of Sciences, the National Academy of Engineering, the Institute of Medicine and the National Research Council.
Doctors have transplanted pig valves into human hearts for years, and scientists have injected human cells into lab animals for even longer.
But the biological co-mingling of animal and human is now evolving into even more exotic and unsettling mixes of species, evoking the Greek myth of the monstrous chimera, which was part lion, part goat and part serpent.
In the past two years, scientists have created pigs with human blood, fused rabbit eggs with human DNA and injected human stem cells to make paralyzed mice walk.
Particularly worrisome to some scientists are the nightmare scenarios that could arise from the mixing of brain cells: What if a human mind somehow got trapped inside a sheep's head?
The "idea that human neuronal cells might participate in 'higher order' brain functions in a nonhuman animal, however unlikely that may be, raises concerns that need to be considered," the Academies report warned.
In January, an informal ethics committee at Stanford University endorsed a proposal to create mice with brains nearly completely made of human brain cells.
Stem cell scientist Irving Weissman said his experiment could provide unparalleled insight into how the human brain develops and how degenerative brain diseases like Parkinson's progress.
Stanford law professor Hank Greely, who chaired the ethics committee, said the board was satisfied that the size and shape of the mouse brain would prevent the human cells from creating any traits of humanity.
Just in case, Greely said, the committee recommended closely monitoring the mice's behavior and immediately killing any that display human-like behavior.
The Academies' report recommends that each institution involved in stem cell research create a formal, standing committee to specifically oversee the work, including experiments that mix human and animal cells.
Weissman, who has already created mice with 1 percent human brain cells, said he has no immediate plans to make mostly human mouse brains, but wanted to get ethical clearance in any case.
A formal Stanford committee that oversees research at the university would also need to authorize the experiment.
Living factories
Few human-animal hybrids are as advanced as the sheep created by another stem cell scientist, Esmail Zanjani, and his team at the University of Nevada-Reno.
They want to one day turn sheep into living factories for human organs and tissues and along the way create cutting-edge lab animals to more effectively test experimental drugs.
Zanjani is most optimistic about the sheep that grow partially human livers after human stem cells are injected into them while they are still in the womb.
Most of the adult sheep in his experiment contain about 10 percent human liver cells, though a few have as much as 40 percent, Zanjani said.
Because the human liver regenerates, the research raises the possibility of transplanting partial organs into people whose livers are failing.
Zanjani must first ensure no animal diseases would be passed on to patients.
He also must find an efficient way to completely separate the human and sheep cells, a tough task because the human cells aren't clumped together but are rather spread throughout the sheep's liver.
Zanjani and other stem cell scientists defend their research and insist they aren't creating monsters -- or anything remotely human.
"We haven't seen them act as anything but sheep," Zanjani said.
Zanjani's goals are many years from being realized.
He's also had trouble raising funds, and the U.S. Department of Agriculture is investigating the university over allegations made by another researcher that the school mishandled its research sheep.
Zanjani declined to comment on that matter, and university officials have stood by their practices.
Ethical boundaries
Allegations about the proper treatment of lab animals may take on strange new meanings as scientists work their way up the evolutionary chart.
Human stem cells have been injected into mice and now sheep. Such research blurs biological divisions between species that couldn't until now be breached.
Drawing ethical boundaries that no research appears to have crossed yet, the National Academies recommend a prohibition on mixing human stem cells with embryos from monkeys and other primates.
But even that policy recommendation isn't tough enough for some researchers.
"The boundary is going to push further into larger animals," New York Medical College professor Stuart Newman said. "That's just asking for trouble."
Newman and anti-biotechnology activist Jeremy Rifkin have been tracking this issue for the last decade and were behind a rather creative assault on both interspecies mixing and the government's policy of patenting individual human genes and other living matter.
Years ago, the two applied for a patent for what they called a "humanzee," a hypothetical -- but very possible -- creation that was half human and chimp.
The U.S. Patent and Trademark Office finally denied their application this year, ruling that the proposed invention was too human: Constitutional prohibitions against slavery prevent the patenting of people.
Newman and Rifkin were delighted, since they never intended to create the creature and instead wanted to use their application to protest what they see as science and commerce turning people into commodities.
And that's a point, Newman warns, that stem scientists are edging closer to every day: "Once you are on the slope, you tend to move down it."
Animal-Human Hybrids Spark Controversy
Maryann Mott
National Geographic News
January 25, 2005
Scientists have begun blurring the line between human and animal by producing chimeras—a hybrid creature that's part human, part animal.
Chinese scientists at the Shanghai Second Medical University in 2003 successfully fused human cells with rabbit eggs. The embryos were reportedly the first human-animal chimeras successfully created. They were allowed to develop for several days in a laboratory dish before the scientists destroyed the embryos to harvest their stem cells.
In Minnesota last year researchers at the Mayo Clinic created pigs with human blood flowing through their bodies.
And at Stanford University in California an experiment might be done later this year to create mice with human brains.
Scientists feel that, the more humanlike the animal, the better research model it makes for testing drugs or possibly growing "spare parts," such as livers, to transplant into humans.
Watching how human cells mature and interact in a living creature may also lead to the discoveries of new medical treatments.
But creating human-animal chimeras—named after a monster in Greek mythology that had a lion's head, goat's body, and serpent's tail—has raised troubling questions: What new subhuman combination should be produced and for what purpose? At what point would it be considered human? And what rights, if any, should it have?
There are currently no U.S. federal laws that address these issues.
Ethical Guidelines
The National Academy of Sciences, which advises the U.S. government, has been studying the issue. In March it plans to present voluntary ethical guidelines for researchers.
A chimera is a mixture of two or more species in one body. Not all are considered troubling, though.
For example, faulty human heart valves are routinely replaced with ones taken from cows and pigs. The surgery—which makes the recipient a human-animal chimera—is widely accepted. And for years scientists have added human genes to bacteria and farm animals.
What's caused the uproar is the mixing of human stem cells with embryonic animals to create new species.
Biotechnology activist Jeremy Rifkin is opposed to crossing species boundaries, because he believes animals have the right to exist without being tampered with or crossed with another species.
He concedes that these studies would lead to some medical breakthroughs. Still, they should not be done.
"There are other ways to advance medicine and human health besides going out into the strange, brave new world of chimeric animals," Rifkin said, adding that sophisticated computer models can substitute for experimentation on live animals.
"One doesn't have to be religious or into animal rights to think this doesn't make sense," he continued. "It's the scientists who want to do this. They've now gone over the edge into the pathological domain."
David Magnus, director of the Stanford Center for Biomedical Ethics at Stanford University, believes the real worry is whether or not chimeras will be put to uses that are problematic, risky, or dangerous.
Human Born to Mice Parents?
For example, an experiment that would raise concerns, he said, is genetically engineering mice to produce human sperm and eggs, then doing in vitro fertilization to produce a child whose parents are a pair of mice.
"Most people would find that problematic," Magnus said, "but those uses are bizarre and not, to the best of my knowledge, anything that anybody is remotely contemplating. Most uses of chimeras are actually much more relevant to practical concerns."
Last year Canada passed the Assisted Human Reproduction Act, which bans chimeras. Specifically, it prohibits transferring a nonhuman cell into a human embryo and putting human cells into a nonhuman embryo.
Cynthia Cohen is a member of Canada's Stem Cell Oversight Committee, which oversees research protocols to ensure they are in accordance with the new guidelines.
She believes a ban should also be put into place in the U.S.
Creating chimeras, she said, by mixing human and animal gametes (sperms and eggs) or transferring reproductive cells, diminishes human dignity.
"It would deny that there is something distinctive and valuable about human beings that ought to be honored and protected," said Cohen, who is also the senior research fellow at Georgetown University's Kennedy Institute of Ethics in Washington, D.C.
But, she noted, the wording on such a ban needs to be developed carefully. It shouldn't outlaw ethical and legitimate experiments—such as transferring a limited number of adult human stem cells into animal embryos in order to learn how they proliferate and grow during the prenatal period.
Irv Weissman, director of Stanford University's Institute of Cancer/Stem Cell Biology and Medicine in California, is against a ban in the United States.
"Anybody who puts their own moral guidance in the way of this biomedical science, where they want to impose their will—not just be part of an argument—if that leads to a ban or moratorium. … they are stopping research that would save human lives," he said.
Mice With Human Brains
Weissman has already created mice with brains that are about one percent human.
Later this year he may conduct another experiment where the mice have 100 percent human brains. This would be done, he said, by injecting human neurons into the brains of embryonic mice.
Before being born, the mice would be killed and dissected to see if the architecture of a human brain had formed. If it did, he'd look for traces of human cognitive behavior.
Weissman said he's not a mad scientist trying to create a human in an animal body. He hopes the experiment leads to a better understanding of how the brain works, which would be useful in treating diseases like Alzheimer's or Parkinson's disease.
The test has not yet begun. Weissman is waiting to read the National Academy's report, due out in March.
William Cheshire, associate professor of neurology at the Mayo Clinic's Jacksonville, Florida, branch, feels that combining human and animal neurons is problematic.
"This is unexplored biologic territory," he said. "Whatever moral threshold of human neural development we might choose to set as the limit for such an experiment, there would be a considerable risk of exceeding that limit before it could be recognized."
Cheshire supports research that combines human and animal cells to study cellular function. As an undergraduate he participated in research that fused human and mouse cells.
But where he draws the ethical line is on research that would destroy a human embryo to obtain cells, or research that would create an organism that is partly human and partly animal.
"We must be cautious not to violate the integrity of humanity or of animal life over which we have a stewardship responsibility," said Cheshire, a member of Christian Medical and Dental Associations. "Research projects that create human-animal chimeras risk disturbing fragile ecosystems, endanger health, and affront species integrity."
