[Paleopsych] WP: Of Mice, Men and In-Between
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Tue Feb 1 18:37:12 UTC 2005
Of Mice, Men and In-Between
Scientists Debate Blending Of Human, Animal Forms
By Rick Weiss
Washington Post Staff Writer
Saturday, November 20, 2004; Page A01
In Minnesota, pigs are being born with human blood in their veins.
In Nevada, there are sheep whose livers and hearts are largely human.
In California, mice peer from their cages with human brain cells
firing inside their skulls.
These are not outcasts from "The Island of Dr. Moreau," the 1896 novel
by H.G. Wells in which a rogue doctor develops creatures that are part
animal and part human. They are real creations of real scientists,
stretching the boundaries of stem cell research.
Biologists call these hybrid animals chimeras, after the mythical
Greek creature with a lion's head, a goat's body and a serpent's tail.
They are the products of experiments in which human stem cells were
added to developing animal fetuses.
Chimeras are allowing scientists to watch, for the first time, how
nascent human cells and organs mature and interact -- not in the cold
isolation of laboratory dishes but inside the bodies of living
creatures. Some are already revealing deep secrets of human biology
and pointing the way toward new medical treatments.
But with no federal guidelines in place, an awkward question hovers
above the work: How human must a chimera be before more stringent
research rules should kick in?
The National Academy of Sciences, which advises the federal
government, has been studying the issue and hopes to make
recommendations by February. Yet the range of opinions it has received
so far suggests that reaching consensus may be difficult.
During one recent meeting, scientists disagreed on such basic issues
as whether it would be unethical for a human embryo to begin its
development in an animal's womb, and whether a mouse would be better
or worse off with a brain made of human neurons.
"This is an area where we really need to come to a reasonable
consensus," said James Battey, chairman of the National Institutes of
Health's Stem Cell Task Force. "We need to establish some kind of
guidelines as to what the scientific community ought to do and ought
not to do."
Beyond Twins and Moms
Chimeras (ki-MER-ahs) -- meaning mixtures of two or more individuals
in a single body -- are not inherently unnatural. Most twins carry at
least a few cells from the sibling with whom they shared a womb, and
most mothers carry in their blood at least a few cells from each child
they have born.
Recipients of organ transplants are also chimeras, as are the many
people whose defective heart valves have been replaced with those from
pigs or cows. And scientists for years have added human genes to
bacteria and even to farm animals -- feats of genetic engineering that
allow those critters to make human proteins such as insulin for use as
"Chimeras are not as strange and alien as at first blush they seem,"
said Henry Greely, a law professor and ethicist at Stanford University
who has reviewed proposals to create human-mouse chimeras there.
But chimerism becomes a more sensitive topic when it involves growing
entire human organs inside animals. And it becomes especially
sensitive when it deals in brain cells, the building blocks of the
organ credited with making humans human.
In experiments like those, Greely told the academy last month, "there
is a nontrivial risk of conferring some significant aspects of
humanity" on the animal.
Greely and his colleagues did not conclude that such experiments
should never be done. Indeed, he and many other philosophers have been
wrestling with the question of why so many people believe it is wrong
to breach the species barrier.
Does the repugnance reflect an understanding of an important natural
law? Or is it just another cultural bias, like the once widespread
rejection of interracial marriage?
Many turn to the Bible's repeated invocation that animals should
multiply "after their kind" as evidence that such experiments are
wrong. Others, however, have concluded that the core problem is not
necessarily the creation of chimeras but rather the way they are
likely to be treated.
Imagine, said Robert Streiffer, a professor of philosophy and
bioethics at the University of Wisconsin, a human-chimpanzee chimera
endowed with speech and an enhanced potential to learn -- what some
have called a "humanzee."
"There's a knee-jerk reaction that enhancing the moral status of an
animal is bad," Streiffer said. "But if you did it, and you gave it
the protections it deserves, how could the animal complain?"
Unfortunately, said Harvard political philosopher Michael J. Sandel,
speaking last fall at a meeting of the President's Council on
Bioethics, such protections are unlikely.
"Chances are we would make them perform menial jobs or dangerous
jobs," Sandel said. "That would be an objection."
A Research Breakthrough
The potential power of chimeras as research tools became clear about a
decade ago in a series of dramatic experiments by Evan Balaban, now at
McGill University in Montreal. Balaban took small sections of brain
from developing quails and transplanted them into the developing
brains of chickens.
The resulting chickens exhibited vocal trills and head bobs unique to
quails, proving that the transplanted parts of the brain contained the
neural circuitry for quail calls. It also offered astonishing proof
that complex behaviors could be transferred across species.
No one has proposed similar experiments between, say, humans and apes.
But the discovery of human embryonic stem cells in 1998 allowed
researchers to envision related experiments that might reveal a lot
about how embryos grow.
The cells, found in 5-day-old human embryos, multiply prolifically and
-- unlike adult cells -- have the potential to turn into any of the
body's 200 or so cell types.
Scientists hope to cultivate them in laboratory dishes and grow
replacement tissues for patients. But with those applications years
away, the cells are gaining in popularity for basic research.
The most radical experiment, still not conducted, would be to inject
human stem cells into an animal embryo and then transfer that chimeric
embryo into an animal's womb. Scientists suspect the proliferating
human cells would spread throughout the animal embryo as it matured
into a fetus and integrate themselves into every organ.
Such "humanized" animals could have countless uses. They would almost
certainly provide better ways to test a new drug's efficacy and
toxicity, for example, than the ordinary mice typically used today.
But few scientists are eager to do that experiment. The risk, they
say, is that some human cells will find their way to the developing
testes or ovaries, where they might grow into human sperm and eggs. If
two such chimeras -- say, mice -- were to mate, a human embryo might
form, trapped in a mouse.
Not everyone agrees that this would be a terrible result.
"What would be so dreadful?" asked Ann McLaren, a renowned
developmental biologist at the University of Cambridge in England.
After all, she said, no human embryo could develop successfully in a
mouse womb. It would simply die, she told the academy. No harm done.
But others disagree -- if only out of fear of a public backlash.
"Certainly you'd get a negative response from people to have a human
embryo trying to grow in the wrong place," said Cynthia B. Cohen, a
senior research fellow at Georgetown University's Kennedy Institute of
Ethics and a member of Canada's Stem Cell Oversight Committee, which
supported a ban on such experiments there.
But what about experiments in which scientists add human stem cells
not to an animal embryo but to an animal fetus, which has already made
its eggs and sperm? Then the only question is how human a creature one
dares to make.
In one ongoing set of experiments, Jeffrey L. Platt at the Mayo Clinic
in Rochester, Minn., has created human-pig chimeras by adding
human-blood-forming stem cells to pig fetuses. The resulting pigs have
both pig and human blood in their vessels. And it's not just pig blood
cells being swept along with human blood cells; some of the cells
themselves have merged, creating hybrids.
It is important to have learned that human and pig cells can fuse,
Platt said, because he and others have been considering transplanting
modified pig organs into people and have been wondering if that might
pose a risk of pig viruses getting into patient's cells. Now
scientists know the risk is real, he said, because the viruses may
gain access when the two cells fuse.
In other experiments led by Esmail Zanjani, chairman of animal
biotechnology at the University of Nevada at Reno, scientists have
been adding human stem cells to sheep fetuses. The team now has sheep
whose livers are up to 80 percent human -- and make all the compounds
human livers make.
Zanjani's goal is to make the humanized livers available to people who
need transplants. The sheep portions will be rejected by the immune
system, he predicted, while the human part will take root.
"I don't see why anyone would raise objections to our work," Zanjani
said in an interview.
Perhaps the most ambitious efforts to make use of chimeras come from
Irving Weissman, director of Stanford University's Institute of
Cancer/Stem Cell Biology and Medicine. Weissman helped make the first
mouse with a nearly complete human immune system -- an animal that has
proved invaluable for tests of new drugs against the AIDS virus, which
does not infect conventional mice.
More recently his team injected human neural stem cells into mouse
fetuses, creating mice whose brains are about 1 percent human. By
dissecting the mice at various stages, the researchers were able to
see how the added brain cells moved about as they multiplied and made
connections with mouse cells.
Already, he said, they have learned things they "never would have
learned had there been a bioethical ban."
Now he wants to add human brain stem cells that have the defects that
cause Parkinson's disease, Lou Gehrig's disease and other brain
ailments -- and study how those cells make connections.
Scientists suspect that these diseases, though they manifest
themselves in adulthood, begin when something goes wrong early in
development. If those errors can be found, researchers would have a
much better chance of designing useful drugs, Weissman said. And those
drugs could be tested in the chimeras in ways not possible in
Now Weissman says he is thinking about making chimeric mice whose
brains are 100 percent human. He proposes keeping tabs on the mice as
they develop. If the brains look as if they are taking on a distinctly
human architecture -- a development that could hint at a glimmer of
humanness -- they could be killed, he said. If they look as if they
are organizing themselves in a mouse brain architecture, they could be
used for research.
So far this is just a "thought experiment," Weissman said, but he
asked the university's ethics group for an opinion anyway.
"Everyone said the mice would be useful," he said. "But no one was
sure if it should be done."
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