[Paleopsych] WP: Of Mice, Men and In-Between

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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.
    How Human?

    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.
    Immunity Advantages

    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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