[Paleopsych] NS: Half human, half beast?

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Half human, half beast?

      * 15:50 21 June 2005
      * Jamie Shreeve

    ON THE surface, it looked like a dry and somewhat technical report on
    stem cells. But inside there was something extraordinary. The
    guidelines for research on embryonic stem cells issued by the US
    National Academy of Sciences in April took meticulous care to address
    a kind of experimentation that sounds more like science fiction than
    science. In a section titled "Interspecies Mixing", the authors
    concluded that there were "valid scientific reasons" for creating
    chimeras - living entities composed of both human and animal cells.
    You may have seen mention of chimeras in the press recently. As stem
    cell technology pushes forward, expect to hear a lot more.

    In Greek mythology, the chimera was a monstrous creature with the head
    of a lion, the body of a goat and the tail of a serpent. The most
    famous chimeras scuffling about in our collective consciousness are
    probably the tortured demi-beasts concocted by the megalomaniacal
    scientist in H. G. Wells's The Island of Doctor Moreau. In real-life
    laboratories, mildly chimeric creatures have long been commonplace -
    mice and other animals with human immune systems, kidneys, skin, and
    muscle tissue, all created for the purpose of better understanding
    human diseases. Scientists have also been adding parts of animals to
    human beings for decades, usually to rescue some faulty original part.
    In the 1920s, Russian-born French scientist Serge Voronoff made a
    fortune purporting to treat flagging virility by grafting strips of
    monkey testicle onto the scrotums of wealthy gentlemen - chimeras all,
    at least for the brief time before their immune systems spat back the
    grafts. Today, pig heart valves are routinely transplanted into heart
    patients with far greater success.

    None of this research has caused any public outcry, perhaps because
    the amount of mixing is so small, or the borrowed part is not visible
    - one can imagine a different reaction to, say, pig nose transplants.
    But stem cell technology has made the creation of more potent
    human-animal mixtures both easier and more urgent.

    Already, researchers have created monkeys with brains that are
    partially human, mice with functioning human photoreceptor cells in
    their retinas and sheep with organs that are up to 40 per cent human.
    And there's a lot more to come, not least a plan to create a mouse
    with a brain made entirely of human neurons.

    There is no sinister intent behind these experiments: chimeras would
    be hugely useful in biomedical research. But there's no denying that
    organisms assembled by mixing humans and animals are troubling on many
    levels. A mouse that's 1 per cent human might be OK. But what about 10
    per cent? Or 50 per cent? What if such a creature turned out to have
    human attributes? And what new responsibilities would such an
    ambiguous being pose to a society accustomed to a clean moral and
    legal distinction between human beings and the rest of the animal

    "We don't treat all humans that well and we certainly don't treat
    animals well," says Francoise Baylis, a bioethicist at Dalhousie
    University in Halifax, Nova Scotia, who helped draft Canada's
    guidelines on chimeras.

    "So how do we treat these new beings?"

A chimera's worth

    The reason for all this sudden interest in chimeras is the immense
    medical potential of stem cells. Isolated from the inner cell mass of
    a very early embryo called a blastocyst, human embryonic stem cells
    have the ability to morph into any other kind of cell in the body.
    They might one day be transplanted into patients with heart disease,
    diabetes and a host of other ailments to regenerate damaged tissue.
    Stem cell research is progressing rapidly (New Scientist, 28 May, p
    8), but as yet no one knows how the cells would behave once
    transplanted into the human body - how they might differentiate,
    migrate and form new tissues. Testing this in people would clearly be
    unethical, which means studying them in animals first. And implanting
    human stem cells in animals inevitably entails creating chimeras.

    Hence all the recent institutional angst, not just from the National
    Academy of Sciences (NAS), but also in a report on human reproductive
    technologies delivered by the UK's parliamentary Select Committee on
    Science and Technology in March, and in recent deliberations of the
    Medical Research Council of Canada.

    One problem the policy-makers have to grapple with is that scientists
    do not yet know how much transplanted human cells will contribute to a
    developing animal's body or organ functions, including its brain. It
    is clear, though, that the answer might be "a lot". A few years ago,
    Esmail Zanjani at the University of Nevada, Reno, injected human stem
    cells into sheep embryos around halfway through gestation. The
    resulting sheep had human cells in almost all their tissues, including
    blood, bone, liver, heart and nervous system. Some organs were up to
    40 per cent human. That in itself seems unproblematic, as Zanjani's
    sheep show no human tendencies whatsoever.

    But it does raise two serious questions.

    The first concerns the gonads, and presents a particularly unsettling
    scenario. If embryonic human stem cells were injected into an animal
    fetus, especially at a very early stage, it is quite possible that
    they would migrate into the developing organism's germ line to produce
    human sperm or eggs. If two such chimeras were to mate, it's possible
    that a human sperm would fertilise a human egg, resulting in a human
    embryo growing inside the uterus of an animal. It is highly
    implausible that such an unsuitably accommodated fetus would come to
    term. But to eliminate the prospect, the NAS committee dealt with the
    issue with a swift hand: under no circumstances, it recommended,
    should any two chimeras be allowed to breed.

    The second problem concerns the brain, and finding the right
    regulatory solution is more difficult. Trying to prevent contentious
    experiments from happening will not suffice - they already have.
    Eugene Redmond of Yale University and his colleagues have injected
    human neural progenitor cells - stem cells that have already taken the
    first developmental step towards becoming a brain cell - into the
    brains of vervet monkeys with the intention of exploring them as a
    treatment for Parkinson's disease. And a team at Harvard University
    transplanted neuronal progenitor cells into fetal monkeys to see if
    they would grow, migrate and differentiate along with their monkey
    counterparts (they did), while still others have treated mouse brains
    to a similar human neural dusting.

    The problem is how to reap the knowledge gained from such experiments
    while ensuring that the subjects do not become disturbingly
    knowledgeable themselves. Is it possible that you could end up with a
    creature possessing a human-like brain - and human-like cognitive
    abilities, such as intelligence and self-awareness - trapped in the
    skull of an animal?

    The answer to that question seems to depend on three factors: the
    stage in development at which the cells are introduced, the amount of
    human material added, and how closely related the animal is to us.

    While it is highly unlikely that human stem cells transplanted into an
    adult animal will have any effect on its cognitive abilities or body
    plan, a fetus would stand a much higher chance of being "humanised".
    And the earlier in gestation you introduce the stem cells, the more
    humanised it is likely to become. Very early embryos would be most
    receptive of all, which is why most scientists shy away from such an
    experiment. Though no formal regulations address the issue in the UK,
    British stem cell researchers have an informal agreement among
    themselves not to pursue it. "People have sensitivities about this,"
    says Stephen Minger, a stem cell biologist at King's College London.
    Canadian guidelines prohibit funding for experiments that introduce
    human stem cells into an unborn animal at any stage, a policy that led
    Derek van der Kooy, a stem cell researcher at the University of
    Toronto, to wait until his mouse subjects were 1 day old before
    transplanting human retinal stem cells into their eyes to see if they
    would develop into photoreceptors. The experiment worked, but
    according to van der Kooy, would have been much more informative if it
    had been carried out at an earlier stage of development.

    In the US, transfer of human stem cells into mammalian blastocysts is
    prohibited in federally-funded research. But under the NAS guidelines,
    anyone with private or state funding, including biotech companies,
    could conduct such an experiment, provided that they gain approval
    from the appropriate review boards and "no other experiment can
    provide the information needed". The latter requirement shouldn't be a
    block: many researchers say this would be the best way to observe the
    "pluripotency" of human embryonic stem cells - their capacity to
    differentiate into all kinds of tissue.

    But so far, only one American scientist, Ari Brivanlou of The
    Rockefeller University in New York, seems eager to go down that road.
    "It's a little uncomfortable that I understand my chicken, frog and
    mouse cells better than my human cells," says Brivanlou, who plans to
    inject human embryonic stem cells into 3 to 5-day-old mouse
    blastocysts, then implant the embryo in a mouse uterus.

    "We have to know how many cell lines contribute to the pancreas, how
    many to the nervous system, and so on. If we don't know answers to
    these basic questions, we will never go to the next step of using stem
    cells clinically."

    Perhaps even more provocative than the question of when human stem
    cells are inserted into an animal is the matter of where. No
    experiment has drawn more attention to this issue than the one
    proposed by Irving Weissman and his colleagues at Stanford University,
    California, and StemCells Inc., a private company he co-founded. Two
    years ago, Weissman came up with an ingenious idea to create an
    experimental model to study human brain cancers and drug therapies. He
    imagined transplanting human neuronal stem cells into the brains of a
    strain of mouse that loses its own neurons just before birth. The
    result would be a mouse with a brain composed almost entirely of human

    Well aware of the ethical pitfalls involved in such research, Weissman
    sought the advice of Hank Greely, a bioethicist at Stanford's law
    school, before proceeding. Greely organised a committee to review the
    experiment. Its recommendation was that the project be allowed to
    proceed, but with built-in "stopping points" to examine whether the
    mouse's brain was developing any unusual structures or, after its
    birth, exhibiting any odd or human-like behaviour. If so, the work
    should be halted pending further review (see Graphic, page 40).

    Perhaps the committee should also have advised hiring a good PR agent.
    Weissman is still months or even years away from attempting his
    experiment - he is reportedly having trouble breeding the neuronally
    deficient mice - but it has already drawn "this shall not stand"
    rhetoric from the conservative talk-show host Bill O'Reilly, the
    anti-biotech activist Jeremy Rifkin, and numerous religious
    commentators and bloggers.

    Some scientists are uncomfortable too. "Eight years ago, people said
    it was slander that we would suggest that scientists would even
    attempt anything like this," says Stuart Newman, a developmental
    biologist at New York Medical College in Valhalla, New York. In 1997,
    Newman teamed up with Rifkin in a failed attempt to patent a method
    for creating a human-animal chimera - not so they could conduct the
    experiment, but to block others from doing so and to raise public
    awareness of the inherent dangers. "Now Irving Weissman is saying
    he'll have a mouse with a human brain. I don't come at this from any
    moral or religious perspective. I'm concerned about the social uses of
    science and the possibility of technology coming back and biting us.
    In this case, maybe literally."

    Weissman has little time for such arguments. "You will find
    bioethicists, religious people and politicians who will try to stop
    this research," he says. "They must be reminded that if they succeed,
    and it's the kind of research that could result in real and new
    therapies, then I personally hold them morally responsible for the
    suffering and death of those patients."

    In any case, the chances of one of Weissman's mice standing up and
    saying "Hi, I'm Mickey!", as Greely puts it, are vanishingly small.
    Wherever consciousness resides in our minds, it is almost certainly
    not on the cellular level, but rather in the vastly complex
    interactions that take place in the unique architecture of the human
    brain. Mouse brains are less than one-thousandth the size of human
    brains in volume, and are far simpler in their organisation. To create
    an animal with a brain possessing any human attributes you would
    probably have to use an animal much closer to us in evolution, and
    early in its development. A chimpanzee, for instance.

    While still unlikely, the mere chance that such an experiment might
    produce a "humanzee" has not gone unnoticed by ethicists and
    policy-makers. A working group at The Phoebe R. Berman Bioethics
    Institute at Johns Hopkins University in Baltimore, Maryland, is
    already wrestling with the problem of human-primate chimeras. And the
    NAS report recommends that the transfer of human stem cells into the
    early embryos of apes or other primates "should not be permitted at
    this time".

The yuck factor

    Those last three words have been a red rag to some, who see in them
    the top of a slippery slope towards the acceptance of an abomination.
    But there may be legitimate reasons not to fence off that slope too
    securely without considering areas that might be useful to explore.
    Consider a disease such as severe autism, which diminishes or even
    erases cognitive capacities that are considered uniquely human:
    language, social and moral judgement, and the ability to read the
    intentions of others or understand that they have intentions in the
    first place. Terrence Deacon, a biological anthropologist at the
    University of California, Berkeley, and a member of the Johns Hopkins
    working group, says that if embryonic stem cells could be cloned from
    an autistic individual and transplanted into a monkey brain early in
    its development, perhaps the mechanisms of the disease could be
    illuminated by observing differences in brain structure and social
    behaviour between the autistic monkeys and controls who received
    normal human stem cells.

    "This is science fiction," says Deacon. "But the point is, if I can
    imagine how it might help this disorder, there are probably dozens of
    cases that I can't imagine. We need to create a system of rules that
    is both sensitive to the problem and capable of discerning

    For a lot of people, perhaps most, the creation of an animal even
    slightly "humanised" in its thoughts or feelings is morally wrong, no
    matter what the potential biomedical pay-off. But it is not easy to
    pinpoint why. The most often heard reason is some variation on "the
    yuck factor", or what Leon Kass, head of The President's Council on
    Bioethics in the US, calls "the wisdom of repugnance": if you have a
    gut feeling that something is wrong, it probably is, whether or not
    you can articulate the rational basis for the feeling. Perhaps it is
    the inherent "unnaturalness" of the chimera that makes people bristle
    at it; perhaps mixing animals and humans violates some fundamental
    moral taboo. On the other hand, our species has performed unnatural
    acts upon nature for centuries - hybridising farm animals such as
    mules, grafting plants onto each other, let alone performing heart
    transplants and in vitro fertilisation. And while some moral taboos,
    such as cannibalism and incest, appear to be universal, others, such
    as homosexuality and interracial marriage, have lost their authority.
    "In the 1800s, it was considered morally unacceptable to give blood
    transfusions," says Cynthia Cohen, a bioethicist at the Kennedy
    Institute of Ethics at Georgetown University in Washington DC. "When
    there is reason to change the taboos, we change them."

    Cohen argues that the real problem is that chimeras denigrate what it
    means to be human. Writing in a forthcoming issue of the Kennedy
    Institute of Ethics Journal, she, van der Kooy and his colleague at
    the University of Toronto, Phillip Karpowicz, argue that what is at
    risk is human dignity: a being with only some degree of humanness
    imprisoned in an animal body is not free to experience all the
    cognitive endowments, emotions and moral rights our species uniquely

    The "human dignity" argument underscores a devilish catch-22: the
    better a chimera serves as a research model for actual human biology,
    the more risk there is that it will acquire human attributes that
    would preclude or even criminalise its use in research. This is an
    amplified version of the dilemma that society already has to confront
    over the use of chimpanzees and other higher primates in research.

    But what if one were to look at a highly humanised chimera from the
    other direction, seeing it not as a denigration of the human, but an
    elevation of the animal?

    "I don't think that taking an individual with a lower moral status and
    conferring a higher moral status on it is wrong for the animal," says
    Robert Streiffer, a bioethicist at the University of
    Wisconsin-Madison. "It could even be beneficial, if it reminded us in
    a useful way that the categorical difference between a human being and
    the rest of nature is really not so categorical."

    Another highly speculative benefit of a true human-animal chimera
    might be its role as a sort of privileged go-between. With a hand in
    one world and a paw in the other, perhaps it could provide unimagined
    insights into the lives and minds of non-human primates, and in so
    doing advance our understanding of all animals. But what if it were
    trapped between those two worlds, able neither to realise its
    humanity, nor to live in peace with its animal self? Such a creature
    would be as wretched as the ones crafted by the hand of Doctor Moreau,
    "thrown out to live a year or so, to struggle and blunder and suffer".
    Perhaps the best argument against too potent a mix of human and animal
    would be the emotional torment suffered by a being so unspeakably
    alone in the world. But such thoughts are still safely in the realm of
    science fiction.

    Jamie Shreeve is a science writer based in New Jersey. His latest
    book, The Genome War (Knopf, 2004), was one of The Economist's Books
    of the Year

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