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Except for the three million human brain cells injected into his
cranium, XO47 is just an average green vervet monkey. He weighs about
12 pounds and measures 34 inches from the tip of his tail to the
sutured incision on the top of his head. His fur is a melange of black,
yellow and olive, with white underparts and a coal-black face. Until
his operation, two days before I met him, he was skittering about an
open-air enclosure on the grounds of a biomedical facility on the
Caribbean island of St. Kitts. Afterward, he was caged in a hut shared
with half a dozen other experimental monkeys, all of whom bore
identical incisions in their scalps. Judging from the results of
previous experiments, the human neural stem cells inserted into their
brains would soon take hold and begin to grow, their fibers reaching
out to shake hands with their monkey counterparts. The green vervets'
behavior was, and will remain, all monkey. To a vervet, eye contact
signals aggression, and when I peered into X047's cage, he took
umbrage, vigorously bobbing his head in a stereotypical threat display.
Still, it was hard not to stare.
By virtue of the human material added to his brain, XO47 is a chimera
-- that is, an organism assembled out of living parts taken from more
than one biological species. The word comes from the monstrous creature
of Greek mythology -- part lion, part serpent and part goat -- that is
slain by the hero Bellerophon. Less fearsome chimeras occur naturally
-- lichen, for instance, is a mix of fungus and algae. Most, however,
are created in the laboratory by scientists like Dr. Eugene Redmond of
Yale University, the soft-spoken, 65-year-old psychiatrist and
neurosurgeon who operated on XO47. He set up the St. Kitts Biomedical
Foundation on this island because that is where the monkeys are -- an
overabundant feral population of them, ideally suited for research.
Redmond has transplanted immature human brain cells into a region of
XO47's brain that produces dopamine, a neurochemical that is depleted
in the brains of people with Parkinson's disease. If the human cells
can take hold and differentiate and bolster the monkey's own
dopamine-producing machinery, a similar operation on a Parkinson's
patient, the reasoning goes, should have an even greater chance of
success.
Redmond is of the opinion that the insertion of a few human cells into
a monkey brain is no big deal, and most biologists would agree. But
many bioethicists and policy makers are alarmed by recent research
developments that have made chimeric experiments more common and
increasingly capable of producing human-animal amalgamations that are
more ambitious, more ''unnatural'' -- and thus more troubling -- than
Redmond's vervets.
Driving the surge in chimeric experimentation is the enormous but still
untested promise of human stem cells. In theory, stem cells isolated
from an early human embryo can transform themselves into virtually any
kind of cell in the body, kindling hope that one day they may be
transplanted into human patients to provide new tissue wherever it is
needed -- heart muscle for cardiac patients, insulin-producing cells
for diabetics, nerve cells to repair crushed spinal cords and so on.
But there are serious hurdles to overcome before this dream can be
realized, including figuring out what controls the differentiation of
stem cells and combating their tendency to form tumors. Clearly it is
unethical to study the unknown actions of stem cells in human subjects.
One obvious solution is to insert the cells into animals and watch how
they develop. Depending on what kind of stem cells are used and where
they are put in the animal, it may also be possible to pluck some
particular human biological feature or disease trait out of its natural
context and recreate it in an animal model, where it can be examined
and manipulated at will.
While the objections to stem-cell research have largely revolved around
the ethics of using human embryos, there is another debate bubbling to
the surface: how ''human'' are chimeric creatures made from human stem
cells? Fueling the anxiety has been the lack of coherent regulations in
the United States governing the creation of chimeras. The President's
Council on Bioethics has twice taken up the issue in recent weeks, and
Senator Sam Brownback, the Kansas Republican and outspoken social
conservative, has introduced legislation to restrict chimeric
experiments. Meanwhile, the National Academy of Sciences is expected to
issue guidelines later this month as part of a widely anticipated
report on the proper use of human stem cells. While the academy's
recommendations will carry considerable clout, compliance will be
voluntary.
Few people argue that all experiments mixing human and animal material
should be banned outright. But where should the lines be drawn? ''Some
scientists are completely upset with even a single human cell in a
monkey brain,'' says Evan Snyder, a neurobiologist who has conducted
chimeric experiments with Redmond. ''I don't have problems with putting
in a large percentage of cells -10 or 20 percent -- if I felt it could
help a patient. It comes down to what percentage of human cells starts
making you squirm.''
Francoise Baylis, a bioethicist at Dalhousie University in Halifax,
Nova Scotia, and a co-author of Canada's stem-cell guidelines, squirms
not at a percentage of human cells but at the place where awareness
begins. ''We have to be sure we are not creating beings with
consciousness,'' she says. The very existence of biologically ambiguous
creatures could lead to ''inexorable moral confusion'' in a society
with two ancient and irreconcilable codes of conduct governing the
treatment of humans and animals. That said, all modern genetic
research, including the sequencing of the human genome itself,
underscores how trivial the biological difference really is between a
human being and the rest of life. Ninety-nine percent of our genome is
shared with chimpanzees. Thirty-one percent of our genes are
interchangeable with those of yeast. Does the nearness of our kinship
with the rest of nature make the prospect of a quasi-human chimera
among us less of a threat to our collective psyche or more of one?
Chimeras have been with us for some time. In 1988, Dr. Irving Weissman
and his colleagues at Stanford University created a lab model for AIDS
by endowing a mouse with an entirely human immune system. Since then,
scientists have tailored mice and other animals with human kidneys,
blood, skin, muscles and various other components. Baboon and chimp
hearts have been transplanted into human chest cavities, pig cells into
the brains of Parkinson's disease patients and, more routinely, pig
heart valves into people with heart disease, including Jesse Helms, the
former U.S. senator.
For most of us, a senator with a partly porcine heart or a mouse with a
human immune system is not sufficient to provoke the kind of
instinctive queasiness known among ethicists as ''the yuck factor.''
The man most identified with that term, Dr. Leon Kass, the bioethicist
and current chairman of the President's Council on Bioethics, is of the
opinion that widespread feelings of repugnance may be an alarm that
something is morally wrong, even if you are not able to articulate
precisely why. The mouse and the senator may not trigger a yuck because
they look just like a rodent and a person. But what about a
normal-looking mouse with a headful of human brain cells or a
human-animal embryo that is only briefly alive and never seen?
If you want to get a peek at a real live chimera, drive about five
miles east from downtown Reno, Nev., until you come to a farm that
looks pretty much like any other farm. The gate will be locked, but
from the road you can see some pens holding sheep that look pretty much
like any other sheep. Pound for pound, however, these may be the most
thoroughly humanized animals on the planet. They are the work of Esmail
Zanjani, a hematologist in the College of Agriculture, Biotechnology
and Natural Resources at the University of Nevada at Reno. Several
years ago, Zanjani and his colleagues began injecting fetal lambs with
human stem cells, mostly ones derived from human bone marrow. He said
he hoped that the cells would transform into blood cells so that he
could use the sheep to study the human blood system. According to
Zanjani, when he examined the sheep he discovered that the human cells
had traveled with their lymphatic system throughout the sheep's body,
developing into blood, bone, liver, heart and assorted other cells,
including some in the brain. While some scientists are skeptical of his
findings, Zanjani told me that some have livers that are as much as 40
percent humanized, with distinct human structural units pumping out
uniquely human proteins.
While the idea of partly humanized sheep might make some people a
little uncomfortable, it isn't easy to see where they trespass across
some unambiguous ethical line. But according to Dr. William Hurlbut, a
physician and consulting professor in human biology at Stanford, who
serves with Kass on the President's Council for Bioethics, the seeing
is exactly the point. What if, instead of internal human organs,
Zanjani's sheep sported recognizably human parts on the outside --
human limbs or genitals, for instance, ready for transplant should the
need arise? Hurlbut maintains that this is scientifically plausible.
But it would be wrong. Every living thing has a natural trajectory
through its life beginning at conception, and in Hurlbut's view, a
visible chimera would veer dangerously off course.
''It has to do with the relationship between signs and their meaning,''
he told me. ''Human appearance is something we should reserve for
humans. Anything else that looks human debases the coinage of truth.''
Understanding the world as divided into distinct categories is a
fundamental organizing principle of civilization. We conceive of the
living aspect of that world as separated into species, with boundaries
around them that should not be purposively muddled. The underlying
validity of our categorical constructs is not as important as how we
use them to make sense of the world. Our minds have evolved to be
hypersensitive to the borders between species, just as we see a rainbow
as composed of six or seven distinct colors when it is really a
continuum of wavelengths of light. ''When we start to blend the edges
of things, we're uneasy,'' Hurlbut says. ''That's why chimeric
creatures are monsters in mythology in the first place.''
It is easy to marshal rational arguments to counter this thinking. The
limitations of a typological concept of species, which goes back to
Aristotle, are well known. Some species interbreed with closely related
ones on the borders of their habitats. Evolutionary biologists cannot
agree on how to define what a species really is in the first place, so
it is hard to see how the boundaries between them can be absolute. Even
if species boundaries do have a natural integrity, how alarming is it
to find that those walls can be perforated by artificial means? We have
been engaging in unnatural acts upon nature for centuries, grafting
plants onto one another or breeding dogs in visible shapes and sizes
that diverge wildly from their natural state -- let alone performing
heart transplants and in vitro fertilizations. I'm not sure I would
undergo a crisis of truth at the sight of a sheep with a human arm,
especially if it were the best means available for replacing a lost
one. But everyone has a squirm threshold. What would you make of a
sheep with a human face?
The reason Zanjani's chimeras look like perfectly ordinary sheep is
that he injected them with stem cells in a late stage of their fetal
development, when their body plans were already laid down. The reason
he was allowed to conduct the experiment at all is that he works in the
United States, as opposed to Canada or Great Britain where such
chimeric research is restricted. Older fetuses are not as
impressionable as younger ones, and embryos are the most vulnerable of
all. And the younger the human stem cell you insert, the more powerful
an influence it can have on the body and brain of the host animal. The
way to produce the most homogenous blend of human and animal would thus
be to inject fully potent human embryonic stem cells into the very
early embryo of, say, a mouse. This is the experiment that policies in
those countries are most keen to prevent.
It is also the one that Ali Brivanlou is poised to begin. For several
years, Brivanlou, a 45-year-old developmental biologist at Rockefeller
University in New York, has been arguing that one of the best ways to
understand the usefulness of stem cells for regenerative medicine is to
first insert them in an animal embryo and see how they divide and
differentiate in a living system. The experiment is explicitly
prohibited by the institutions that supply the stem-cell lines approved
by the Bush administration, so he is using private funds to develop his
own lines. He plans to insert them into 3-to-5-day-old mouse embryos,
which he will then implant in the wombs of female mice. Brivanlou is
anxiously awaiting the publication of the National Academy of Sciences
guidelines before proceeding, but he says he doubts that they will
prove an impediment. In his view, showing the potency of stem cells
only in a petri dish is like testing the power of a new car by revving
its engine in the garage. He wants to take the car out on the track and
see how it might perform some day on the open road.
''This experiment must be done,'' he says. ''We can't go directly from
culture to a patient. That would be extremely dangerous.''
But his experiment is one that most are very reluctant to undertake,
even in the private sector. When I inquired at Geron Corporation, a
biotechnology company in California, whether scientists there were
considering such work, I received a terse e-mail reply that ''the
company is not, has not and will not pursue inter-species stem-cell
chimeras.''
Robert Lanza, vice president for medical and scientific development at
Advanced Cell Technology in Worcester, Mass., says much the same thing.
''I personally don't want to engage in those kinds of experiments, and
I won't have any of my scientists do that work,'' he says. ''Sure, we
could reach our endpoints quicker that way. But it takes you into very
murky water.''
Why all the shuddering? For starters, there is the gonad quandary. If
the experiment really works, the human cells should differentiate into
all of the embryo's cell lineages, including the one that eventually
forms the animal's reproductive cells. If the mouse were male, some of
its sperm might thus be human, and if it were female, some of its eggs
might be human eggs. If two such creatures were to mate, there would be
a chance that a human embryo could be conceived and begin to grow in a
mouse uterus -- a sort of Stuart Little scenario, but in reverse and
not so cute.
''Literally nobody wants to see an experiment where two mice that have
eggs and sperm of human origin have the opportunity to mate and produce
human offspring,'' says Dr. Norman Fost, professor of pediatrics and
director of the bioethics program at the University of Wisconsin and a
member of the National Academy of Sciences committee reviewing
stem-cell research policies. ''That's beyond anybody's wildest
nightmare.''
Is the concern over the reproductive issue overblown? It is, of course,
biologically impossible for a human fetus to be delivered from a rodent
uterus. Moreover, for a human embryo to be conceived, the chimeras
would have to be born first in order to mate, and Brivanlou says he has
no intention of allowing them to come to term. He plans to terminate
them and examine the fate of the human cells after a week. Still, there
remains the question of what kind of being would be present during
those seven days. Nobody knows. Does even the fleeting, prenatal
existence of a chimera of unknown aspect cross a moral line -- not
because of what it might look like or become but simply for what it is?
Brivanlou is not troubled by that question. He sees the other methods
of testing the stem cells' power -- in vitro or in the body of an older
fetus or of a fully developed animal -- as inadequate, and he says he
wants the science to be allowed to follow its natural course. ''One
thing that is important to remember -- we've been here before,'' he
says. ''In the 70's, there was a huge debate around whether recombinant
DNA should be allowed. Now they do it in high-school labs. For any new
technology that emerges, the first reaction is fear. Time will take
care of that. When people take the time to think, it becomes routine.''
During my visit to St. Kitts, I watched as Gene Redmond, dressed in
blue surgical scrubs in the operating room, drilled into the skull of a
vervet monkey. Once he penetrated the skull, Redmond positioned a
four-inch hypodermic needle on a mount over the hole and ever so slowly
lowered it into the monkey's cerebral cortex, down through structures
associated with emotion and on until it reached its target in the basal
ganglia at the base of the brain. He let the brain settle around the
needle for a while and then injected a solution of donor cells into the
target.
If he were performing this operation on a human patient, the procedure
would be more or less the same. But he would need a much longer needle.
If it is not some categorical essentialism that draws a bright line
between us and the rest of the animals, surely it is the size and power
of our brains. They are the physical address of everything we think of
as uniquely human -- our rational thinking, intelligence, language,
complex emotions and unparalleled ability to imagine a future and
remember the past. Not surprisingly, chimeric experiments that seed the
brain of an animal with a little neural matter of our own are uniquely
suspect, especially those that meddle with the sites of higher function
in the cortex.
''If you create stem-cell lines that might produce dopamine and want to
put them in an animal first to see if they retained their stability,
that's not problematic,'' Norman Fost maintains. ''But what if you want
to study brain cortex? You'd want to create a stem-cell line that looks
and acts like cortex and put this in an animal. In the toughest case,
you'd want to put it in a very early stage of development. This is
extremely hypothetical, but suppose these cells completely took over
the brain of the animal? A goat or a pig with a purely human brain.
Unlikely, but imaginable. That would certainly raise questions about
what experiences that animal was having. Is it a very smart pig? Or
something having human experiences? These are interesting questions
that no one has thought about before because they haven't had to.''
The scientist most responsible for making people think about those
questions -- and squirm and fume -- is Irving Weissman. Several years
ago, Weissman and his colleagues at Stanford and at StemCells Inc., a
private company he helped to found, transplanted human neural stem
cells into the brains of newborn mice. The human cells spread
throughout the mouse brain, piggybacking on the host's developmental
pathways to eventually make up as much as 1 percent of some parts of
the host's neural tissue. Once again, the ultimate purpose of the
chimera was to create a research model for human brain function and
disease. While somewhat successful in this regard, Weissman said he
felt his model was hampered by the 99 percent of it that was still
mouse. So he came up with an ingenious idea: why not make a mouse with
a brain composed entirely of human neurons? In theory, at least, this
could be achieved by transplanting human neural stem cells into the
fetal brain of a strain of mouse whose own neurons happen to die off
just before birth. If the human stem cells took up the slack and
differentiated along the same lines as in the earlier experiment, you
might just end up with a living newborn mouse controlled by a
functioning brain that just happened to be composed of human cells.
Before proceeding with this experiment, Weissman said he thought it
might be a good idea to solicit some ethical input. He contacted Hank
Greely, a bioethicist at Stanford's law school, who put together a
committee to review the benefits and risks involved. The members agreed
that the human neuronal mouse could be an extremely beneficial tool to
study the effects of pathogens and disease in the human brain and the
action of new drugs. They identified several areas of risk. The most
difficult one to articulate, as Greely told the National Academy of
Sciences panel reviewing the use of human stem cells, was the
''nontrivial chance of conferring significant aspects of humanness on
the nonhuman organism.''
''Though exceedingly remote, we thought this possibility was reason for
caution and concern,'' Greely told me recently. His committee, which
has yet to publish its report, did not find that risk alone was
sufficient grounds for canceling the experiment. Instead, the members
suggested that Weissman incorporate into the experimental protocol a
series of ''stopping points.'' Some of the fetal mice should be
terminated and examined before birth, and if there should appear any
''disquieting or disturbing results,'' the experiment should be
suspended pending further ethical review. Results deemed troubling
would include any evidence that the transplant was shaping the
architecture of the mouse's neural edifice, as opposed to just
contributing the bricks. Mice have sensory structures in their brains
called ''whisker barrels,'' for instance, which we lack, while we have
a far more complicated visual cortex. Shrunken whisker barrels or
swollen visual cortex in the fetal mice brains would be a red flag. If
everything appeared normal, the remaining animals could be brought to
term and monitored for the appearance of any odd, and especially
humanlike, behavior, which would again warrant stopping the experiment
and seeking additional input from the ethical community.
Weissman is still months or even years away from actually trying his
human neuron mouse experiment, and it has already drawn ''This shall
not stand'' rhetoric from Jeremy Rifkin, the anti-biotech activist,
Bill O'Reilly and numerous religious commentators and bloggers.
The real problem with Weissman's proposed mouse, however, may turn out
to be not that it is too human but that it is not human enough. The
basic structure of our nerve cells is not all that different from those
of any other mammal, including a mouse's. But because our brains are so
much bigger, the cells that compose them reach across greater
distances, and the timing of their development is much longer. How
likely is it that human nerve cells will develop into a whole
functioning brain in the tiny arena of a fetal mouse's skull? Weissman
concedes that his proposed chimeric experiment may not succeed. But,
hypothetically speaking, what if you could conduct the analogous
experiment in an animal with a brain more like our own, like a monkey
or a chimpanzee? Strictly from a biomedical perspective, a human-ape
chimera could be the ultimate research model for human biology and
disease -- one that is completely human in everything but its humanity.
''If someone were to try Irv's mouse experiment with a great ape or
even a monkey, I'd get real worried,'' Greely says. ''I'd want to make
sure people thought long and hard about that.''
The danger, of course, is in how difficult it would be to know when
you've slipped over the edge. While Greely's committee has been
brooding over Weissman's mouse and the National Academy has been
pondering its recommendations for the use of embryonic stem cells,
another ethics group has been meeting at the Phoebe R. Berman Bioethics
Institute at Johns Hopkins University to grapple with the especially
dicey issue of human/primate chimeras. Could the introduction of human
cells into nonhuman primate brains cause changes that would make them
more humanlike? How would one tell? Would it be morally problematic to
create a chimera with a significant degree of humanlike consciousness,
cognition or emotion? Should such experimentation be banned? If such
chimeras were to be created, what legal rights and protections should
they have, distinct from other animals?
The report of the Working Group on Interspecific Chimeric Brains is
expected to be published later this spring in a scientific journal.
While the group's recommendations remain confidential until then, a
rough idea of the boundary they might draw between allowable and
prohibited research is suggested by two experiments that have already
been conducted. One was carried out in 2001 by Evan Snyder, then at
Harvard University and now director of the stem-cell program at the
Burnham Institute in La Jolla, Calif. Snyder and his colleagues
implanted human neural stem cells into the brains of 12-week-old fetal
bonnet monkeys, aborted them four weeks later and found that the human
cells had migrated and differentiated into both cerebral hemispheres,
including into regions of the developing monkey cortex. Like Redmond,
Snyder discounts any possibility that had the monkeys been brought to
term the relatively small number of human cells in their brain would
have had any effect on their normal cognition and behavior.
''Even if I were to make a monkey with a hippocampus composed entirely
of human cells, it's not going to stand up and quote Shakespeare,''
Snyder says. ''Those sophisticated in human functioning know that it's
more than the cellular components that make a human brain. It's the
connections, the blood vessels that feed them; it's the various
surfaces on which they migrate, the timing by which various synaptic
molecules are released and impact other things, like molecules from the
bloodstream and from the bone.''
It's quite likely that the members of the Johns Hopkins committee (it
includes distinguished philosophers, bioethicists, neuroscientists,
primatologists and stem-cell researchers) will conclude that an
experiment like Snyder's is ethically safe. A relatively small
scattering of human cells could be introduced into a primate brain,
late in its development when there would be no chance the human cells
could influence its fundamental architecture. But a result of another
experiment, performed in the late 1980's by Evan Balaban, who is now at
McGill University in Montreal, might give the group pause about mixing
human and primate tissue in a very early fetus. Balaban removed a
section from the midbrain of a chick embryo, grafting in its place the
corresponding piece of proto-brain from an embryonic quail. While many
of the embryos failed to develop, a few matured and eventually hatched.
The newborn chicks were normal in most respects -- except they crowed
like quails.
''One could imagine that if you took a human embryonic midbrain and
spliced it into a developing chimpanzee, you could get a chimp with
many of our automatic vocalizations,'' says Terrence Deacon, a
biological anthropologist at the University of California at Berkeley
and a member of the Johns Hopkins committee. ''It wouldn't be able to
talk. But it might laugh or sob, instead of pant-hoot.''
Of course, Deacon adds quickly, such an experiment would be highly
unethical. The notion of a chimpanzee normal except for its human
sobbing would probably exceed the squirm threshold of the other members
of the Johns Hopkins group. Perhaps it is not what a human-animal
chimera would be that violates some fundamental categorical construct
in our minds, or what it would look like, as William Hurlbut maintains,
as much as what it could do -- whether it would have a brain that makes
it act in a way that is uncomfortably familiar. ''Humanness'' surely
resides in the emergent layers building the vastly complex architecture
of the human brain.
But is there a clear biological distinction between us and the rest of
creation, one that should never be confounded by the scuffling of
strange new feet in laboratory basements? Deacon has devoted a great
deal of thought and research to such questions. While his is hardly the
only view, after a career spent comparing the brains of living primates
and the skulls of fossilized hominids, he says that there is little
evidence for the sudden appearance of some new thing -- a uniquely
human gene, a completely novel brain structure in the hominid lineage
-- that sets us distinctly apart. Obviously, there has been an overall
increase in brain size. But the telling difference is in more subtle
shifts in proportion and connections between regions of the brain, ''a
gerrymandering of the system'' that corresponds to a growing reliance
on the use of language and other symbolic behavior as a means of
survival. This shift, which Deacon believes began as long as two and a
half million years ago, is reflected most prominently in the swollen
human prefrontal cortex.
''We humans have been shaped by the use of symbols,'' he says. ''We are
embedded in a world of human creation, where demands for success and
reproduction are all powerfully dependent on how well we swim through
our symbolic niche.''
This raises some fascinating questions, not just about the chimeras we
might create with our scalpels and stem cells but also about the ones
we may already have fashioned by coaxing humanlike behaviors from
animals who have the latent capacity to express them. In the wild,
chimpanzees and other apes do not engage in any symbolic behavior
remotely comparable to what humans have evolved. But in the laboratory
they can learn to communicate with sign language and other means on a
par with the skills of a toddler. The difference is that the toddler's
symbolic behavior becomes increasingly enriched, while the chimpanzee
hits a wall. How much further could a bioengineered chimera go? Could
it swim in our symbolic niche well enough to communicate what is going
on inside its hybrid mind? What could it teach us about animals? What
could it teach us about us? And what is the price of the knowing?
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