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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.

 

 

Of Mice, Men and In-Between

 

By Rick Weiss

 

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 medicines.

 

" 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 patients.

 

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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