Stretching the boundaries of stem cell research.

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http://www.washingtonpost.com/ac2/wp-dyn/A63731-2004Nov19Of Mice, Men and In-BetweenScientists Debate Blending Of Human, Animal FormsBy Rick WeissWashington Post Staff WriterSaturday, November 20, 2004; Page A01In 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 MomsChimeras

(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 BreakthroughThe

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 AdvantagesPerhaps

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."Note: For more important information on how money and greed may be endangering your health, Final

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