LinkMay 3, 2005
Chimeras on the Horizon, but Don't Expect Centaurs
By NICHOLAS WADE
Common ground for ethical research on human embryonic stem cells may have been laid by the National Academy of Sciences in the well-received guidelines it proposed last week. But if research on human embryonic stem cells ever gets going, people will be hearing a lot more about chimeras, creatures composed of more than one kind of cell. The world of chimeras holds weirdnesses that may require some getting used to.
The original chimera, a tripartite medley of lion, goat and snake, was a mere monster, but mythology is populated with half-human chimeras - centaurs, sphinxes, werewolves, minotaurs and mermaids, and the gorgon Medusa. These creatures hold generally sinister powers, as if to advertise the pre-Darwinian notion that species are fixed and penalties are severe for transgressing the boundaries between them.
Biologists have been generating chimeras for years, though until now of a generally bland variety. If you mix the embryonic cells of a black mouse and a white mouse, you get a patchwork mouse, in which the cells from the two donors contribute to the coat and to tissues throughout the body. Cells can also be added at a later stage to specific organs; people who carry pig heart valves are, at least technically, chimeric.
The promise of embryonic stem cells is that since all the tissues of the body are derived from them, they are a kind of universal clay. If biologists succeed in learning how to shape the clay into specific organs, like pancreas glands, heart muscle or kidneys, physicians may be able to provide replacement parts on demand.
Developing these new organs, and testing them to the standards required by the Food and Drug Administration, will require growing human organs in animals.
Such creations - of pigs with human hearts, monkeys with human larynxes - are likely to be unsettling to many.
"I think people would be horrified," said Dr. William Hansen, an expert in mythology at Indiana University.
Chimeras grip the imagination because people are both fascinated and repulsed by the defiance of natural order. "They promote a sense of wonder and awe and for many of us that is an enjoyable feeling; they are a safe form of danger as in watching a scary movie," Dr. Hansen said.
From the biologists' point of view, animals made to grow human tissues do not really raise novel issues because they can be categorized as animals with added human parts. Biologists are more concerned about animals in which human cells have become seeded throughout the system.
"The mixing of species is something people do worry about and their fears need to be addressed," said Dr. Richard O. Hynes of the Massachusetts Institute of Technology, the co-chairman of the National Academy of Sciences committee that issued the research guidelines.
Foreseeing the need for chimeras if stem cell research gets near to therapy, Dr. Hynes's committee delved into the ethics of chimera manufacture, defining the two cases in which human-animal chimeras could raise awkward issues. One involves incorporating human cells into the germ line; the other is involves using a human brain, creating a human or half human mind imprisoned in an animal body.
In the case of human cells' invading the germ line, the chimeric animals might then carry human eggs and sperm, and in mating could therefore generate a fertilized human egg. Hardly anyone would desire to be conceived by a pair of mice. To forestall such discomforting possibilities, the committee ruled that chimeric animals should not be allowed to mate.
Still, there may in the future be good reason to generate mice that produce human oocytes, as the unfertilized egg is called. Tissues made from embryonic stem cells are likely to be perceived as foreign by the patient's immune system. One way around this problem is to create the embryonic stem cells from a patient's own tissues, by transferring a nucleus from the patient's skin cell into a human oocyte whose own nucleus has been removed.
These nuclear transfers, which are also the way that cloned animals are made, are at present highly inefficient and require some 200 oocytes for each successful cloning. Acquiring oocytes from volunteers is not a trivial procedure, and the academy's recommendation that women who volunteer should not be paid is unlikely to increase supply. Chimeric mice that make human oocytes could be the answer.
There are also sound scientific reasons for creating mice with human brain cells, an experiment that has long been contemplated by Dr. Irving Weissman of Stanford. Many serious human diseases arise through the loss of certain types of brain cell. To test if these can be replaced with human neural stem cells, Dr. Weissman injected human brain cells into a mouse embryo and showed that they followed the rules for mouse neural stem cells, migrating to the olfactory bulb to create a regular stream of new odor-detecting neurons.
The mice may have been perplexed by their deficient sense of smell but probably not greatly so because human cells constituted less than 1 percent of their brain. Dr. Weissman decided it would be useful to have a mouse with a much larger percentage of human brain cells, but he sought ethical guidance before trying the experiment.
He plans to let such mice develop as fetuses and to curtail the experiment before birth, to see if their human brains cells have arranged themselves in the architecture of a mouse brain or human brain.
Given the nine months it takes for a human brain to be constructed, it seems unlikely that the developmental program of the human neurons would have time to unfold very far in the 20-day gestation of a mouse.
Contrary to the plot of every good horror movie, the biologists' chimera cookbook contains only recipes of medical interest. But if there were no limits, could they in fact turn chimeras of myth into reality? That depends on the creature.
If embryonic cells from human and horse were mixed together,
the cells of each species would try to contribute to each part of the body, as in the patchwork mouse, but in this case with goals so incompatible it is hard to see any viable creature being formed. Centaurs, in any case, have six limbs, and that would be fine for an insect but violates the standard mammalian body plan.
A much greater chance of creating a viable chimeric creature would come from injecting human embryonic stem cells into a monkey or ape. For this reason the academy committee has firmly ruled out such experiments as unethical. But to continue a little on the path of fantasy, humans are still very similar to chimpanzees, their closest surviving cousins, and an embryo constructed of cells from each may be viable enough to be born.
This chimerical creature would probably not be as enjoyable as the chimeras of mythology but more of a problem human - a Caliban-like personage with bad manners and difficult habits.
"If something were half human and half animal, what would our moral responsibilities be?" says Richard Doerflinger of the United States Conference of Catholic Bishops. "It might be immoral to kill such a creature. It's wrong to create creatures whose moral stature we are perplexed about."
Evidently the first rule of chimeric chemistry is not to make creatures whose behavior straddles the perceived division between the human and animal worlds.
(Didn't I see this one in 'Alien Resurrection'?)
