"Now That Chimeras Exist, What if Some Turn Out Too Human?"
Sharon Begley, Science Writer

May 6, 2005; New York, NY (WSJ; p. B1) -- If you had just created a mouse with human brain cells, one thing you wouldn't want to hear the little guy say is, "Hi there, I'm Mickey." Even worse, of course, would be something like, "Get me out of this &%#ing body!" It's been several millennia since Greek mythology dreamed up the chimera, a creature with the head of a lion, the body of a goat, and the tail of a serpent. Research on the "chimera front" was pretty quiet for 2,500 years. But then in 1984 scientists announced that they had merged embryonic goat cells with embryonic sheep cells, producing a Geep. (It's part wooly, part hairy, with a face only a nanny-goat could love.) A human-mouse chimera made its debut in 1988: SCID-hu is created when human fetal tissue -- spleen, liver, thymus, lymph node -- is transplanted into a mouse. These guys are clearly mice, but other chimeras are harder to peg. In the 1980s, scientists took brain-to-be tissue from quail embryos and transplanted it into chicken embryos. Once hatched, the chicks made sounds like baby quails.

              More part-human chimeras are now in the works or already in lab cages. StemCells Inc. of Palo Alto, CA, has given hundreds of mice human-brain stem cells, for instance. And before human stem cells are ever used to treat human patients, notes biologist Janet Rowley of the University of Chicago, they (or the cells they develop into) will be implanted into mice and other lab animals. "The centaur has left the barn more than people realize," says Stanford University Law Professor and Bioethicist Henry Greely.

              Part-human creatures raise enough ethical concerns that a National Academy of Sciences Committee on Stem Cells veered off into chimeras. It recommended last week that some research be barred, to prevent some of the more monstrous possibilities -- such as a human-sperm-bearing mouse mating with a human-egg-bearing mouse and gestating a human baby. "We're not very concerned about a mouse with a human spleen," says Prof. Greely. "But we get really concerned about our brain and our gonads."

[As I indicated earlier, in critiquing Nicholas Wade's article on Tuesday in The New York Times , theres not enough real estate in the murine uterus to sustain a placenta of adequate dimensions for very long, so a mouse/rat pregnancy would be doomed or futile; however, in a female great ape, it might actually have the room, were it not for the fact that a human blastocyst probably has all kinds of antigens on its surface that would preclude implantation in the xeno-uterus (which needs all kinds of lock-and-key handshakes with fibronectin to sink into the hormonally prepared lining; recall that even within a species, like canines, not all sperm routinely fertilize all eggs following artificial insemination {closely related to the concept of true speciation in biology (subject to genetic drift after isolation) is the definition of "language" in peoples who were physically adjacent for centuries but linguistically isolated for more than 500 years. Random Spaniards and Portuguese can still understand each other with a translator being present, but this not true for French and Germans without one informant spending the time to become bilingual}. Sperm from different mammalian species look histologically/morphologically very different under the light microscope, but we would have to ask a veterinarian about the possibility of a Great Dane stud's (sire) sperm being used to fertilize a Chihuahua bitch's (dam) eggs when she is in heat (estrous) using IVF and/or a drill-down technique in which a single sperm is used to penetrate the cumulous around the egg. This is now done routinely in male-factor infertility in humans, but I suspect has not been attempted in pets because it's so expensive), but I believe that such speculation has already been suggested by the story of Tarzan, in which a human-looking being develops no language skills at all if not raised by a human family before a certain age.-- Steve Coles]

             That's why his Stanford colleague, Irving Weissman, asked Prof. Greely to examine the ethical implications of a mouse-human chimera. StemCells, co-founded by Prof. Weissman, has already transplanted human-brain stem cells into the brains of mice that had no immune system (and hence couldn't attack the foreign cells). The stem cells develop into human neurons, migrate through the mouse brain and mingle with mouse cells. The human cells make up less than 1 percent of the mouse brain, and are being used by the company to study neurodegenerative diseases. But Prof. Weissman had in mind a new sort of chimera. He would start with ill-fated mice whose neurons all die just before or soon after birth. He planned to transplant human-brain stem cells into their brains just before their own neurons died off. Would that lead the human cells to turn into neurons and replace the dead-or-dying mouse neurons, producing a mostly human brain in a mouse?

              Such a chimera could bring important scientific benefits. The SCID-hu mouse, though it hasn't yielded a cure for AIDS, has been "a very valuable animal model," says Ramesh Akkina of Colorado State University, Fort Collins, who directs a lab that uses this part-human mouse. "It has human T cells circulating, which will allow us to test gene therapy for AIDS" in a way that will be more relevant to patients than all-animal models. The co-creator of SCID-hu, Michael McCune of the Gladstone Institute of Virology and Immunology, San Francisco, notes that because the human organs last for months in the mice (they would die in days in a lab dish), "it is possible to study the effects of HIV" in many kinds of human cells in a living system. Similarly, studying living human neurons in a living mouse brain would likely yield more insights than studying human neurons in a lab dish or mouse neurons in a mouse brain. "You could see how pathogens damage human neurons, how experimental drugs act, what happens when you infect human neurons with prions [which cause mad-cow disease] or amyloid [associated with Alzheimer's]," says Prof. Greely. "The big concern is, could you give the mouse some sort of human consciousness or intelligence?"

             "All of us are aware of the concern that we're going to have a human brain in a mouse with a person saying, 'Let me out,' " Prof. Rowley told the President's Council on Bioethics when it discussed chimeras in March. To take no chances, scientists could kill the mice before birth to see if the brain is developing mouse-y structures such as "whisker barrels," which receive signals from the whiskers. If so, it's a mouse. If it is developing a large and complex visual cortex, it's too human. "If you saw something weird, you'd stop," says Prof. Greely. "If not, let the next ones be born, and examine them at different ages to be sure they're still fully mouse."

             To reduce the chance that today's chimeras will be as monstrous as the Greeks' were, the U.S. Patent Office last year rejected an application to patent a human-chimp chimera, or humanzee. But that, of course, just keeps someone from patenting one -- not making one.