Blurring boundaries

High up on the bluffs overlooking the Pacific Ocean in southern California, strange animals scurry about in their cages. They eat, drink, copulate and occasionally try to run away from human hands that enter their confined quarters. If you didn't know better, you would think they were ordinary mice. But these particular animals contain a hidden component not present in their naturally conceived cousins. Inside their brains are living human neurons that help them to see, hear and think.


Fred Gage, a biologist at the Salk Institute, has created these part-human animals to understand how human neurons degrade or die in people suffering from neurodegenerative diseases such as Parkinson's and Alzheimer's. Studying and perturbing brain cells in their natural environment—which is to say, inside a functioning brain—provide the best hope for developing therapies to prevent or overcome disease symptoms. But experimentation on human brains is obviously unacceptable, and so scientists are hoping that animals with a small percentage of human brain cells will provide a substitute for human subjects.


Many people, however, are deeply disturbed by this research. U.S. President George W. Bush believes that scientists like Gage have stepped across a moral line that must be defended, even at the cost of biomedical progress. In his 2006 State of the Union address, he implored Congress to "pass legislation to prohibit the most egregious abuses of medical research [including] creating human-animal hybrids," because "human life is a gift from our Creator" that should never be "devalued."


Animal chimeras: from absurdity to reality


To understand the fear and anger evoked by chimeras, it is useful to go back in scientific history to March 1984, when an animal unlike any other ever born, or seen, adorned the cover of Nature, the international journal of science. The journal's audience of scientists was treated to an unforgettable photograph of an animal with a head that was mostly goat, an upper torso that was wooly sheep, with other body parts that alternated between the two species types. "It behaved like a goat," according to its creator, Danish embryologist Steen Willadsen , "but did not quite smell like one, preferring the company of sheep." This first geep (as the animal became christened) was physically healthy, long-lived, and even fertile. Additional geeps were created by Willadsen over the next several years.

The geep is an alluring example of a laboratory-created chimera, named by scientists in honor of the creature from Greek mythology with the head of a lion, the torso of a goat, and a tail sprouting the head of a venomous snake. Like other mythological species composites, the chimera was imagined as a monster because it violated a perceived "natural order" in which each species is divinely created as a separate and unique category. Indeed, a chimera's potential violation of nature was so profound that rational thinkers have always assumed it couldn't possibly exist, and the word chimera has become a metaphor for a wishful idea without any basis in reality.


Willadsen, unlike most scientists, was unwilling to accept the natural limitations imposed by traditional beliefs. "The role of the [biological] scientist," he said, "is to break the laws of nature, rather than to establish, let alone accept them." With this spark of irreverence, Willadsen created not only geeps but other species composites including a cow-sheep creature that he cooked and ate after completing his analysis. (The same refusal to accept conventional wisdom provided him with the confidence to bypass fertilization in the invention of the cloning technology used to create Dolly and thousands of other subsequently cloned animals.) Building upon Willadsen's pioneering work, other scientists combined even more distant species, creating chicken-turtle and chicken-mouse fetuses, for example (which were dissected before hatching). In all of these instances, chimeras were used as models to study basic biological processes.


Animal rights activists who reject all types of animal experimentation will obviously object to chimera creation as well. But, in fact, chimeric animals are no more likely to suffer than any other animal bred by people for food or research. Each of Willadsen's chimeras was created in a petri dish by mixing together cells from two embryos. The cells stuck together, but didn't fuse, which is why the composite embryos produced animals with species-distinct component parts.


(A chimera is different than a hybrid, which is formed by cross-species fertilization. A hybrid animal like the mule has cells that are all genetically equivalent and halfway between a donkey and a horse. George W. Bush was obviously not aware of this distinction when he gave his State of the Union address.)


Because of the fundamental similarity in the body plans of all vertebrate species, live-born chimeras are typically healthy -- albeit bizarre-looking -- animals. And so dual-animal-species chimera production should pose no ethical problems beyond those encountered in traditional animal research.


Stem cells and animal-human chimeras


Until the year 2000, chimera production and analysis was just an esoteric tool for basic research on animal development, with little direct clinical relevance. But explosive advances in stem cell biology have provided scientists with the ability to create animal chimeras containing human component parts, and these partial-human chimeras could potentially revolutionize biomedical analysis and therapy.


The significance of stem cells lies in the fact that they are, in essence, embryonic or otherwise immature precursors to the cells that function within our mature tissues and organs. The mother of all stem cells is the embryonic stem (ES) cell, which exists naturally in 10-day old embryos. ES cells have the capacity to form everything in the human body. During normal development, ES cells divide repeatedly, giving rise to an array of stem cell types that each have a more restricted capacity to form only one or a few tissues or organs.


Human stem cells at many different stages, from embryonic to adult, can now be cultivated in laboratory petri dishes. And chimeras can now be produced by inserting these stem cells into animal fetuses or embryos. Biomedical scientists are hopeful that a more sophisticated understanding and ability to control both animal development and human stem cells will someday allow the production of animals with human organs formed in place of animal organs.


Remarkably, progress along these lines has already been made. Alan Flake at Children's Hospital in Philadelphia and Esmail Zanjani at the University of Nevada, incorporated human stem cells into early sheep fetuses while they were growing in their mothers' wombs. After birth, a wide variety of lamb tissues including blood, cartilage, muscle and heart displayed human contributions of up to 40%, although external body features were always entirely animal-like.


In another type of chimera experiment, Yair Reisner at the Weizmann Institute in Israel implanted nondescript human kidney stem cells into mice, and coaxed the cells to multiply and develop into miniature, but fully functional, human kidneys that actually secrete urine. Results obtained from these lines of research and others suggest that the personalized therapeutic potential of stem cells might be most fully exploited in conjunction with the developmental potential provided through chimeras to create fully functional, replacement kidneys, livers, and hearts.


Where is the line?


Although pigs with human hearts will, upon first description, cause people to shudder, education and self-interest is likely to drive the acceptance of chimeras developed strictly for organ transplantation. As long as they look like animals and behave like animals, most people will view them as animals because internal organs by themselves do not tug upon our emotions.  (But ask yourself whether an animal such as the following is acceptable to provide an arm to someone who lost their own in accident.)

The debate line shifts, however, when scientists begin to chimerize the essential features of mentality that distinguish us as human beings. Educated people understand that human mentality emerges from human brains, which is why chimeric mice with human brain cells are liable to perturb many more people.


Last December, Gage injected human embryonic stem cells into the brain regions of developing mouse fetuses still inside their mother's uterus. The human cells became "active human neurons that successfully integrate into the adult mouse forebrain," where higher brain function is localized, Gage explained. Although Gage's mice have brains that are less than 1 percent human, Stanford professor Irving Weissman believes that mice with brains made entirely of human cells would make a better "model" for human neurological diseases, and he's proposed creating them. Would a mouse with a 100 percent human brain cross a moral red line?


No biologist thinks a mouse-size brain filled with human cells could produce anything remotely resembling human consciousness.  But the presence of a biologically human brain inside an organism able to propel and feed itself is typically accepted as clear biological evidence that the organism is a human being. This logic would force an ethical person to grant the chimeric mouse I've just described a right to life, which is patently absurd. Yet if we follow our intuition and decide that this mouse is not a human being, we are forced to conclude that the presence of a fully-human brain inside an alert, responsive organism is not a sufficient criterion for inclusion within the family of human beings, which not only violates common sense but challenges the very foundation of universal human rights.


The moral conundrums provoked by animal-human chimeras multiply tremendously when the companion species is not a mouse but a non-human primate with a far larger brain capacity. So far, scientists have only integrated small numbers of human neurons into monkey brains. Although members of the scientific community have no intention of creating chimeras with even minimal human-specific mental attributes, the fact is that modern biotechnology has moved such ambiguous beings from the realm of mythology to the realm of possibility. And this fact elicits the greatest challenge to western thought, which is that the existence of a strict line separating human beings from non-human beings may simply by a figment of our imagination.