Human-Animal Chimeras: Biological Research & Ethical Issues
A chimeric mouse in which the albino (white skin and pink eye) and brown skin (and black eye) are derived from either the host embryo or embryonic stem cells.
Credit: NIH

In Greek mythology, the Chimera was a magnificent monster. It was an unusual mélange of animals, with a lion's head and feet, a goat's head sprouting off its back, and a serpentine tail. It wrought great destruction, until the hero Bellerophon killed the monster, with the aid of the winged horse, Pegasus.

In scientific terms, the word "chimera" retains the essence of its mythical roots. A chimera is made of cells that are derived from two (or sometimes more) organisms. These "parent" organisms may be of the same or different species. The defining feature of a chimera is that the individual cells in its body are not all the same; they are genetically distinct. Instead of a mixture of genes from each parent organism, a given cell contains the genetic information of only one parent organism. Thus, a chimera is made up of populations of cells that are genetically identical to each of its parent organisms. 

Some examples of chimeras are already familiar to most people. For instance, tissue chimeras result from organ transplants or tissue transplants (such as a bone marrow transplant). Following the transplant, the recipient acquires two genetically distinct tissue and cell types, according to a 2007 review article by Richard R. Behringer, a professor of genetics at the University of Texas MD Anderson Cancer Center in Houston, Texas, published in the journal Cell Stem Cell. 

Chimeras can also occur in nature. Author Vivienne Lam listed several examples of natural chimerism in humans in a 2007 article published in The Science Creative Quarterly (University of British Columbia) journal. Microchimerism occurs when only a small population of cells is genetically different from the rest. For example, during pregnancy, a mother and developing fetus can swap stem cells through the placenta. 

Another example is tetragametic chimerism. Here, two separate sperm fertilize two separate eggs, which would ideally result in a set of fraternal twins. However, if the two embryos somehow fuse together creating a single fetus with genetically distinct cells, tetragametic chimerism occurs. 

Most often, however, chimeras are created in a laboratory for research purposes. When the cells of different parent organisms come together to form a chimera, they can incorporate into multiple parts of the chimera's body. These cells can be somatic cells — any cell in the body except for reproductive cells — or they may be incorporated into germline tissues, where specialized reproductive cells, or gametes, such as sperm and egg cells, are produced, according to Behringer. 

Examples of such research tools include chimeric mice, which are bred for use in genetic research. These animals contain two types of mouse cells that express different genes: one where all the mouse genes are intact, and the other where one copy of a particular gene is deleted, or "knocked out." A series of mating steps using such chimeric mice ultimately results in some offspring in which the gene of interest is completely knocked out in all cells, according to a Scitable article published by Nature Education. This helps researchers to fully understand the function and relevance of that particular gene within a live model organism. 

Various interspecies chimeras have also been created. For instance, 1984 marked the development of the first goat and sheep chimera, called the "geep," according to the University of Wisconsin-Madison. The areas of the geep body that contained sheep cells and DNA were wooly, whereas the areas with goat cells and DNA were hairy. 

Human-animal chimeras are a further example of an interspecies chimera, generated when human cells are introduced into animals. This can be done through a variety of techniques. Human cells and tissues can be grafted into embryos, fetuses or adult vertebrate animals, Behringer said. Human-animal chimeras are also produced by introducing human stem cells into animals during various developmental stages, be it embryonic, fetal or postnatal (after birth), according to a 2007 article, also published in the journal Cell Stem Cell.

According to the National Institutes of Health (NIH), two unique properties make stem cells useful in research: the ability to replicate and restore their populations without much limitation and the ability to form many different cell and tissue types during early development. 

Stem cells derived from adult organs and tissues are somewhat limited in the types of cells that they can form. On the other hand, stem cells that are derived from human embryos (which can also be engineered in the lab) or cells that are genetically engineered to revert to a stem-cell-like state are considered to be "pluripotent," according to the Boston Children's Hospital. This means that these cells have the ability to develop or "differentiate" into all the major cell and tissue types of the human body. 

So when human stem cells are used to generate human-animal chimeras, especially during early embryonic stages, they have the ability to incorporate into various parts of the chimera body, including the germline, and can form a range of cell and tissue types.

Human-animal chimeras serve as a useful living test environment to help scientists better understand the underpinnings of human biology and the mechanisms of human disease. As Behringer pointed out in his article, using laboratory animals as models of human biology or diseases doesn't fully replicate human physiology. "Thus, the primary goal of human-animal chimera research is to produce human cellular characters in animals," he wrote.

Such research has been conducted for decades now. For instance, in 1974, a group of researchers from Denmark reported the first successful transplantation of many different human fetal organs into a laboratory mouse model called the nude mouse. Their experiments, published in a 1974 article in the journal Nature, showed that human fetal lungs, kidneys, pancreas, thymus, adrenal glands, testes and ovaries were all able to establish themselves and develop within in the nude mouse.

Experiments conducted in recent years have focused on expanding the potential uses of the human-animal chimeric model. In a 2004 article published in the journal Blood, the authors described experiments in which human hematopoietic stem cells, or blood-forming stem cells, were transplanted into 55- to 60-day-old sheep fetuses. In addition to forming the components of blood and the immune system, these stems cells can form cells such as bone and muscle. The authors found that hematopoietic stem cells were also capable of forming functional human liver cells. The researchers suggested that such a chimeric model could provide a means of generating large numbers of human liver cells to treat genetic diseases in fetuses or newborns where the liver cells are deficient. 

Another research group introduced human embryonic stem cells into the brains of 14-day-old embryonic mice. These experiments, described in a 2005 article published in the journal PNAS, showed that the human embryonic stem cells formed many different functional neural cell types. These cells continued to develop into mature and active human neurons within the forebrain of the mouse. The authors highlighted the importance of having a live environment in which to study human neural development. In addition, they proposed that such chimeras could aid in developing new models of neurodegenerative and psychiatric diseases, as well as provide a potential means to speed up the screening of therapeutic drugs.

The "Chimera of Arezzo" statue from around 400 B.C., found in Arezzo, an ancient Etruscan and Roman city in Tuscany.
The "Chimera of Arezzo" statue from around 400 B.C., found in Arezzo, an ancient Etruscan and Roman city in Tuscany.
Credit: Carole Raddato

How should people think of an animal once scientists begin to imbue it with human characteristics? This question forms the crux of many ethical debates centered on the generation of human-animal chimeras.

For instance, there may be many instinctive objections to creating such chimeras. There's the "yuck factor," or an immediate feeling of repugnance, said a 2003 article published by Project Muse. This feeling may be explained by a perception that creating human-animal chimeras is somehow taboo and that some boundaries have been crossed. 

"As such, these beings threaten our social identity, our unambiguous status as human beings," the authors, Jason Scott Robert and Francoise Baylis, wrote. But then they go on to ask, "What makes for unambiguous humanness?"

The generation of human-animal chimeras in some sense obscures the lines that define the identities of species. For instance, if human pluripotent cells were allowed to integrate into an animal's germline tissue, it is possible for the chimera to generate human eggs or sperm. And one may very well ask that if human neurons integrate into animal brains, is there the possibility of enhancing an animal's capabilities and experiences to a human level?

Ultimately, Robert and Baylis summed up the inherent conundrum in evaluating the ethics of generating human-animal chimeras like this: "When faced with the prospect of not knowing whether a creature before us is human and therefore entitled to all the rights typically conferred on human beings, we are, as a people, baffled."

For some ethicists, the rights of human-animal chimeras are tied to the notion of "moral status." 

"Moral status is a concept that refers to the moral importance that an individual has, independent of the concerns or interests of others," said Robert Streiffer, an associate professor of bioethics and philosophy at the University of Wisconsin-Madison. "Some things have no moral status. A chair only matters morally if other people care about it (because, for example, it is their property). But other things do have moral status. A person or an animal matters even if no one else cares about that individual."

Streiffer noted that an individual's moral status determines the kinds of research for which it may be used. In the case of human beings, there are strict limits on the types of research that can be conducted on nonconsenting individuals. "This reflects society's view that human beings have a very high degree of moral status." he said. "In contrast, the regulations on research using nonhuman animals allow research on nonconsenting individuals that sacrifices their most fundamental interests — their interests in avoiding pain and death — in the hopes that others can ultimately benefit. This reflects society's view that animals have a lower degree of moral status."

Streiffer went on to explain that although the many different theories ground an individual's moral status in different characteristics, ultimately these are determined by the physical characteristics of an individual's body. Under the "graded theory" of moral status, if the physical makeup of the individual is changed enough in certain ways, it could in theory alter that individual's moral status. Therefore, it is possible to begin research with an animal, which is afforded weaker protections, but ultimately change it in such a way that it acquires a higher moral status. 

"As a worst-case scenario, one could imagine an individual who has the same moral status as you or I have, but continues to be treated as animals are usually treated in research," Streiffer told Live Science. "This would be egregiously unethical."

Current federal policy in the form of NIH guidelines and recommendations put forth by various scientific organizations take into consideration ethical concerns and recent advancements in research and technology.

In September 2015, the NIH placed a temporary moratorium on funding research in which human pluripotent cells are introduced into nonhuman vertebrate animals prior to the gastrulation stage of embryonic development. During gastrulation the three germ layers, or three main tissue layers that ultimately give rise to all the cells and tissues of the body, are formed. When human pluripotent cells are introduced early on into animal embryos, the human cells have a chance of incorporating all through the organism, says Carrie Wolinetz, the associate director for science policy at NIH. "You have less control over where they [pluripotent cells] are going to go," she said.

Wolinetz noted that the ethical concerns regarding human-animal chimeras have not really changed much over the years. "People are really worried about integration of human cells into the germline and into the brain," she said. Though she characterized the idea of an animal having human cognition as a "science fiction scenario," Wolinetz emphasized the need to make sure that the integration of human cells into an animal brain does not cause changes in the animal's behavior and cognition that affect its welfare or cause any kind of distress.

In August 2016, following workshops and discussions with researchers and animal welfare experts, the NIH published proposed changes to its current guidelines. The ethical concerns detailed above formed much of the basis for these guidelines. The NIH proposed the establishment of a steering committee that would provide oversight for funding decisions involving certain types of research. According to a blog post authored by Wolinetz, the first type involves research in which "human pluripotent cells are introduced into nonhuman vertebrate embryos, up through the end of gastrulation stage, with the exception of nonhuman primates, which would only be considered after the blastocyst stage." The second involves areas of research in which "human cells are introduced into postgastrulation nonhuman mammals (excluding rodents), where there could be either a substantial contribution or a substantial functional modification to the animal brain by the human cells." 

In addition, the NIH proposed changes to the current human stem cell guidelines. 

In speaking about the proposed changes, Wolinetz told Live Science that they constitute a "recognition that science has moved beyond where the guidelines [initially] started."

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