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Interspecies research involving the mixture of animal and human genetic materials is important in stem cell research and the study of developmental biology. This research paper examines some approaches to such research, the reasons why the creation of animal-human entities are important, and the ethical objections and concerns surrounding such research.
Research involving the mixture of animal and animal genetic materials (intraspeciﬁc animal animal chimeras) can be traced to the grafting experiments conducted by Murray and Huxley in 1925 (Murray and Huxley 1925) and has contributed signiﬁcantly to the advancement of biomedicine. In the 1970s and 1980s, the creation of somatic cell hybrids through the fusion of human and animal cells has contributed to the mapping of the human genome and the study of the interplay between nuclear and mitochondrial genomes. The creation of transgenic animals by introducing a human gene into the germ line of an animal is a technique that has long been employed in pharmaceuticals and in the creation of a model for human disease. For many scientists, the creation of human-animal entities is deemed to be indispensable in stem cell research and in the study of developmental biology.
The creation of living human-animal entities, however, is also disquieting because of the ethical controversies that surround it. Concerns for such research are especially pressing, for example, when stem cells from the human brain are introduced to animal embryos to study cell differentiation and proliferation in the prenatal period. The outcome of introducing undifferentiated human stem cells or stem cells from the human brain to animals during their formative development is too unpredictable. Would the human neural cells overwhelm the host animals, giving them the mental capacity of humans? For some, the entities that such experiments would create are “simply too horrible to contemplate” (Wade 2002). Besides the issue of the moral status of the human-animal entity, some philosophers and scientists have asked if it is wrong to cross the species barrier in the ﬁrst place. Clarity on these issues is important if stem cell scientists working in this area are to know the ethical limits of their research (Hug 2009).
Terminology And Examples
Before discussing the main ethical concerns surrounding research involving the creation of human-animal entities, it is important to clarify some of the basic terminology associated with it.
Even among scientists, the term chimera conveys different meanings, with geneticists, cell biologists, embryologists, molecular scientists, and other specialists offering somewhat different definitions (Karpowicz et al. 2005). Broadly deﬁned, a chimera refers to a biological organism that contains cells from two or more animals from different species, or from “different embryonic origins” (Streiffer 2005). A human-animal chimera is an organism created by combining distinct populations of human and animal cells. There are several ways of doing this, including introducing human embryonic stem cells into nonhuman blastocysts. The form a chimera takes depends essentially on the kind of biological material used (somatic cells, embryonic stem cells, the total cell mass of an embryo) and the stage of the development of the host organism (embryo, fetus, neonate, adult).
Hybrid And Cybrid
Hybrids are organisms created by the process in which “a member of one species contributes the egg and a member of a second species contributes the spermatozoon” (Bonnicksen 2009). Hybrids occur in nature, mostly with the help of breeders, ranging from the common mule (the offspring of a male donkey and female horse) and the hinny (the offspring of the female donkey and male horse) to the very rare liger (the offspring of a male lion and female tiger). The term hybrid cannot be restricted only to progeny resulting from the sexual reproduction involving animals from different species; a hybrid can also be a “product of cross-species nuclear transfer due to the possession of nuclei and mitochondria from different species” (Hug 2009).
According to the UK Department of Health, cybrids are “embryos created by removing the nucleus of an animal egg and inserting the nucleus of an adult cell from a different individual (and possibly from a different species)” (U.K. Department 2007). Described variously as “interspecies embryo,” “pseudohybrid,” “interspecies hybrid embryo,” “interspecies cytoplasmic hybrid,” “nuclear-cytoplasmic hybrid,” and “cytoplasmic hybrid embryo,” cybrids are created by a technique called “interspecies somatic cell nuclear transfer (SCNT)” or iSCNT. Due to the shortage of human eggs from which to produce embryos for hES cells research and the risks involved in egg donation, the creation of cybrids is deemed necessary because it would allow scientists to conduct their research without the need to obtain human eggs.
Reasons For Creating Human-Animal Entities
There are numerous reasons why scientists create human-animal entities. The most obvious reason is that scientists want to use these entities to better study human diseases in the hope of ﬁnding cures for them. Human-animal entities are helpful for scientists because they provide animal models where diseases can be emulated and studied. An example of this is the creation of the SCID-hu mouse in the 1980s by grafting human stem cells, human fetal liver cells, fetal thymus cells, and bone marrow in immunodeﬁcient mice. By creating mice with a human immune system, scientists were able to study more closely how the latter works. The SCID-hu mouse is often regarded as the cornerstone for research in human immunology. Another example is the famous OncoMouse, a transgenic mouse which scientists from Harvard “genetically engineered to contain a human cancer-causing gene” in 1988 to study the heritable presuppositions and development of cancer (Sagoff 2003).
The creation of human-animal entities in the laboratory is also needed because scientiﬁc consensus and regulations in many countries, for example, the US Food and Drug Administration (FDA), require stem cells to be tested on animals before they are applied to human subjects. These tests will inevitably produce chimeras because they require human pluripotent stem cells to be introduced into animal research subjects. Scientists have created chimeras to study a variety of diseases and their possible treatments. For example, chimeras are needed to serve as assay systems that facilitate the study of tumorigenicity and test various therapeutic applications of stem cells. Researchers in San Diego have injected hES cells capable of synthesizing pancreatic hormones such as insulin into diabetic mice with damaged kidneys in order to test the effectiveness of stem cell therapies. Scientists at Tulane University have conducted similar experiments using multipotent stromal cells procured from human marrow. Human-animal chimeras are also created to develop treatments for neurodegenerative disorders (Baylis and Fenton 2007).
The creation of cytoplasmic hybrid embryos by transferring human somatic cell nuclei to an enucleated egg of bovine origin offers a viable solution to the shortage of human eggs needed to conduct research on hES cells. A UK House of Commons Report stated more than 30 eggs or oocytes are required to produce a hES cell line for each patient. Human eggs are difﬁcult to obtain. Although some women may be motivated to donate their eggs to help a couple trying to conceive for altruistic reasons, many are less forthcoming when the donated eggs are used for research. The process of egg donation may pose some risks and cause some discomfort and inconveniences, making egg donation for research less attractive. In addition, the issue of compensating donors has been ethically contentious even if compensation comes in the form of reimbursements for expenses incurred. Although excess eggs procured for fertility procedures may be another source of human eggs used for research, they may not be sufﬁcient because of the poor quality that may have caused the infertility in the ﬁrst place.
Finally, interspecies entities are created in the hope that a substitute tissue or organ may be procured for patients who suffer organ failure due to disease or injury and are in need of transplantation. All transplantation that replaces the heart valves of patients suffering from cardiac disease with porcine heart valves is now routine. But attempts to use animal organs and tissues to replace diseased human ones have been unsuccessful because animal organs do not integrate properly with the human organism. Scientists have tried to create human-animal chimeras that can serve as hosts for human organs or tissues. Such research is deemed important because it has the potential to address the shortage of transplantable human organs that would save the lives of many patients suffering from end-stage organ failure.
The Unnaturalness Argument
A major objection to the creation of human animal entities for research is often described as the Unnaturalness Argument, which maintains that the creation of human-animal entities should be prohibited because such creations would disrupt the order of the natural world. Indebted to Aristotelian philosophy, which holds that every living creature, in exercising certain biological functions appropriate to it, is achieving its potential and arriving at its true end or telos, the Unnaturalness Argument stresses that these operations of nature must be valued and respected. This ontology is the basis for traditional natural law theory to which the Unnaturalness Argument is closely associated. In concert with traditional natural law theory, the Unnaturalness Argument asserts that to alter or disrupt the natural development of creatures to its appropriate ends is a moral wrong. As Karpowicz, Cohen, and van der Kooy point out, according to this view, “it is a moral good for each kind of being to be aligned with its appropriate end and a moral wrong to alter its natural functioning in ways that distort or violate this end” (Karpowicz et al. 2005). It follows that to transfer human cells into nonhuman animals in ways that would disrupt and alter their end or goal (telos) is unnatural and therefore morally wrong.
Some philosophers and ethicists, however, have questioned the alleged connection between unnaturalness and wrongfulness that the Unnaturalness Argument makes. Karpowicz et al., for instance, argue that “Nature does not come with some sort of built-in ethical import that can be read from it, such that living beings’ typical ways of functioning always must be kept intact” (Karpowicz et al. 2005). The natural world itself is in constant ﬂux as organisms are subjected to evolution and change. There is therefore no reason to think that nature itself provides certain moral requirements that prohibit human beings from inﬂuencing in some ways how human and nonhuman organisms function. These philosophers therefore maintain that this argument against the creation of human-nonhuman chimeras must be rejected “on grounds that it equates, and thereby confuses, biological description with the justiﬁcation of ethical norms” (Karpowicz et al. 2005).
In addition, the Unnaturalness Argument appears to impose a demand that is virtually impossible to meet because it would entail endless speculations about the telos or purpose of every living organism. Philosophers argue that even if the Unnaturalness Argument is right in its basic intuition that wrongness stems from unnaturalness, there surely must be exceptions where countervailing considerations such as the promise of therapeutic solutions to diseases or advancing scientiﬁc knowledge would justify the creation of human-animal entities for research. In this case, the Unnaturalness Argument must provide principled grounds to discern which interventions are ethically objectionable and which ones are not. But, as Karpowicz et al. point out, this it fails to do: “The basic difﬁculty with the “unnaturalness” argument is that it does not explain when an intervention into nature is ethically acceptable and when it is not … No bright light is provided by the “unnaturalness” argument to help one distinguish between appropriate and inappropriate interventions” (Karpowicz et al. 2005).
A number of writers have associated the Unnaturalness Argument with what Leon Kass has called the “wisdom of repugnance” (Kass 1997). In a famous essay, Kass argues emphatically that this sense of repugnance must be taken seriously: “Indeed, in this age in which everything is held to be permissible so long as it is freely done, in which our given human nature no longer commands respect, in which our bodies are regarded as mere instruments of our autonomous rational wills, repugnance may be the only voice left that speaks up to defend the central core of our humanity. Shallow are the souls that have forgotten how to shudder” (Kass 1997). Some scientists and philosophers have registered their feeling of repugnance (the “yuk factor”) for research involving animal-human entities. In an interview with The New York Times Magazine, physician and biologist William Hurlbut at Stanford is reported to have said that “When we start to blend the edges of things, we’re uneasy … That’s why chimeric creatures are monsters in mythology in the ﬁrst place” (Shreeve 2005).
Opponents of this view have argued that the “yuk factor” must be rejected because it has been used to rationalize racial discrimination, for example, against interracial marriage. Others have pointed out that within Western culture there are examples of practices, such as blood transfusion, that were once considered abhorrent but are now not only acceptable but have become a moral and civic responsibility. However, proponents of the “yuk factor” caution against brushing aside too quickly such feelings of repulsion or repugnance. Moral philosophers like Mary Midgley argue that feeling and morality should not be hastily divorced from each other. “Feeling is an essential part of our moral life, though of course not the whole of it,” she writes. “Whenever we judge something to be wrong,” she continues, “strong feeling necessarily accompanies the judgements” (Midgley 2000). Even opponents of the “yuk factor” must concede that we react to an act in a certain way because we intuitively know that it is wrong even though we are unable to provide the moral reasons for our reaction. Proponents of the “yuk factor” maintain that the feeling of repugnance should never be taken as the last word on a particular moral issue. It is but the beginning of our moral response, which must be subjected to careful exploration and reﬂection. But neither should it be brushed aside as simply emotional or visceral response. The “wisdom of repugnance” should be seen as a species of human moral intuition.
Species Integrity Argument
An important discussion concerning the ethics of interspecies research has to do with whether it is morally acceptable to cross the species boundary by creating human-nonhuman entities. Ethicists who argue that it is morally unacceptable to do so base their arguments on three assumptions. The ﬁrst is that there is a distinct boundary between species, especially between humans and nonhumans. The second assumption is that species boundaries are relevant such that crossing them would be morally questionable. And the third is that the creation of human-nonhuman chimeras constitutes the “crossing” and therefore “violation” of the species boundaries. It was Aristotle who deﬁned species as similar biological systems that belong to the same “natural kind,” with an essential and immutable nature. As Cynthia Cohen puts it, some ethicists following this idea would argue that to “violate those boundaries is to destroy the essence of species and invite chaos in the natural world” (Cohen 2007).
Since Aristotle, biologists have developed diverse views about species and how boundaries between them should be drawn. For instance, in the eighteenth century, the father of biological taxonomy, Carolus Linnaeus, categorized organisms according to their appearance, while other biologists have used different criteria. Even setting species boundaries by using current knowledge of genetics is problematic. For example, although at ﬁrst blush setting the species boundary between humans and chimpanzees on the basis of genetics appears to be quite straightforward, the problem arises when one needs to decide on the threshold of genetic similarity. As Karpowicz et al. explain, “What threshold would produce the most accurate phylogeny between these organisms? If one were to restrict the relevant genetic grouping to a subset of the eukaryotic genome, one might not only distinguish between humans and chimpanzees, but also establish separate species categories among humans” (Karpowicz et al. 2005).
These important objections notwithstanding a number of philosophers have objected to the creation of human-nonhuman chimeras on the basis of some version of species realism. Mary Midgley, for example, advocates a kind of species integrity argument against the creation of chimeras when she maintains that such creatures “stand for a deep and threatening disorder, something not just confusing but dreadful and invasive” (Midgley 2000). Robert Streiffer argues that although there is much disagreement about species boundaries, the concept itself is not morally superﬂuous (Streiffer 2005, 2006). Some philosophers who take this approach would argue that human beings, in particular, must be distinguished from nonhuman animals because they are in possession of personhood and therefore enjoy a higher moral status. The creation of a chimeric creature by introducing signiﬁcant amount of human stem cells in a nonhuman embryo, for example, would be morally objectionable because it may turn an animal into a compromised human being, thereby making its moral status ambiguous (Cohen 2003).
Even antirealists like François Baylis and Jason Scott Robert argue that the idea of crossing species boundaries is morally signiﬁcant even though ﬁxed lines between species do not exist in the scientiﬁc sense. This is simply because people generally believe that lines between species do exist and make “everyday moral decisions on the basis of this belief” (Robert and Baylis 2003). Human beings, they argue, generally “attach considerable symbolic importance to classiﬁcatory systems and actively shun anomalous practices that threaten cherished boundaries”. It is therefore important to acknowledge society’s concern to preserve “boundaries between human and nonhuman animals” (Robert and Baylis 2003). The crossing of such boundaries in the creation of human-nonhuman chimeras for research would therefore cause much anxiety and moral confusion. However, proponents of chimera research like Mark Sagoff point out that there is a gap between vision and reality in Robert and Baylis’ account, stressing that the chimeras currently created for research would not result in the moral confusion they feared (Sagoff 2003). Hilary Bok concurs and argues that the species integrity argument is weak since most chimeras are unlikely to cause moral confusion (Bok 2003).
Human Dignity Argument
The third argument against creating certain forms of human-nonhuman chimeras is that such entities would violate human dignity, a concept that has been given much prominence in bioethics. Human dignity is an important concept found in numerous international documents like the United Nations’ Universal Declaration of Human Rights (1948) and the International Bill of Human Rights (1966). In 2002, the Second World Conference on Bioethics afﬁrmed a “Universal Commitment to the Dignity of the Human Being.” It declared that “full dignity is an attribute of humankind, and that its recognition is a fundamental right of each and every individual which must be respected and protected” (Second World Conference on Bioethics 2002).
Although the concept is widely used, there has been no agreement on how human dignity should be deﬁned or understood. This lack of clarity has led some scholars to adopt minimalistic ideas of what human dignity entails. For example, John Harris (1998) maintains that human dignity simply suggests that a human being should never be used “as a means to the purposes of others” (Harris 1998). Ruth Macklin, however, thinks that human dignity is a superﬂuous concept and interprets it as referring merely to respect for human autonomy or self-determination (Macklin 2003). This view, however, mistakenly sees human dignity and human autonomy as coextensive when they are in fact distinct moral categories that sometimes overlap.
Scholars who appeal to the concept of human dignity often draw from the philosophy of the eighteenth-century Enlightenment philosopher, Immanuel Kant. In Groundwork for the Metaphysics of Morals (1785), Kant argues that human beings possess unconditional and incomparable worth (Wurde) because they are moral agents responsible for their own actions. Dignity is seen in human beings’ ability to set moral goals for themselves and take the necessary actions to achieve them. Kant asserts that “morality, and humanity so far as it is capable of morality, is the only dignity.” And since morality presupposes an autonomous will, Kant argues that “autonomy is therefore the ground of the dignity of human nature.” Although Kant’s notion of human dignity is inﬂuential, some scholars have found it to be inadequate. Human dignity, they argue, is a complex and multifaceted notion. It should not be tied exclusively to autonomy, but should be characterized by a variety of unique and valuable capacities associated with being human.
In addition, scholars belonging to the JudeoChristian tradition have argued that it is inadequate and ethically problematic to associate dignity only with certain capacities. To do so would be to exclude certain human beings who because of illness or severe disabilities no longer possess the capacities associated with dignity. Put differently, the Kantian concept of dignity based on morality or autonomy is not comprehensive enough. Drawing from the medieval theologian Thomas Aquinas, these scholars argue that dignity should be associated with human nature (esse) and not merely with certain distinctive capacities.
According to this approach, even those who do not possess these capacities – people with mental illness, the comatose, the human fetus – should be accorded full dignity simply because they are human beings. This approach is in some ways akin to the species integrity argument discussed above.
Proponents of the human dignity argument maintain that an act is morally unacceptable if distinctive capacities associated with humans are deliberately and wrongfully diminished or eliminated. Examples of such violations include murder, torture, enslavement, rape, or maiming. As Karpowicz et al. explain, “to create a human nonhuman chimera would either diminish or wholly eliminate the possibility that humans could exercise a cluster of capacities and characteristics that are associated with dignity, treating them solely as a means to others’ ends” (Karpowicz et al. 2005). Proponents have sometimes equated the creation of human-nonhuman chimeras with torture or enslavement. This is especially the case, they argue, when a chimeric creature is created with human and nonhuman materials that cause capacities associated with human dignity to become evidently present. These creatures are unable to exercise those capacities at all or can do so only in a very limited way because they are encased in a nonhuman body.
Advocates believe that although the human dignity argument does require further reﬁnements, it is relatively free from the difﬁculties associated with the other arguments against the creation of human-nonhuman chimeras.
Scientists and policy makers see the need to set some limits to the kind of research involving the creation of human-animal chimeras that should be permitted. These limits are mostly dependent on the ethical unease associated with some forms of chimera research. As Cynthia Cohen has helpfully pointed, the degree of unease is related to the following factors: (1) the type of human stem cells used, (2) whether they are differentiated or undifferentiated, (3) where in the animal host are they introduced, (4) how closely related the animal subject is to humans, (5) the age of the animal host, and (6) the expected outcome of the research (Cohen 2007).
Special care must be taken especially when introducing human neural cells or unspecialized embryonic stem cells to nonhuman hosts. Since “it is not now possible to predict the extent of human contributions to such chimeras” (National Research Council et al. 2002), it is prudent to limit the number of stem cells inserted into the animal to the smallest number necessary for the research. It is currently believed that if “the recipient blastocyst were from an animal that is evolutionarily close to a human, the potential for human contributions would appear to be greater” (National Research Council et al. 2002). On the basis of this assumption, it is prudent to select an animal for research that is structurally not closely related to humans. Thus, while certain forms of chimera research should be allowed, others should be strictly prohibited. As Cynthia Cohen has rightly pointed out, “The goal of stem cell chimeric studies is to support, rather than to denigrate, both human dignity and human well-being” (Cohen 2007).
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