Chimeras for the twenty-first century

Abstract

Recent advances in stem cell biology and molecular engineering have improved and simplified the methodology employed to create experimental chimeras, highlighting their value in basic research and broadening the spectrum of potential applications. Experimental chimeras have been used for decades during the generation of murine genetic models, this being especially relevant in developmental and regeneration studies. Indeed, their value for the research and modeling of human diseases was recognized by the 2007 Nobel Prize to Mario Capecchi, Martin Evans, and Oliver Smithies. More recently, their potential application in regenerative medicine has generated a lot of interest, particularly the enticing possibility to generate human organs for transplantation in livestock animals. In this review, we provide an update on interspecific chimeric organogenesis, its possibilities, current limitations, alternatives, and ethical issues.

Keywords:

• Chimera
• organogenesis
• blastocyst complementation
• pluripotent stem cells
• interspecific
• organoids
• tissue engineering
• embryonic stem cells
• ethics

Ethical issues

According to Nakauchi and coworker, eradicating organ scarcity for transplantation would require using just one out of 1000 large animals currently employed in the food industry [46]. Thus, explained in these terms, the use of livestock animals as hosts for human organs should hardly pose any ethical concern in today’s society. Notwithstanding, crossing interspecies barriers between animals and humans has always created public discomfort (commonly referred as the “yuck factor”) [86]. Besides this emotional factor, the bioethical debate about human–animal chimeras can be summarized in three major factors: (1) the development of “human consciousness”, (2) human-like appearance, and (3) human gamete production [87].

Development of human consciousness. Simply put, our brain is what makes us human when compared with the rest of animals. Due to that, most authors consider that, if human cells were to have any chance of triggering any kind of consciousness in an animal host, these experiments would become ethically unacceptable [88]. In fact, paradoxically, those hypothetical chimeric animals could no longer be used for hosting human organs and should be treated as one of our kind [89].

Nowadays, interspecies barriers are too strong for this to happen. Nevertheless, potential risks should be taken into account and minimized. For example, a maximum threshold of human chimerism in an animal brain must be defined, especially in large animals, which could be ideal to understand neuropsychiatric disorders, but are also more susceptible to cause concern [59,88]. Furthermore, targeted blastocyst complementation should be used as it greatly reduces the possibility of injected human cells to colonize other organs like the brain, as a consequence of their competitive advantage to colonize the empty niche [88]. However, it should not be dismissed that some experiments have shown intrinsic competitive advantage of human cells over their animal counterparts, clearly exemplified by Goldman’s experiments of human glial mice chimeras [90,91].

Human-like appearance. Another ethical concern regarding human–animal chimeras is the potential impact that human stem cells could have on the animal’s physical appearance. The creation of a living being that explicitly shows its chimeric condition could blur the limits between humans and animals and challenge the concept of human identity. As Robert and Baylis stated in their dissertation on ethical aspects of chimera generation: “the most plausible objection to the creation of novel interspecies creatures rests on the notion of moral confusion” [86]. Therefore, and despite the chances of this happening being extremely unlikely, preemptive actions should be implemented, for instance, by defining a maximum threshold of systemic chimerism for human cells, or through the implementation of prenatal systematic diagnosis in order to identify any indication of human features in chimeric fetuses [88].

Human gamete production. Humanization of chimeric animals could lead, in theory, to the production of human gametes. In fact, the US National Academy of Sciences (NAS) prohibits the cross-breeding of animals having received human cells or tissues [92]. However, once again, the odds for this to occur are extremely low, given that the interspecies reproductive barrier is too high. Moreover, sterilization of animals carrying human material would be enough to prevent their reproduction [88]. Other alternatives to minimize this risk have been proposed, such as genetically manipulating human cells to incorporate a suicide gene which could be activated upon germinal differentiation, or to directly inhibit their potential to differentiate toward reproductive cells [93].

In addition to, proper ethical issues discussed above, an epidemiological perspective should also be considered. Organs developed in animal hosts could constitute a source of zoonosis, and there is concern about endogenous viruses integrated into the genome of breeding animals, such as porcine endogenous retroviruses. Undoubtedly, this also raises ethical concerns regarding the obligation to ensure patient safety in potential clinical trials in the future [88].

Regarding regulatory and legal aspects many countries have issued specific legislation and created overview research committees that supervise all experiments involving the introduction of human stem cells or tissues in animals [2]. Useful guidelines are available from the NAS [92], the ISSCR [94,95], and The Academy of Medical Sciences, in the UK [96]. In Spain, the Biomedical Research Law prohibits the creation of human embryos and pre-embryos exclusively for research purposes (Artículo 33 de la Ley de Investigación Biomédica) [97]. In Japan, the Ministry of Education, Culture, Sports, Science and Technology has recently lifted the ban to terminate human–animal chimeras after 14 days thus enabling the potential production of human organs for transplantation, in animals [98].

Disclosure statement

The authors report no declarations of interest.