Research paper for my Ethics and Challenges in Biotechnology class, exploring the challenges posed by animal chimeras. Throughout human history, the ultimate goal of society has been to improve the quality and length of life, especially when combating illnesses and injuries. One such way scientists have succeeded in lengthening human lives is by performing organ transplants, but even with this innovation, 17 people die each day waiting for a donor organ to become available for transplant (Health Resources & Services Administration). This is mostly due to the fickle process of finding a matching donor close enough to feasibly transport the organ from donor to recipient within the window of opportunity. Those who are fortunate enough to receive an organ transplant still face a plethora of potential complications up to and including death. Even without complications, they must take anti-rejection medications for the rest of their lives to help prevent the risk of their immune system rejecting the transplant, which themselves come with inconveniencing side effects. However, a potential alternative to waiting for donor organs or tissues to become available may lie in a non-human source: animal-human chimeras. A chimera is an organism that contains a combination of cells from two species (Oxford University Press). While it may seem like the stuff of ancient mythos, scientists have been developing and studying various animal chimeras for decades, with the initial goal of furthering the understanding of embryonic development (Wu et al., 2016). Today, much of the work on chimeras serves as a proof of concept for creating animal-human chimeras, with the ultimate goal of utilizing them to produce organs or tissues for transplantation into human recipients. In theory, these tissues or organs, genetically human in origin, would be grown by a suitable donor animal and harvested whenever a human patient required them, effectively ‘keeping up’ with the organ transplant waiting list and ensuring most, if not all, patients received the life-saving transplants they require. The first animal chimeras to be developed were rat-mouse chimeras produced by inserting rat inner cell masses (ICMs) into mouse blastocysts and transferring the blastocysts into a mouse uterus (Gardner and Johnson, 1973). The altered blastocysts were monitored throughout gestation and some were allowed to develop into full-term, live offspring, upon which it was discovered the number of rat cells greatly diminished over the course of gestation, with only a few detectable rat cells remaining in the organisms after birth (Wu et al., 2016). While these offspring were undoubtedly animal chimeras, the low proportion of rat cells present was not particularly reassuring for scientists attempting to create animals containing cells of two species at comparable proportions. Prevailing reasoning suggested the rat cells were somehow selected against as a result of the long-ago evolutionary divergence between rats and mice. This theory was later seemingly confirmed in 1980 by Rossart and Frels, who performed a similar experiment using Mus musculus and Mus caroli, two mouse species much more closely related than the mouse and rat species used by Gardner and Johnson (Rossant and Frels, 1980). The rat-mouse and Mus musculus-Mus caroli chimeras, as well as other successful chimeras developed since then, such as the sheep-goat and Bos taurus–Bos indicus chimeras, have helped determine ways to improve success rates while expanding the species boundary, namely through the understanding that “the matching of the species origin of the trophectoderm derivatives and that of the maternal uterus” is one of the main indicators of successful chimera creation (Wu et al., 2016). In 2014, experimentation performed at the University of Rochester Medical Center involving the insertion of human glial cells (cells that develop into brain cells not involved in thinking) into mice resulted in an amplification of the number of human cells present in the mice, as well as increased memory and cognition (Windrem et al., 2014). Researchers also performed the same experiment on mice suffering from multiple sclerosis and found that in those cases, the insertion of human glial cells resulted in the human cells developing into cells that specialize in myelin production, the very protein which cannot be produced by those suffering from multiple sclerosis (Yirka, 2014). This is a groundbreaking development, indicating non-specialized cells from other species are capable of adapting to and improving upon the recipient organism. Unlike the other animal chimeras already discussed which were created by combining genetic information at the embryonic stage, in this instance human glial cells were inserted into already living mice. It is important to emphasize that human glial cells were shown to increase cognition in the mice, which poses ethical concerns for the experimentation of this technology in other animal species. Others testing this boundary include researchers from the Salk Institute who attempted to create pig-human chimeras in which pigs could grow targeted organs made of human tissues. After using human cells from three stages of development and producing 186 later-stage embryos, they concluded: “human tissues appear to slow embryo growth” and organs produced by these embryos “would likely become rejected by humans since they would [contain] so much pig tissues” (American Academy of Anti-Aging Medicine, 2018). What they considered “intermediate” pluripotent stem cells were shown to be most successful in developing hybrid pig-human organs in embryos between 3 and 4 weeks (Galeon, 2017 “Scientists…”). Embryos were only given a small time to develop to avoid the ethical concerns associated with animal-human chimeras. However, a successful example of animal chimeras exhibiting organs containing cells from mostly one species is the work carried out by researchers at the National Institute for Physiological Sciences in which they produced mouse kidneys in rat-mouse chimeras. The researchers themselves cited their work as “proof-of-principle for interspecific blastocyst complementation as a viable approach for kidney generation” (Goto et al., 2019). Hiromitsu Nakauchi, one of the researchers involved in the study, has also produced mouse pancreases in rats via a similar experimental procedure (Galeon, 2017 “Interspecies…”). The developed mice pancreases were transplanted from the rats that grew them into mice suffering from diabetes, which functioned properly for more than a year after only five days of antirejection treatments (Galeon, 2017 “Interspecies…”). In 2021, a joint team of researchers from the United States and China produced 132 monkey-human chimera embryos (Tan et al., 2021). This is the most successful exhibit of animal-human chimeras to date, but its use of Macaca fascicularis also makes it one of the most controversial. The current experimentation did not cultivate specimens past the early embryonic stage, because “the use of primates so closely related to humans raises concerns about unintended consequences, animal welfare and the moral status of hybrid embryos, even if the scientific value of the work may be quite high” (Hotz, 2021). Inserting animal-produced products into humans might sound extreme, but it is not an entirely new practice. Before the development of recombinant gene technology, or genetic engineering, which allowed for the production of human insulin using E. coli, people suffering from diabetes were treated with injections of cow and pig insulin, a discovery made in the 1920s (American Diabetes Association, 2019). In the 1970s, surgeons began to transplant cow and pig heart valves into people, a practice still used to this day because of the success rate (Carmichael). These treatments all involve the introduction of products that are entirely animal in nature, which have been determined to be so similar, structurally and functionally, to the human counterparts that they have been used for decades. The difference with animal-human chimera-produced organs is that the organs will be genetically human, and only grown in an animal. This is because of the methods used to produce animal-animal and animal-human chimeras, the most common being blastocyst complementation. Mutant strains of an animal that are missing targeted tissues or organs are created using CRISPR before blastocysts are taken from them (Straiton, 2019). Stem cells from the donor organism are then injected into the blastocysts, which are moved to a host mother and allowed to fully gestate (Straiton, 2019). Consider a hypothetical pig-human chimera that is being grown to donate a set of kidneys to a human patient. Theoretically, this would involve the creation of a mutant pig strain that does not grow its own kidneys, and creating blastocysts from this strain. Human stem cells would then be injected into the mutant pig blastocyst, which would then be inserted into a host pig mother. The blastocyst would eventually be born as a pig-human chimera, and be raised until the human kidneys it contains are ready to be transplanted into the human patient. The most recent research into animal-human chimeras seems to indicate a world in which animal-human chimeras regularly serve as organ donors is still far off. Even when a chimera containing a fully-human organ or tissue is produced, it must be ensured not to contain viruses or other pathogenic material which could harm human donors. One part of this process would likely include gene editing to remove retroviruses from the chimera’s genetic code (Loike and Kadish, 2018). Before any such experimentation can be allowed to continue further, however, a vast array of legal and ethical considerations must be made to ensure the safety of all involved parties. Ethically, the creation of chimeras of any kind poses concerns. Like other forms of genetic engineering, it can easily be concluded that producing chimeras is in some way “playing God” by creating unnatural organisms. For the most part, the creation of animal chimeras throughout the seventies and into the early two-thousands did not warrant substantial ethical debates on these grounds. This argument has been used against vaccines, antibiotics, and many other medical and scientific practices, and for this reason, cannot solely be used against the formation of any type of chimera (Koplin and Savulescu, 2019). Experimentation such as that performed in 2014 by Windrem and their colleagues, however, has established that animal-human chimeras are capable of developing cognitive abilities beyond that of their solely animal counterparts. This poses a great concern for monkey-human chimeras or other crosses with species closely related to humans. Up until this point, researchers have erred on the side of caution and ensured no such chimeras were allowed to develop past the embryonic stage, but further investigation into this field will likely see this attempted. Where does the line exist past which it becomes immoral to take organs from such a chimera with no consideration for their desires? Currently, there is “no agreed-upon account of moral status” which can be applied to chimeras or even other animal specimens used in research (Savulescu and Koplin, 2021). It is paramount that scientifically based and internationally considered thresholds are established defining the limits of moral status to which chimeras can then be compared on an individual basis. For the same reasons that organs cannot be forcibly removed from a human without their consent, any chimeras which meet the hypothetically established moral status must be granted that same right. Restrictive means to ensure this would be to outright prevent the creation of animal-human chimeras, but another still measured approach would be to “allow the full development of chimeras with humanized brains, but prohibit experimentation until after the chimeric animal's moral status has been determined” (Koplin and Savulescu, 2019). This would require each chimera to be monitored and compared to certain standards which would determine its fate. Ideally, a system to ensure compliance with the established standards would function as a hierarchy where monitorization occurs on the institutional level, state level, regional level, and global level. The various levels would work together in accordance with the standards established on a global scale, such as through a partnership between the World Health Organization and United Nations. Regional medical and scientific bodies would then take responsibility for monitoring research in their areas, such as the Department of Health and Human Services in the United States. State or local entities would then similarly be responsible for their areas, such as the New Jersey Department of Health for laboratories in the entire state. It is likely specific organizations or government departments would be established to maintain such a system over the long term, as opposed to the responsibilities being added to existing bodies, but regardless it would require transparency and high levels of collaboration between them. It is understandable why people would have qualms about receiving organs or tissues grown in an animal, but in the grand scheme of things, as long as clear ethical standards exist which are followed by all involved parties, there should be no reason to prohibit the use of animal-human chimeras to serve as organ donors. Standards could include monitoring all potential donor chimeras for increased signs of intelligence or awareness and not using any animals which do indicate an increase beyond some scientifically-determined metric. Institutions and governing bodies around the world would need to communicate openly about developments occurring in the creation of animal-human chimeras. Eventual recipients of animal-human chimera organs would also need to be given access to all information about the donor, such as its genetic makeup, what lab developed it, and where it was raised, among other information. Most importantly, no one should be forced to make the personal decision for or against using a chimera-donated organ in a transplant. For those who would rather not receive organs or tissues from chimeras, due to their own beliefs or preferences, the traditional human-to-human organ donation system should remain in place. Whether a patient decides to wait it out for a traditionally sourced organ or receives one from a chimera should be decided on an individual basis between the patient and their medical professionals. Imagine a world in which animal-human chimeras are produced regularly to serve as organ donors. A place in which no one dies on the organ transplant list, only for the organ they have waited months for to finally enter the system. A place where adding an event on your calendar noting the birth of the chimera that may eventually provide you the organ you need is commonplace. Now realize that someday, such a world just might exist and that someday could be closer than any of us think. Bibliography
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