Many of the recent developments, including chimera research, in biotechnology have come under scrutiny, especially as the ethics of chimera research are heavily debated. However, chimera research could potentially help us better understand human biology and disease, which could help develop cures for those diseases and contribute to regenerative medicine. How does chimera research work? Why is it important in biomedical research and future medical developments?
This is a mouse-rat chimera! Image Source
The word "chimera" comes from the firebreathing Greek mythological creature that had a body of a lion, head of a goat, and a tail with a snake's head. It terrorized the regions of Caria and Lycia, until it was killed by Bellerophon with the help of Pegasus. Chimeras in scientific research have genes derived from two or more organisms, but unlike a normal organism, chimeras contain two distinct sets of genes from the parent organisms. However, while the most commonly discussed chimeras are animals that are made up of genes from two different organisms, such as a mouse-rat chimera, there are other types of chimeras. For example, a human chimera can exist when a human absorbs a twin in the womb, so the human will have two sets of genes, their orginal set of genes and the other set from their absorbed twin. Human chimeras can also happen when they get a bone marrow transplant, where the bone marrow of the donor are transplanted into the recipient, where the bone marrow stem cells will grow into red blood cells that are genetically identical to the donor. Another common type of human chimera is microchimerism, where a pregnant woman exchanges cells with the fetus, and these cells can stay in the mother's body for years.
This graphic shows the types of cells that pluripotent stem cells can turn into! Image Source
However, chimeras that intend to artificially grow an organism from two different species, called interspecific chimeras, are frequently the subject of debate. In particular, human-animal chimeras, which result from human cells being introduced into animal cells. One way to do this is by grafting human tissue onto animals, or by implanting human stem cells. Stem cells are characterized as cells that can self-renew and differientiate into other cell types. They are also categorized by potency, with pluripotent stem cells being able to give rise to all of the cells of the body, with the exception of the placenta and umbilical cord. These cells are important for the study of chimera research, since the stem cells are injected into an embryonic, fetal, or postnatal host animal. With proper signals, the cells can develop into tissues and organs. For example, when a mouse had a mutation of the Pdx1 gene and couldn't grow a pancreas, scientists injected rat pluripotent stem cells into the mouse embryo, which caused the mouse to grow a rat-sized pancreas.
This graphic shows how induced pluripotent stem cells (iPS cells) are made! Image Source
Pluripotent stem cells are often times the by-product of in-vitro fertilization (IVF) or generated with somatic cells. To illustrate, in an IVF procedure, the couple will typically fertilize multiple zygotes, and choose the healthiest to implant and grow. The other zygotes that aren't used are developed into blastocysts, as the inner cell mass (ICM) of the blastocyst are pluripotent stem cells that can be used for research. However, the usage of human embryos in this process has been heavily criticized, so when induced pluripotent stem cells (iPS cells) were discovered in 2007 by Shinya Yamanaka, it revolutionized biomedical research. Induced pluripotent stem cells are adult somatic cells that have been reprogrammed into becoming stem cells by adding a variety of transcription factors. While induced pluripotent stem cells are undoubtly a groundbreaking discovery, they have not been proven to be entirely safe as they have the possibility of developing into cancer, but so can any stem cell.
This graphic shows how chimeric organogenesis works! Image Source
An important development in chimera research is the possibility of producing organs for transplants. As of now, there are around 114,000 people on the waiting list for an organ transplant in the United States, and it is estimated that around 20 people die everyday due to the lack of available organs. However, chimera research could potentially produce patient-specific and immune-matched organs that could be transplanted, which reduces or possibly eliminates the need for human organ donations. This process would involve obtaining cells from the patient, such as induced pluripotent stem cells, Mesenchymal stem cells, or hematopoietic stem cells, while the host animal, such as a pig or a cow, would have the gene that normally forms the targeted organs knocked out, for example, the Sal1 gene for kidneys, to prevent interference with the host animal's genes. The lack of this organ-forming gene would be identified by the body, so the human stem cells will be used to form the missing organ, which is described as, "Human PSCs added at the blastocyst stage could somehow sense this deficiency and be directed to form the missing pancreas". There are three methods to introducing the patient's cells into the host animal. The first method is called blastocyst injection, where the patient's stem cells are injected into the blastocyst of the host animal. However, the success rate of chimerism by blastocyst injections have been notably low, at 0.01%. In addition, the method of aggregation involves aggregatng two or more embryos at similar or different stages, and tends to have a higher chimerism rate than bastocyst injection. The final method of in-utero transplantion injects stem cells into an animal embryo, and according to an article published in the Annals of Translational Medicine, "In utero transplantation is reported to be the most efficient way to limit human cells in the target organ of human-animal chimera." In 2017, a team of researchers successfully grew mouse pancreas in rats, then transplanted the pancreas to mice with diabetes, and the mice were able to have the transplant without tissue rejection or the need for immunosuppressants.
The usage of the patient's own cells to grow organs and tissues has sparked the community's in interest in personalized medicine, as it could help prevent immune rejections, infections, and tumor growth due to the use of immunosuppresants, which makes a tremendous difference for the future of healthcare. Chimera research can also help scientists better understand human systems and disease, as creating a human-animal chimera helps produce more human cellular characteristics in animals, which allows for a better animal model to test drugs and analyze the effect of diseases. This could provide more accurate screenings and results, since researchers could see the impact of the drug on more human tissue. However, issues such as the relatively low success rate of chimerism, contamination of animal cells into the organs, and possible transmission of zoonoses show that organ transplants grown from chimeras are still far from reality.
Many Photoshopped pictures show the horror of human-pig chimeras. However, the possibility of having these human features shown likely isn't possible. Image Source
Yet, a problem with chimera research involves the issue of preventing the human stem cells from contributing to the development of the nervous system in the host animal. According to an article titled "The contribution of human/non-human animal chimeras to stem cell research", "An organism is often considered a “person” once it has the intrinsic capacity to develop into a self-conscious rational being." However, the question remains as to when a chimera is considered human and is therefore entitled to human rights, since our society has different perceptions to killing an animal compared to a human. For example, at what point is killing a chimera is considered murdering, rather than butchering? Is it when the chimera has over 50% of human cells? What if the chimera has one neural cell? While it is unlikely for a chimera to develop obvious human-like features, such as a human face because of the complex cellular interactions needed to develop a face, should we attribute physical likeness to moral status? Can a chimera contain many human internal organs, but still be regarded as an animal? However, as most attribute cognitive ability to moral status, a method known as embryo complementation attempts to control the contribution of human stem cells on certain organs. By using modified organisms to lack the genes for certain organs and filling their organ deficiencies with human stem cells, we can attempt to prevent the stem cells from developing neural tissue, which affects the chimera's human cognition. Another issue is the possibility of producing human gametes from human-animal chimeras, and while this is quite unlikely, a study found that mice were able to produce rat sperm, so it may be possibly to have interspecific gametes. Uncertainty also plays a role in the debate over chimeric research, because in the case that the changes done in chimera research are heritable, what will be the impact on evolution and the ecosystem?
Maybe one day we will be able to improve organ transplants with chimera research! Image Source
Chimeria research brings intriguing opportunities for the future of healthcare, and could possibly save millions of people with the new therapies and organs we may be able to create with this new technology. However, the moral status of chimeras are often debated over, and as with many things in science, what will be the impact of these new developments?
Bibliography
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Levine, Sonya, and Laura Grabel. “The Contribution of Human/Non-Human Animal Chimeras to Stem Cell Research.” Stem Cell Research, vol. 24, Oct. 2017, pp. 128–134., doi:10.1016/j.scr.2017.09.005.
Malewana, Rakitha D. “Human-Animal Chimeras: Biomedical Research.” Nerdynaut, 14 Feb. 2017, www.nerdynaut.com/human-animal-chimeras-biomedical-research.
Lu, Yingfei et al. “Human-animal chimeras for autologous organ transplantation: technological advances and future perspectives.” Annals of translational medicine vol. 7,20 (2019): 576. doi:10.21037/atm.2019.10.13
Hermerén, Göran. “Ethical Considerations in Chimera Research.” Development, Oxford University Press for The Company of Biologists Limited, 1 Jan. 2015, dev.biologists.org/content/142/1/3.
Vidyasagar, Aparna. “Human-Animal Chimeras: Biological Research & Ethical Issues.” LiveScience, Purch, 29 Sept. 2016, www.livescience.com/56309-human-animal-chimeras.html.
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