Human chimera explained

A human chimera is a human with a subset of cells with a distinct genotype than other cells, that is, having genetic chimerism. In contrast, an individual where each cell contains genetic material from a human and an animal is called a human–animal hybrid, while an organism that contains a mixture of human and non-human cells would be a human-animal chimera.^[1]

Mechanisms

Some consider mosaicism to be a form of chimerism,^[2] while others consider them to be distinct.^{[3] [4] [5]}

Mosaicism involves a mutation of the genetic material in a cell, giving rise to a subset of cells that are different from the rest.

Natural chimerism is the fusion of more than one fertilized zygote in the early stages of prenatal development. It is much rarer than mosaicism.

In artificial chimerism, an individual has one cell lineage that was inherited genetically at the time of the formation of the human embryo and the other that was introduced through a procedure, including organ transplantation or blood transfusion.^[6] Specific types of transplants that could induce this condition include bone marrow transplants and organ transplants, as the recipient's body essentially works to permanently incorporate the new blood stem cells into it.

Examples

Natural chimerism

Natural chimerism has been documented in humans in several instances.

• The Dutch sprinter Foekje Dillema was expelled from the 1950 national team after she refused a mandatory sex test in July 1950; later investigations revealed a Y-chromosome in her body cells, and the analysis showed that she was probably a 46,XX/46,XY mosaic female.^[7]
• In 1953, a human chimera was reported in the British Medical Journal. A woman was found to have blood containing two different blood types. Apparently this resulted from her twin brother's cells living in her body.^[8] A 1996 study found that such blood group chimerism is not rare.^[9]
• In 2002, an article in the New England Journal of Medicine described a woman, later identified as Karen Keegan, in whom tetragametic chimerism was unexpectedly identified after she underwent preparations for kidney transplant. Those preparations for the transplant required the patient and her immediate family to undergo histocompatibility testing, the result of which had suggested that she was not the biological mother of two of her three children.^{[10] [11]}
• In 2002, Lydia Fairchild was denied public assistance in Washington state when DNA evidence appeared to show that she was not the mother of her children. A lawyer for the prosecution heard of the case of Karen Keegan in New England, and suggested the possibility to the defense, who were able to show that Fairchild, too, was a chimera with two sets of DNA, and that one of those sets could have been the mother of the children.^[12]

Non-intentional chimerism related to treatments

• Several cases of chimera phenomena have been reported in bone marrow recipients.
  • In 2019, the blood and seminal fluid of a man in Reno, Nevada (who had undergone a vasectomy), exhibited only the genetic content of his bone marrow donor. Swabs from his lips, cheek and tongue showed mixed DNA content.^[13]
  • The DNA content of semen from an assault case in 2004 matched that of a man who had been in prison at the time of the assault, but who had been a bone marrow donor for his brother, who was later determined to have committed the crime.^{[14] [15]}
  • In 2008, a man was killed in a traffic accident that occurred in Seoul, South Korea. A DNA analysis to identify him revealed that his blood, along with some of his organs, appeared to show that he was female. It was later determined that he had received a bone marrow transplant from his daughter.
• Another instance of treatment-related human chimerism was published in 1998, where a male human had some partially developed female organs due to chimerism. He had been conceived by in-vitro fertilization.^[16]

Human-animal chimeras

Human-animal chimeras include humans having undergone non-human to human xenotransplantation, which is the transplantation of living cells, tissues or organs from one species to another.^[17]

Patient derived xenografts are created by xenotransplantation of human tumor cells into immunocompromised mice, and is a research technique frequently used in pre-clinical oncology research.^[18]

• The first stable human-animal chimeras to actually exist were first created by Shanghai Second Medical University scientists in 2003, the result of having fused human cells with rabbit eggs.^[19]
• In 2017, a human-pig chimera was reported to have been created; the chimera was also reported to have 0.001% human cells, with the balance being pig.^{[20] [21] [22]} The embryo consisted mostly pig cells and some human cells. Scientists stated that they hope to use this technology to address the shortage of donor organs.^{[23] [24]}
• In 2021, a human-monkey chimera was created as a joint project between the Salk Institute in the US and Kunming University in China and published in the journal Cell.^[25] This involved injecting human stem cells into monkey embryos. The embryos were only allowed to grow for a few days, but the study demonstrated that some of these embryos still had human stem cells surviving at the end of the experiments. Because humans are more closely related to monkeys than other animals, it means there is more chance of the chimeric embryos surviving for longer periods so that organs can develop. The project has opened up possibilities into organ transplantation as well as ethical concerns particularly concerning human brain development in primates.^[26]

Chimera identification

Non-artificial chimerism has traditionally been considered to be rare due the low amount of reported cases in medical literature.^[27] However, this may be due to the fact that humans might not often be aware of this condition to begin with. There are usually no signs or symptoms for chimerism other than a few physical symptoms such as hyper-pigmentation, hypo-pigmentation, Blaschko's lines, body asymmetry or heterochromia iridum (possessing two different colored eyes).^[28] However, these signs do not necessarily mean an individual is a chimera and should only be seen as possible symptoms. Again, forensic investigation or curiosity over an unexpected maternity/paternity DNA test result usually leads to the accidental discovery of this condition. By simply undergoing a DNA test, which usually consists of either a swift cheek swab or a blood test, the discovery of the once unknown second genome is made, therefore identifying that individual as a chimera.^[29]

Chimerism and intersex

The concept of a "human hermaphrodite" resulting from chimerism is largely a misconception. Most intersex individuals are not chimeras,^[30] and most human chimeras are not observed to have intersex traits.^[31] Theoretically, if a gynandromorphic human chimera were to have fully functioning male and female gonad tissue, such an individual could self-fertilize;^{[32] [33]} this hypothesis is backed by the fact that hermaphroditic animal species commonly reproduce in this way, and it has been observed in a rabbit.^[34] However, no such case of functional self-fertilization has ever been documented in humans;^[35] and it is non-existent or extremely rare in mammals,^{[36] [37] [38] [39] [40]} especially in humans.^{[41] [42] [43] [44]} While humans are known to have sex characteristics that diverge from typical males or typical females, these individuals fall under the social umbrella of intersex conditions and traits, and some consider the term "hermaphrodite" to be a slur when applied to them.^{[45] [46] [47]}

Legislation

The Human Chimera Prohibition Act

On 11 July 2005, a bill known as The Human Chimera Prohibition Act was introduced into the United States Congress by SenatorSamuel Brownback

however, it died in Congress sometime in the next year. The bill was introduced based on findings that science has progressed to the point where human and nonhuman species can be merged to create new forms of life. Because of this, ethical issues may arise as the line blurs between humans and other animals, and according to the bill with this blurring of lines comes a show of disrespect for human dignity. The final claim brought up in The Human Chimera Prohibition Act was that there is an increasing amount of zoonotic diseases. With that being said, the creation of human-animal chimeras can allow these diseases to reach humans.^[48]

On 22 August 2016, another bill, The Human-Animal Chimera Prohibition Act of 2016, was introduced to the United States House of Representatives by Christopher H. Smith. It identifies a human-animal chimera as:

• a human embryo into which a nonhuman cell or cells (or the component parts thereof) have been introduced to render the embryo's membership in the species Homo sapiens uncertain;
• a chimera human/animal embryo produced by fertilizing a human egg with nonhuman sperm;
• a chimera human/animal embryo produced by fertilizing a nonhuman egg with human sperm;
• an embryo produced by introducing a nonhuman nucleus into a human egg;
• an embryo produced by introducing a human nucleus into a nonhuman egg;
• an embryo containing at least haploid sets of chromosomes from both a human and a nonhuman life form;
• a nonhuman life form engineered such that human gametes develop within the body of a nonhuman life form; or
• a nonhuman life form engineered such that it contains a human brain or a brain derived wholly or predominantly from human neural tissues.

The bill prohibits the attempts to create a human-animal chimera, the transfer or attempt to transfer a human embryo into a nonhuman womb, the transfer or attempt to transfer a nonhuman embryo into a human womb, and the transport or receipt of an animal chimera for any purpose. Penalties for violations of this bill include fines and/or imprisonment of up to 10 years. The bill was referred to the Subcommittee on Crime, Terrorism, Homeland Security, and Investigations on October 11, 2016, but died there.^[49]

Patenting

In the U.S., efforts into creating a chimeric entity appeared to be legal when the topic first came up. Developmental biologist Stuart Newman, a professor at New York Medical College in Valhalla, N.Y., applied for a patent on a human-animal chimera in 1997 as a challenge to the U.S. Patent and Trademark Office and the U.S. Congress, motivated by his moral and scientific opposition to the notion that living things can be patented at all. Prior legal precedent had established that genetically engineered entities, in general, could be patented, even if they were based on beings occurring in nature.^[50] After a seven-year process, Newman's patent finally received a flat rejection. The legal process had created a paper trail of arguments, giving Newman what he claimed was a victory. The Washington Post ran an article on the controversy that stated that it had raised "profound questions about the differences—and similarities—between humans and other animals, and the limits of treating animals as property."^[50]

Notes and References

1. Web site: Sarah Taddeo, Jason S. Robert . 2014-11-04 . "Hybrids and Chimeras: A Consultation on the Ethical and Social Implications of Creating Human/Animal Embryos in Research" (2007), by the HFEA . The Embryo Project at Arizona State University . Hybrid embryos are embryos created by mixing human sperm and animal ova, or animal sperm and human ova. Human chimera embryos are human embryos that have had animal cells added to them during early development. … Lastly, transgenic human embryos are human embryos that have had animal genes inserted into them early in development..
2. Web site: Chimaera - an overview ScienceDirect Topics . 2024-01-20 . www.sciencedirect.com . Another form of chimera is the mosaic, which is a composite individual derived from a single fertilized egg..
3. Madan . Kamlesh . 2020-09-01 . Natural human chimeras: A review . European Journal of Medical Genetics . 63 . 9 . 103971 . 10.1016/j.ejmg.2020.103971 . 1769-7212 . A chimera is an organism whose cells are derived from two or more zygotes as opposed to a mosaic whose different cell lines are derived from a single zygote. free . 32565253 .
4. Anderson . D. . Billingham . R. E. . Lampkin . G. H. . Medawar . P. B. . 1951-12-01 . The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle . Heredity . en . 5 . 3 . 379–397 . 10.1038/hdy.1951.38 . 1365-2540 . In the current embryological (which is also the classical) sense, a "chimaera" is an organism whose cells derive from two or more distinct zygote lineages, and this is the sense which the term "genetical chimaera" is here intended to convey. "Genetical mosaic" is less suitable, because a mosaic is formed of the cells of a single zygote lineage..
5. Santelices . B. . 2004-11-01 . Mosaicism and chimerism as components of intraorganismal genetic heterogeneity . Journal of Evolutionary Biology . en . 17 . 6 . 1187–1188 . 10.1111/j.1420-9101.2004.00813.x . 15525401 . 1010-061X . Mosaicism originates by intrinsic genetic variations caused, among other processes, by somatic mutations, while chimerism originates from allogenic fusion or grafting. As such, chimerism is much rarer and involves a much larger genetic change than mosaicism..
6. Rinkevich. B.. June 2001. Human natural chimerism: an acquired character or a vestige of evolution?. Human Immunology. 62. 6. 651–657. 10.1016/s0198-8859(01)00249-x. 0198-8859. 11390041.
7. Ballantyne . KN . Kayser . M . Grootegoed . JA . 2011 . Sex and gender issues in competitive sports: investigation of a historical case leads to a new viewpoint . . 46. 8. 614–7. 10.1136/bjsm.2010.082552 . 21540190 . 3375582.
8. Bowley . C. C. . Ann M. Hutchison . Joan S. Thompson . Ruth Sanger . July 11, 1953 . A human blood-group chimera . British Medical Journal . 2. 4827. 81 . 10.1136/bmj.2.4827.81 . 13051584 . 2028470.
9. 8741872. 1996. Van Dijk. B. A.. Blood group chimerism in human multiple births is not rare. American Journal of Medical Genetics. 61. 3. 264–8. Boomsma. D. I.. De Man. A. J.. 10.1002/(SICI)1096-8628(19960122)61:3<264::AID-AJMG11>3.0.CO;2-R. 10.1.1.149.9001. 9787758 .
10. Yu . Neng . Kruskall . Margot S. . Yunis . Juan J. . Knoll . Joan H.M. . Uhl . Lynne . Alosco . Sharon . Ohashi . Marina . Clavijo . Olga . Husain . Zaheed . Yunis . Emilio J. . Yunis . Jorge J. . 2002-05-16 . Disputed Maternity Leading to Identification of Tetragametic Chimerism . New England Journal of Medicine . 346 . 20 . 1545–1552 . 10.1056/NEJMoa013452 . 0028-4793 . 12015394 . free.
11. Wolinsky . Howard . March 2007 . A mythical beast. Increased attention highlights the hidden wonders of chimeras . EMBO Reports . 8 . 3 . 212–214 . 10.1038/sj.embor.7400918 . 1469-221X . 1808039 . 17330063.
12. Web site: She's Her Own Twin . . August 15, 2006 . September 17, 2013 . https://web.archive.org/web/20131028052231/https://abcnews.go.com/Primetime/story?id=2315693 . October 28, 2013 . dead.
13. Web site: Man who had transplant finds out months later his DNA has changed to that of donor 5,000 miles away . . December 12, 2019 . Heather . Murphy. 2019-12-09.
14. News: DNA at the Fringes: Twins, Chimerism, and Synthetic DNA. The Daily Beast. 2015-10-07. Murphy. Erin E..
15. Web site: Schlueter . Roger . Bone marrow transplant could give you new DNA . . 2020-02-08 . en . 2018-02-01.
16. Strain . Lisa . John C.S. Dean . Mark P. R. Hamilton . David T. Bonthron . 1998 . A True Hermaphrodite Chimera Resulting from Embryo Amalgamation after in Vitro Fertilization . The New England Journal of Medicine . 338 . 3. 166–169 . 10.1056/NEJM199801153380305 . 9428825. free .
17. https://web.archive.org/web/20050113212657/http://www.who.int/transplantation/xeno/en/ Xenotransplantation
18. 22508028. 3928688. 10.1038/nrclinonc.2012.61. 2012. Tentler. J. J.. Patient-derived tumour xenografts as models for oncology drug development. Nature Reviews. Clinical Oncology. 9. 6. 338–50. Tan. A. C.. Weekes. C. D.. Jimeno. A. Leong. S. Pitts. T. M.. Arcaroli. J. J.. Messersmith. W. A.. Eckhardt. S. G..
19. News: Animal-Human Hybrids Spark Controversy. https://web.archive.org/web/20050127063859/http://news.nationalgeographic.com/news/2005/01/0125_050125_chimeras.html. dead. January 27, 2005. Mott. Maryann. January 25, 2005. National Geographic News. August 6, 2015.
20. News: Human-pig 'chimera embryos' detailed. Gallagher. James. 2017-01-26. BBC News. 2017-06-03. en-GB.
21. News: Human-Pig Hybrid Created in the Lab—Here Are the Facts. https://web.archive.org/web/20170126234725/http://news.nationalgeographic.com/2017/01/human-pig-hybrid-embryo-chimera-organs-health-science/. dead. January 26, 2017. 2017-01-26. 2017-06-03.
22. News: Scientists create human/pig hybrid. January 26, 2017. The Independent. 2017-06-03. en-GB.
23. News: Human-Pig Hybrid Created in the Lab—Here Are the Facts. https://web.archive.org/web/20170126234725/http://news.nationalgeographic.com/2017/01/human-pig-hybrid-embryo-chimera-organs-health-science/. dead. January 26, 2017. 2017-01-26. 2017-01-27.
24. Wu. Jun. Platero-Luengo. Aida. Sakurai. Masahiro. Sugawara. Atsushi. Gil. Maria Antonia. Yamauchi. Takayoshi. Suzuki. Keiichiro. Bogliotti. Yanina Soledad. Cuello. Cristina. Valencia. Mariana Morales. Okumura. Daiji. 2017-01-26. Interspecies Chimerism with Mammalian Pluripotent Stem Cells. Cell. en. 168. 3. 473–486.e15. 10.1016/j.cell.2016.12.036. 0092-8674. 5679265. 28129541.
25. Tan. Tao. Wu. Jun. Si. Chenyang. Dai. Shaoxing. Zhang. Youyue. Sun. Nianqin. Zhang. E.. Shao. Honglian. Si. Wei. Yang. Pengpeng. Wang. Hong. 2021-04-15. Chimeric contribution of human extended pluripotent stem cells to monkey embryos ex vivo. Cell. English. 184. 8. 2020–2032.e14. 10.1016/j.cell.2021.03.020. 0092-8674. 33861963. 233247345. free.
26. Web site: Human–Monkey Hybrids: Have We Crossed a Boundary? The American Spectator USA News and Politics . 2021-06-26 . The American Spectator USA News and Politics . en.
27. Boklage . Charles . Embryogenesis of chimeras, twins and anterior midline asymmetries . Human Reproduction (Oxford, England) . 2006 . 21 . 3 . 579–591 . 10.1093/humrep/dei370 . 16253966 . 4 January 2024.
28. Web site: Madan . Kamlesh . Natural human chimeras: A review . 4 January 2024.
29. Web site: National Society of Genetic Counselors : Blogs : Chimerism Explained: How One Person Can Unknowingly Have Two Sets of DNA. nsgc.org. 2020-03-15. 2020-02-02. https://web.archive.org/web/20200202124939/https://www.nsgc.org/p/bl/et/blogaid%3D1084. dead.
30. Web site: Intersex Definitions . 2022-10-31 . interACT: Advocates for Intersex Youth . en-US.
31. Web site: 2014-07-31 . Intersex and the City: C is for Chimera . 2022-10-31 . Intersex and the City . Many people assume this is how all intersex people came to be. My mom even said when I was a baby, people hypothesized that I was twins (I’m not). Chimeras seem to play into an old cultural myth that a “hermaphrodite” must essentially be two people.
32. Irmak . M. Kemal . 2010-11-01 . Self-fertilization in human: Having a male embryo without a father . Medical Hypotheses . en . 75 . 5 . 448–451 . 10.1016/j.mehy.2010.04.021. 20452130 .
33. Bayraktar . Zeki . 28 February 2017 . Potential autofertility in true hermaphrodites . The Journal of Maternal-Fetal & Neonatal Medicine . 31 . 4 . 542–547 . 10.1080/14767058.2017.1291619 . 28282768 . 22100505.
34. Frankenhuis . M. T. . Smith-Buijs . C. M. . de Boer . L. E. . Kloosterboer . J. W. . 1990-06-16 . A case of combined hermaphroditism and autofertilisation in a domestic rabbit . The Veterinary Record . 126 . 24 . 598–599 . 0042-4900 . 2382355.
35. 10.1080/14767058.2017.1291619 . 28282768 . Potential autofertility in true hermaphrodites . Bayraktar . Zeki . The Journal of Maternal-Fetal & Neonatal Medicine . 31 . 4 . 542–547. 2018. 22100505.
36. Book: MD. Randolph M. Nesse. Why We Get Sick: The New Science of Darwinian Medicine. Williams. George C.. 2012-02-08. Knopf Doubleday Publishing Group. 978-0-307-81600-9. 185. en. No species of mammal is hermaphroditic.. Randolph M. Nesse. George C. Williams (biologist).
37. Book: Smith, John Maynard. Did Darwin Get It Right?: Essays on Games, Sex and Evolution. 2012-12-06. Springer Science & Business Media. 978-1-4684-7862-4. 102. en. Animals are less often hermaphrodites-no mammals or birds are so. John Maynard Smith.
38. Schärer. Lukas. 2017. The varied ways of being male and female. Molecular Reproduction and Development. en. 84. 2. 94–104. 10.1002/mrd.22775. 28032683. 1098-2795. Of note, the otherwise well-studied insects, birds, and mammals are strikingly absent here—with not a single species among these groups showing hermaphroditism (for details on a supposedly hermaphroditic scale insect, however, see Gardner and Ross, 2011).. free.
39. Book: Maxwell, Kenneth E. . The Sex Imperative: An Evolutionary Tale of Sexual Survival . 2013-11-11 . Springer . 978-1-4899-5988-1 . 152 . en . Hermaphroditism is rare in vertebrates; fish are the most advanced forms that display it, and it does not occur in mammals except as partial hermaphroditism resulting from natural or experimentally imposed hormone imbalance.
40. Book: Gorshkov, Victor G.. Physical and Biological Bases of Life Stability: Man, Biota, Environment. 2012-12-06. Springer Science & Business Media. 978-3-642-85001-1. en. No cases of hermaphroditism or parthenogenesis are found among birds and mammals..
41. Book: Phelan, Jay . What Is Life?: A Guide to Biology w/Prep-U . 2009-03-02 . Macmillan . 978-1-4292-8079-2 . 243 . en . But although hermaphroditism is common among invertebrates and occurs in some fish and other vertebrates, contrary to urban legends, human hermaphrodites do not exist..
42. Book: Mills, Alex . Biology of Sex . 2018-01-01 . University of Toronto Press . 978-1-4875-9337-7 . 309 . en . In the past, the term hermaphrodite was widely applied in such cases, but humans are not hermaphroditic. In a truly hermaphroditic species, individuals have functional sets of male and female organs..
43. Book: Turpin . Raymond . Human Afflictions and Chromosomal Aberrations: International Series of Monographs in Pure and Applied Biology: Modern Trends in Physiological Sciences . Lejeune . Jérôme . 2013-10-22 . Elsevier . 978-1-4831-4668-3 . 230 . en . Hermaphroditism in the strict sense of the term does not exist in the human species. … may be equipped with both masculine and feminine gonads always more or less abnormal, incapable of simultaneously producing male and female gametes and not functional. This abnormal individual is therefore not a hermaphrodite but an intersex individual..
44. Book: Dawson, Ernest Rumley . The Causation of Sex in Man: A New Theory of Sex Based on Clinical Materials Together with Chapters on Forecasting Or Predicting the Sex of the Unborn Child and on the Determination Or Production of Either Sex at Will . 1917 . . 154 . en . they certainly do not possess the complete and active sexual organs of both sexes, and so are not true hermaphrodites: they are known as false or pseudo-hermaphrodites … These false hermaphrodites may appear to possess the genital organs of both sexes, but they do not really do so..
45. Knight . Kyle . 2017-07-25 . "I Want to Be Like Nature Made Me": Medically Unnecessary Surgeries on Intersex Children in the US . Human Rights Watch . en . It is now considered pejorative and outdated, although a small number of intersex people have reclaimed the term..
46. Book: Dreger, AD . Intersex in the age of ethics . 1999 . Hagerstown, Md. : University Pub. Group . Internet Archive . 978-1-55572-125-1.
47. Web site: What is Intersex? Frequently Asked Questions . 2022-10-31 . interACT: Advocates for Intersex Youth . en-US . Some intersex people have reclaimed this word for themselves, but it is usually considered a slur. … it is not possible for one person to have both a fully developed penis and vagina..
48. Web site: Brownback. Samuel. S.659 – Human Chimera Prohibition Act of 2005 (Introduced in Senate - IS). The Library of Congress THOMAS. 20 May 2015. 2005-03-17. 2016-07-04. https://web.archive.org/web/20160704101035/http://thomas.loc.gov/cgi-bin/query/z?c109:S.659:. dead.
49. Web site: Text - H.R.6131 - 114th Congress (2015-2016): Human-Animal Chimera Prohibition Act of 2016. Smith. Christopher H.. 2016-10-11. congress.gov. 2019-11-14.
50. News: U.S. Denies Patent for a Too-Human Hybrid. Weiss. Rick. February 13, 2005. The Washington Post. August 8, 2015.