A Chimera is an organism that is made up of more than one genetically distinct type of cell. Chimeras can either form naturally or be artificially produced in the laboratory by three mechanisms: mixing stem cells from two different individuals, introducing stem cells into a fully developed tissue, or combining two fully developed tissues into one organism. Scientists study chimeras to answer fundamental questions about stem cell biology, organ transplant biology, embryonic development, human diseases, and genetics, as well as to test drug effectiveness. Although many types of chimeras are possible, the formation of human-only, animal-only, and human-animal chimeras is described here.
HUMAN CHIMERAS
In 2002, human chimerism (the condition of being a chimera) was publicized in the popular media with the case of a 52-year-old woman who needed a kidney transplant. To find a potential kidney donor, the woman and her immediate family submitted blood samples for genetic screening. The results were surprising: The tests indicated that the woman did not have biological similarities to two of the three sons to whom she had given birth. To solve this conundrum, doctors examined samples of the woman’s mucus, hair, and skin and determined that she was a tetragametic chimera; that is, a chimera formed when two of a mother’s eggs are fertilized by two of the father’s sperm, and the resulting two embryos fuse to form one person. Tissues (e.g., the skin, muscle, etc.) of tetragametic chimeras either can be composed of cells from both original embryos or can be made up of cells from only one of the embryos. In the case described above, the woman’s blood cells were derived from only one of the fused twins, whereas her other tissues were made up of cells from both twins.
With only 30 reported cases, human chimeras appear to be relatively rare. However, because naturally occurring chimeras rarely have identifiable features, the rate of human chimerism may be higher than reported. Genetic testing of several tissue types can usually identify human chimeras, although these tests can be complicated and expensive.
Thus, testing for human chimerism usually only occurs when rare, outward physical symptoms of chimerism are observed. The physical symptoms of chimerism may include ambiguous genitalia, hermaphroditism (having both male and female sex organs), patchy colored skin, or two differently colored eyes.
Recently, in vitro fertilization has been shown to increase the rate of tetragametic chimerism in embryos. This may result from the embryos being grown in close contact before implantation into the mother’s uterus or from an increased chance that an egg with two nuclei will be fertilized by two different sperm. Either way, with the increased use of in vitro fertilization, diagnosing chimerism may be increasingly relevant when considering maternity/paternity cases, blood donation, or organ donation.
In addition to tetragametic chimeras, other types of chimeras exist in the human population. These include parthenogenetic chimeras, androgenetic chimeras, microchimerism, and organ transplant patients. A parthenogenetic chimera is formed when an egg that has not undergone meiosis (a cellular process that decreases the egg’s genetic material by half) is fertilized by two sperm. In this case, the two sperm provide double the typical dosage of genetic material from the father, which pairs with the doubled genetic material from the mother and results in chimera formation. Only one case of human parthenogenetic chimerism has been reported.
The reverse scenario, androgenetic chimerism, occurs when one sperm fertilizes one normal egg and another sperm fertilizes an egg that is empty of genetic material. Normally, this second fertilization event would not produce a living zygote (fertilized egg). However, in some rare cases, the genetic material from the father in the empty egg may duplicate itself, producing a zygote that contains genetic material from only the father. This father-only zygote then fuses together with the normal zygote to form a chimera. In contrast to parthenogenetic chimeras, no known androgenetic chimeras have been born alive.
Microchimerism occurs when a small amount of cells are transferred between the mother and the fetus during pregnancy. Recently, scientists have run studies showing that microchimerism might be very common in humans. In fact, up to 50 percent of mothers may carry their children’s cells in their blood decades after giving birth. During pregnancy, the fetus may also absorb some of the mother’s cells. After birth, children could possibly carry their mother’s cells with them throughout their lives. In cases in which a mother has multiple children, the mother may absorb cells from the first child into her body and then pass these cells onto other children during her subsequent pregnancies. Thus, individuals who have older siblings may have cells in their bodies that are derived from their older brothers and sisters. Researchers think that microchimerism may help the mother’s immune system tolerate the fetus during pregnancy. Some scientists also believe that the breakdown of this system of tolerance may cause some autoimmune diseases in women.
Finally, humans that have undergone organ transplants or bone marrow transplants using human donors can be considered artificially created chimeras.
ANIMAL CHIMERAS
Animal chimera formation occurs by the same methods as in humans. Because animal models are used to help understand human disease and mammalian development, many tetragametic chimeras are artificially generated for research. Both same-species and cross-species animal chimeras have been generated in the laboratory. In the 1960s, scientists showed that same-species mouse chimeras could be created by juxtaposing stem cells from two different mice in a test tube and then transferring these cells into a female mouse.
Scientists have expanded this technology to other animal types such as rats, birds, and sheep. Cross-species chimeras have also been created by scientists. In 1984, researchers combined embryos from a sheep and a goat. The resulting “geeps” were sterile and could not produce living offspring. Despite this setback, researchers believe that the practical benefits of producing interspecies chimeras will enable the rearing of embryos from endangered species using females from other species.
HUMAN-ANIMAL CHIMERAS
Artificially created human-animal chimeras can be formed using fully differentiated, mature adult cells or by transplanting embryonic cells into either an adult or another embryo.
In cases using fully differentiated adult cells, tissues can be grafted from an animal to a human and vice versa. In the medical clinic, these chimeras are formed by organ transplantation when a human receives an organ (e.g., a heart) from an animal donor (e.g., a pig). In the lab, scientists often create human-animal chimeras for their research. Frequently, scientists will create a human-animal chimera by transplanting diseased human cells into a mouse with no immune system. Cancer researchers use this technique to graft human cancer cells into mice and then study how cancer grows and is affected by drug treatments. In contrast, liver biologists have found that a mouse transplanted with human liver cells can grow a functional human liver. These mice are used to study how viruses affect the human liver and how the human liver responds to certain drugs.
The most ethically controversial human-animal chimeras created with fully differentiated adult cells are those generated by mixing human nerve cells with an animal’s central nervous system. The ethical consideration for these studies stems from the idea that human cognizance might be transferred to animals. Nevertheless, these neural chimeras have been created by two methods: human neural stem cells are purified from fetuses and transplanted into embryos or newborn animals, or human embryonic stem cells are differentiated into neurons in the lab and then transplanted into embryos, newborns, or adult animals. Neural human-animal chimeras have been created using rats, mice, and monkeys with the aim of using them as models for studying human neural development and neurodegenerative diseases.
Finally, stem cell biologists create human-animal chimeras with embryonic stem cells by injecting human embryonic stem cells into adult or embryonic animals. To create human-animal chimeras using stem cells, human stem cells are injected into an immune-deficient adult animal to produce a special type of tumor called a teratoma. This type of tumor can grow all of the different types of cells in the body. Stem cell biologists use chimeras generated from stem cells to understand how the different cells of the body are generated from stem cells.
U.S. law does not currently prohibit the production of human-animal chimeras. In 2005, a Human Chimera Prohibition Act was proposed in the Senate by Senator Samuel Brownback, but this act was never voted into law. However, recommended ethical standards for experiments involving human-animal chimeras were published by the International Society for Stem Cell Research in 2007.
