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First Posted: Aug 5, 2010
Aug 5, 2010

Chimera/What is It?/Does It Occur in All Animals?

Chimera in Horses
Dunbar's Gold

Typically seen in non-human zoology (but also discovered to a rare extent in humans), a chimera is an animal that has two or more different populations of genetically distinct cells that originated in different zygotes involved with sexual reproduction; if the different cells emerged from the same zygote, it is called a mosaicism.

Chimeras are formed from four parent cells (two fertilized eggs or early embryos fused together). Each population of cells keeps its own character and the resulting animal is a mixture of tissues.

This condition is either inherited, or it is acquired through the infusion of allogeneic hematopoietic cells during transplantation or transfusion. In nonidentical twins, chimerism occurs by means of blood-vessel anastomoses. The likelihood of offspring being a chimera is increased if it is created via in vitro fertilization. Chimeras can often breed, but the fertility and type of offspring depends on which cell line gave rise to the ovaries or testes; varying degrees of intersexuality may result if one set of cells is genetically female and another genetically male.

Tetragametic Chimerism

Tetragametic chimerism is a form of congenital chimerism. This condition occurs through the fertilization of two separate ova by two sperm, followed by the fusion of the two at the blastocyst or zygote stages. This results in the development of an organism with intermingled cell lines. Put another way, the chimera is formed from the merging of two nonidentical twins in a very early (zygote or blastocyst) phase. As such, they can be male, female, or hermaphroditic.

As the organism develops, it can come to possess organs that have different sets of chromosomes. For example, the chimera may have a liver composed of cells with one set of chromosomes and have a kidney composed of cells with a second set of chromosomes. This has occurred in humans, and at one time was thought to be extremely rare, though more recent evidence suggests that it is not as rare as previously believed...

Most chimerae will go through life without realizing they are chimeras. The difference in phenotypes may be subtle (e.g., having a hitchhiker's thumb and a straight thumb, eyes of slightly different colors, differential hair growth on opposite sides of the body, etc.) or completely undetectable. Another telltale of a person being a chimera is visible Blaschko's lines.

Affected persons may be identified by the finding of two populations of red cells or, if the zygotes are of opposite sex, ambiguous genitalia and hermaphroditism alone or in combination; such persons sometimes also have patchy skin, hair, or eye pigmentation (heterochromia). If the blastocysts are of opposite sex, genitals of both sexes may be formed, either ovary and testis, or combined ovotestes, in one rare form of intersexuality, a condition previously known as true hermaphroditism.

Note that the frequency of this condition does not indicate the true prevalence of chimerism. Most chimera composed of both male and female cells probably do not have an intersex condition, as might be expected if the two cell populations were evenly blended throughout the body. Often, most or all of the cells of a single cell type will be composed of a single cell line, i.e. The blood may be composed prominently of one cell line, and the internal organs of the other cell line. Genitalia produce the hormones responsible for other sex characteristics. If the sex organs are homogeneous, the individual will not be expected to exhibit any intersex traits.

Natural chimeras are almost never detected unless they exhibit abnormalities such as male/female or hermaphrodite characteristics or uneven skin pigmentation. The most noticeable are some male tortoiseshell cats or animals with ambiguous sex organs.

Chimera may also show, under a certain spectrum of UV light, distinctive marks on the back resembling that of arrow points pointing downwards from the shoulders down to the lower back; this is one expression of pigment unevenness called Blaschko's lines.

The existence of chimerism is problematic for DNA testing, a fact with implications for family and criminal law. The Lydia Fairchild case, for example, was brought to court after DNA testing apparently showed that her children could not be hers. Fraud charges were filed against her and her custody of her children was challenged. The charge against her was dismissed when it became clear that Lydia was a chimera, with the matching DNA being found in her cervical tissue. Another case was that of Karen Keegan, who was also in danger of losing her children, after a DNA test for a kidney transplant seemed to show she wasn't the mother of her children.

The tetragametic state has important implications for organ or stem-cell transplantation. Chimeras typically have immunologic tolerance to both cell lines.

Microchimerism

Microchimerism is the presence of a small number of cells that are genetically distinct from those of the host individual. Apparently, this phenomenon is related to certain types of autoimmune diseases, however, the mechanisms responsible for this relationship are unclear.

Chimeras in Research

In biological research, chimeras are artificially produced by physically mixing cells from two different organisms. Chimeras are not hybrids, which form from the fusion of gametes from two species (like a donkey and a horse) that form a single zygote that will develop as much as it can (in this case into a live mule if the parents are jackass and mare, or a hinny if the parents are stallion and jenny); in comparison, chimeras are the physical mixing of cells from two independent zygotes: for example, one from the donkey and one from the horse. "Chimera" is a broad term and is often applied to many different types of mixing of cells from two different species.

Some chimeras can result in the eventual development of an adult animal composed of cells from both donors, which may be of different species - for example, in 1984 a chimeric geep was produced by combining embryos from a goat and a sheep. The "geep" has been a very important contributor to answering fundamental questions about development, and the techniques used to create it may one day help save endangered species. For example, if one tried to let a goat embryo gestate in a sheep, the sheep's immune system would reject the developing goat embryo; however, if one used a geep that shared markers of immunity with both sheep and goats, the goat embryo might survive. It may be possible to extend this practice for the purpose of preventing the extinction of some endangered animal species.

Such interspecies chimeras such as the "geep" are made in the laboratory and rarely with the purpose of generating living hybrid animals. Intraspecies chimeras are created by transplanting embryonic cells from an animal with one trait into an embryo of an animal with a different trait. This practice is common in the field of embryology and has been a very important contributor to our current understanding of human and animal biology. For example, by mixing embryonic cells of differently coloured or otherwise genetically distinct mice (of the same species), researchers have been able to see how embryos form and which organs and tissues are related (arise from the similar cell lineages).

Hybridomas are not true chimeras as described above because they do not result from the mixture of two cell types but result from fusion of two species' cells into a single cell and artificial propagation of this cell in the laboratory. Hybridomas have been very important tools in biomedical research for decades.

In August 2003, researchers at the Shanghai Second Medical University in China reported that they had successfully fused human skin cells and dead rabbit eggs to create the first human chimeric embryos. The embryos were allowed to develop for several days in a laboratory setting, then destroyed to harvest the resulting stem cells. Because of the high therapeutic potential of human embryonic stem cells and the United States moratorium on using discarded embryos from in vitro fertilisation clinics as well as other concerns about using human embryos directly for research, scientists are trying to find alternative paths of research. However, increasingly realizable projects using part-human, part-animal chimeras as living factories not only for biopharmaceutical production but also for producing cells or organs (see hybridomas) for xenotransplantation raise a host of ethical and safety issues.

During November 2006, UK researchers from Newcastle University and King's College London applied to the Human Fertilisation and Embryology Authority for a three-year license to fuse human DNA with cow eggs. The proposal is to insert human DNA into a cow's egg which has had its genetic material removed and then create an embryo by the same technique that produced Dolly the Sheep. This research was attempted in the United States several years before and failed to yield such an embryo. In April 2008 the researchers from Newcastle University reported that their research had been successful. The resulting embryos lived for 3 days and the largest grew to a size of 32 cells. The researchers are aiming for embryos that live for 6 days so that embryonic stem cells can be harvested.

In 2007, scientists at the University of Nevada School of Medicine created a sheep that has 15% human cells and 85% sheep cells.

...Underlying Biology

The ability to make mouse chimeras comes from an understanding of early mouse development. Between the stages of Fertilization of the egg and the implantation of a blastocyst into the uterus, different parts of the mouse embryo retain the ability to give rise to a variety of cell lineages. Once the embryo has reached the blastocyst stage it is composed of several parts, mainly the trophectoderm, the inner cell mass, and the primitive endoderm. Each of these parts of the blastocyst gives rise to different parts of the embryo, the inner cell mass gives rise to the embryo proper while the trophectoderm and primitive endoderm give rise to extra embryonic structures that support growth of the embryo. Two to eight cell stage embryos are competent for making chimeras, since at these stages of development the cells in the embryos are not yet committed to give rise to any particular cell lineage, they could give rise to the inner cell mass or the trophectoderm. In the case where two diploid eight cell stage embryos are used to make a chimera, chimersim can be later found in the epiblast, primitive, endoderm and trophectoderm of the mouse blastocyst. It is possible to dissect the embryo at other stages so as to accordingly give rise to one lineage of cells from an embryo selectively and not the other. For example subsets of blastomeres can be used to give rise to chimera with specified cell lineage from one embryo. The Inner Cell Mass of a diploid blastocyst for example can be used to make a chimera with another blastocyst of eight cell diploid embryo, the cells taken from the inner cell mass will give rise to the primitive endoderm and to the epiblast in the chimera mouse. From this knowledge ES cell contributions to chimeras have been developed. ES cells can be used in combination with eight cell and two cell stage embryos to make chimeras and exclusively give rise to the embryo proper. Embryos that are to be used in chimeras can further be genetically altered in order to specifically contribute to only one part of chimera. An example is the chimera built off of ES cells and tetraploid embryos , tetraploid embryos which are artificially made by electrofusion of two two-cell diploid embryos .The tetraploid embryo will exclusively give rise to the trophectoderm and primitive endoderm in the chimera...


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