THE TRUTH ABOUT CHIMERAS

By | November 20, 2007 | archive, textbook

The country around was beset by a frightful monster, the Sphinx, a creature shaped like a winged lion, but with the breast and face of a woman. She lay in wait for the wayfarers along the roads to the city and whomever she seized she put a riddle to, telling him if he could answer it, she would let him go. No one could, and the horrible creature devoured man after man until the city was in a state of siege.

– Edith Hamilton, from her book Mythology

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This “frightful monster” appeared in the famous Greek tale of Oedipus, an unfortunate fellow who was accursed with the fate of murdering his father and marrying his mother. The Sphinx, outsmarted by Oedipus, kills herself and thus Oedipus rescues the city of Thebes. This narrative stands out because the monster here did not possess merely the savageness of beast, but also had the intelligence of man – a deadly combination.

The Chimera was another famous creature in Greek mythology that had parts of various creatures: it had the head of a lion, the body of a goat, and the backside of a serpent. Because of that, other creatures similarly made from parts of different beings were called chimeras as well, and they appear in ancient Egypt, Persian, Japanese, Chinese and Hindu artifacts.

The ancients’ fantasies that the strengths of individual creatures may somehow be fused into one entity is intriguing, especially those of hybrid creatures with human and animal features, such as merpeople, centaurs, and the aforementioned sphinxes. With the advent of modern scientific technology, however, they may not remain just fantasies.

To understand how modern genetic engineering can produce chimeras, we must understand the genetic basis of such entities. Chimeras, from a geneticist’s point of view, are living creatures that contain two or more genetically distinct lines of cells that originated from two or more different zygotes. (This is different from another genetic phenomenon called mosaicism, where different cell lines may emerge from one single zygote.) In essence, chimeras are complexes of two genetically different animals.

Scientists have noted long ago the existence of natural chimeras, and these usually occur within the same species. An example is the extremely rare fertile male tortoiseshell cat that carries both male and female chromosomes as a result of fusion between the brother and sister embryos during fetal development. Another example is the parasitic chimerism that occurs naturally in the lifecycle of the leftvent fish. The immature male leftvent attaches itself to a female fish, and fuses its body to that of the female, and a chimera is thus formed. The male then loses most of its organs and focuses on the development of the testes instead, thereby reaching sexual maturity. The female nourishes the male via their interconnected circulatory systems.

Chimerism in the human species has already popped up in the form of popular culture. Some examples are the novel Next, written by Michael Crichton (of Jurassic Park), and popular TV shows such as CSI and House that featured plots with chimerism. The public adores such intense “scientific” plotlines, but how realistic are they? The truth is, even though human chimerism is quite rare, there have already been thirty to forty cases of human chimerism documented as of 2003.

There are two specific types of chimerism that can occur in humans. The first type is microchimerism, where only a small portion of the body has a distinct cell line from the rest of the body. This typically arises when foreign cells have stabilized inside a host. These foreign cells may originate from the maternal-fetal exchange during pregnancy. The fetus may pass on its stem and progenitor cells to the mother via the placenta, and these cells, because they are undifferentiated, may be able to survive and proliferate in the maternal system. Maternal stem cells may also be transferred to the fetus in the same way. A related type of microchimerism may occur between twins as well. Indirect transfer of cell material (for example, blood transfusions and transplants) between two individuals may also produce microchimerism in the recipient.

The second type is called tetragametic chimerism. This occurs when two separate ova are fertilized by two sperm and produce two zygotes. When these zygotes fuse, it forms an organism that has two distinct cell lines, and the resulting fetus may be male, female or hermaphroditic. It usually occurs with fraternal (or dizygotic) twins, and often forms from zygotes produced from artificial in vitro insemination. As a result, the individual may have “populations” of cells: one set of DNA may appear in his or her liver and another set may appear in his or her lung.

Even though there are two or more different sets of DNA in human chimeras, it may or may not be manifested as physical abnormalities. It may appear as phenotypic differences in eye colours, differential hair growth and colouring, “checkerboard” skin patterns, or missing or extraneous sexual organs. In 1998, at the University of Edinburgh, doctors examined a man who had complaints about an undescended left testicle. When they examined him, they were shocked to find an ovary and a fallopian tube in the male patient!

Most human chimeras, however, are not even aware of their conditions, because many of them appear completely normal. The most famous cases of chimerism to date are the linked cases of Lydia Fairchild and Karen Keegan. Fairchild was pregnant with her third child when she separated with her partner, James Townsend. In order to obtain state welfare, she had to prove that she was the biological mother of her two born children. It was discovered, through DNA testing, that it was impossible that she was the biological mother of her two children because she bore no genetic similarity to them whatsoever. A case of welfare fraud ensued because the prosecutors believed the DNA results to be irrefutable. Even the testimony of Dr. Leonard Dreisbach, the obstetrician who had helped Fairchild give birth, did little to persuade the court in Fairchild’s favor. The judge, perplexed by seemingly conflicting evidence, ordered that the third child, when born, to be tested as well. Surprisingly, the third child also showed no genetic similarities as well.

Fortunately for Fairchild, Karen Keegan also had similar experiences. Keegan needed a kidney transplant, and DNA testing for a compatible match with her two eldest sons showed that she had no genetic similarities to them at all. However, the doctors who worked with Keegan were familiar with the concept of chimerism and suggested that Keegan undergo further testing. Testing of her brothers and husband proved that her sons were related to them. Subsequent sampling of her skin and hair proved to be futile, but eventually matching DNA was found in her thyroid gland. It was the publication of this case, in the New England Journal of Medicine, which offered new insight on the case of Lydia Fairchild. Fairchild was found later on to be a chimera, with the second set of DNA found from her cervical smear. It was concluded that both Keegan and Fairchild were tetragametic chimeras.

These cases challenge the blind faith which the scientific community places on the irrefutability of DNA testing. Forensic science cannot rely on DNA testing as the sole source of evidence, as it has done previously, as the criminal or victim may be a chimera. From the previous cases mentioned, current maternity and paternity testing methods will have to be re-evaluated. The greatest impact of chimerism, however, was made on the scientific-medical field, because it asks two leading questions: how does chimerism affect individuals, and what can be accomplished through chimerism?

Current research indicates two opposing views of chimerism in humans. One hypothesis is that the presence of foreign cells in the body during development (as in microchimerism) creates an abnormal environment that causes growth of various types of autoimmune diseases, such as Type 1 diabetes, scleroderma, and lupus. The other hypothesis is that these foreign cells actually facilitate the body’s ability to self-repair. Since chimeras are able to receive organs from individuals with either sets of DNA, some research studies are looking into using chimeras as a basis for improving the existing organ transplant process that has lower risks of organ rejection. Chimeras have a great immunological tolerance to at least two different cell lines. All these theories have great potential for improving medicine drastically in the future.

Most promise of future chimera studies, however, lies in the area of genetic engineering of cells. Chimeras can be artificially produced by physically mixing two zygotes together. Animal chimeras have already been produced – a “geep” chimera comprised of goat and sheep cells, and a rat-mouse chimera. While true genomic chimeras of human and animal origin have yet to be produced, some surprising studies to date are those that have succeeded in producing hybrid embryos, or cybrids.

In 2003, Chinese scientists at the Shanghai Second Medical University were successful in their attempts to produce stem cells through the merging of rabbit eggs and human skin cells. This human-animal hybrid was supposedly the first of its kind to be produced. They were promptly destroyed after a few days to allow for the extraction of the live stem cells. The overall process can be simplified into the following: the genetic material is removed from an animal ovum, and then human DNA is inserted, thus producing a single zygote that has animal-human origins. This process could potentially be the cheapest way to produce human stem cells for research purposes.

Yet another controversial study had been conducted by Stanford University of California. A group of scientists from the Institute of Cancer/Stem Cell Biology have already successfully created mice with brains that have one percent human cells. Their next goal is to create mice with one hundred percent human brains. Their goal is to study Parkinson’s and Alzheimer’s diseases through analysis of the pattern of brain growth. Opponents of such projects note that problems may arise if the human cells were ever able to migrate and create human reproductive organs. Imagine the horrors if two such mice were able to procreate – it would result in a human embryo, not an animal one. The mice would become parents of a human being!

Fortunately, the only existing projects to date are much less controversial since the cybrids are still mostly human. Do scientists cross the fine line that distinguishes the difference between animals and humans if they produce chimeras that will have a substantial percentage of both human and animal DNA? Does it breach any ethical or moral boundaries? Who will define the boundaries within which these studies are to be conducted? Should a true human-animal chimera ever be created?

Some of those questions can already be answered. The Canadian government has issued the Assisted Human Reproduction Act that prohibits specifically the production of a chimera, as stated in Section 5: “No person shall knowingly . . . create a chimera, or transplant a chimera into either a human being or a non-human life form” or “…create a hybrid for the purpose of reproduction, or transplant a hybrid into either a human being or a non-human life form.” However, the US and the UK have yet to issue any strict regulations regarding chimera research. Even with restrictions, it would be difficult to monitor whether regulations are kept if research is being conducted illegally.

Just how far can this type of research go? Heart transplants already use porcine valves; researchers have already produced pigs with human blood and sheep with partially human organs. With the lack of regulation on chimera production, the possibilities are endless. Like any other technology of the past, chimera technology proves to be a double-edged sword that can offer great benefit and also pose great harm to humanity. How far it advances depends on society. Perhaps one day we may encounter an animal that functions and thinks like a human …Animal Farm, anyone?

About Vivienne Lam

Vivienne Lam is a S/A/F, 24, enjoys looking at DNA bands under UV light and taking strolls along the corridors in the COPP Building perusing fellow Biochemistry alumni. On a more serious note, she is a Masters candidate in Botany, currently working on various podocarps and mycoheterotrophs in her research. She hopes to see, in the future, a genetically modified mango that is at least 80% mango fruit instead of 80% mango seed.