Hello everyone and welcome to this week's blog post. In this article, we will be discussing human chimeras. I will first describe what a chimera is and how they form, before covering some of their uses in medicine.
A chimera is an organism which is made up of cells from two or more genotypes. Essentially, this means that they have two or more sets of DNA as their genetic material comes from two or more different individuals. These organisms are called chimeras, after the Chimera in Greek mythology (a fire-breathing, three-headed monster which had the body and head of a lion, the head of a goat and a snake as its tail).
A chimera is when two zygotes (an egg which has been fertilised by a sperm) fuse together, thus creating a structure which contains two sets of chromosomes. As the organism develops, different tissues and organs in the body receive their genetic information from either one or both sets of chromosomes. For example, the eyes may receive genetic information from one zygote, while the blood cells may receive their genetic information from both so that the organism has red blood cells of two different blood types.
This can result in an organism having different coloured eyes, different parts of the skin being different colours and, in some cases, possessing both male and female reproductive organs. Despite that, in most cases, chimeras can not be distinguished by their appearance. Instead, they are only detected by change, due to tests for organ suitability or blood typing.
Chimeras can also be formed naturally later during pregnancy. One way this occurs is when one of the fetuses dies early on during pregnancy and is absorbed by the other. As this occurs during the early stages of pregnancy, many of the cells are pluripotent stem cells. Consequently, when they are absorbed by the other twin, they can divide and differentiate to form complete tissues.
In addition, chimeras can also be formed when connections form between the placentas of two twins during pregnancy. This causes stem cells to be transferred between the two individuals, resulting in one or both of the individuals becoming chimeras.
Chimeras resulting from the genetic exchange between fetuses in the womb is quite rare. Nevertheless, microchimerism is much more common. Microchimerism is where are very small proportion of the cells of an organism are from another organism. According to research carried out by a team of pathologists in 2015, microchimerism occurs in almost all pregnancies (when fetal cells detach themselves from the foetus and travel to different organs in the mother).
In this study, the researchers found male DNA inside the brains of 26 women who'd had or were carrying male children, which proved that microchimerism occurred in humans, Furthermore, a separate study published in 2012 in the PLoS ONE journal found that male DNA was found in the brain of a 101-year-old woman, which suggests that microchimerism can last for many decades.
Medical procedures performed today can also form human chimeras - specifically bone marrow transplants. This is called artificial chimerism. While blood transfusions temporarily replace some of a patient's blood with cells of a different genome, bone marrow transplants will cause the patient to produce genetically different blood cells for life. This is because blood cells are formed from stem cells found in the bone marrow. Consequently, as blood cells have a short life-span so are constantly being replaced, it is possible for all of someone's blood cells to have different genes to the genes in the rest of their body.
The symptoms of human chimerism differ from person to person. These symptoms include having multiple blood types, having both female ovaries and male testes, or having gonads which have tissue from both ovaries and testes (ovotestes). Additionally, some also have different-coloured eyes or different pigment colours on different parts of their skin. Chimerism can also cause certain autoimmune diseases, which need to be treated.
Chimera viruses (viruses which contain fragments of DNA from different organisms fused together) can be used in the treatment of human diseases. For example, there is a group of herpesviruses (read my blog post about them here) which can infect humans for life and sometimes cause cancer. One of these viruses is the Kaposi Sarcoma herpesvirus, which causes Kaposi's sarcoma (a rare type of cancer).
One of the weaknesses of this cancer is that it can only grow if the virus stays inside the human - if the virus is eliminated, then the cancer stops spreading. A research team from the Institute of Molecular Medicine in Lisbon discovered that, if a specific protein (called LANA) was removed from the virus, this prevented it from causing cancer and maintaining infection. They then proceeded to produce a chimera virus (a mouse virus fused with a human viral gene that inhibits this protein) that could be used in the future to cure this form of cancer.
Scientists have also experimented with created hybrid embryos, which contain both human and animal cells. Scientists have been able to create rat/mouse chimeras since around 2019 when a mouse was formed with pancreatic tissue from a rat. This was achieved by using CRISPR-Cas9 technology (read my blog post about it here) to delete the genes that coded for the pancreas from the fertilised mouse egg cells. When the embryo had developed further, they then introduced rat stem cells to see whether these cells could grow and form the missing organ.
This experiment did not have the intended effect - instead of growing a pancreas, the rat stem cells actually produced a gall bladder, even though rats have not had a gall bladder for millions of years (thus suggesting that rats have always maintained the ability to grow gall bladders, but this ability is inactivated by other genes).
The researchers then increased the complexity of chimeras by attempting to combine human and pig cells to produce a human-pig chimera. This was much harder than producing the rat-mice chimeras as pigs and humans are much more evolutionary separated so have very different anatomies and don't share as many genes.
Once the researchers injected human stem cells into pig embryos, some of these cells survived and formed human-pig chimeras. To avoid ethical concerns about the creation of mature chimeras, these embryos were only kept alive for 3-4 weeks after fertilisation.
The next step is to try to grow complete human organs inside pigs. This has the potential to revolutionise medical treatment as it would drastically increase the number of organs available transplants, thus decreasing waiting times and reducing the number of people who die while waiting for a transplant.
Unfortunately, we are still a long way from this becoming a reality. Despite the decades of research into creating human-animal chimeras, there is so much that scientists do not currently understand about the early development of cells, that it is currently not possible to grow specific organs.
In addition, there are many ethical concerns about the creation of human-animal chimeras. For example, some worry that human-animal chimeras could gain human-like consciousness. This would make its creation and any research using the organism unethical. Further, there are also concerns about the unethical treatment of animals in this type of research. Consequently, any research which brings human-animal hybrid embryos to term in the United States is banned.
Nonetheless, in the short term, these chimeras help scientists gain more knowledge about early human development, especially about how human stem cells differentiate and grow to form tissues. In addition, some believe that these chimeras may also provide a realistic drug-testing platform which doesn't require humans to be at risk.
Moreover, ethical guidelines about the creation of human-animal chimeras are changing. Indeed, in 2019, Japan changed its guidelines to allow embryos containing both animal and human cells to be carried to term. This was partly based on evidence that human stem cells in human-animal chimeras are unable to affect the brain or other neural passages. As a result, research conducted in Japan may pave the way for human-animal chimeras to be allowed in other countries as well.
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