PART 2

CAUSATION:

One recipe for chimerism begins during pregnancy with twins–or triplets, octuplets, etc. There is a genuine medical syndrome called “vanishing twin syndrome”, where one of the embryos dies in utero, and the other absorbs its cells and becomes a divided. That ovum still has its original genes, but they become be mixed with those of its less fortunate womb-mate. This  only occurs in  fraternal twins, since identical twins already share the exact same DNA.

The syndrome is caused by irregularities in the disappearing twin’s DNA that prevent it from fully developing. These irregularities in that baby’s genes cannot be prevented, controlled, or even known about until later life; and many times, they are formed during conception. The survival of the viable co-twin may be compromised. Survival chances of a co-twin in vanishing baby syndrome are great if the failure of the twin happens in the first trimester of pregnancy. The mother experiences no health problems but may only visually have some mild vaginal bleeding as a sign that one of the embryos has been lost. The earlier the loss of the vanishing fetus during gestation, the more likely no one will notice; and the chances of survival of both mother and the other fetus are good.

In some cases, all the blood cells in a person who received a bone marrow transplant will match the DNA of their donor. But–in other cases–the recipient may have a mix of both their own blood cells and donor ones, A blood transfusion will also temporarily give a person cells from someone else, but in a bone marrow transplant, the new blood cells are permanent. Even if both twins survive to term, it is possible for their cells to mingle.

One of the more common outcome types is blood chimerism. Blood cells that form in the bone marrow are sturdy and mobile. They will more than likely survive while traveling through the placenta in the exchange from one of the chimeric twins to the other. Statistically, about 8% of fraternal twins end up with blood chimerism. In the case of triplets, the chance for blood chimerism rises up to 21%.

Even non-twins can become a chimera. In that instance of vanishing twin syndrome, all vestiges of the other twin are absorbed and disappear.  In 5% of pregnancies, multiple embryos occur which could lead to a twin birth, but not all the time. Of those, 25% of the time one may fail to survive a full 9 months. In that case, the embryo is sometimes taken directly back up into the mother’s tissues; or, that twin can combine with its twin. Either way, the surviving baby becomes a chimera. After examining rates of numerous embryos and vanishing twin syndrome, scientists estimate that perhaps 1 in 80 pregnancies may result in a vanishing twin pregnancy.

A person can also become a chimera if they undergo a bone marrow transplant. During such transplants, which can be used for example to treat leukemia, a person will have their own bone marrow destroyed and replaced with bone marrow from another person. Bone marrow contains stem cells that develop into red blood cells. This means that a person with a bone marrow transplant will have blood cells, for the rest of his/her life, that are genetically identical to those of the donor and are not genetically the same as the other cells in their own body.

The patient’s diseased bone marrow is replaced with a healthy donor’s marrow. The new bone marrow produces new blood cells. The recipient then has blood that is made from the marrow of the donor. The new blood is being made by someone else’s DNA—new DNA.  Even the blood type may change to the donor’s.

In cases of organ transplant, the organ from the healthy donor replaces the damaged or diseased tissue in the recipient. This transplanting of the new organ can make the recipient into a chimera. When placed into the recipient, the transplanted organ does not change and retains both the donor’s cells and his/her DNA. Then, the recipient has two different types of cells. Most of the body will have its original set of cells of the recipient with its original DNA. But, the new organ will have donor cells and DNA.

Documented cases of chimerism in humans like Fairchild and Keegan are presumably rare, but the actual incidence rate is unknown. Human chimerism is typically marked by certain characteristics, such as two distinct red blood cell lineages, two different colored eyes, patches of different colored or textured hair, patchy skin pigmentation, genital ambiguity, or autoimmune issues. Neither Fairchild nor Keegan exhibited those traits showing obvious signs of chimerism.

Indeed, most human chimeras are not even aware of their conditions, because many of them appear completely normal. Some researchers speculate that chimerism in humans occurs as often as instances of fraternal, or non-identical, twins. The rate of fraternal twins has been steadily increasing due to rising use of assisted reproductive technologies and fertility treatments.

More commonly, people may exhibit so-called microchimerism—when a small fraction of their cells are from someone else. For example, this can happen when a woman becomes pregnant, and a small number of cells from the fetus migrate into her blood and travel to different organs and remain there.  In some cases, fetal cells may stay in a woman’s body for years. The oldest woman to have fetal cells in her brain was 94 years old, suggesting that these cells can sometimes stay in the body for a lifetime.

Despite being unrecognized or asymptomatic, microchimerisms are not necessarily completely benign. Increased rates and amounts of cellular fetal microchimerisms are associated with several placental syndromes, including preeclampsia, fetal growth restriction, and potential implications in wound healing, autoimmunity, cancer, and possibly cardiovascular disease. Cells of fetal origin transferred to the mother and cellular maternal microchimerism and also transfer of maternally originating cells to the fetus. Because of this bidirectional transfer of cells, a woman may host cells of fetal origin from several pregnancies and even cells of maternal origin from her own mother. Furthermore, the same woman might host other cells transferred from her mother during fetal life, including cells possibly stemming from older siblings, a vanishing twin, or prior maternal termination of pregnancy. In addition, there can be  cells of neither fetal nor maternal origin stemming from maternal blood transfusion.

It is a tangled web that is now under active study. This new field represents an exciting new area of research on predictors and possibly mediators of long-term female health and disease. If chimerism is not diagnosed, there can be an occurrence of false negative DNA tests in trying to determine paternity.

For example, foreign DNA originating from the fetus during pregnancy may affect how well the woman tolerates the pregnancy. Excessive foreign DNA postpartum is associated with improved wound healing, suggesting a beneficial association. Excessive cffDNA during pregnancy is associated with spontaneous preterm labor, suggesting a detrimental association. Excessive cFMC in maternal tissue and/or circulation long term is associated with Hashimoto’s thyroiditis, systemic lupus erythematosus, Sjögren’s syndrome, and appears to be generally detrimental.

The first human fusion chimera was described in 1962 in a true hermaphrodite with one ovary and one ovotestis, and two different colored eyes, one brown and one hazel. In 1969, three researchers from the University of California, San Francisco, collected white blood cells from women pregnant with boys and found that some of those women had what appeared to be a Y chromosome. This controversial finding was confirmed by subsequent studies. Cells from the male fetuses were ending up circulating in the mother’s blood supply and vice versa.

In a 2012 study, researchers analyzed the brains of 59 women ages 32 to 101, after they had died. They found 63 % of these women had traces of male DNA from fetal cells in their brains. A 2015 study suggested that this happens in almost all pregnant women, at least temporarily. The researchers tested tissue samples from the kidneys, livers, spleens, lungs, hearts, and brains, of 26 women who tragically died while pregnant or within one month of giving birth. The study found that the women had fetal cells in all these tissues. The researchers knew that the cells were from the fetus, and not from the mother, because the cells contained a Y chromosome (found only in males) and the women had all been carrying sons. The  women’s own chromosomal makeup was XX, no Y.

Scientists have noted long ago the existence of naturally occurring chimeras, and these usually occur within the same species, examples include:  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; 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. It is hard to know what to say about that  poor leftvent male.

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. It is the most controversial area of chimera study and involves science, politics, legislation and law, and morality. 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.

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. In 2017, a human-pig chimera was reported to have been created with only 0.001% human cells, the balance being pig. The involved scientists stated that they hoped to use the technology to address the shortage of donor organs.

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. 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 ogan  transplantation as well as ethical concerns particularly concerning human brain development in primates, which is the primary ethical and legal concern about introducing human cells into other animals.

That possibility led to the introduction of The Human Chimera Prohibition Act on July 11, 2005. The bill died in Congress sometime in the next year. The author envisioned ethical issues that could as occur when the line blurred between humans and other animals. The bill was killed because the legislators believed that blurring of lines would eventually show disrespect for human dignity. The final claim brought up in The Human Chimera Prohibition Act debates was that there were an increasing amount of zoonotic diseases, and that the creation of human-animal chimeras might allow these diseases to reach humans.

The Human-Animal Chimera Prohibition Act of 2016, was introduced. It identified a human-animal chimera as having several possible means of creation, especially a nonhuman life form engineered such that it contained a human brain or a brain derived wholly or predominantly from human neural tissues. That would create the possibility of rendering the embryo’s membership in the species Homo sapiens uncertain and would dilute the distinctive attributes of humanity.

The bill intended to prohibit all 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. Proposed penalties for violations of this bill included 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.

A brilliant and thoughtful developmental biologist, Stuart Newman, applied for a patent on a human-animal chimera in 1997 as a challenge to the US Patent and Trademark Office and the US Congress, motivated by his moral and scientific opposition to the notion that living things can be patented at all. 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 his victory.

Those ethical and legal dilemmas notwithstanding, the questions still remain: how does chimerism affect individuals, what can be accomplished through chimerism, and how can it be safely studied?

Creating human cells and tissues in other animals relies on a cutting-edge fusion of technologies, including recent breakthroughs in stem-cell biology and gene-editing techniques. The methodology, machinery, and laboratories already exist. By modifying genes, scientists can now easily change the DNA in pig or sheep embryos so that they are genetically incapable of forming a specific tissue. Then–by adding stem cells from a person–they hope the human cells will take over the job of forming the missing organ, which could then be harvested from the animal for use in a transplant operation. Sounds great; how far should it be allowed to go? Stated another way, can we afford not to pursue such beneficial sources of transplant tissues and organs?

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. Another potential for chimera studies lies in 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 chimera comprised of goat and sheep cells, a rat-mouse chimera. 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. They were promptly destroyed after a few days to allow for the extraction of the live stem cells. This process could potentially be the cheapest way to produce human stem cells for research purposes.

Another controversial study had been conducted by Stanford University of California. A group of scientists 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 stated goal is to study Parkinson’s and Alzheimer’s diseases through analysis of the pattern of brain growth.

Opponents of such projects note that real problems may arise if the human cells were ever able to migrate and create human reproductive organs. It seems unimaginable, but also theoretically possible, that two such mice could procreate resulting in a human embryo, not an animal one. The mice would become parents of a human being. It would take more than King Solomon or a political legislature to solve that existential problem.

Fortunately, that worst case scenario has not yet happened. However, the machinery to make it  happen exists, and is not even terribly difficult. Even with restrictions, it would be difficult to monitor whether regulations are kept if research is being conducted illegally. 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—especially in the US and UK 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. Studies have led experts to conclude that chimerism is not the rarity they once thought it was. The rise of accessible genetic testing in recent years has shown that it is–as the Washington researchers write–“frequent and widely distributed.”

The world’s voters, humanists, ethicists, theologians, and legislators may yet have to deal with such a possibility. 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? That is perhaps the most important part of this mysterious piece of animal and human biology and society.