Chimeras: From Mythology to the Lab
In Greek mythology, the chimera is often described and depicted as a monster, as in this image, that represents impending disaster. While chimeras in Greek literature are fictional and symbolic, the concept of chimeras in science, simply defined as an organism made of cells from two organisms, are real, and they represent scientific progress and its potential to impact human health.
Scientists have been working with chimeras for decades to better understand mammalian biology and disease. That research primarily engineered mixed species of mice, but scientists have also developed human-mouse chimeras that have become a staple of infectious disease and cancer research.
More recently an international team of scientists reported engineering large animal chimeras using human induced pluripotent stem (hiPS) stem cells to produce chimeric pig embryo that contained human cells. The chimerism of human cells in a pig embryo demonstrated that this approach is applicable in a larger species. Significantly, this research could lead to new frontiers in regenerative medicine and advances such as improved systems for disease modeling and sources for human organs and tissues for transplant.
How does it work?
To develop these chimeric pigs, scientists injected precisely staged, uniquely-labeled hiPS cells into pig blastocysts and transplanted them into sows (female pigs). Scientists identified and tracked the rare human cells among the pig cells and, after 28 days of the 114-day gestation period, stopped the experiment to prevent embryos with potentially high numbers of human cells from developing a mature nervous system. The pig embryos were then analyzed for the presence of human cells.
Researchers found human cells were present in just 25 percent of the pigs, and within that group a low number of human cells were randomly and broadly distributed in many tissues. Most of the pigs that contained human cells were smaller than those without, suggesting that human cells inhibited normal development.
Where is the Science?
Chimeric research with pigs provides a pathway toward potentially engineering donor organs for humans. However, the above research demonstrated that the cells were randomly distributed throughout the tissue, never developing into organs made entirely of human cells. However, this potential problem may have a solution. A proof-of-principle demonstration from earlier experiments using rat-mouse chimeras showed that it is possible to direct chimeric cells to develop into a specific organ.
This concept is one that relies on functional cell replacement. Using CRISPR-Cas technology in the rat-mouse study, scientists deleted a key gene required for pancreas formation in mouse embryos and added rat cells, which still contained the pancreas-forming gene. Normally, in the absence of the pancreas-forming gene the mouse would not develop a pancreas and die, however in this study the rat cells functionally replaced the mouse cells, allowing the mice to survive. If this cell replacement approach is possible in pigs, it may be possible to develop organs largely or completely comprised of human cells.
What are the ethical concerns?
Human-animalchimera research is a sensitive but critical aspect of biomedical research that raises several ethical issues. The two most pressing involve the potential of large numbers of human cells forming the animal brain, providing human qualities to the animal, and the incorporation of human cells into the germline, allowing animals to pass on human genes to progeny. These issues have led the International Society for Stem Cell Research (ISSCR) and other institutions to support rigorous review by a panel of experts that provide input on the conduct of the research, the ethical implications, and animal welfare, among other issues. The ISSCR, recognizing the valuable insights into human biology and disease that this research provides, addressed these issues in an advisory report, and in its 2016 Guidelines for Clinical Research and Translation.
What is the potential?
This research provides a foundation for future study into the potential of using human-pig chimeras to develop human organs.
Scientists and physicians have studied pig-to-human transplants for more than a decade, as they search for solutions to the world-wide organ shortage. Several countries have waiting lists for donor organs, but the need far exceeds the availability. In practice, pig tissues such as heart valves and islet cells have been transplanted into humans. But there are risks: the tissue could be rejected by the recipient; and to a lesser extent, zoonotic viruses (from one species to another) could be transferred to the recipient; or worse, through the recipient to others throughout the population.
Contrary to the mythological chimeras that represent danger, scientifically engineered chimeras hold great promise for the many people around the world who suffer from organ failure and disease. In years to come, organs developed through this research could extend the lives and enhance the quality of life for millions.