Researchers have created chimeric human-monkey embryos from human stem cells and primate embryos. A new technology enabled them to keep the chimeric embryos alive in the Petri dish for up to 19 days without transplanting them into a uterus. The researchers examined the communication between human and monkey cells within the embryo. The advances in chimeric research could help in the future to gain new insights into developmental biology and evolution. In addition, chimeras with a human component could be used as model organisms for research into diseases or for drug tests. They could even be used as a source for donor organs. However, all of these approaches raise important ethical questions.
In order to research human diseases or to test drugs for use in humans, researchers usually use animal models. In many cases, however, transferability is questionable. When looking for reliable alternatives, some research teams are looking, among other things, with the extent to which human stem cells can multiply in other species and are accessible for further investigation. So far, chimera research is at an early stage. Chimeras have existed between rodents, particularly mice and rats, since the 1970s. With the aim of growing donor organs, attempts have been made to grow human organs in pigs. But apart from ethical concerns, it has so far not been possible to create chimeras that contain a relevant number of human cells.
Chimeras as model organisms?
A team led by Tao Tan from the Kunming University of Science and Technology in China has now grown chimeric embryos from humans and monkeys for the first time. “Since we cannot conduct certain types of experiments on humans, it is important that we have better models to better study and understand human biology and disease,” says co-author Juan Carlos Izpisua Belmonte of the Salk Institute for Biological Sciences in the USA. “An important goal of experimental biology is the development of model systems that make it possible to study human diseases under in vivo conditions.”
To create the chimeras, the researchers cultivated fertilized egg cells from macaques. After six days, they injected human pluripotent stem cells into the resulting blastocysts. In order to be able to identify the human cells in further examinations, they marked them with a fluorescent protein. One day after the injection, they were able to detect human cells in all 132 embryos. For ethical reasons, they did not implant the chimeric embryos in a uterus, but instead allowed them to grow in the Petri dish. This was made possible by a newly developed technology that enables monkey embryos to be kept alive outside the body for longer periods of time – up to 20 days.
Interaction between human and monkey cells in the embryo
In the course of the study, the survival rate of the embryos decreased sharply. On day ten, 103 chimeric embryos were still alive, on day 19 only three. In addition, the human cells only developed further in some of the survivors. On the ninth day after fertilization, the researchers found human cells in around half of the embryos, and on day 13 in around one in three. Compared to control non-chimeric embryos grown in the same manner, the chimeras developed somewhat more slowly. The researchers also observed that the human cells tended to form their own groups within the organism and separate from the monkey cells.
“In the past, the creation of human-animal chimeras suffered from the poor efficiency and integration of human cells into the host species,” says Izpisua Belmonte. Attempts to breed human and mouse or human and pig chimeras have probably failed because the species are evolutionarily too far apart and the cells in the chimeric embryos therefore have too different a developmental rhythm. The current experiment with humans and macaques was by far the most successful so far. “The creation of a chimera between a human and a non-human primate, a species that is more closely related to humans along the evolutionary timeline than any previously used species, gives us a better insight into the extent to which there are evolutionary barriers to the creation of There are chimeras and whether there are means by which we can overcome them, ”says Izpisua Belmonte.
Ethical discourse required
To identify such possible evolutionary barriers, the researchers analyzed and compared the transcriptome of the human and monkey cells in the chimeras. This provides information about which genes are active in the cells. In addition, they examined the communication between the cells. “With these analyzes, we identified several communication channels that were either new or reinforced in the chimeric cells,” explains Izpisua Belmonte. “If we understand which pathways are involved in the communication of the chimeric cells, we can possibly improve this communication and increase the efficiency of chimerism in a host species that is evolutionarily further removed from humans.” the option of growing human organs in pigs and making them available for transplants.
Apart from the scientific hurdles on this path, ethical considerations also play a major role in all research on human-animal chimeras. In a comment on the study, also published in the journal Cell, Henry Greenly of Stanford University and Nita Farahany of Duke University in Durham point out that public discourse is crucial. “Surprising the public with unexpected and often troubling research results can have serious consequences for this research and these researchers, but also for public confidence in science in general,” they write. It would be even more complicated if, unlike in this experiment, the embryos were implanted in a uterus and had the opportunity to grow. This is currently not a research goal – at least with regard to primates – and it is unclear to what extent it would be possible at all. “And yet such future experiments are at least plausible now,” said Greenly and Farahany. “We have to start thinking about this possibility.”
Source: Tao Tan (Kunming University of Science and Technology, Yunnan, China) et al., Cell, doi: 10.1016 / j.cell.2021.03.020