An international team led by the Spanish Juan Carlos Izpisúa generates chimeric human-monkey embryos


In biology, the term chimera refers to those animals generated by mixing embryonic cells of two different individuals, of the same or different species. In recent years, the formation of interspecies chimeras has been a promising strategy for various applications of regenerative medicine, including the generation of organs and tissues for transplants.

Now scientists from China and the US have injected human stem cells in primate embryos and have been able to cultivate these chimeric embryos for a considerable period of time: up to 20 days. The job, published in the magazine Cell, has implications for the development of new models of human biology and disease.

"This type of research is important to develop knowledge about cell communication and biological development during embryogenesis and evolution, as well as for a variety of research applications and regenerative medicine," he explains to SINC Juan Carlos Izpisúa Belmonte, researcher of the Salk Institute of Biological Sciences and lead author of the study.

These studies could lead to the culture of replacement human tissues, such as those of the heart and kidneys. Also test candidate drugs for human diseases with more precision than animal models, or understand aging

Juan Carlos Izpisúa Belmonte

The Spanish specialist emphasizes the importance of this type of study: "As we cannot carry out certain types of experiments in humans, it is essential that we have better models to study and understand human diseases with greater precision under conditions. in vivo".

"For example, it could one day lead to the possibility of growing surrogate human tissues, such as those of the heart and kidneys. It could also help test candidate drugs for human disease with more precision than traditional animal models, or understand processes such as the aging, the main risk factor for Alzheimer's, heart disease or cancer, "he adds.

In order to Josep M. Canals, expert in stem cells and regenerative medicine from the University of Barcelona (UBNeuro) who has not participated in the Izpisúa study, "the model used of human-monkey chimeras shows differences in the early stages of development between these two species. This type of approach opens up a fascinating field of research that can explain the differences and specificities of the beginning of human development ".

But, despite their relevance, "these models will rarely provide therapeutic solutions through the transplantation of organs developed by these chimeras, although the authors point to this possibility," points out SINC Canals.

The first step was taken in 2019

The breakthrough that made the current study possible came in 2019, when Izpisúa Belmonte's team -In collaboration with Weizhi Ji, of the Kunming University of Science and Technology, in Yunnan (China), also the author of the new work— generated a technology that allowed macaque embryos remain alive and grow outside the body for a long period of time, but that "did not include chimeras, that is, cells of more than one species," emphasizes the Spanish researcher.

However, in the current study, each of the monkey embryos (which were in the blastocyst phase, that is, with six days of development) 25 human cells. The cells were derived from an induced pluripotent cell line known as extended pluripotent stem cells, which have the potential to contribute to both embryonic and extra-embryonic tissues.

After one day, human cells were detected in 132 embryos. At 10 days, 103 of the chimeric embryos were still developing. Survival soon began to decline and, on the 19th, only three chimeras were still alive. However, the authors note that the percentage of human cells in the embryos remained high throughout the time they continued to grow.

"Historically, the generation of chimeras between humans and animals has endured a low efficiency and integration of human cells in the host species ", states Izpisúa Belmonte.

Each of the monkey embryos was injected with 25 human cells. After one day, human cells were detected in 132 embryos. At 10 days, 103 of the chimeric embryos were still developing. On the 19th, only three chimeras were still alive

"Creating a chimera between a human and a non-human primate - a species more closely related to us than all previously used species, such as the mouse or the pig - will provide the best understanding of whether there are evolutionary barriers to evolution. generation of these chimeras and if there is any means to overcome them, "he continues.

However, it must be taken into account that "all the experiments in this article have been carried out in the laboratory and no implantation has been carried out in animals for tissue or organ development beyond the early embryonic stages. Therefore, no it is known if this would be scientifically possible and if these chimeras could develop to more complex stages ", Canals clarifies.

Of course, he insists, "the differences that are shown on a cellular scale between the two species suggest that a development to later stages would not be viable. And the implantation of these pre-embryos in uteri that nowadays the legislation does not allow, would have ethical considerations -very relevant scientists ".

The ethical dilemmas of this technique

In addition to these purely technical concepts, this work is not without its ethical issues. In a related article, also published in the magazine Cell, the possible considerations on the generation of chimeras of human and non-human primates are exposed.

"Medicine needs better models to understand human biology and disease and to conduct experiments on them that would be ethically problematic in humans," the authors write. "But as we develop new living models that are closer to humans, we get closer to the same ethical problems that we try to avoid."

In addition to technical problems, this work is not without ethical dilemmas. In a related article, also published in Cell, the possible considerations on the generation of chimeras of human and non-human primates are exposed

According to Canals, "as in all work carried out with human pluripotent stem cells, ethical considerations are determined by their potential to generate a human being when it develops in the context of gestation within the uterus of a woman."

"In this article they go one step further, mixing human cells with monkey pre-embryos. But in no case are these pre-embryos implanted in the uterus of pregnant monkeys to take development beyond pure laboratory research: the studies are limited to the field of research ", he specifies.

Of course, it must be borne in mind that this is the first article that shows the possibility of making human-monkey chimeras and, therefore, opens the door to possible studies that go further in the development of chimeras in countries where controls research ethics are not so strict.

"If implantation studies of these chimeras are carried out in pregnant uteri, the ethical complications would be very serious due to the generation of possible new primate species that could have unexpected and uncontrollable consequences", predicts Canals.

People are concerned about chimera research, which is understandable. It is our responsibility as scientists to follow all current ethical, legal and social standards. All our work is always governed by these guidelines

Juan Carlos Izpisúa Belmonte

Izpisúa Belmonte defends his work in this way: "Before starting consultations and ethical reviews were carried out both at the institutional level and through outreach to unaffiliated bioethicists with experience in state and national policies in this area of ​​research. This process helped guide our experiments, which focused entirely on chimeric embryos. ex vivo".

"People are concerned about chimera research, which is understandable. It is our responsibility as scientists to work reflectively, following all current ethical, legal and social standards. All of our work is always governed by these guidelines and will be subject to the review and approval of all relevant committees", he concludes.

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