For the first time, Chinese and foreign scientists have constructed a better research model of human-monkey chimeric embryos and it is more controversial.
For the first time, Chinese and foreign scientists constructed embryos composed of human cells and non-human primate cells, and the experiment ended after these embryos survived in vitro for 19 days.
On April 15th, the top academic journal Cell published online a study jointly completed by the State Key Laboratory of Nonhuman Primate Biomedicine jointly established by the province and the Ministry/Institute of Primate Translational Medicine of Kunming University of Science and Technology and Salk Institute of Biology of the United States. Researchers injected human stem cells into cynomolgus monkey embryos and were able to cultivate chimeric embryos for a long time, providing a new perspective for developmental biology and evolution. At the same time, the study also triggered a wide range of ethical discussions.
The correspondent authors of this study are Professor Juan Carlos Izpisua Belmonte of Salk Institute of Biology in the United States and researcher Wu Jun (now assistant professor of Southwest Medical Center of the University of Texas), Professor Tan Tao, Professor Niu Yuyu and Academician Ji Weizhi of Kunming University of Science and Technology Institute of Primate Translational Medicine.
"Because we can’t carry out certain types of experiments on human bodies, there must be better models to study and understand human biology and diseases more accurately." Izpisua Belmonte said, "An important goal of experimental biology is to develop a model system to study human diseases under living conditions."
The press release of the Primate Translational Medicine Research Institute of Kunming University of Science and Technology wrote that the study answered basic scientific questions such as how heterogeneous chimeric cells interact and how to adjust the differences of development procedures, and provided new ideas for solving the problems of low efficiency of heterogeneous chimerism, which was of guiding significance for organ regeneration research.
Chimera between human cells and macaque cells
The scientific research on interspecific chimera has already begun. In the 1970s, interspecific chimeras of mammals began to appear, which were first produced in rodents and used to study the early development process.
In recent years, heterogeneous chimerism in large animals has also made a series of breakthrough progress. For example, a study published in Cell in January 2017 by Izpisua Belmonte and Wu Jun showed that they realized the chimerism of human stem cells in early embryos of pigs. In December 2019, a study published in Protein & Cell magazine by Academician Zhou Qi, Li Wei and Haitang from the Institute of Zoology, Chinese Academy of Sciences and the Innovation Institute of Stem Cell and Regenerative Medicine, China Academy of Sciences showed that they got the cynomolgus monkey-pig chimera for the first time, creating the world’s first "pig-monkey hybrid" creature and died within one week after birth. In December, 2020, the research published in Cell-Stem Cell by Wu Jun and others also showed that they produced the world’s first chimeric embryo of horse and mouse.
These studies have brought a new direction for the further study of chimera, such as how the evolutionary differences between different species affect each other in chimera, the interaction, communication and competition between cells and so on.
On October 31st, 2019, Tan Tao, Niu Yuyu and Ji Weizhi collaborated with Salk Institute of Biology and Shenzhen Huada Institute of Life Sciences to publish their research results online in Science magazine. The research team realized the culture of cynomolgus monkey embryos in vitro for 20 days, and the cultured embryos showed highly consistent morphological and gene expression characteristics with the embryos developed in vivo.
In this latest study, the researchers first isolated fertilized eggs from monkeys, and after growing them in Petri dishes for 6 days, 132 monkey embryos were injected with human expanded pluripotent stem cells (hEPS), which can grow into different cell types inside and outside the embryos.
Through immunofluorescence research, that is, the antibody binds to the fluorescently labeled stem cells, the research team observed that human stem cells survived, and compared with previous experiments in pig tissues, the relative efficiency of integration was higher. Overall, this study evaluated the chimeric ability of human expanded pluripotent stem cells (hEPS) in cynomolgus monkeys. Izpisua Belmonte said, "Chimeras of human and nonhuman primates are closer to humans than all other species on the evolutionary time axis, which can help us better understand whether evolution imposes barriers on chimera generations and whether we can overcome these barriers."
Scientific research needs and ethical challenges
Why do you want to do this kind of research? Wu Jun said in an interview with reporters that human organ transplantation and exploring the unknown mysteries in developmental biology are in urgent need of such research.
From the perspective of organ transplantation, the World Health Organization (WHO) estimates that the 130,000 organ transplants performed each year only account for 10% of the actual demand, and the available organs are extremely short. Researchers hope that cultivating human cells in pig tissues similar in size, physiology and anatomical structure to human organs can alleviate this problem.
Wu Jun told reporters that human organ transplantation is a very important development of modern medicine. By removing diseased and necrotic organs and replacing them with healthy and energetic organs, patients with life-threatening diseases can be revived.
Wu Jun mentioned at that time, "One of my ideals is to obtain functional and independent human organs through stem cell technology, so as to provide legal and effective organ sources for patients who need organ transplantation. Of course, this is only the ultimate goal. This road still seems to have a long way to go. Our research only opens a door for these futures. More research needs the joint efforts of scientific researchers from all over the world. "
Wu Jun and others had previously integrated human cells into early pig tissues, which marked the first step in producing transplantable human organs from large animals. However, the proportion of human cells is quite low, which may be due to the huge evolutionary distance between the two species (90 million years), so the research team began to study a closer species — — Chimera formation in rhesus monkeys. Izpisua Belmonte said so vividly, "Human cells in pig tissues are similar to cells trying to find common ground between Chinese and French, while human cells in macaques are more like two closely related languages, such as Spanish and French."
Although these chimeras with macaques will not be used for human organ transplantation, they reveal valuable information about how human cells develop and integrate and how cells of different species communicate.
In the long run, researchers not only hope to use chimeras to study early human development and design disease models, but also hope to find new methods to screen new drugs and produce transplantable cells, tissues or organs.
These studies provide a new platform for studying how specific diseases occur. For example, a specific gene that may be related to a certain cancer can be modified in human cells. Then, using these engineering cells to observe the progress of diseases in the chimeric model may show more applicable results than the typical animal model, in which diseases may form different processes.
Chimeric disease models can also be used to test the efficacy of pharmaceutical compounds and obtain results that can better reflect human reactions. Chimera can also provide unique insights for aging research. Izpisua Belmonte said that researchers do not know whether organs are aging at the same speed, or whether one organ drives all other organs to age and acts as the master switch of the aging process. For example, by using chimerism to grow organs of ordinary mice in long-lived species (such as naked moles), scientists can begin to explore which organs may be the key to aging and which signals are involved in their survival. Of course, it can’t be ignored that the review articles published in the same period of Cell and the news articles on the website of Nature all pay attention to the potential ethical considerations of constructing human/non-human primate chimeras.
"In this field, there are more and more reasonable experiments, using the silver beast as the source of organs and tissues." Alfonso Martinez Arias, a developmental biologist in universitat pompeu fabra, Spain, told Nature that experiments with domestic animals such as pigs and cattle are "more promising and will not challenge ethical boundaries". He said, "there is still a complete field of organ-like, and there is hope to get rid of animal research."
Combining human cells with closely related primate embryos also raises questions about the status and identity of chimeras. Insoo Hyun, a bioethicist in case western reserve university, USA, said, "Some people may think that you have created a morally ambiguous entity there." He also said that the research team of this latest study completely followed the existing guidelines. Nature also pointed out that if these human-monkey mixed embryos are implanted into animals, they will eventually develop into some kind of creature or even be born, then the ethical problems they face are obviously much more complicated.