Human stem cell research has taken a step forward.
On April 15th, a paper published in the authoritative journal "Cell" caused a sensation in the scientific community. This article was entitled "Chimeric contribution of human extended pluripotent stem cells to monkey embryos." pluripotent stem cells to monkey embryos ex vivo). The paper stated that the research team injected human stem cells into the embryos of non-human primate cynomolgus monkeys for the first time, and the proportion of human cells reached expectations.
Human-monkey chimeric embryos survived for nearly 20 days.
Chimeric embryos are to allow cells from different species to survive in the same embryo.
"Science" magazine believes that by introducing human stem cells into the embryos of other animals, people can one day create new hearts and kidneys, saving patients who need to receive transplants.
"The research of chimeric gene technology in this kind of embryos can implant some specific human genes into the embryonic genes of animals, thereby providing in vitro models for the research and development of drugs, vaccines, reagents, etc., which is of positive significance for disease research." Zhu Tongyu, director of the Shanghai Key Laboratory of Organ Transplantation and deputy dean of Zhongshan Hospital affiliated to Fudan University, told a reporter from China Business News.
But ethical challenges also come with breakthroughs in science and technology.
While this groundbreaking research has attracted great attention from the scientific community, it has also received controversy from the public and academic circles.
This research was jointly established by the Institute of Primate Translational Medicine of Kunming University of Science and Technology and the provincial and ministerial non-human primate biomedical state key laboratory academician Ji Weizhi team, Tan Tao, Niu Yuyu, Dai Shaoxing research group and the United States Salk Biological Research It was completed by Juan Carlos Izpisa Belmonte and Wu Jun from the University of Texas Southwestern Medical Center.
In this latest study, researchers cultured cynomolgus monkey fertilized eggs in vitro, and injected 25 human expanded pluripotent stem cells into 132 cynomolgus monkey blastocysts on the 6th day after fertilization.
Three cynomolgus monkey blastocysts injected with human stem cells were still alive on the 19th day of fertilization.
The researchers found that during the continuous growth of human-monkey chimeric blastocysts, the percentage of human cells reached 4%.
Academician Ji Weizhi, one of the leaders of the research project, believes that the result that human cells accounted for 4% proves that human-monkey chimeric embryos are more efficient than human stem cells and other species.
Before human-monkey chimera blastocysts, other teams at home and abroad have also made human-pig chimeric embryos and human-mouse chimeric embryos. Among these chimeric embryos, the ratio of human stem cell chimerism is only 0.001%~0.01 %.
Since the 1970s, scientists have been studying cross-species chimeras to understand how early development proceeds, or to find potential medical applications.
Some of the results of the experiment are encouraging. In 2017, scientists transplanted pancreas developed from mouse stem cells into rat embryos and cured the latter’s diabetes.
Researchers have implanted human stem cells into pig embryos.
After a few weeks, about every 100,000 cells, only 1 cell belongs to humans.
Monkey embryos are most similar to human embryos in terms of development process and morphology. It is ideal to choose non-human primates that are closest to humans, and it also has a better reference value for clinical applications.
It is of great significance to use non-human primates to study the cutting-edge basic scientific issues of biomedicine and the mechanisms of complex diseases.
Belmont also pointed out in a statement after the study that through transcriptome analysis, the study found that there are some new communication pathways between human cells and monkey cells in chimeric embryos.
In past chimera studies, the integration of human cells into host tissues was very inefficient.
If we can understand the role of these pathways, it is expected that people will overcome barriers between different species and increase the efficiency of chimera generation for future research.
In the long run, researchers hope to use these chimeras to study early human development, develop disease models, screen potential new drugs, and make cells, tissues, or organs that can be used for transplantation.
"The latest research has once again confirmed the feasibility of human-monkey chimeric embryos. After the normal development of chimeric blastocysts, the proportion of human cells can also reach the expected. However, there is still a long way to go to truly cultivate allogeneic organs. Go.” Academician Ji Weizhi said that human-monkey chimeric embryos are still in the first step of basic research on heterogeneous chimerism, but they will have important reference value for the completion of in vitro organ cultivation in the future.
He predicted that with the current speed of scientific and technological development, it is expected that the cultivation of in vitro organs will be completed in the next 10 years or so.
Zhu Tongyu also mentioned the issue of organ size.
The kidney of the cynomolgus monkey used in this study is very small, only the size of a thumb, which may not be suitable for humans. The organ sizes of pigs and humans are relatively close, but the integration efficiency of human-pig chimera is low, so it needs more in the future. More similar research to provide more technical insights.
The challenge of stem cell technology to the clinic
The publication of this latest research result is also a major breakthrough in the human science community.
Prior to the study of human-monkey chimera blastocysts, many related studies had been published in top journals such as Cell, Science and Nature.
Under the premise of following the relevant international and national guidelines, last year, researchers mapped the developmental lineage of human embryos grown in vitro for 14 days for the first time, and developed a system for monkey embryos to be grown in vitro to 20 days, thus gaining a deeper understanding of primate embryos. Some important issues of early development laid the foundation for this research.
With the rapid development of biotechnology and medicine, research on human stem cells will provide a basis for studying human development and genetic diseases.
However, due to technical limitations, the current culture system can only support the development of monkey embryos up to 20 days in vitro.
Academician Ji Weizhi believes that before successfully cultivating in vitro organs, researchers need to have a deeper understanding of key basic scientific issues and make further breakthroughs in key technologies.
Academician Ji Weizhi said that there are at least three key issues to be resolved before stem cell research moves towards clinical application: first, the mechanism of stem cell pluripotency; second, stable and uniform-quality stem cell expansion in vitro; third, the safety of stem cells And preclinical evaluation of effectiveness.
In response to some people who are not familiar with basic biology and medical principles, this is called "human-monkey hybridization", Academician Ji Weizhi clearly clarified.
He said: "Human-monkey chimeric embryos are definitely not human-monkey hybrids. Hybridization means creating new species through gene fusion. This human-monkey chimeric embryo is a chimera formed by injecting human stem cells into monkey blastocysts. The model enables human stem cells to survive in a non-human environment."
But he admitted that ethical issues do exist in the in vitro cultivation of human embryo sacs.
However, the essence of human-monkey chimeric embryos is that monkey embryos are used as the environment for the development of human stem cells, and reproductive mosaicism does not essentially occur, which does not violate related ethical issues.
"With the development of science and technology, I believe that some research ethics restrictions will also be revised to adapt to the development of science." Academician Ji Weizhi said.
"Exploring the unknown fields of science is worthy of encouragement. This research is a good attempt. At this stage, there are no ethical issues involved." A researcher from the Chinese Academy of Sciences told the CBN reporter.
He said: "Whether stem cells can differentiate into a certain organ, how many kinds of organs can be differentiated into, and how they compete with the recipient's own cells, these scientific issues are very worthy of discussion, and more attention should be focused on these aspects."
The above-mentioned researcher told CBN reporters that if the tissues of two different species can really grow together well, then in the future, we can further explore whether people can grow organs for human use in animals.
"This is an ethical issue that may be faced in the future. Whether this organ can be implanted into the human body requires clinical trials. From the current stage, if researchers can prove that the two tissues can grow together, it is already very remarkable. "
A review article published by "Cell" also pointed out that the above discussion is currently limited to the research itself.
If these human-monkey hybrid embryos do not just stay in the stage of in vitro experiments, but enter in vivo experiments, are implanted in animals, and finally develop into some kind of organism, or even be born, obviously, the ethical issues they face will be complicated. Much.
Some scientists also believe that this type of research on chimeras is highly sensitive due to disputes over the sources of organs and tissues.
For example, Alfonso Martinez Arias, a developmental biologist at a Spanish university, believes that compared with monkeys, using cows and pigs for research can avoid the risk of challenging ethical boundaries.
There are also scientists who propose to explore related research in the field of organoids without using animals.
The director of the cardiology department of a tertiary hospital in Shanghai told China Business News that the use of stem cells in clinical practice is an inevitable trend. In some countries, including some domestic hospitals, stem cell therapies have been used for certain diseases, but their differentiation is now controllable. There are still some doubts about the reliability of disease treatment, the potential for tumorigenicity, the ethics of embryonic stem cell application, the controllability of induced pluripotent stem cells, iPS cells, and the consistency of cell batches.