Chimera Blastocyst CREDIT Weizhi Ji, Kunming University of Science and Technology.
Chimera Blastocyst CREDIT Weizhi Ji, Kunming University of Science and Technology.

EXPERT REACTION: Human-monkey hybrid embryos may help scientists understand human biology and disease

Embargoed until: Publicly released:
Peer-reviewed: This work was reviewed and scrutinised by relevant independent experts.

Experimental study: At least one thing in the experiment was changed to see if it had an impact on the subjects (often people or animals) – eg: changing the amount of time mice spend on an exercise wheel to find out what impact it has on weight loss.

Cells: This is a study based on research in micro-organisms, cells, tissue, organs or non-human embryos.

Researchers in China and the US have injected human stem cells into primate embryos to create hybrid or chimeric embryos that they grew for up to 20 days. Developing these sorts of embryos may be one way to conduct research that is ethically problematic to conduct in humans, although an accompanying editorial highlights that these chimeric embryos themselves raise ethical challenges for society. The researchers hope that these chimeric embryos could be used to study early human development and to model disease, but also to develop new approaches for drug screening, as well as potentially generating transplantable cells, tissues, or organs.

Journal/conference: Cell

Link to research (DOI): 10.1016/j.cell.2021.03.020

Organisation/s: Salk Institute, USA

Funder: This work was supported by the National Key Research and Development Program, the National Natural Science Foundation of China, Major Basic Research Project of Science and Technology of Yunnan, Key Projects of Basic Research Program in Yunnan Province, High-level Talent Cultivation Support Plan of Yunnan Province and Yunnan Fundamental Research Projects, UCAM, and the Moxie Foundation.

Media release

From: Cell Press

Researchers generate human-monkey chimeric embryos

Investigators in China and the United States have injected human stem cells into primate embryos and were able to grow chimeric embryos for a significant period of time--up to 20 days. The research, despite its ethical concerns, has the potential to provide new insights into developmental biology and evolution. It also has implications for developing new models of human biology and disease. The work appears April 15 in the journal Cell.

"As we are unable to conduct certain types of experiments in humans, it is essential that we have better models to more accurately study and understand human biology and disease," says senior author Juan Carlos Izpisua Belmonte, a professor in the Gene Expression Laboratory at the Salk Institute for Biological Sciences. "An important goal of experimental biology is the development of model systems that allow for the study of human diseases under in vivo conditions."

Interspecies chimeras in mammals have been made since the 1970s, when they were generated in rodents and used to study early developmental processes. The advance that made the current study possible came last year when Izpisua Belmonte's team--collaborating with Weizhi Ji of Kunming University of Science and Technology in Yunnan, China, also an author on the new paper--generated technology that allowed macaque embryos to stay alive and grow outside the body for an extended period of time.

In the current study, six days after the monkey embryos had been created, each one was injected with 25 human cells. The cells were 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. After 10 days, 103 of the chimeric embryos were still developing. Survival soon began declining, and by day 19, only three chimeras were still alive. Importantly, though, the percentage of human cells in the embryos remained high throughout the time they continued to grow.

"Historically, the generation of human-animal chimeras has suffered from low efficiency and integration of human cells into the host species," Izpisua Belmonte says. "Generation of a chimera between human and non-human primate, a species more closely related to humans along the evolutionary timeline than all previously used species, will allow us to gain better insight into whether there are evolutionarily imposed barriers to chimera generation and if there are any means by which we can overcome them."

The investigators performed transcriptome analysis on both the human and monkey cells from the embryos. "From these analyses, several communication pathways that were either novel or strengthened in the chimeric cells were identified," Izpisua Belmonte explains. "Understanding which pathways are involved in chimeric cell communication will allow us to possibly enhance this communication and increase the efficiency of chimerism in a host species that's more evolutionarily distant to humans."

An important next step for this research is to evaluate in more detail all the molecular pathways that are involved in this interspecies communication, with the immediate goal of finding which pathways are vital to the developmental process. Longer term, the researchers hope to use the chimeras not only to study early human development and to model disease, but to develop new approaches for drug screening, as well as potentially generating transplantable cells, tissues, or organs.

An accompanying Preview in Cell outlines potential ethical considerations surrounding the generation of human/non-human primate chimeras. Izpisua Belmonte also notes that "it is our responsibility as scientists to conduct our research thoughtfully, following all the ethical, legal, and social guidelines in place." He adds that before beginning this work, "ethical consultations and reviews were performed both at the institutional level and via outreach to non-affiliated bioethicists. This thorough and detailed process helped guide our experiments."

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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Professor Megan Munsie is from the School of Biomedical Sciences and Melbourne Medical School at the University of Melbourne

Today’s announcement that scientists have made human-primate chimera embryos and cultured them in the lab for two weeks will take many by surprise.

Some will find the idea of mixing human cells with any animal embryo – let alone a primate embryo – highly questionable. For the researchers who led the study, the rationale was clear. They had long been interested in addressing the shortage of life-saving organs for human transplantation by creating human-pig chimeras.

While they had previously created a pig fetus that contained human cells, the contribution was low and the goal to create transplantable organs elusive. How to solve this challenge led to the current experiment. The researchers were not attempting to create human-monkey chimeras with a view to harvesting organs. Rather, they created a laboratory model to explore what happens to the transferred human cells in an attempt to identify ways to enhance survival and ultimately improve human chimerism in pig and other evolutionarily distant species.

While this study undoubtedly provides important insights into developmental biology, it also raises ethical questions that warrant careful consideration around application and oversight. This work will and should stimulate important conversations about where boundaries should lie.

Last updated: 16 Apr 2021 1:14pm
Declared conflicts of interest:
None declared.
Bernard Tuch is a Consultant Endocrinologist and Director of the NSW Stem Cell Network

The authors have shown great skills in achieving survival of human cells in a monkey embryo.  If implanted in utero, it could lead to the generation of human-type kidneys to be implanted in those with kidney failure.

This would help resolve the relative lack of transplantable kidneys.  However, the availability of monkeys for this purpose is quite limited. Moreover, the law would need to be altered to allow this, something that today seems unlikely.

Last updated: 16 Apr 2021 1:12pm
Declared conflicts of interest:
None declared.
A/Professor Kuldip Sidhu is co-founder and director, CK Cell Technologies and Conjoint with University of New South Wales Medicine.

Mixing human embryonic stem cells (hESC) with embryos from other species during embryonic development, known as ‘blastocyst complementation’, is emerging as a powerful platform to generate humanised functional organs/tissues for regenerative medicine. The present paper is a step towards that direction, where the authors have attempted to create chimeras (mixed embryos) using hESC and monkey early embryos, by using a protocol for an extended development period to about 20 days and using a 2D culturing system.

They seem to have successfully tweaked the molecular developmental stages of chimeric lines, both human and monkey. Their data indicate notionally the onset of chimerism more for pre-implantation stage rather than post-implantation stage, albeit revealing important developmental mechanisms that are similar in both these species.

However, there are some limitations in this study that the paper did not take into consideration or mention about the state of hESC, ‘primed’ or ‘naïve’, that has a great bearing in chimerism. Also, the protocol used for whole embryo explant method as a 2D system to gain on timing in development appraisals has its own limitations, a 3D system could be more ideal. Thirdly cross-species complementation is crucial, although primates are close to humans, but initial hostility for compatibility causes apoptosis that has not been taken into consideration as in the previous studies.

Last updated: 16 Apr 2021 1:10pm
Declared conflicts of interest:
None declared.

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