A team of Chinese researchers and the Spanish doctor Miguel Ángel Esteban announced this Thursday the birth, in a laboratory in Shanghai, of a monkey with cells from two different monkey embryos. The scientific community calls these hybrid organisms chimeras, in reference to to the mythological monster with the head of a lion, the belly of a goat and the tail of a dragon. It is the first time that this type of macaque chimeras has gone this far. Researchers say these creatures may have promising applications in medicine, such as generating animals with neurological diseases that precisely mimic human diseases, such as Parkinson’s and Alzheimer’s.
An embryo begins with an egg fertilized by a sperm. That single resulting cell will divide and in the following days will give rise to a few totipotent cells: with the capacity to generate an entire animal, including the placenta. These totipotent cells generate other pluripotent cells, which can still give rise to any type of cell in the body – brain, bone, liver, muscle – but no longer the placenta. In 2012, Kazakh-American biologist Shoukhrat Mitalipov’s team achieved the birth for the first time of chimeric monkeysthrough the aggregation of totipotent cells from different embryos.
The Chinese scientist’s group Tianqing Li He took a step further in 2018. From a single embryonic cell, he managed to cultivate a line of pluripotent stem cells in his laboratory, in such a way that they continue to multiply indefinitely, but without differentiating into specialized tissues. Tianqing Li’s team injected these laboratory cells into a macaque embryo and also managed the birth of chimeric monkeysbut the contribution of injected origin barely reached between 0.1% and 4.5% of the cells.
Doctor Miguel Ángel Esteban, from the Guangzhou Institute of Biomedicine and Health, and his Chinese colleagues have taken another leap. The researchers removed cells from embryos as young as seven days old and obtained cell lines capable of multiplying indefinitely in the laboratory. They then labeled those pluripotent stem cells with green fluorescent protein coming from a jellyfish. And the scientists finally injected those cells into monkey embryos that were just four days old. Twelve pregnant females gave birth to six live babies, but only one of the newborn monkeys had a high percentage of chimerism in the brain, heart, kidneys, liver and other organs: between 21% and 92%, depending on the fabric.
“The big leap is to go from a low contribution to a percentage in which you can say: this is a true chimerical animal,” explains Esteban. The average achieved was 67%: two out of every three cells. Fluorescent green could be seen in the eyes and fingertips of the monkey—a crab-eating macaque. The animal, with respiratory failure and hypothermia, was euthanized on its tenth day of life. The results are published this Thursday in the specialized magazine cell.
The Spanish biologist Marta Shahbazi explains the relevance of the new study, in which she has not participated. The researcher remembers that the chimera technique in mice, developed in 1989, already represented “a revolution” at the time, because it allowed the generation of genetically modified rodents, thanks to the manipulation of embryonic stem cells that are cultured indefinitely in the laboratory. “If we want to know what the function of a gene is in a mouse, we can delete the gene in embryonic stem cells and then use those modified cells to generate chimeras. If cells contribute to gametes [óvulos y espermatozoides]some of the descendants of the chimeric mice will have the gene deleted in all the cells of their body and we will be able to analyze what happens to them, and therefore discover the function of the gene,” says Shahbazi, from the Laboratory of Molecular Biology, in Cambridge ( United Kingdom).
The fathers of this technique in mice—the Italian Mario Capecchi and the British Oliver Smithies and Martin Evans—won the 2007 Nobel Prize in Medicine. “In the case of monkeys, if chimeras could be generated efficiently, we could study the consequences of eliminating or modifying specific genes in monkeys,” says Shahbazi. “It is important to mention that in this new study only one chimeric monkey was born, therefore, the efficiency is still low,” she emphasizes.
The macaque with cells from two different embryos was born in the Primate Neurobiology Laboratory of the Chinese Academy of Sciences, in Shanghai. Doctor Miguel Ángel Esteban’s group has collaborated with the teams of his colleagues Qiang Sun and Zhen Liu. Esteban himself already announced two months ago the generation of a humanized kidney sketch in a pig embryo, in an experiment on the frontier of bioethics. It was the first human organ created inside an animal and has brought the dream of manufacturing closer spare parts for the people.
Esteban explains by phone that his new technique for obtaining chimeric monkeys, based on a specific chemical cocktail, could represent “a spectacular advance” in the genetic modification of primates, by allowing the introduction of multiple mutations and markers to know which cells are altered. In addition to imitating human diseases in laboratory animals, the doctor highlights a conceptual demonstration. “Human cells, if they acquire this same level of pluripotency, could differentiate in vitro into tissues that, in principle, would closely resemble the tissues of the embryo. This can be used for cell transplants or to study diseases in a laboratory dish,” he predicts.
The Spanish researcher, born 53 years ago in the Valencian town of Castellón de la Plana, adds a third hypothetical application: the conservation of species. The monkey born in Shanghai had cells from two different embryos, but of the same species. Esteban points out that the technique could be carried out with two different species: one in imminent danger of extinction and another in a good state of conservation, in such a way that the resulting chimera would have eggs or sperm from the threatened species. “Banks of embryonic cells from various species of monkeys could be created and in the future, when unfortunately many of them are disappearing, use this type of technology for the conservation of non-human primates,” he believes.
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