Imagine pigs with human hearts or mice whose brains have a spark of human intelligence. Scientists are cultivating a flock of such experimental creations, called chimeras, by injecting potent human cells into mice, rats, pigs and cows. They hope the new combinations might one day be used to grow human organs for transplants, study human illnesses or to test new drugs.
In the latest advance, researchers in the U.S. and China announced earlier this month that they made embryos that combined human and monkey cells for the first time. So far, these human-monkey chimeras (pronounced ky-meer-uhs) are no more than bundles of budding cells in a lab dish, but the implications are far-reaching, ethics experts say. The use of primates so closely related to humans raises concerns about unintended consequences, animal welfare and the moral status of hybrid embryos, even if the scientific value of the work may be quite high.
“There were lots of breakthroughs in this experiment,” says bioethicist Nita Farahany of Duke University. “A remarkable step has been taken scientifically that raises urgent issues of public concern. We need to figure out what the right pathway forward is to help guide responsible progress.”
Scientists have been creating partly human chimeras for years. Researchers use rats with human tumors to study cancer, for example, and mice with human immune systems to conduct AIDS research. What makes the latest experiment unique is that the scientists injected human stem cells, which can become any kind of tissue, into an embryo of a closely related primate.
To make them, researchers from the Salk Institute for Biological Studies in La Jolla, Calif., and China’s Kunming University of Science and Technology injected human stem cells—made by reprogramming mature skin or blood cells—into 132 embryos from macaque monkeys. Six days after the monkey embryos had been created at the State Key Laboratory of Primate Biomedical Research in Kunming, researchers injected each one with 25 human stem cells labeled with a fluorescent red protein.
“We put them together in a petri dish in the laboratory, to see how they interact with one another,” says Juan Carlos Izpisua Belmonte, director of the Salk gene expression laboratory, who led the research effort. The next day, the monkey embryos glowed. Human cells had become integrated into all of them, far more effectively than in previous experiments with embryos from other species such as pigs, they reported on April 15 in Cell.
So far, these human-monkey chimeras can’t survive longer than 19 days. “It’s never been our intention and never will be to create a living chimera in a monkey host,” says Dr. Izpisua Belmonte.
Even so, the new chimera experiment highlights a dilemma. When human stem cells are injected into an animal embryo at such an early stage of development, there so far is no way to control where they go or limit what type of adult cells they become, other scientists say.
“It does show that the human stem cells tend to migrate far and wide through the monkey embryo,” says Insoo Hyun, a bioethicist at Case Western Reserve University in Cleveland, who is involved in international oversight of such research. “That is what leads to the theoretical concern: There is a chance that in an uncontrolled way it may lead to a mixing of human cells that may result in human cells developing in the brain or the heart or from head to toe across the body.” That means researchers can’t target the stem cells to create specific organs or avoid random changes to the animal’s brain—at least not yet.
In a glimpse of the potential effects, researchers at the University of Rochester in 2014 transplanted human fetal brain cells called astrocytes into young laboratory mice. They discovered that within a year the human cells had taken over the mouse brains. Moreover, standard tests for mouse memory and cognition showed that the altered mice were smarter.
In such ways, stem-cell chimeras have “the potential to radically humanize the biology of laboratory animals,” Dr. Hyun says.
It has long been a politically charged field of research, bioethicist Henry Greely at Stanford University says. In his 2006 State of the Union Address, President George W. Bush called the creation of human-animal hybrids one of “the most egregious abuses of medical research.” Seven countries ban or restrict it. Since 2015, the U.S. National Institutes of Health has refused to fund experiments that involve human stem cells added to early animal embryos.
Policy makers, however, might relax some restrictions this year. An NIH spokeswoman says that the organization is awaiting the release next month of updated guidelines from the International Society for Stem Cell Research “to ensure our position reflects the input from the community, which has been very thoughtful.” The agency lifted restrictions on fetal-tissue research earlier this month.
“I believe that NIH is eager to move on,” says Dr. Hyun, who led the committee that updated the society’s guidelines for experiments involving human-primate chimeras.
Dr. Izpisua Belmonte says he welcomes oversight. At his urging, the recent experiment was reviewed beforehand not just by institutional review boards in the U.S. and China but also by three independent bioethics experts. “Not everything that we scientists can do should be done,” he says. “Experiments like this certainly raise many concerns.”
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Research using primates is increasingly difficult in Europe and the U.S. The Salk team collaborated with scientists in China to take advantage of their growing expertise in keeping monkey embryos alive outside the body. China singled out the creation of primate disease models as a national goal in 2011, aiming to create gene-altered monkeys suitable for studying treatments or cures for a variety of human brain diseases and disorders such as autism.
While major technical hurdles remain, scientists in China already are using tools of embryo engineering, such as cloning, to speed up the breeding of primates given new traits through modern gene-editing techniques.
“As long as it is an embryo in a dish we are not concerned,” Dr. Greely says of the human-monkey chimera. “If you actually try to gestate such a thing, particularly if you can bring it successfully to term, then the issues get more significant.”
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Corrections & Amplifications
Juan Carlos Izpisua Belmonte, director of the Salk gene expression laboratory, said, “It’s never been our intention and never will be to create a living chimera in a monkey host.” An earlier version of this article incorrectly quoted him as saying “house” rather than “host.” (Corrected on April 26, 2021)
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