Chinese researchers have successfully created chimeric embryos by combining human stem cells and monkey blastocysts, a groundbreaking advance with both practical and ethical implications for the future of medicine.
Researchers have tried to create chimeras with animals such as pigs. But this study, conducted in China, with assistance from researchers in the U.S., aimed to examine how chimeras may form when using reproductive cells from species closer to humans. The team, whose study was published April 15 in Cell, found improved embryo formation when using blastocysts taken from the crab-eating macaque.
"It was striking that we found human and monkey cells collaborating with each other, making the embryo," said co-first author Jun Wu, an assistant professor of molecular biology at the University of Texas Southwestern Medical Center who co-led the project as a scientist at the Salk Institute for Biological Studies in San Diego. "There's an interaction between human and monkey cells, even at this early stage, which suggests that human and monkey cells are close enough that they can activate each other."
Chimeric embryos interest scientists because of their potential to eventually help solve the organ-donor crisis, where demand for organs far outpaces supply. More than 100,000 people in the U.S. were on the transplant waiting list as of February, according to the Health Resources and Services Administration. Stem cells used to form chimeric embryos can be nudged to promote the growth of specific organs that, superficially, look like the organ of the host species but are actually the organ of the species that gave its stem cells to the embryo.
In 2010, for example, Japanese scientists used chimeras to generate a rat pancreas inside of a mouse that they had genetically modified to be unable to produce a pancreas on its own. The rat stem cells complemented the defect in this mouse by forming a rat pancreas.
To determine how human cells could reproduce within monkey embryos in the new study, researchers injected 25 extended human pluripotent stem cells into 132 blastocysts from the crab-eating macaque. These pluripotent stem cells differ from typical stem cells because they can generate any type of tissue, rather than just their source tissue. Usually, pluripotent stem cells come from embryos, but new technology can reprogram adult stem cells from skin, hair or other tissues to create pluripotent stem cells.
Over time, the researchers found embryos developing with cells from two distinct lineages, meaning that these embryos were human-monkey chimeras. After one day, the researchers saw that human cells remained in all of the injected blastocysts, forming embryos, but this number began to drop as the study proceeded, and by around 20 days, all had perished.
According to Wu, the survival of these embryos is tied not necessarily to their chimeric character, but the fact the study was performed in vitro, rather than in a womb.
And though Wu and his colleagues have been able to show that human cells paired with a monkey blastocyst can form a chimeric embryo, they currently have no intention of moving it from a petri dish to a live uterus.
"I think research like this generates fear and excitement at the same time, so I think a balanced, step-by-step approach is always better," Wu said in an interview with The Academic Times.
He notes that research into chimeric embryos is heavily regulated by the International Society for Stem Cell Research, which has published a set of guidelines governing this research. Currently, placing a chimeric human-monkey embryo in the womb of a monkey is not allowed.
"That is neither what was done here nor the long-term goal (at least with nonhuman primates) of this research," law professors Henry T. Greely of Stanford University and Nita A. Farahny of Duke University, who were not involved in Wu's research, wrote in a supporting article on the ethics of the study. "It remains altogether unclear whether such results are, or ever will be, possible. And yet, those future experiments are now at least plausible. We must begin to think about that possibility."
As for now, Wu believes that the guidelines preventing that type of experiment are sensible. Before moving away from in vitro experiments on human-monkey chimeras and, if ever, into a womb, scientists need to better understand what is occurring inside the chimeric embryos, and how they form.
"The purpose is not to generate live human-monkey chimera; that was not the purpose of this study at all," Wu said. "We just need to understand why the human cells can survive better in monkeys so that we can later compare with the pig. To help us to improve human cell survival in the pig, that was the purpose of the research."
While 94 million years of evolution separate pigs and humans, according to Wu, primates are much closer to people's evolutionary timeline. This study, therefore, sought to answer questions that could lead to greater success in generating chimeric embryos from species other than monkeys.
The medical industry will likely never use monkeys to harvest human organs. They are simply too small. Instead, because of their larger size and availability, pigs are a much better option. One problem, however, is the difficulty of forming robust human-pig chimeric embryos.
"Although we find that human cells can contribute to early pig embryos, the level of contribution is very, very low," Wu said. "I think that's far from being practical, and we want to know why."
The study, "Chimeric contribution of human extended pluripotent stem cells to monkey embryos ex vivo," published April 15 in Cell, was authored by Tao Tan, Chenyang Si, Shaoxing Dai, Youyue Zhang, Nianqin Sun, E. Zhang, Honglian Shao, Wei Si, Pengpeng Yang, Hong Wang, Zhenzhen Chen, Ran Zhu, Yu Kang, Zongyong Ai, Tianqing Li, Weizhi Ji and Yuyu Niu, Kunming University of Science and Technology; Jun Wu, University of Texas Southwestern Medical Center; Reyna Hernandez-Benitez, Travis Berggren, May Schwarz and Juan Carlos Izpisua Belmonte, Salk Institute for Biological Studies; and Llanos Martinez Martinez and Estrella Nuñez Delicado, Universidad Católica San Antonio de Murcia.