Introducing pig-human embryos and a rat-mouse

For the first time, biologists have succeeded in growing human stem cells in pig embryos (The New York Times, 2017).

The approach involves generating stem cells from a patient’s skin, growing the desired new organ in a large animal like a pig, and then harvesting it for transplant into the patient’s body. Since the organ would be made of a patient’s own cells, there would be little risk of immune rejection.

The human organ growing pigs would be examples of chimeras, animals composed of two different genomes. They would be generated by implanting human stem cells into an early pig embryo, resulting in an animal composed of mixed pig and human cells. To create chimaeras, scientists generally inject pluripotent stem cells, which can become any type of organ, from one species into the early embryo of a second species (Nature, 2017). In theory, the foreign cells should differentiate and spread throughout the body, but in practice, producing viable hybrid embryos has proven difficult.

To get around this, a team led by Jun Wu and Juan Carlos Izpisua Belmonte of the Salk Institute for Biological Studies in La Jolla, California, used CRISPR gene editing technology to create mouse embryos without the genes that cause organs to form. The scientists then injected rat stem cells into the mouse embryos and implanted the embryos into a mouse’s uterus. Because the rat cells still contained genes for organ formation, the resulting chimaeras had organs that were composed largely of rat cells. The animals lived for up to two years, the normal lifespan of a mouse.

Next, the researchers attempted to hybridise humans and pigs. The team injected more than 2,000 pig embryos into 41 surrogate sowswith one of three types of human induced pluripotent stem cell; normal cells, cells that were primed to develop into tissue or “intermediate” cells that were neither normal nor fully primed. All of the human cells had been modified to produce a green fluorescent protein so that they could be identified within the newly created chimaeras. They had 18 pregnancies and 186 embryos a month later. However, many of the embryos were much smaller than normal and seemed to grow more slowly. The researchers saw signs of human cells, but they were rare. Jun Wu said “It is fair to say they engraft, but the level is low.” Only about 1 in 100,000 of the cells in the pig–human chimaeras were human.

One problem may be that porcine pregnancies last just 114 days, compared with 9 months for humans. And pigs and humans are much more distantly related than rats and mice. Jun Wu said tweaking genes in the pig embryos, so that they can’t form certain tissues, for example, might help give the human cells more room to develop. He said the fact he and his colleagues found surviving human cells at all after 4 weeks of development is “remarkable.” He said “I think it’s encouraging. Before we dream about all these downstream applications, we need to know if the evolutionary distance [between humans and pigs] prevents human cells from contributing at all.”

Jacob Hanna, a developmental biologist at the Weizmann Institute of Science in Rehovot, Israel, said “I think it’s a very important, very exciting paper. He said researchers will want to see whether the human cells in the chimaeras have normal DNA structure and gene expression.

But Hiromitsu Nakauchi, a stem cell researcher at Stanford University said that the low number of human cells in the pig–human chimaeras meant the hybrids are still a long way from serving any useful purpose, such as organ donors. He said “It’s a good try, but the result seems like more a negative result.”

Hiromitsu Nakauchi’s group is using similar methods to create human–sheep chimaeras, in part because he suspects that sheep embryos may be better able to take up human cells than pig embryos can. But Jun Wu, said pigs will probably be the best organ donors, because their large litter sizes would allow quicker production of organs. Pig organs are also close to the same size as human ones.

Many technical and ethical barriers have yet to be overcome, but the research is advancing alongside the acute need for organs; some 76,000 people in the United States alone are awaiting transplants. Creating chimeras, especially those with human cells, may prove controversial, given the possibility that test animals could be humanised in undesirable ways. One would be if human cells should be incorporated into a pig’s brain, endowing it with human qualities. Almost no one wants a talking pig.

Another untoward outcome would be if human cells should come to compose the pig’s reproductive tissues. Few people want to see what might result from the union between a pig with human sperm and a sow with human eggs.

In 2015 the National Institutes of Health (NIH) instituted a moratorium on using public funds to insert human cells into animal embryos. The ban is still in place, and it’s unclear whether the Trump administration would continue to consider lifting the moratorium or whether new objections would be raised to using public funds for this line of research. Carrie D Wolinetz, the associate director for science policy at the NIH, said “We have no indication one way or another that they have any opinions on this.”

Insertion of human stem cells into the early embryos of monkeys was prohibited in 2009, and remains so because monkeys, given their evolutionary closeness to humans, might easily have their brains altered by human cells.

Hiromitsu Nakauchi said “This isn’t dangerous research. We’re not creating monsters.”

Insoo Hyun, a medical ethicist at Case Western Reserve University, said “There isn’t a need to get into a debate about moral humanization if scientists target the organs where the human cells will go. Scientists are not making chimeras just for fun — it’s to relieve the dire shortage of transplantable organs.”

Concern about human cells’ incorporation into a lower animal’s brain is not without basis. Dr. Steven Goldman of the University of Rochester Medical Center found in 2013 that mice injected with a special type of human brain cell had enhanced learning abilities. But other forms of humanised mice, such as mice engineered to have a human immune system, are routine laboratory animals that seem to occasion little angst.

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