For the first time, biologists have succeeded in growing human stem cells in animal embryos, shifting from science fiction to the realm of the possible the idea of developing human organs in animals for later transplant.
The approach involves generating stem cells from a patient’s skin, growing the desired new organ in a large animal, 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 animals would be examples of chimeras, animals composed of two different genomes. They would be generated by implanting human stem cells into an early embryo, resulting in an animal composed of mixed animal and human cells.
One team of biologists, led by Jun Wu and Juan Carlos Izpisua Belmonte at the Salk Institute, has shown for the first time that human stem cells can contribute to forming the tissues of an animal, despite the 90 million years of evolution between the two species.
Another group, headed by Tomoyuki Yamaguchi and Hideyuki Sato of the University of Tokyo, and Hiromitsu Nakauchi of Stanford, has reversed diabetes in mice by inserting pancreas glands composed of mouse cells that were grown in a rat. The Salk team’s report was published in Cell and the Stanford-Tokyo team’s in Nature.
The two reports together establish the feasibility of trying to grow replacement human organs in animals, though such a goal is still far off.
“I think this is very promising work in principle,” said Rudolf Jaenisch, a stem cell expert at the Whitehead Institute in Cambridge, Masschusetts.
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 an animal’s brain, endowing it with human qualities. Almost no one wants a talking animal.
Another untoward outcome would be if human cells should come to compose the animal’s reproductive tissues. Few people want to see what might result from the union between an animal with human sperm and an animal with human eggs.
Izpisua Belmonte’s and Nakauchi’s teams have both pursued a strategy of directing the human donor cells to generate specific organs in the recipient species. This is desirable for both technical and ethical reasons.
Nakauchi has disabled the master gene in rats for making a pancreas so that when mouse stem cells are injected into the early embryo of such a rat, the growing embryo has no choice but to construct its pancreas of pure mouse cells, instead of the usual mixture of rat and mouse cells.
The result provides proof of principle that Type 1 diabetes can be treated by growing a pancreas from an individual’s cells in another animal, Nakauchi and colleagues conclude.
The next step is to repeat the experiment in bigger animals, which produce organs of a more suitable size for use in humans. Izpisua Belmonte’s team has now shown that human stem cells do survive in the animal’s embryos and help form their organs, although not very efficiently.
“The human cell doesn’t contribute much. To the brain we observed little or no contribution at all,” said his colleague Wu.”This is good news because we can guide the human cells to the organ we want.”
Both Izpisua Belmonte and Nakauchi said there was a long way to go before human organs could successfully be grown in animals. Chimeras will be more immediately useful in studying human embryogenesis, testing drugs and following the progress of disease.
Both scientists expressed confidence that ethical concerns about chimera research could be addressed. Chimeras are typically mosaics in which each organ is a mixture of the host and donor cells. But new techniques like the Crispr-Cas gene editing system should allow the human cells in an animal embryo both to be channelled into organs of interest and to be excluded from tissues of concern like the brain and reproductive tissues.
“This isn’t dangerous research. We’re not creating monsters,” Nakauchi said.
“There isn’t a need to get into a debate about moral humanisation if scientists target the organs where the human cells will go,” said Insoo Hyun, a medical ethicist at Case Western Reserve University.”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 reduce animal’s mind is not with out basis. Dr. Steven Goldman of the College of Rochester Clinical Center discovered in 2013 that mice injected with a particular style of human mind mobile experienced enhanced understanding talents. But other kinds of humanized mice, this sort of as mice engineered to have a human immune system, are schedule laboratory animals that appear to be to event very little angst.
Dr. Izpisua Belmonte’s insertion of human stem cells into pig embryos was not influenced by the N.I.H. moratorium on this sort of chimeras mainly because he utilized personal cash. His experiment was accredited by the authorities in Spain and in California, and following their guidance, the improvement of the pig chimeras was stopped following four weeks in the womb.
Dr. Nakauchi moved his lab to Stanford from Tokyo in 2014 mainly because Japanese rules do not permit chimera exploration, only to be strike with the N.I.H. moratorium a year afterwards, which prevented him from generating chimeras with human cells. His mouse pancreas experiment has taken eight or nine many years to finish. “I have been in a very aggravating problem,” he said.