Editorial: “Human-animal hybrids mean boom time for bioethicists“
THE chimeras of ancient mythology were monstrous combinations of lions, snakes and goats. We may soon have something almost as startling. A team of biologists is paving the way for growing entirely human organs inside pigs. The aim is to duplicate inside a host animal the kidney, say, of someone needing an organ transplant.
Experiments building up to such organ farms have been carried out in pigs, mice and rats in Japan. So far, regulations there have made the next stage impossible – using human stem cells to make human-animal chimeras. But last week, the Japanese government announced new rules which should allow and his group at the University of Tokyo to grow animals that are partly human.
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“We are ready to do the experiment,” says Nakauchi. On the surface, his concept is relatively simple (see “This little piggy grew a human kidney“). He will produce a line of pigs that lack the organ he wants to farm – kidneys for instance. Separately, he will obtain human induced pluripotent stem (iPS) cells, capable of developing into any type of cell in the body. When the iPS cells are injected into an early stage embryo – a blastocyst – from the kidney-deficient line of pigs, they mix with the pig’s own cells. All organs end up being composed of a mix of pig and human cells. All, that is, except the kidney, which is purely human. The hope is that the kidney would be accepted by the patient’s body with little or no suppression of the immune system needed.
“The hope is that a patient would accept a kidney with no suppression of the immune system needed”
In a series of landmark experiments between 2010 and 2013, Nakauchi has got every element of the system working in mice. Some of it has been translated to pigs (see “Replacement parts“), which researchers believe would be the most suitable hosts for human organs because their organs are of roughly the same size and shape as ours.
Researchers contacted by Â鶹´«Ă˝ said one of the biggest hurdles for Nakauchi’s system is the presence of stray pig cells in the target human organ. “All organs are composed of a complex mixture of cell types,” says , a stem-cell scientist at the University of Oxford. Knocking out pancreatic cells in a pig pancreas still leaves blood vessels. If these are transplanted into humans, they could trigger an immune response that rejects the organ, says Fairchild.
Nakauchi told Â鶹´«Ă˝ about unpublished experiments in which he claims to have solved the problem. He has engineered mice that are unable to grow their own veins and arteries as well as a pancreas. “Combining the two different mutations, we should be able to make an organ where not just the organ but also the vessels are from human iPS cells,” says Nakauchi. “So we can now avoid immune rejections due to contaminating pig cells.”
“If Nakauchi has done this, the implications will be huge,” says Charles Murry, a cardiovascular stem-cell scientist at the University of Washington in Seattle. “ and ensure the employment of a generation of bioethicists.”
“It could revolutionise transplantation medicine and ensure the jobs of a generation of bioethicists”
“Rejection of blood vessels is the bane of solid organ transplantation and is the reason most hearts and kidneys fail after the first year,” he says.
There are several steps Nakauchi needs to take before the final goal will be within sight. He is working to ensure that the research meets ethical standards around the world. US guidelines, for instance, allow human-animal chimeras, so long as they don’t breed and the human cells do not “contribute in a major organised way to the brain”. The guidelines reflect popular concerns over breeding animals that have human elements in their sperm and eggs, brains, eyes an d skin (Nature, ).
Developmental biologist Davor Solter at the Institute of Medical Biology in Singapore is “laughable”, and points out that brain structure – not the nature of individual cells – makes our brains distinctive. “Human brain cells in a mouse brain are going to do the things that mouse brains do. They don’t carry human thoughts.”
Nonetheless, Nakauchi says he has found a way to prevent iPS cells from becoming brain or gonad cells. His team has tweaked mouse iPS cells by adding a gene that controls their differentiation, forcing them to form only some organs. The tweaked cells cannot develop into sperm, eggs, brain cells, skin or eyes. The work is being prepared for publication. If it can be replicated in humans cells, it should clear the way for research in the US. “Given sufficient resources and resolve, if it really works in mice, it should be doable in pigs,” says Murry.
The next step for Nakauchi’s team is to prove pig-human chimeras are viable. So far, they have mixed cells from mice and rats. Going further might be the biggest challenge of all.
“I am doubtful the embryo made from a pig blastocyst with human iPS cells will work,” says Solter. He points out that although mouse-mouse chimeras successfully develop to adulthood, most of Nakauchi’s rat-mouse chimeras have not been viable. The greater the evolutionary distance between two species, he says, the less chance their chimeras have of surviving.
Why remains unclear. Solter points out that pig blastocysts are enormous and “bizarre”. They grow into 10-centimetre-long strips, containing hundreds of thousands of cells. Sibling blastocysts wrap around each other in utero. are about a fifth of a millimetre long and contain some 150 cells. “I think these two structures will most likely be incompatible. The human cells will disrupt the morphology of the pig blastocysts and they will abort.”
Nakauchi says that if pig-human chimeras aren’t the best animals for organ harvesting, a monkey-human chimeras might work. In the meantime, he has already taken steps towards testing his model further: his team have been working on mouse blastocytes that are injected with human iPS cells to see how these chimeras fare. So far, regulations have meant Nakauchi has had to destroy the lumps of cells after two weeks. The recent changes in Japanese guidelines mean he may soon be able to repeat the experiments, but this time implant the blastocytes into a female and see what develops.
Correction: When this article was first published on 26 June 2013, it confused the mice in Hiromitsu Nakauchi’s potential future experiements with pigs.
This article appeared in print under the headline “Get your spares at the organ farm”
