Originally published 2019-08-16.
In the summer of 2019 Japan became the first country to give the go-ahead for an experiment that would put human cells into animal embryos and then transfer those embryos into surrogate animals. The project, led by stem-cell scientist Hiromitsu Nakauchi, aims one day to grow human organs, starting with the pancreas, inside animals such as rats, mice and eventually pigs. Despite alarming headlines at the time, the plan was not to produce a half-human creature. The embryos were to be studied for only a couple of weeks, and nothing was to be carried to birth any time soon.
Here is what was approved, how the technique works, what came before it, and why scientists and ethicists are still debating it.
What Japan approved in 2019
On 26 July 2019 the journal Nature reported that an expert panel of Japan's science ministry had approved Nakauchi's proposal, with final ministry sign-off expected later that year. Nakauchi led research groups at both the University of Tokyo and Stanford University in California, and he had been preparing for this kind of work for about a decade.
The approval was possible because Japan changed its rules in March 2019. Until then, animal embryos containing human cells could only be grown for 14 days and could not be transplanted into a surrogate womb. The new guidelines allow such embryos to be implanted in animals and, in principle, brought to term, provided each project is reviewed and approved.
Nakauchi's initial plan was modest. According to Scientific American, which republished Nature's report, mouse embryos would be grown for up to 14.5 days and rat embryos for about 15.5 days, roughly the point at which organs begin to take shape. Only later did he hope to seek permission for pig embryos grown for up to 70 days.
Pixabay
How the technique works
The method is known as blastocyst complementation, and the organisms it creates are usually called chimeras rather than hybrids. A hybrid mixes genes in every cell, as a mule does. A chimera is an animal made of two populations of cells, each with its own DNA.
The steps go like this:
- Scientists create an animal embryo that lacks a gene essential for building a particular organ. For the pancreas, the embryo simply cannot make one on its own.
- They inject human induced pluripotent stem (iPS) cells into the embryo at a very early stage. iPS cells are adult cells, such as skin or blood cells, that have been reprogrammed to behave like embryonic stem cells, so they can develop into almost any tissue.
- The hope is that the human cells fill the empty "niche" and build the missing organ, while the rest of the animal develops from its own cells.
If it worked fully, a pig could one day grow a pancreas, kidney or liver made largely of a patient's own cells, which could then be transplanted with a much lower risk of rejection.
Earlier results that paved the way
The idea had already worked between closely related species. In 2017 Nakauchi's team injected mouse iPS cells into rat embryos that could not make a pancreas. The rats grew pancreases made of mouse cells. Tissue from those organs was then transplanted into diabetic mice, where it helped control their blood sugar.
Doing the same with human cells is far harder. In 2018 Nakauchi's group placed human iPS cells into sheep embryos engineered to lack a pancreas. After 28 days, the embryos contained very few human cells and nothing resembling an organ. Other researchers have reported similar trouble with pig embryos. The large evolutionary distance between humans and these animals seems to cause the human cells to be outcompeted or eliminated early, which is one reason Nakauchi wanted to proceed step by step, starting with rodents and studying what limits human cell growth.
Why organs grown in animals matter
The motivation is a chronic shortage of organs for transplant. In the United States alone, more than 100,000 people are on transplant waiting lists at any time, and many die before an organ becomes available. People with type 1 diabetes, kidney failure or liver disease could all benefit if replacement organs could be grown to order.
Chimera research is one of several routes being explored. Others include gene-edited pig organs transplanted directly into people, lab-grown "organoids", and 3D bioprinting. Each faces its own technical and ethical barriers, and none is yet a routine treatment.
The ethical questions
The main fear raised by bioethicists is that human cells could stray beyond the target organ, for example into the developing brain, and alter an animal's cognition in ways no one can predict. Others raise concerns about animal welfare, about creating animals mainly to harvest their organs, and about where society should draw the line between human and animal.
Nakauchi argued that his design addressed the brain concern. "We are trying to do targeted organ generation, so the cells go only to the pancreas," he told Nature. Ethicists remained cautious but welcomed the gradual approach. Tetsuya Ishii, a science-policy researcher at Hokkaido University, said that moving forward in careful stages "will make it possible to have a dialogue with the public."
The debate was not new. In 2017, after researchers reported that they had grown early pig embryos containing a tiny proportion of human cells, medical ethicist Carolyn Neuhaus was quoted by Gizmodo urging careful public discussion before any such technology reached patients. Stem-cell biologist Paul Knoepfler raised the same questions when news of the Japanese approval broke:
Human-animal hybrid embryo work moves forward, especially in Japan. How much hope is there for organ transplantation via this route? How do we resolve the thorny bioethical considerations? https://t.co/rLJwpDgLbZ
— Paul Knoepfler (@pknoepfler) July 26, 2019
Common myths about human-animal embryos
- "Scientists are creating human-animal hybrids." The work produces chimeras, animals with some human cells, not creatures with mixed human and animal DNA in every cell.
- "A half-human animal will be born." The approved experiments stopped at around two weeks of development. Even successful organ-growth experiments aim for animals that look and behave like ordinary animals.
- "Japan has no rules." Each project must be reviewed by expert panels and approved by the government, under guidelines rewritten specifically for this research.
- "Organ farms are just around the corner." Human cells still contribute very poorly to animal embryos. Years of basic research remain before any clinical use.
Japan's decision did not open the door to science fiction. It allowed one carefully watched line of research to move from the dish into the womb, with tight limits, in the hope of easing one of medicine's most painful shortages.
Sources: Nature, 26 July 2019; Scientific American: Japan approves first human-animal embryo experiments. Images: unlim3d (123RF) and Pixabay.
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