Should human experimentation be prohibited

Hybrid of humans and animals : Japan allows chimera experiments for organ cultivation

The idea is simple: take human stem cells and inject them into an early animal embryo. If, for example, a pig is no longer able to produce an organ, for example the pancreas, due to a genetic defect, the human cells step in during development and form the vital organ that produces insulin. A pig grows with a human pancreas, which can then be removed and implanted in, for example, seriously ill diabetes patients. Hiromitu Nakauchi will be the first scientist to test this idea. The Japanese Ministry of Education and Science has now issued new regulations that allow the researcher, who works at the University of Tokyo and Stanford University in California, to insert human stem cells into mouse and rat embryos and grow in the uterus of corresponding surrogate animals until birth allow.

Mouse with pancreas made from rat cells

Nakauchi made a name for himself in 2010 when he succeeded in using the method to grow a pancreas in mice, which consisted almost exclusively of rat cells. The mouse embryos lacked a gene (pdx-1), so that in the course of embryonic development they would not have been able to form a pancreas themselves and would have died. But the injection with embryonic stem cells ("induced pluripotent stem cells", ipS) from the rat "saved" the animals. In 2017, Nakauchi then showed that in the reverse experiment - in which a pancreas grew from mouse cells in rat embryos - pancreatic organs were created that healed mice with diabetes, i.e. made them independent of insulin injections. According to Nakauchi, other organs were also able to grow with the technology, such as the kidney and thymus - but so far not human ones.

With the new guidelines, researchers in Japan now have better opportunities to test the method for its applicability in humans than in the USA, for example. Such experiments are not expressly prohibited there, but the National Institutes of Health, the main source of funding for such science, declared a moratorium on chimeric experiments in 2015.

In Germany, the Embryo Protection Act prohibits such experiments, at least as soon as human (stem) cells are involved. For example, Paragraph 7 forbids, with the threat of up to five years imprisonment, "combining cells with a human embryo which contain genetic information other than the cells of the embryo and which is able to differentiate itself further with it". It is also explicitly forbidden to transfer a human embryo to an animal, including mixtures of human and animal cells, in other words "chimeras".

In Japan, a committee of experts from the Ministry of Science will decide which experiments can be approved in detail - probably in August. For the time being, Nakauchi only wants to grow chimeric mouse-human embryos for around 14 days, i.e. not allow them to grow until birth. In the case of the corresponding rat experiments, termination is planned after around 15 days. If these experiments turn out to be promising, according to the journal "Nature", Nakauchi wants to breed chimeric embryos in pigs for up to 70 days.

Is it ethical to grow chimeras?

Nakauchi has no ethical concerns: "For my part, I do not consider this type of experiment to be unethical," he told Tagesspiegel some time ago. "Such experiments can be extremely useful, for example, to produce human tissue for drug testing, for research and, of course, for organ replacement therapy."

One concern is that animals, which, depending on the experiment, consist of 10, 50 or 70 percent human cells, may also develop more or less human characteristics - for example if the human cells are not restricted to the desired organ, such as the kidney , but also end up in the brain or the reproductive organs. Nakauchi believes, however, that this "scattering effect" can be controlled: "It is relatively easy to control the differentiation of stem cells in certain organs and tissues."

The German Ethics Council had already dealt with the concerns about chimera experiments in 2011 and then took a position. For example, the transfer of human cells into the brains of mammals - with the exception of primates - is "ethically permissible".

"It is very important to understand that if we breed these chimeras, we are not creating a new species," says Nakauchi. Chimeras are a mixture of cells, each with their own genetic background, says the researcher. Quite different to "hybrids", in which the genetic material of different species or different variants of a species is mixed. Such mixed states can also be inherited via the mixed inheritance. "The chimeric state is not passed on to the next generation." And if you were to create a chimeric monkey with a human brain, for example, says Nakauchi, then the germ cells would be either human or monkey. Nevertheless, it is probably a good idea not to let the mouse-human chimeras grow until they are born, but to stop their development beforehand.

Lots of open questions to explore

How far he will get with his experiments is still open. What worked with mouse-rat chimeras does not necessarily have to work with combinations of human and pig cells or mouse-human mixtures. For example, human stem cells in sheep embryos, which cannot develop a pancreas, do not seem to grow properly. In any case, last year at a conference of the American Association for the Advancement of Science in Austin, Texas, Nakauchi reported that after four weeks the sheep embryos contained hardly any human cells and certainly no functioning human pancreatic organ. Nakauchi suspects that the genetic makeup of the two species is too different for the two cell types to work together - compatibility problems as once between Apple and IBM computers.

There is another reason why Nakauchi's chimera technique is not likely to be used in the short or medium term: the human organs in the chimera are flushed with animal blood and blood vessels and nerves run through, they have to interact with animal hormones that are not always perfectly tailored, and become metabolic products that do not appear or appear differently in humans. This means that even an organ basically consisting of human cells would always contain a lot of animal components and would probably trigger a dangerous rejection reaction in the patient after a transplant.

Xenotransplantation the more practical approach

Nakauchi thinks that the pig in which the human organ grows has to be adapted even further. "For example, human blood cell development could be established in the animal's bone marrow." The pig's blood would then be "more human". In fact - quite independently of Nakauchi's chimera experiments - there are efforts to genetically adapt pigs, for example, so that their organs can be transferred to humans. Such "xenotransplantations" are only possible if the pig cells can no longer be recognized as "foreign" by the human immune system. For this purpose, certain genes are modified so that the surface of the pig cells is freed of typical "animal" tissue features. These measures have meant that pig hearts in monkeys have survived and functioned for over a year. These findings from xenotransplantation could play into the hands of Nakauchi, as they would reduce the "distance" between pigs and humans and make it more likely that the chimeric organs could be transferred to humans.

Eckhard Wolf from the Ludwig Maximilians University in Munich, who himself researches pigs for xenotransplantation, considers Nakauchi's strategy to be immature, also for very practical reasons. "If at some point you have a pig whose organs are accepted by the human body, then you can breed it on a large scale," says Wolf. "With the chimera approach, on the other hand, you have to start from scratch every time, that is, obtain new stem cells from the patient, create a chimera and harvest the organ." To standardize this in such a way that a drug authority grants approval, Wolf considers it very difficult.

"There is no reason why a human liver cannot grow in a pig," Nakauchi is convinced. "If it doesn't work because certain factors are missing, then we'll just replace them." And if you took monkeys instead of pigs, goats or sheep, he was "almost certain that it will work."

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