Researchers have succeeded in transplanting cultured human brain tissue into the brains of rats. The organoids then fused with the brains of the rodents, they sent neural signals and reacted to environmental stimuli that the rats felt with their whiskers, reports a team of scientists led by Sergiu Pașca from Stanford University in "Nature". Such experimental animals should help to research therapies for neurodegenerative and neuropsychiatric diseases in humans.
Because researchers would like to use brain organoids, i.e. tiny brain -like structures that are bred from human stem cells. But organoids can only imitate human brains to a certain extent: the problem is that they do not train blood vessels. You cannot absorb nutrients. And this means that they don't survive for long. In addition, you do not receive the stimuli necessary for full growth. The brain of a human infant grows and its neurons also combine because it has to absorb new sensory impressions. However, since there are no blood vessels nor networked circuits as in the brain of a living being, certain diseases of organoids cannot be examined, says Agnieszka Rybak-Wolf from Max-Delbrück-Center for Molecular Medicine in Berlin, according to a broadcast of the Science Media Center. "Therefore, brain organoids often fail in the modeling of complex human brain diseases that are related to the formation of circuits such as autism or schizophrenia."
To circumvent this problem and stimulate brain organoids to grow, neuroscientist Pașca and his team planted the cultivated tissue structures in the brains of newborn rats – in the expectation that the human and animal cells would grow together. The team placed the organoids in a specific brain region called the somatosensory cortex, a part of the cerebral cortex. In the area, stimuli are picked up, which are captured by the whiskers and other sensory organs of the rats. From this brain region, the signals are then transmitted to other areas and processed there.
However, human brain cells ripen much more slowly than those of rats. For this reason, the researchers had to wait more than six months before the organoids were completely integrated into the rat brain. After that it was shown that both parts were well overgrown - almost as if you had "added another transistor to a circuit," said Pașca at a press conference.
The transplantation procedure is still too expensive
Molecular biologist Paola Arlotta from Harvard University is enthusiastic about the new results. "It is an important step to be able to design organoids in such a way that they reflect more complex properties of the brain," she says. However, Arlotta is also convinced that the transplant procedure is probably still too expensive and too complex to serve as a standard research instrument at the moment. In her opinion, it is therefore now important to find out how individual human neurons – not just fully developed organoids – can be implanted in a rat brain.
The research group around Pașca wanted to make sure that the human cells in the rat heads are also functional. Therefore, it has changed the neurons in the organoid in such a way that they fire when they are stimulated with the light of a fiber optic cable embedded in the rat brain. The team then trained the rats so that they had to lick an output to drink water. The light was always switched on during training. When the researchers activated the light in the hybrid brains afterwards, the rats also licked the pouring. As a result, the human cells had integrated well enough into the rat brain to control the behavior of the animals. And also when the researchers plucked the wheels of the rats, the human cells fired. Apparently they were able to receive sensory information.
Can diseases be researched with hybrid brains?
Now Pașca and his colleagues wanted to prove that brain disorders could actually be examined in the human-nagers chimera. To do this, create brain organoids from the stem cells of three people with a genetic illness called Timothy syndrome. This disease causes symptoms similar to autism. The brain tissue bred from such cells looked as far as other organoids, but when the researchers transplanted them into rats, they did not grow as big as the rest, and their neurons did not fired in the same way.
Neuroscientist Rusty Gage of the Salk Institute for Biological Studies in La Jolla, California, is pleased with the new results. In 2018, he described in Nature Biotechnology that human organoids can be integrated into the brains of adult mice. Since mice don't live as long as rats, Pașca and his colleagues hoped that the brains of newborn rat babies would adopt the new cells more easily than adult animals. "We are facing major challenges," says Gage. "But I believe that this transplant procedure will become a valuable tool."
Some of the challenges are ethical. Many people are concerned that the creation of human-rag chimars could harm the animals or produce animals with human-like brains. In 2021, a committee of the US National Academies of Sciences, Engineering and Medicine published a report with the following conclusion: Human brain organoids are still too primitive to develop a awareness of gaining a human-like intelligence or other skills that require a legal regulation could. Pașca says that his team's transplanted organoids do not cause seizures or memory gaps in the rats. The behavior of the animals also did not seem to have changed significantly.
Arlotta, who is a member of the board of the National Academies, is convinced that with the progress of science, new, previously unknown problems could arise. "We can't even discuss the issue and then let it rest." In her view, concerns about human organoids need to be weighed against the needs of people with neurological and psychiatric disorders. Brain organoids as well as human-animal chimeras could reveal the mechanisms underlying these diseases. They would make it possible to test therapies for diseases such as schizophrenia and bipolar disorder. "I think," says Arlotta, "we have a responsibility as a society to do everything we can."
