The implanted human brain tissue was created in the lab using a technique that allows scientists to turn skin cells into the equivalent of embryonic stem cells – the cells from which all others develop over time. and as the embryo grows. In the lab, scientists can nudge these cells down the developmental path, growing them into one of approximately 200 types of cells in the human body.
The researchers created clumps of these cells that look like parts of the brain. The clusters, known as organoids, resembled the cerebral cortex, the outermost layer of the brain associated with some of its most advanced processes, including language, memory, thought, learning, decision making, and more. decision, emotion, intelligence and personality.
Using syringes, scientists injected human brain tissue into the brains of two- to three-day-old rat pups. The rat brain cells then migrated to human tissues and formed connections, incorporating the human cells into their brain machinery.
“We’re not removing that part of the rat’s brain. What basically happens is the rat tissue is pushed aside,” said Sergiu Pasca, professor of psychiatry and behavioral sciences at Stanford, who led the study.
Human brain tissue was about a fifth of an inch when transplanted, but had grown and by six months it was about a third of the hemisphere of the rat brain. The brain is organized into two hemispheres, right and left, each responsible for different functions.
Deep within the rat brain, human and rat cells are connected in the thalamus, the area critical for sleep, consciousness, learning, memory, and information processing from all senses except smell.
“Overall, I think this approach is a step forward for the field and offers a new way to understand disorders,” which involve brain cell dysfunction, said MRC group leader Madeline A. Lancaster. Laboratory of Molecular Biology at Cambridge. , England, who did not participate in the study.
“Ethically, there can be animal welfare concerns, and so, as with all animal experimentation, the benefits must always be weighed against the risks to the animal,” said Lancaster. “But I have no concerns about whether human transplants would make the animal more ‘human’ because the size of these transplants is small and their overall organization is still lacking.”
Pasca said the researchers had extensive discussions with animal welfare ethicists in preparation for the experiments. He said the rats in the study showed no signs of anxiety and there was no evidence they were in pain or having seizures.
Japanese stem cell pioneer Yoshiki Sasai is credited with developing the first neural organoid in 2008, but these had limited impact because they lacked the vessel system that carries blood throughout the body, a said Lancaster. This deficiency caused organoid cell stress and death.
“This study overcomes this limitation by transplanting organoids into the rat brain where the organoids can vascularize,” Lancaster said. “The result is much more mature structures, connections and activity” from the transplanted tissue inside the rat.
In one experiment, the Stanford team took skin cells from a person with a rare inherited genetic condition called Timothy syndrome, which has some of the hallmarks of autism and epilepsy. Using the ability to transform skin cells into other cell types, the researchers created brain organoids from the patient and implanted them into one side of the rat’s brain.
For comparison, they transplanted organoids from a healthy person into the other side of the brain of the same rat. They found that after five to six months, Timothy syndrome cells were smaller and involved in very different electrical activity than healthy brain cells. Fewer than 100 people worldwide have been diagnosed with Timothy syndrome.
“I’m not entirely surprised by the results, but it’s super cool,” said Bennett Novitch, a member of the Broad Center of Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles, who has no participated in the study. . In 2021, Novitch and his colleagues developed organoids that produced brain waves, the electrical impulses that brain cells use to communicate with each other.
He said Stanford scientists have shown that human brain organoids can not only be integrated into rat brains, but also used to modify the animal’s behavior.
In a complex experiment, they created clumps of human brain cells that had been customized so that individual neurons could be activated by a specific frequency of blue laser light. These clumps were then injected into rat brains and after three months the scientists threaded ultra-thin fiber optic cables into the rats’ brains so the researchers could radiate blue light.
The rats were placed in glass boxes with a spout. The researchers then conditioned the rats to wait for water only after their brains received a pulse of blue light. The rats grew to associate blue light with receiving water, showing that the implanted human cells were now involved in the complex reward-seeking machinery within. their brains.
“It’s a very difficult experiment to do,” Novitch said.
He noted, however, that using rats implanted with human brain tissue for drug testing would work for small studies, but not for pharmaceutical companies because of the speed and scale required.
Pasca said he hopes to teach other researchers how to use his group’s techniques to study different brain disorders.
“There are enough problems in neuroscience to solve to last for many years to come,” he said. “The challenge of understanding psychiatric disorders is immense.”
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