Discovery & Innovation

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>>> Transplant of human brain tissue into rats could help study autism, other disorders

The approach is expected to prompt new research into epilepsy, schizophrenia and intellectual disabilities


Washington Post

By Mark Johnson

October 12, 2022


https://www.washingtonpost.com/science/2022/10/12/brain-tissue-rats-stanford/


Stanford scientists transplanted human brain cells into the brain of a rat. The light flickering on and off shows the human cells as they work inside the brain.

In work that could boost our understanding of brain disorders and enable discovery of new drugs to treat them, researchers at Stanford University School of Medicine transplanted human brain tissue into rats, where it became a functional part of their brains.

Their study, published Wednesday in the journal Nature, took seven years to complete and involved extensive ethical discussions about animal welfare and other issues. The study’s most immediate applications will involve research into conditions such as autism, epilepsy, schizophrenia and intellectual disabilities.

The implanted human brain tissue was created in the lab using a technique that allows scientists to change skin cells into the equivalent of embryonic stem cells — the cells from which all others develop as the embryo grows. In the lab, scientists can nudge these cells down the developmental pathway, growing them into any one of the 200 or so types of cells in the human body.

Researchers created clumps of these cells that resemble parts of the brain. The clumps, 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, emotion, intelligence and personality.

Using syringes, the scientists injected the human brain tissue into the brains of rat pups two to three days old. Rat brain cells then migrated to the human tissue and formed connections, incorporating the human cells in their brain’s machinery.

“We don’t remove that part of the rat brain. Essentially what happens is that the rat tissue is pushed aside,” said Sergiu Pasca, professor of psychiatry and behavioral sciences at Stanford, who led the study.

The human brain tissue measured roughly one-fifth of an inch when transplanted, but it expanded and by six months accounted for about one-third of the hemisphere of the rat’s brain. The brain is organized into two hemispheres, right and left, each responsible for different functions.

Deep inside the rat’s brain, human and rat cells connected in the thalamus, the area critical for sleep, consciousness, learning, memory and processing information from all of the senses, except for smell.

“Overall, I think this approach is a step forward for the field, and offers a new way to understand disorders” that involve the malfunction of brain cells, said Madeline A. Lancaster, a group leader at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, who did not participate in the study.

“Ethically, there may be concerns about animal welfare, and so just like all animal experimentation, the benefits should always be weighed against the risks to the animal,” Lancaster said. “But I do not have any concerns around whether the human transplants would cause the animal to become more ‘human,’ since the size of these transplants are small and their overall organization is still lacking.”

Pasca said researchers had extensive discussions with ethicists about animal welfare in preparation for the experiments. He said the rats in the study displayed no signs of anxiety, nor was there evidence they suffered pain or seizures.

Japanese stem cell pioneer Yoshiki Sasai is credited with developing the first neural organoid in 2008, but these have had limited impact because they lacked the system of vessels that carries blood throughout the body, Lancaster said. This deficit caused the organoid cells to become stressed and die.

“This study overcomes this limitation by transplanting organoids into the rat brain where the organoids can become vascularised,” 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 genetic condition called Timothy syndrome, which has some of the characteristics of autism and epilepsy and has been diagnosed in fewer than 100 people worldwide. Using the ability to change skin cells into other types of cells, 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 same rat’s brain. They discovered that after five to six months, the Timothy syndrome cells were smaller and involved in very different electrical activity than the healthy brain cells.

“I’m not entirely surprised by the findings, 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 at Los Angeles, who was not involved in the study. In 2021, Novitch and colleagues developed organoids that produced brain waves, the electrical pulses that brain cells use to communicate with one another.

He said the Stanford scientists showed that human brain organoids could not only be integrated into the rat brain, but also used to change 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 switched on by a specific frequency of blue laser light. Those clumps were then injected into rat brains, and after three months the scientists threaded ultrathin fiber-optic cables into the rat brains so the researchers could beam in blue light.

The rats were placed in glass boxes with a water spout. The researchers then conditioned the rats to expect water only after their brains had received a pulse of blue light. The rats grew to associate the blue light with receiving water, showing that the implanted human cells were now involved in the complex reward-seeking machinery inside their brains.

“This is very difficult experimentation to do,” Novitch said.

He noted, however, that using rats implanted with human brain tissue for testing drugs 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 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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