Scientists have transplanted human brain cells into the brains of baby rats in a bid to shed new light on neurological disorders like autism and schizophrenia.
It’s part of an effort to better study human brain development and diseases affecting this most complex of organs, which has long been shrouded in mystery.
The implanted human brain cells grew and formed connections with the brain tissue of the rats, integrating so well that they could sense whisker movements and drive the animals’ behaviour.
"Many disorders such as autism and schizophrenia are likely uniquely human" but "the human brain certainly has not been very accessible," said Dr Sergiu Pasca, senior author of the study published on Wednesday in the journal Nature.
Approaches that don’t involve taking tissue out of the human brain are “promising avenues in trying to tackle these conditions”.
The research builds upon the team’s previous work creating brain "organoids," tiny structures resembling human organs that have also been made to represent others such as livers, kidneys, prostates, or key parts of them.
To make the brain organoids, Stanford University scientists transformed human skin cells into stem cells and then coaxed them to become several types of brain cells.
Those cells then multiplied to form organoids resembling the cerebral cortex, the human brain’s outermost layer, which plays a key role in things like memory, thinking, learning, reasoning, and emotions.
Scientists transplanted those organoids into rat pups two to three days old, a stage when brain connections are still forming.
The organoids grew so that they eventually occupied a third of the hemisphere of the rat’s brain where they were implanted. Neurons from the organoids formed working connections with circuits in the brain.
Human neurons have been transplanted in rodents before, but generally in adult animals, usually mice.
Pasca, a psychiatry professor at the Stanford School of Medicine, said this is the first time these organoids have been placed into early rat brains, creating "the most advanced human brain circuitry ever built from human skin cells and a demonstration that implanted human neurons can influence an animal's behaviour".
Neurons from the organoids "set up shop" in the rats' brains, say the researchers, forming working connections with indigenous circuits.
For example, when researchers stimulated the rats’ whiskers with puffs of air, they found that human neurons in the rat’s brains fired in response, suggesting that the cells were able to pick up sensory information.
Rat whiskers detect nearby objects and surfaces, helping them avoid collisions.
In a separate experiment, Pasca and his colleagues also managed to condition the rats to expect water when the human-organoid tissue in their brains was activated.
Studying disorders in a living brain
To examine a practical use of this approach, scientists transplanted organoids into both sides of a rat’s brain: one generated from a healthy person’s cells and another from the cells of a person with Timothy syndrome, a rare genetic condition associated with heart problems and autism spectrum disorder (ASD).
Five to six months later, they saw the effects of the disease related to the activity of the neurons.
There were differences in the two sides’ electrical activity, and the neurons from the person with Timothy syndrome were much smaller and didn’t sprout as many extensions that pick up input from nearby neurons.
Researchers, whose study was funded partly by the National Institutes of Health, said they could do the same sorts of experiments using organoids made from the cells of people with disorders such as autism or schizophrenia – and potentially learn new things about how these conditions affect the brain, too.
Dr Flora Vaccarino of Yale University – who previously grew lumps containing cerebral cortex that were made with DNA from people with autism – said the study moves the field forward.
"It’s extremely impressive what they do here in terms of what these cells can actually show us in terms of their advanced development… in the rat," said Vaccarino, who wasn’t involved with the study.
How ethical are experiments on animals?
Such experiments in animals also raise ethical concerns. For example, Pasca said he and his team are cognisant of the rats’ well-being and whether they still behave normally with the organoids inside them, which he says they do.
Cognitive tests roughly 200 days post-transplantation showed that the rats were no more fearful than control rats, retained similar memory capabilities, and did not experience seizures, say the researchers.
Still, Pasca does not believe this should be tried in primates. Ethicists also wonder about the possibility of brain organoids in the future attaining something like human consciousness, which experts say is extremely unlikely now.
Some scientists are studying human brain organoids outside of animals.
For example, researchers at ETH Zurich in Switzerland published a study in Nature earlier this month describing how they are growing brain-like tissue from stem cells in the lab and then mapping the cell types in various brain regions and genes regulating their development. Some are using these structures to study autism.
Pasca said brain organoids could also be used to test new treatments for neuropsychiatric disorders, the largest cause of disability worldwide.
Such research, he said, should help scientists make strides that have been extremely difficult until now because it’s so hard to get at the human brain – which is "the reason why we’re so much more behind in psychiatry compared to any other branch of medicine in terms of therapeutics".