Schizophrenia, autism research may have found a promising new avenue
Schizophrenia, which refers to a spectrum of disorders that all involve a disconnection from reality, affects approximately 24 million (or 1 in 300) people worldwide. A new study published in Autism Research shows that about 100 in 10,000 (or 1 in 100) children around the world are diagnosed with autism spectrum disorder, a developmental disability caused by differences in the brain. This is an increase from the 2012 global prevalence report which found that 62 in 10,000 children were autistic. Very little is known about the causes of either schizophrenia or autism, but genetics and brain chemistry have been cited as causes. Research into these debilitating conditions is therefore critical to have any chance at their prevention and treatment. In this article by The Wall Street Journal, research by neuroscientists at Stanford University, in which they transplanted tiny blobs of neural tissue known as organoids into the brains of newborn rats, is said to be expanding a pathway for exploring brain development and the mechanics of some diseases. According to neuroscientists, such research could probe the molecular underpinnings of hard-to-study psychiatric conditions such as autism and schizophrenia. – Nadya Swart
Scientists Grow Human Cells in Rat Brains to Study Autism, Schizophrenia
Researchers transplant tiny spheres of human tissue into rat brains to better understand some conditions
Bioengineered human tissue transplanted into rat brains generated hybrid neural circuits that affected the animals' behavior, researchers said, expanding a pathway for exploring brain development and the mechanics of some diseases.
Neuroscientists at Stanford University transplanted tiny blobs of neural tissue known as organoids into the brains of newborn rats. The human cells grew and made functional connections within the rat brain, generating hybrid neural circuits, the researchers said in a study published Wednesday in the journal Nature.
Such circuits are the information highways of nervous systems, processing sensory information to drive behaviors, including movement, learning, memory and motivation. Transplanting brain-like organoids offers researchers a unique opportunity to study how abnormalities in the connectivity, activity or shape and size of human neurons might manifest as disease.
"We can use this to do experiments that we cannot do with humans," said Vincenzo De Paola, a neuroscientist at Duke-NUS medical school in Singapore and Imperial College London who wasn't involved in the work. Such research could probe the molecular underpinnings of hard-to-study psychiatric conditions such as autism and schizophrenia, neuroscientists said.
That promise will need to be weighed against ethical concerns about animal welfare and how to classify animals with chimeric brains, or brains that have both human and animal cells, some researchers and ethicists said.
"This whole line of research has introduced complex gray areas," said Nita Farahany, a Duke University neuroethicist who wasn't involved in the study.
One point of debate will be whether animals implanted with human brain-like organoids should be more protected under rules governing animal research, Dr. Farahany said. A 2021 report by the U.S. National Academies of Science, Engineering and Medicine said neural organoid research including transplants of human tissue into animals presented concerns including the potential for animal suffering or the augmentation of their cognitive abilities.
Sergiu Pasca, a Stanford University neuroscientist who led the work published in Nature, said he and his colleagues found no evidence in their experiments of detrimental effects such as memory deficits, increased anxiety or seizures in rats transplanted with human brain-like organoids.
Dr. Pasca and his colleagues took skin cells from healthy volunteers and from patients with Timothy syndrome, a rare genetic condition associated with autism and epilepsy. They turned back the cells' molecular clock to transform them into a kind of stem cell that can morph into any kind of cell in the body. They then coaxed them into developing into various types of brain cells, which organized themselves into blob-resembling tissue from the cerebral cortex, the outermost layer of the brain. The organoids were then transplanted into the brains of the newborn rats, where they continued to grow.
A few months after transplant, normal human neurons in rat brains were six times as large and had more branchlike structures called dendrites, which neurons use to make connections to other neurons, than neurons in organoids that remained in lab dishes. Neurons in organoids transplanted from patients with Timothy syndrome were much smaller and had fewer branches. The differences between normal and diseased neurons only became apparent after cells developed in the rats' brains, the researchers said.
The findings emphasize the limits of using brain-like organoids in petri dishes to study brain development and neuropsychiatric conditions, according to the researchers.
"Some of these deficits associated with disease are only going to reveal themselves within the context of a circuit," Dr. Pasca said. "Psychiatric disorders are disorders of circuits, and they result in behavioral changes because they change circuits in a specific way."
This isn't the first time scientists have transplanted brain-like organoids into lab animals' brains. In 2018, a team from the Salk Institute for Biological Studies in La Jolla, Calif., and San Diego State University showed that neurons in brain-like blobs formed active connections with mouse neurons. In a study from June, which has yet to be peer reviewed, international researchers found that human neurons transplanted into the visual cortex of mice responded to visual stimuli, showing how adaptable neurons are.
The new study goes further in examining behavior after integrating human brain tissue into rodent brains. When the Stanford researchers puffed air on their rats' whiskers, human neurons in the region of the rats' brains that received sensory information became active. In another set of experiments, Dr. Pasca and his team altered human neurons to become active when exposed to blue light. They transplanted organoids containing the bioengineered neurons into rats' brains and trained the animals to associate flashes of blue light beamed into their brains through a fiber optic cable with a water reward. When they stimulated the neurons with blue light, the rats looked for water.
"That's beautiful," said Gyorgy Buzsaki, a New York University neuroscientist not involved in the study. "They show that indeed there must be connections, functional connections between the organoid and the host."
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