This cross-section of the rat brain shows that tissue from the human brain fluoresces the organoid in the human brain in light green color. These transplanted clusters of human neurons could aid the study of brain disorders, the scientists say.
Pasca Laboratories / Stanford Medicine
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Pasca Laboratories / Stanford Medicine
This cross-section of the rat brain shows that tissue from the human brain fluoresces the organoid in the human brain in light green color. These transplanted clusters of human neurons could aid the study of brain disorders, the scientists say.
Pasca Laboratories / Stanford Medicine
Scientists have demonstrated a new way to study conditions such as autism spectrum disorder, ADHD, and schizophrenia.
A team from Stanford University, the approach involves transplanting a group of live human brain cells from a lab dish into the brain of a newborn rat. report in the magazine Nature.
The cluster, known as a brain organoid, then went on to grow in ways that mimic the human brain and could allow scientists to see what’s wrong in a wide range of neuropsychiatric disorders.
“It’s definitely a step forward,” said Paola Arlotta, a prominent brain organoid researcher at Harvard University, who was not involved in the study. “The ultimate goal of this work is to begin to understand the characteristics of complex diseases such as schizophrenia, autism spectrum disorder, bipolar disorder.”
But this advance may be unsettling for some, says bioethicist Insoo Hyundirector of life sciences at the Museum of Science in Boston and a member of Harvard Medical School’s Center for Bioethics.
“People tend to assume that when you transfer biological material from one species to another, you transfer the nature of that animal to another,” Hyun said, adding that even the most advanced brain organoids are still very rudimentary versions of a human brain.
Scientific Obstacle Clearing
Success in transplanting human brain organoids into living animals seems to have removed a major barrier to their use as human disease models. It also represents the culmination of seven years of work supervised by Dr. Sergiu Pascaa professor of psychiatry and behavioral sciences at Stanford.
Organic substances in the human brain are made from pluripotent stem cells, can be coaxed into becoming many different types of brain cells. The cells are grown in a rotating vessel called a bioreactor, which allows the cells to spontaneously form brain-like spheres the size of a small pea.
After a few months, the organoids grown in the lab stopped growing, says Pasca, whose lab at Stanford invented the transplant technique. The individual neurons in the cluster are still relatively small and make relatively few connections, he said.
“No matter how long we keep them in a dish, they don’t become as complex as the human neurons in the real human brain,” says Pasca. That may be one reason organoids, he said, have not yet revealed much about the origins of complex neuropsychiatric disorders.
So Pasca’s team set out to find an environment for the organics that would allow them to continue to grow and mature. They found one in the brains of newborn mice.
“We discovered that [organoid] Over a period of several months, the volume increased about nine times, says Pasca.
The transplanted cells did not seem to cause problems for the mice, Pasca said, as they functioned normally as they grew.
“The rat tissue was just pushed to the side,” he said. “But now you also have a group of human cells that are integrated into the circuit.”
Human cells begin to make connections with mouse cells. Meanwhile, the rat’s blood vessels began delivering oxygen and nutrients to human cells.
A link with the senses
Pasca’s team placed each organoid in an area of the rat brain that processes sensory information. After a few months, the team performed an experiment that showed that human cells were responding to whatever the mice sensed.
“When you stimulate the antennae of a mouse, most human neurons engage in an electrical activity following that stimulation,” says Pasca.
Another experiment showed that human cells can even influence the behavior of a mouse.
The team trained the mice to associate the stimulation of their human cells with a reward – a glass of water. Finally, the mice started looking for water whenever human cells were stimulated.
In one final experiment, Pasca’s team set out to show how implanted organoids could help identify brain changes associated with a specific disorder in humans. They chose Timothy syndromeA very rare genetic disorder that affects brain development in ways that can cause symptoms of autism spectrum disorder.
The team compared organoids made from stem cells of healthy people with organoids made from stem cells of patients with this syndrome. In the lab, clusters of cells look the same.
“But once we transplanted and looked at it 250 days later, we discovered that while the control cells grew significantly, the patient cells did not,” says Pasca.
A better model, with ethical concerns
The experiments show that Pasca’s team has developed a better model for studying brain disorders in humans, Arlotta said.
The key seems to be to give the implanted organoids sensory information that they don’t develop in a treat, she said, noting that an infant’s brain needs this kind of stimulation for normal development.
“Those are the things that we get after we are born, especially when we begin to experience the world and hear sounds, see lights, etc.,” she said.
But as brain organoids become more like actual human brains, scientists will have to consider the ethical and social implications of this study, Arlotta said.
“We need to be able to see it, consider it, discuss it, and stop it if we think we’re going to be at a point one day where we shouldn’t be making progress,” he said. she said. “I think we’re very, very far away from that moment right now.”
Even the most advanced brain organoids, Hyun said, are nothing remotely quite like the capabilities of the human brain. However, much of the ethical discussion has focused on the possibility that an organoid could achieve human-like consciousness.
“I think it was a mistake,” Hyun said. “We don’t know exactly what ‘human-like consciousness’ our consciousness is, and the closer issue, the more important one, is the health of the animals used in the study.”
He said that was not an issue in the Pasca lab experiments because the organics did not appear to harm the animals or change their behavior.
If the organoids in the human brain were grown in larger, more complex animal brains, clusters of cells could grow in ways that would damage the animals, Hyun said.
“What I care about,” he said, “is the next thing.”
