Oct 15, 2022 - Science

Human cells transplanted into rat brains could offer new insights on diseases

A transplanted human organoid labeled with a fluorescent protein in a section of the rat brain. Credit: Stanford University

A transplanted human organoid labeled with a fluorescent protein in a section of the rat brain. Credit: Stanford University

Lab-grown clusters of human neurons transplanted into the brains of young rats and connected to their brain circuitry offer a new way to study the human brain, researchers reported this week.

Why it matters: The living human brain is largely inaccessible to scientists, hindering the study of autism spectrum disorders, schizophrenia and other conditions.

  • The approach is "a step forward for the field and offers a new way to understand disorders," Madeline Lancaster, a developmental biologist at the Medical Research Council's Laboratory of Molecular Biology in Cambridge, U.K., told Axios in an email. Lancaster developed brain organoid techniques but wasn't involved in the new research.

How it works: Brain organoids are clumps of cells a few millimeters in diameter that are made from stem cells that develop into neurons.

  • Organoids made from human cells offer scientists a model that's more similar to the human brain than animal models, like rats.
  • But organoids in a dish can only develop so much. Without the blood vessels that support living cells, the neurons stop growing and they don't form circuits, leaving the organoids far less complex than the human brain and limiting what scientists can glean from them about brain disorders.
  • Scientists have tried to take advantage of an animal's more complex environment to create more sophisticated organoids: when they are transplanted into adult rats, previous research has shown organoids continue to mature.

What's new: Scientists led by neurobiologist Sergiu Paşca at Stanford University transplanted organoids — about 1 to 1.5 millimeters in diameter — into the developing brains of young rats.

  • After three months, individual neurons grew larger than they did in a dish and the organoids grew to about nine times the size they were when they were implanted, covering about one-third of the rat's brain hemispheres, the team reported this week in the journal Nature.
  • The human neurons and rat neurons began to form connections, which didn't affect the behavior of the rats.
  • The researchers then tested whether the human neurons integrated into the rat brain circuitry by blowing air at the rat's whiskers. They found the human neurons were active in response.

In another experiment, the researchers demonstrated that the human neurons can also drive the rat's behavior.

  • A technique called optogenetics was used to activate the human neurons in rats when they drank from a water bottle (a reward).
  • Over time, the rats began to go to the water bottle when the neurons were activated. Rats that didn't have the transplant, or whose human neurons weren't turned on, didn't drink from the bottle.

The impact: Paşca and others aim to use organoids to study brain disorders.

  • The team transplanted cells from patients with Timothy syndrome, a rare genetic disease, and saw defects in the neurons as they grew, which hadn't been seen in organoids that weren't transplanted.
  • "We have a moral imperative to find better models to study these conditions, and tackling difficult conditions such as psychiatric disorders will require bold new approaches," Paşca said in a press conference.

What's next: "There are interesting possibilities when you are looking at this general model for repairing the brain after some injury," says neurosurgeon Isaac Chen from the Presbyterian Medical Center of Philadelphia, who studies brain organoid transplantation.

  • A first step would be to see whether transplanted organoids could be integrated into an animal with an injury, he adds.

The big picture: Brain organoid research brings ethical and legal concerns, along with debates about the limits of the research.

  • As of now, organoids still aren't organized like human brain tissue, and "putting human organoid-derived cells in the brain [of an animal] does not in any way make their consciousness human," says Jeantine Lunshof, a bioethicist at Harvard University who studies the ethics of organoids.
  • A current concern, though, is whether organoids might be transplanted to non-human primates. Paşca says there is no need: "It's not something that we would do or that I would encourage doing."
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