Scientists have re-created a pain pathway in the brain by growing four key clusters of human nerve cells in a dish.
This laboratory model could be used to help explain certain pain syndromes, and offer a new way to test potential analgesic drugs, a Stanford team reports in the journal Nature.
"It's exciting," says Dr. Stephen Waxman, a professor at Yale School of Medicine who was not involved in the research.
Currently, prospective pain drugs are typically tested in animals — whose responses are often different than a human's — and in individual nerve cells, which may not reflect the behavior of entire brain networks.
With this new system, known as a brain assembloid, "we have a miniature nervous system that might be a very useful platform," Waxman says.
A pathway with several stops
The model is the result of an effort to re-create the signaling chain that occurs after exposure to painful stimuli, says Dr. Sergiu Pașca, a professor at Stanford University who led the project.
Touch a hot stove, for example, and special cells in the skin "send that information all the way to the spinal cord," Pașca says. "Then the spinal cord will relay it up to the thalamus deep in the brain, and then all the way to the outer layer of the brain, which is the cortex."
To approximate this pathway in the lab, Pașca's team created four different brain organoids, spherical clumps of human nerve cells that grow in a dish. The team coaxed each organoid to resemble one specific type of brain or spinal tissue found along the pain pathway.
"And then we put them together, really put them in close proximity, and watched them as they connected with each other," Pașca says.
After more than six months developing in the lab, the resulting assembloid had created a pathway linking the four organoids. The nerve cells also spontaneously began "working in a coordinated fashion across the four parts of this assembloid," Pașca says.
Chili peppers and pain syndromes
To test the model, the team exposed it to capsaicin, the chemical that makes chili peppers painfully hot.
"Then you start seeing that information traveling," Pașca says. "The neurons that sense these signals get activated and they transmit that information to the next station and the next station, all the way to the cortex."
Next, the scientists tried creating assembloids using cells with genetic variants linked to abnormal pain perception.
One of these variants causes a rare condition called erythromelalgia, or man-on-fire syndrome.
"These individuals feel searing, burning, scalding pain in response to mild warmth," Waxman says.
The scientists found that assembloids with the gene variant produced much more spontaneous communication between organoids, suggesting a heightened sensitivity to pain.
Results like that suggest that organoids are already a useful way to study both nervous system diseases and the pathways they affect, says Dr. Guo-li Ming, a professor at the University of Pennsylvania's Perelman School of Medicine who also had no role in the new study.
For all its complexity, the pain pathway in a dish is a highly simplified version of what goes on in a person, Ming adds. For example, humans have two major pathways that carry pain signals to the brain, while the model system includes just one.
As a result, the model can detect a painful stimulus, but doesn't produce an emotional response, Pasca says.
"So we don't believe that this pathway that we've built is in any way feeling pain," he says.
And these clusters of human cells are likely to become even more valuable as scientists find ways to re-create larger and more complex parts of the nervous system.
For example, Ming's own lab has developed a model of a human neural tube, the structure in an embryo that eventually becomes into a baby's brain and spinal cord. Her goal is to understand how neurological disorders develop early in life.
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