Pain is an essential part of life. It’s a defense mechanism that keeps the body safe. For most people, pain is fleeting. But for some, it is a chronic and debilitating experience. More than 30 percent of people worldwide suffer from chronic pain.1 Yet, effective treatments for pain disorders are limited and often addictive. In fact, the Food and Drug Administration has approved only one new non-opioid pain reliever in more than two decades.
Studying the neural pathways of pain perception is technically challenging in animal models and humans. Information about painful stimuli is conveyed to the brain via the ascending somatosensory pathways.2 These pathways consist of discrete groups of neurons that sequentially link peripheral organs, such as the skin, to the spinal cord and then to various regions in the brain. Even though scientists have studied various components of these circuits in animal models, a comprehensive understanding of how these neural networks develop and function has eluded them. Neural organoids, three-dimensional cultures of neurons that resemble their in vivo counterparts structurally and functionally, help fill these gaps.3
Now, for the first time, researchers have recreated a functional somatosensory neural pathway in a dish using human cells. These human ascending somatosensory assembloids, integrate somatosensory, spinal, thalamic and cortical organoids.4 Their findings, published in Nature, could help researchers tease apart the mechanisms of various sensory disorders and aid the screening of novel drug candidates.
“This is important groundbreaking work,” said Kirsty Bannister, a pain neuroscientist at Imperial College London who was not involved in the study. “It will accelerate our understanding of how these circuits function and the processes that underpin their development. That knowledge is invaluable.”
Sergiu Pasca, a neuroscientist at Stanford University and coauthor of the study, pioneered the creation of neural assembloids in 2017.3 He found that individual organoids for human cortical and forebrain networks were capable of forming meaningful connections in a dish. Building on this technology, Pasca and his team have now generated a four-component sensory circuit. To form the individual organoids, the team first converted human skin cells into pluripotent stem cells, which they transformed into neurons with sensory, spinal, thalamic, or cortical identity, thus producing the corresponding neuronal clusters.
Sergiu Pasca is a neuroscientist at Stanford University who pioneered the creation of neural assembloids.
Pasca Lab
The integration of the organoids into an assembloid happened organically, said Pasca. The team simply placed the four neuronal clusters in sequence—sensory, spinal, thalamic, and cortical—and left them to grow and find their own connections. “When you put them together, there are remarkable self-organizing forces at play that allow the cells, which now come with their own instructions, to come together and force some of those circuits,” Pasca said. “I was super excited to see them.” After 200 days, a centimeter-long sausage-shaped human somatosensory assembloid emerged.
To test its functionality, the team activated the sensory organoid using capsaicin—a substance found in chili peppers that activates pain receptors—and measured the neuronal activity of all organoids in the assembloid. Not only did the sensory neurons respond to the stimulus, but the four organoids exhibited synchronous activity.
Pasca noted that the circuit is far from complete. “It’s not vascularized, doesn't have immune cells, and is not coupled to other circuits in the brain,” he said. “But the question is: Is it useful? Is it more than the sum of its parts?”
The answer to this came through an application for the model. Pain disorders in humans can manifest in two ways: hypersensitivity or insensitivity to painful stimuli. Different mutations in the gene SCN9A, which encodes for a sodium channel that is abundant on the peripheral sensory neurons, can cause these conditions. Pasca and his colleagues used CRISPR-mediated gene editing to introduce these mutations to the assembloids to assess their effects on neural activity throughout the organoids. The hypersensitivity genetic mutation increased synchrony between the organoids, which was diminished in systems with the mutation that caused pain insensitivity.
Though the study is a major step forward, experts in the field are cautious. “While these assembloids can tell us something about circuit integration, they cannot model the pain experience,” Bannister said. The circuit reproduced here is only one half of pain perception. It lacks the descending pathway that creates the feeling of pain. Bannister would like to see a model that integrates these pathways to reflect how the brain talks back to the spinal cord to modulate nociception.
- Cohen SP, et al. Chronic pain: an update on burden, best practices, and new advances. The Lancet. 2021;397(10289):2082-2097.
- Colloca L, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3(1):1-19.
- Birey F, et al. Assembly of functionally integrated human forebrain spheroids. Nature. 2017;545(7652):54-59.
- Kim J il, et al. Human assembloid model of the ascending neural sensory pathway. Nature. 2025.
