Despite the dominant model for the brain holding it as a single organ developing from one early progenitor cell population being at the forefront for decades, new research led by Stanford Medicine reveals the brain may actually be two separate systems that arose separately over hundreds of millions of years of evolution. Published in Nature Neuroscience on September 18, 2026, by senior author Kyle Loh, Ph.D., associate professor of developmental biology, and co-first authors Carolyn Dundes and Rayyan Jokhai, the study promotes promising frontiers in our understanding of the brain and treating certain neurological diseases.
The brain is made up of the forebrain, midbrain, and hindbrain — all of which were originally believed to trace to the same developmental origins. However, these new findings propose that the brain combines two ancient nervous systems: one for essential functions such as breathing and controlling heartbeat, and the other for those such as language, mathematics, abstract thought, and existential reflection. While the forebrain is associated with complex thought processes such as language, consciousness, and abstract reasoning, the hindbrain rather sits toward the back of the skull and specializes in controlling necessary, automatic processes for survival such as breathing, sleeping, heartbeat regulation, and hunger, as well as directing muscles in the face, tongue, and throat that are important for speaking and swallowing.
When examining one of the earliest stages of embryonic development, the researchers noticed a key insight: The hindbrain didn’t emerge as a later branch of the pathway responsible for producing the forebrain and midbrain. Instead, it followed its own pathway as it developed in parallel with the other regions. Looking across more than 550 million years of evolutionary history, the team found evidence of the two-origin arrangement in chickens, zebrafish, and even acorn worms, particularly noting how jellyfish, which separated from humans about 600 to 700 million years ago, possess two nervous systems positioned at different ends of their bodies. This relationship proposed the idea that the two organs may slowly have grown closer to each other, enabling the human brain to eventually become far more complex. As Loh explained, “evolution could play around with the forebrain, and make mistakes and give rise to all the fancy things like memory and creativity.”
In the formal investigation, initial insights were explored by examining developing mouse embryos, where two different populations of brain progenitor cells were identified: one expressing the Otx2 gene destined to form the forebrain and midbrain, and the other expressing the Gbx2 gene fated to develop into the hindbrain. The researchers found that these populations remained separate and did not overlap, even at the earliest stages of development examined.
This distinction became increasingly clear as the team studied chromatin (a material that packages DNA in cells and helps to control which genes are available for use and which remain inaccessible). The anterior neural ectoderm, which is to become the forebrain and midbrain, and the posterior neural ectoderm, which is to become the hindbrain, were found to have fundamentally different chromatin configurations — the differences effectively committing the respective cells to distinct development paths from the beginning.
Using this discovery, the researchers sought to solve a major lab challenge: Create human hindbrain neurons. This would allow further study of serious diseases involving the brain stem such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). With their newfound insights, the team successfully guided human pluripotent stem cells (capable of becoming any cell in the human body) into becoming functional hindbrain motor neurons for the first time in a lab. The cells behaved like genuine hindbrain neurons by producing electrical signals (action potentials) and creating proteins associated with specific regions of the hindbrain that control facial and swallowing muscles.
With this success, the team is hopeful about the progress of researching diseases such as SMA and ALS through the ability to grow hindbrain neurons in a dish, enabling the study of what goes wrong during these diseases with far greater precision. Additionally, due to the fact that the hindbrain contains neural circuits that regulate hunger among the systems influenced by weight-loss drugs such as semaglutide, this newfound success may prove particularly useful in that area of medicine. Looking to the future, the researchers now want to investigate where the spinal cord comes from in the developmental cycle and determine more precisely how both diseases disrupt hindbrain neurons.
Reflecting on the study and its hopeful implications, Jokhai noted that “now we have a model to better understand these devastating diseases, and work toward regenerative therapies for them.” He remarked, “This is a very exciting new frontier in brain research.”
