Two Brains in One Skull

For centuries, scientists thought of the brain as a single, unified organ. New research from Stanford Medicine, published in Nature Neuroscience on September 18, overturns that model. The human brain is two distinct organs that evolved independently over hundreds of millions of years, packaged together in one skull.

The split

The adult brain has three main regions: the forebrain, midbrain, and hindbrain. The forebrain handles higher-level thinking: language, consciousness, abstract reasoning. The hindbrain, at the back of the skull, controls the automatic functions that keep us alive: breathing, sleeping, heartbeat regulation, and the muscles of the face, tongue, and throat.

The prevailing theory held that a single progenitor cell early in development gives rise to the entire brain. The Stanford team, led by Kyle Loh, discovered that this is wrong. The forebrain and midbrain arise from one progenitor cell expressing the gene Otx2, while the hindbrain arises from a completely different progenitor cell expressing Gbx2. These two cell populations are mutually exclusive from the earliest stages of development.

The researchers found this by examining developing mouse embryos during gastrulation, the stage when the body first takes shape. The hindbrain follows a separate developmental path running in parallel to, not branching off from, the pathway that creates the forebrain and midbrain.

Why lab-grown hindbrain neurons kept failing

This discovery explains decades of frustration in neuroscience. Scientists had been trying to coax forebrain and midbrain progenitor cells into becoming hindbrain cells. The Stanford study shows that is fundamentally impossible. The two progenitor populations have different chromatin configurations that lock each cell into its respective fate, like travelers on parallel tracks that never cross.

As graduate student Rayyan Jokhai put it: "Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible."

Armed with this knowledge, the team successfully grew functional human hindbrain motor neurons in a petri dish for the first time. These lab-grown neurons exhibited action potentials and produced proteins identifying hindbrain segments that control facial and swallowing muscles.

550 million years of separation

The researchers traced the two-origin pattern back through 550 million years of evolution. They found it in chickens, zebrafish, and acorn worms, which share a distant common ancestor with humans. Jellyfish, which diverged from humans about 600 to 700 million years ago, have two nervous systems at different ends of their body.

"Our research suggests that evolution took two existing neural systems and pushed them together spatially," Loh said. "Having the brain as one organ would probably be more efficient, but we rely on this primordial way to make the brain as two separate pieces."

Why this matters for disease

The inability to grow hindbrain neurons in the lab has hampered research into devastating brain stem diseases. Spinal muscular atrophy (SMA) is a leading genetic cause of death in children under 1 year old. Amyotrophic lateral sclerosis (ALS) affects both the forebrain and hindbrain. In both disorders, hindbrain neurons gradually cease to function, patients lose the ability to swallow and eventually to breathe.

Now that hindbrain neurons can be grown in a dish, researchers have a model to study these diseases and work toward regenerative therapies. There is also an unexpected connection to obesity treatment: the hindbrain contains circuits that regulate hunger, which is how weight-loss drugs like semaglutide work.

The word "brain" implies a single organ with a single origin. It turns out to be two ancient nervous systems, operating as one, in a partnership that has lasted 550 million years.