For as long as neuroscience has existed, the brain has been treated as one organ with one origin story: a single population of embryonic cells that branches out to build the forebrain, midbrain, and hindbrain alike. A new study led by Stanford Medicine says that story is wrong. The brain, it turns out, may really be two ancient nervous systems that fused together over hundreds of millions of years of evolution, and never actually merged their instructions.

Two Brains, Two Origins

The adult brain is usually described as three regions: the forebrain (language, reasoning, consciousness), the midbrain, and the hindbrain, the brain stem that quietly runs breathing, heartbeat, sleep, and swallowing in the background. The textbook model held that all three trace back to a single progenitor cell early in development.

Working with mouse embryos at the earliest stage of development, gastrulation, graduate students Rayyan Jokhai and Carolyn Dundes found something different: two entirely separate progenitor populations, present from the start and never overlapping. One, marked by the gene Otx2, becomes the forebrain and midbrain. The other, marked by Gbx2, becomes the hindbrain. Neither one is a branch of the other, they run in parallel from day one.

A Split Written Into the DNA Packaging

The team went a layer deeper and looked at chromatin, the packaging that determines which genes a cell can actually access. The future forebrain/midbrain tissue and the future hindbrain tissue turned out to have fundamentally different chromatin configurations from the earliest moments examined, effectively locking each population onto its own developmental track.

That finding also explains a decades-old lab problem: scientists have never been able to reliably grow human hindbrain neurons in a dish. According to Jokhai, earlier attempts were likely trying to coax forebrain and midbrain progenitors into becoming hindbrain cells, something this study shows simply isn’t possible, because the two cell types were never interchangeable to begin with.

Growing the Neurons Nobody Could Grow

Once the team understood the hindbrain’s separate origin, they used that insight to guide human pluripotent stem cells directly into functional hindbrain motor neurons for the first time. The lab-grown cells fired real action potentials and expressed the marker proteins of the hindbrain regions that control facial movement and swallowing, genuine hindbrain neurons, made to order.

A 500-Million-Year-Old Pattern

Curious how far back this split goes, the researchers checked the same two-origin pattern in chickens, zebrafish, and acorn worms, animals separated from humans by hundreds of millions of years of evolution. They even point to jellyfish, whose two separate nervous systems sit at opposite ends of the body, as a hint that vertebrate brains may have formed when evolution pushed two pre-existing nervous systems into the same physical space rather than growing one system from scratch.

“Evolution took two existing neural systems and pushed them together spatially,” says senior author Kyle Loh. “We rely on this primordial way to make the brain as two separate pieces.”

Why It Matters for ALS and SMA

This isn’t just a tidy evolutionary story, it opens a door that’s been shut for a long time. Diseases like spinal muscular atrophy and ALS progressively damage hindbrain motor neurons, eventually taking away a patient’s ability to swallow and breathe. Because brain stem tissue can’t be sampled from living patients, researchers have had almost no direct way to study what goes wrong. Lab-grown hindbrain neurons change that, and the hindbrain’s role in hunger regulation, the same circuitry targeted by drugs like semaglutide, adds a second reason to pay attention to this part of the brain.

The team’s next step is tracing where the spinal cord fits into this two-origin picture, and pinning down exactly how ALS and SMA disrupt hindbrain neurons at the cellular level.

Sources:
Press release: Stanford Medicine
Original paper: Jokhai, R.T. et al. (2026). “Two parallel neural ectoderm progenitors contribute to the developing brain.” Nature Neuroscience.