Human Brain Is Two Separate Organs, Stanford Medicine-Led Research Finds

Discovery Overturns Prevailing Model of Brain Development

For centuries, scientists have considered the brain a single, unified organ. New research led by Stanford Medicine reveals that what we call the brain is actually two distinct organs that evolved independently over hundreds of millions of years. This finding overturns the prevailing model of brain development, which held that there is a single progenitor cell early in development giving rise to the entire brain.

Previous Theory vs. New Findings

The old model suggested all parts of the brain shared a common developmental origin, centered on the idea of a single progenitor cell. However, the new research demonstrates that the human brain consists of two ancient nervous systems cleverly packaged together:

• A more primitive part that regulates heartbeating, breathing, and other vital functions
• Another part responsible for uniquely human capabilities like poetry, mathematics, and self-reflection

This discovery helps explain why scientists have struggled for decades to grow certain types of brain cells in the laboratory. It also opens new avenues for studying devastating diseases affecting the brain stem, such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease).

Key Scientific Findings

The breakthrough emerged from studying the earliest moments of embryonic development during a stage called gastrulation. Researchers identified two different brain progenitor cells:

These two cell populations never overlap and remain mutually exclusive from the earliest stages of development. Additionally, the team examined chromatin (DNA packaging) in these cells and found fundamentally different configurations:

• Anterior neural ectoderm (future forebrain/midbrain) has one chromatin configuration
• Posterior neural ectoderm (future hindbrain) has a distinct chromatin configuration

These differences "locked" each progenitor cell into its respective fate, like travelers on parallel tracks that never cross.

Evolutionary Context

The two-origin brain pattern was found across multiple species:

• Chickens
• Zebrafish
• Acorn worms (tiny ocean-floor creatures sharing a distant common ancestor with humans)

Even jellyfish, which diverged from humans approximately 600 to 700 million years ago, possess two nervous systems at different ends of their body. As Kyle Loh, PhD, associate professor of developmental biology, noted: "Our research suggests that evolution took two existing neural systems and pushed them together spatially."

Laboratory Advances

Armed with this knowledge, researchers for the first time successfully coaxed human pluripotent stem cells to become functional hindbrain motor neurons in the laboratory. These lab-grown neurons displayed authentic hindbrain characteristics:

• Waves of electrical activity called action potentials
• Production of proteins identifying hindbrain segments controlling facial and swallowing muscles

Disease Implications and Future Directions

The research has significant implications for treating conditions affecting the brain stem:

• Spinal muscular atrophy (SMA): A leading genetic cause of death in children under 1 year of age
• Amyotrophic lateral sclerosis (ALS): Often diagnosed between ages 40 and 70, affecting both forebrain and hindbrain

Because hindbrain neurons gradually cease functioning in these disorders, leading to loss of swallowing and ultimately breathing, the ability to grow these neurons in a dish opens new possibilities for understanding what goes wrong. This approach may also connect to obesity treatment-since the hindbrain contains circuits that regulate hunger, similar to how weight-loss drugs like semaglutide work.

Researchers plan to extend their studies to determine the developmental origins of the spinal cord and to learn exactly how SMA and ALS compromise hindbrain neuron function. As Jokhai stated: "Now we have a model to better understand these devastating diseases, and work toward regenerative therapies for them."

Collaboration and Funding

Contributions came from the California Institute of Technology and the University of California, San Francisco. The research was supported by numerous grants including those from the National Institutes of Health (DP5OD024558, DP2GM146258, R00GM121852, R01DK115728, R01DE027538, T32GM119995, T32GM007365, T32GM007790, F31DE031154), the National Science Foundation, the California Institute for Regenerative Medicine, the Spinal Muscular Atrophy Foundation, and others.