“The Brain Is Actually Two Organs”: Stanford Medicine Uncovers a Secret of Evolution Spanning Hundreds of Millions of Years

A study has found that the human brain is not one organ but two organs that evolved independently over hundreds of millions of years.

Researchers at Stanford Medicine said on the 18th (local time) that they would publish a paper on the findings in the international journal Nature Neuroscience. Kyle Rowe, an associate professor of developmental biology at Stanford Medicine, is the corresponding author; graduate students Carolyn Dundes and Ryan Jokai are co-first authors.

According to the researchers, the adult brain is divided into the forebrain, midbrain and hindbrain. The forebrain is responsible for language, consciousness and abstract thought, while the hindbrain (brain stem), at the back of the skull, handles life-sustaining functions such as breathing, sleep, heartbeat and hunger regulation.

Until now, the scientific community had thought that a single progenitor cell at an early stage of development gave rise to the entire brain. But after observing mouse embryos, the researchers found that the brain originates from two different progenitor cells.

Cells expressing the Otx2 gene differentiated into the forebrain and midbrain, while cells expressing the Gbx2 gene differentiated into the hindbrain. The two cell populations were mutually exclusive and did not overlap from the earliest stages of development.

“Previous attempts to make hindbrain neurons tried to turn forebrain and midbrain progenitor cells into hindbrain cells,” Jokai said. “Our study shows that this is impossible.”

Building on this discovery, the researchers became the first to differentiate human pluripotent stem cells into functional hindbrain motor neurons. The neurons cultured in the lab showed action potentials and produced proteins found in hindbrain regions that control facial and swallowing muscles.

The findings are expected to be used in research on brain stem diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). SMA is a leading genetic cause of death in infants younger than 1 year, while ALS is primarily diagnosed between ages 40 and 70.

In both diseases, specific hindbrain neurons gradually lose function, causing patients to lose the ability to swallow and eventually to breathe. Research has been difficult because brain stem tissue cannot be obtained from living patients.

The researchers found the same dual-origin pattern in chickens, zebrafish and acorn worms. Jellyfish, which diverged from humans 600 million to 700 million years ago, also have two nervous systems at opposite ends of their bodies.

“It appears that evolution pushed the two existing nervous systems together spatially,” Professor Rowe said. “It would be more efficient to make the brain a single organ, but we still use the primitive approach of making the brain in two pieces.”

“We now have a model that will help us better understand these devastating diseases and move toward regenerative therapies,” Jokai said. The researchers plan to investigate the developmental origins of the spinal cord and how SMA and ALS impair hindbrain neuron function.

Researchers from the California Institute of Technology (Caltech) and the University of California, San Francisco (UCSF), also participated in the study.