For centuries, scientists have treated the brain as a single, unified organ. Now, new research out of Stanford Medicine suggests the brain is actually two distinct organs that evolved independently over hundreds of millions of years—and were later packaged together.
The discovery explains why scientists have struggled for decades to grow certain types of brain cells in the laboratory. It also opens new avenues for studying diseases that affect the brain stem, such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (AMS), also known as Lou Gehrig’s disease.
Two brains
The new research focuses on the hindbrain—part of the brainstem that controls essential, automatic functions such as breathing, sleeping and regulating heartbeat—and the earliest moments of embryonic development.
In the study, published in Nature Neuroscience, the Stanford team discovered that the hindbrain follows a separate developmental path, running in parallel to—rather than branching off from—the pathway that creates the forebrain and midbrain.
Examining developing mouse embryos, the researcahers identified two different brain progenitor cells. One, which expresses a gene called Otx2, is destined to become the forebrain and midbrain. The other, which expresses a gene called Gbx2, is committed to forming the hindbrain. They showed that these two cell populations never overlap—they are mutually exclusive from the earliest stages of development.
The team then examined the DNA packaging, or chromatin, in these cells. They found that the anterior neural ectoderm (future forebrain and midbrain) and posterior neural ectoderm (future hindbrain) have fundamentally different chromatin configurations. These differences essentially locked each progenitor cell into its respective fate.
“Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible,” Jokhai said.
Armed with this knowledge, the 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 all the hallmarks of authentic hindbrain cells: they exhibited waves of electrical activity and made proteins that identify the segments of the hindbrain that control facial and swallowing muscles.
After their success, the researchers looked back over 550 million years of evolutionary time. They found the same two-origin brain pattern in chickens, zebrafish and acorn worms, tiny creatures living on the ocean floor that share a distant common ancestor with humans.
“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.”
The research has implications for investigating treatments for SMA, ALS and other conditions affecting the brain stem. The ability to grow these neurons in a dish opens new possibilities for understanding what goes wrong.
There’s even an unexpected connection to obesity treatment: the hindbrain contains circuits that regulate hunger—which is precisely how weight-loss drugs like semaglutide work.