Scientists Say the Human Brain May Have Started as Two Separate Organs That Fused Together

The vertebrate brain may preserve an evolutionary seam more than 500 million years old.

People love to blame the “reptilian brain.” Snap at someone, start a fight, inhale a family-size bag of chips—apparently the lizard inside your skull made you do it.

Neuroscientists have long regarded this an oversimplification of the brain structure we’ve inherited from multi-million-year-old ancestors. But a new study suggests there may be a very different kind of ancient divide hidden inside the human brain.

Stanford-led researchers found that the forebrain and midbrain appear to arise from one embryonic cell lineage, while the hindbrain—in charge of autonomic and motor functions—develops from another. The researchers argue that these two developmental programs may descend from separate neural systems that evolution eventually pushed together.

Stanford Medicine went so far as to describe the finding as evidence that the brain is really “two separate organs.”

“The brain is one organ,” senior author Kyle Loh, a developmental biologist at Stanford University, told Nature. “But it’s built in two different parts that connect and work together.”

Why It Didn’t Work

A model of the human brain dating back decades held that early neural tissue had broad potential to generate the forebrain, midbrain, and hindbrain. Some stem-cell methods implicitly followed the same logic, treating early neural cells as a common starting point that could later be pushed toward different regions.

An influential 2009 Nature Biotechnology study showed how blocking two signaling pathways could efficiently turn human pluripotent stem cells into neural cells. In other words, researchers had found a reliable way to push highly versatile stem cells onto a neural developmental path. From there, scientists learned to steer those cells toward developing into specific roles. A 2011 Nature study used developmental signals to produce midbrain dopamine neurons from human pluripotent stem cells, an important step toward modeling and potentially treating Parkinson’s disease.

The new study suggests a neural development fork comes earlier than many researchers assumed. It suggests that by the time these early neural cells appear, they may already be divided into two distinct populations: one destined for the forebrain and midbrain, and another destined for the hindbrain.

In mouse embryos about 7.5 days after conception, the team found two mutually exclusive groups of neural progenitors. One switched on Otx2, a gene that helps establish the front and middle regions of the developing brain, and occupied the territory destined for the forebrain and midbrain. The other switched on Gbx2, a gene associated with hindbrain development, and contributed to the hindbrain. Genetic lineage tracing showed that descendants of the Gbx2-marked population remained restricted to the hindbrain.

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The researchers then recreated the two early states using human pluripotent stem cells. When they exposed those cells to signals instructing them to become the “wrong” region, they largely resisted. Even their chromatin—the molecular packaging that controls access to DNA—had diverged in ways that anticipated their future identities.

“Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible,” Rayyan Jokhai, a developmental biologist and graduate researcher at Stanford University, said in a statement.

Quite a While Ago

The divide may reach astonishingly far back in evolutionary time.

The researchers found comparable anterior and posterior neural programs in macaques, chickens, zebrafish, and even acorn worms. The latter marine invertebrates share a common ancestor with humans from roughly 550 million to 600 million years ago. That suggests the developmental split was already established deep in the history of animals with bilateral body plans.

Jellyfish offer an intriguing yet speculative clue to what may have come before. Their lineage diverged from ours even earlier, around 600 to 700 million years ago, and many jellyfish species possess two distinct nervous systems positioned at different parts of the body.

The Stanford team argues that, somewhere along the lineage leading toward vertebrates, evolution may have brought two pre-existing neural systems into closer physical proximity until they became the tightly integrated brain we know today. This all raises the possibility that this merger happened after the jellyfish lineage split away and before the ancestor shared with acorn worms.

“Our research suggests that evolution took two existing neural systems and pushed them together spatially,” Loh noted. “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.”

Elusive Neurons: Unlocked

Armed with that developmental roadmap, the researchers were able to do something that had proved difficult for years: generate specific human hindbrain motor neurons from pluripotent stem cells.

Rather than trying to push anterior neural progenitors backward, the team generated posterior progenitors directly using a different combination of developmental signals. They then guided those cells into motor neurons characteristic of rhombomeres 5 and 6, segments of the hindbrain involved in controlling muscles of the face and throat.

The resulting neurons carried the expected hindbrain markers and behaved like functioning nerve cells. They showed spontaneous calcium activity and fired electrical impulses when stimulated.

That could give researchers a new way to study amyotrophic lateral sclerosis and spinal muscular atrophy, diseases in which damage to motor neurons can eventually compromise swallowing and breathing. Researchers cannot easily obtain living human brainstem tissue, so growing the relevant neurons in a dish could make it possible to watch disease processes unfold much more closely. For now, though, this is a research model, not a treatment.

Alex Pollen, a neurobiologist at the University of California, San Francisco, told Nature that the study provides strong evidence for two developmental tracks, but said it is difficult to rule out a fleeting common progenitor that existed before them.

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Ultimately, the study suggests that evolution may have assembled one extraordinarily integrated organ from developmental programs that began separately. And we can even see this ancient boundary as the brain first takes shape.

The study was published in the journal Nature Neuroscience.