Our brain may be a hybrid of two ancient nervous systems that were packaged together hundreds of millions of years ago. This is based on the finding that the front and back brain regions in people and several other species develop from two distinct cell types in embryos, instead of sharing the same developmental origin, as previously thought.

“Our research suggests that evolution took two existing neural systems and pushed them together spatially,” says Kyle Loh at Stanford University. “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.”

Loh and his colleagues studied early stages of mouse embryo development and found its brain develops from two types of early progenitor cells, proliferative cells with a limited capacity of self-renewal. One type expresses a gene called OTX2 and turns into the neurons found in the front part of the brain, comprising the forebrain and midbrain. The other expresses a gene called GBX2 and becomes the neurons in the back part of the brain, the hindbrain.

The researchers then conducted experiments using human cells in a dish and found that the neurons of the hindbrain and those of the forebrain and midbrain also develop from different progenitor cells. “We’ve shown for the first time that the front of the brain arises from a totally different progenitor cell than the back of the brain,” says Loh.

This explains why it has been so hard to grow human hindbrain tissue in a lab. “It was actually a summer student’s failed experiment that got us into this,” says Loh. Researchers have typically tried making hindbrain neurons from the progenitor cells that are destined to become forebrain and midbrain neurons, which doesn’t work, he says.

Armed with this knowledge, the team was able to grow functional human hindbrain motor neurons in a dish for the first time by starting with the correct type of progenitor cell.  

The hindbrain coordinates fundamental life-sustaining processes, such as breathing, sleeping, eating and the beating of the heart, whereas the forebrain is the centre of higher-level thought. Conditions like amyotrophic lateral sclerosis (ALS), the most common type of motor neuron disease, and spinal muscular atrophy cause speech and swallowing difficulties because they affect the hindbrain. Recently, scientists also discovered that GLP-1 drugs like Ozempic and Wegovy suppress appetite in mice by acting on the hindbrain.

Now that it is easier to grow human hindbrain neurons in a dish, it should assist ALS and spinal muscular atrophy research, and allow us to investigate the precise mechanisms of how GLP-1 drugs work in people, says Loh.

The researchers also studied early-stage embryos of chickens, zebrafish and acorn worms, and found their nervous systems are similarly derived from two different types of progenitor cells. This suggests our shared two-origin brain system arose at least 550 million years ago.

But jellyfish, which we diverged from around 600 to 700 million years ago, have two separate nervous systems. These may have joined up in our distant ancestors because it improved their overall processing power, says Loh. “You get more efficient communication when things are closer together,” he says.

Having our brains develop along two separate pathways might also have facilitated the evolution of complex thought, says Loh. While the hindbrain was taking care of all the basic functions for keeping us alive, “evolution could play around with the forebrain, and make mistakes and give rise to all the fancy things like memory and creativity”, he says.