Your brain may be one organ today, but scientists have uncovered a hidden split that may date back more than 500 million years

The human brain works as a single, highly integrated organ. But new research from Stanford Medicine suggests its developmental history may be much more complicated.

Scientists have found evidence that the human brain develops from two distinct populations of progenitor cells, rather than from one shared developmental system.

The two populations follow separate paths from an extremely early stage of embryonic development, eventually producing different regions of the brain.


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The finding challenges a long-standing assumption in developmental neuroscience and may help explain why some human brain cells have been so difficult to produce in the laboratory.

It also points much further back in evolutionary history.

The researchers found evidence of a similar developmental division in animals separated from humans by more than 500 million years of evolution.

The discovery is not simply about how the brain evolved.

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The researchers used their findings to produce functional human hindbrain motor neurons from pluripotent stem cells, potentially creating a new laboratory model for studying neurological diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).

The brain may have two very different starting points

The adult brain can be subdivided into three parts with unique functions, including the forebrain, midbrain and hindbrain.

The forebrain consists of structures responsible for the functions related to complex cognitive processing such as language, abstract thinking and some components of consciousness. The hindbrain, in turn, regulates the most basic bodily functions such as breathing, heartbeat regulation, swallowing and sleep.

Despite all these distinctions, scientists considered the main brain structures as derivatives of a single population of neural stem cells.

However, the recent study conducted at Stanford showed something quite unexpected.

In particular, the researchers discovered two populations of cells during a specific stage of embryo development called gastrulation.

One of these populations exhibited Otx2 activity and gave rise to the forebrain and midbrain.

Another population with active expression of Gbx2 led to the development of the hindbrain.

Thus, these populations did not convert from one to another but had completely different paths of development.

Also, the authors of the study investigated the chromatin, which represents the DNA packaging material in the cell nucleus.

They found drastic differences in chromatin landscapes between the cells that were destined to become the anterior and posterior parts of the brain.

A laboratory breakthrough came from understanding the split

The finding may provide the means for overcoming a practical problem that has plagued scientists for years.

Researchers have managed to generate several types of human brain cells from stem cells grown in lab dishes. But generating true hindbrain cells has proven a lot trickier.

The reason, according to the study, is that scientists may have tried to coax the cells down the path of hindbrain development when they had already been destined by nature to turn into forebrain or midbrain cells.

Once researchers realised that hindbrain cells arise from their own unique progenitor cells, they came up with a way to guide human pluripotent stem cells on that developmental path.

The resulting cells acted like true hindbrain motor neurons.

They produced electrical impulses called action potentials and expressed genes encoding proteins associated with hindbrain regions responsible for controlling muscles needed for facial movements and swallowing.

The result provides researchers with something they have been lacking until now – a laboratory model of human hindbrain neurons derived from stem cells.

Such models could allow researchers to study the development, function and degeneration of individual neurons without having to rely exclusively on cells taken from patients suffering from neurodegenerative diseases.

An evolutionary split that may be hundreds of millions of years old

Subsequent to this observation, the researchers questioned how recently the division in the developmental process occurred in humans.

The researchers analysed the developmental processes in multiple organisms, such as chickens and zebrafish. Also, they studied the acorn worm, which is a tiny creature belonging to a distant branch of the evolutionary tree.

The results indicated that the separation between the two developmental neural systems appeared to be extremely old.

According to the researchers, the pattern might occur earlier than 550 million years.

Moreover, the researchers gave an example of jellyfish, which diverged from the common lineage of humans about 600 to 700 million years ago. This example represents an animal with the organisation of its nervous system into multiple parts.

This research revealed a potential evolutionary aspect: instead of developing in one piece from a single developmental process, the vertebrate brain developed from the fusion of two old neural systems.

Thus, the unity of the current brain is a mask for the older division of its development.

Furthermore, it gives a new perspective on the brain: its various parts do not have to be identical due to their joint activity in the future.

The discovery could help scientists study ALS and SMA

The laboratory findings could be particularly useful for research into diseases that damage motor neurons in the hindbrain.

In spinal muscular atrophy, a genetic disorder, motor neurons progressively deteriorate, causing severe muscle weakness. The disease can be especially devastating in infants and young children.

ALS affects motor neurons and can involve both brain and spinal regions. As the disease progresses, patients can lose the ability to speak, swallow and eventually breathe independently.

Studying these neurons in living patients is difficult. Researchers cannot routinely collect brainstem tissue from patients for laboratory experiments.

Stem-cell-derived hindbrain neurons could provide an alternative. Scientists could potentially use these cells to examine disease mechanisms, test treatments and investigate why particular neurons become vulnerable.

The new model could also have relevance beyond neurological disease. The hindbrain contains circuits involved in regulating appetite and other automatic functions, making its cells relevant to research into metabolism and treatments that act on pathways associated with weight control.

The Stanford team now plans to investigate the developmental origins of the spinal cord and explore in greater detail how diseases such as ALS and SMA affect hindbrain neurons.

The discovery does not mean the human brain is literally two separate organs. Instead, it reveals that the organ we experience as one integrated system may have two distinct developmental beginnings.

That ancient split may have survived evolution while the two systems became increasingly interconnected — leaving scientists with a brain that looks unified from the outside but carries traces of a much older history within its cells.

FAQ

1. Have scientists proven the existence of two brains in human beings?

No. The study did not prove the existence of two brains in human beings but rather that two separate groups of progenitors develop different parts of the brain through two unique developmental processes.

2. How old is this development process?

Through studies on different animals, the team of researchers was able to establish that two systems of development might be at least 550 million years old.

3. Why is this discovery relevant to ALS and SMA studies?

Up to now, scientists have had challenges when developing functional hindbrain motor neurons from human stem cells in a laboratory setup.

4. What does the hindbrain control?

The hindbrain controls different important functions like breathing, heartbeat control, sleeping and actions performed using the muscles in the mouth, face, tongue and throat.