A human brain starts as a single cell. Over time, that lone cell gives rise to an extraordinarily complex organ containing roughly 170 billion cells. One of the biggest questions in developmental neuroscience is how all of those cells end up in the right places to form a functioning brain.
Researchers at Cold Spring Harbor Laboratory now believe the answer may be surprisingly simple. Their new work offers insights into how the brain organizes itself during development and could eventually influence research in fields ranging from biology to artificial intelligence.
How Brain Cells Determine Their Identity
Stan Kerstjens, a postdoctoral researcher in Professor Anthony Zador's laboratory, explains the challenge in terms of positional information.
"The only thing a cell 'sees' is itself and its neighbors," he explains. "But its fate depends on where it sits. A cell in the wrong place becomes the wrong thing, and the brain doesn't develop right. So, every cell must solve two questions: Where am I? And who do I need to become?"
In a study published in Neuron, Kerstjens, Zador, and collaborators from Harvard University and ETH Zürich propose a new theory describing how the developing brain achieves this remarkable level of organization.
Beyond Chemical Signals
For decades, scientists have largely believed that cells communicate positional information through chemical signals. According to Kerstjens, that explanation works well in relatively small systems with limited numbers of cells.
The developing brain, however, contains billions of neurons that must each arrive at the correct location. Because chemical signals weaken as they travel, researchers have long wondered how cells located deep within a growing brain can accurately determine where they are.
Kerstjens suggests that part of the answer may come from a process that resembles the way human populations spread over generations.
"Consider how human populations spread across a country over generations," he says. "Descendants settle near their parents, so people who share ancestry end up in neighboring regions, producing large-scale geographic structures without long-range communication. We argue that a similar principle operates in the developing brain. Cells that descend from the same progenitor tend to remain near one another."
Testing a Lineage-Based Model
To investigate the idea, the researchers developed what they describe as a "lineage-based model of scalable positional information."
They first used theoretical calculations to explore whether the concept could work. Next, they examined patterns of gene expression in developing mouse brains, looking at both individual cells and larger cellular groups. Finally, they tested the model in zebrafish and found similar results, suggesting the mechanism may operate across brains of different sizes.
The findings indicate that chemical signaling and cellular lineage may work together to provide positional information during development.
Implications for Biology and Artificial Intelligence
Although the research focuses on the brain, Kerstjens says the underlying principle could apply to many other developing tissues, including tumors.
The theory may also have relevance for future self-replicating AI systems. Just as brain cells can inherit information across generations of cells, future AI models that pass information from one generation to the next could potentially rely on similar organizational principles.
Perhaps the most significant implication is what the work could reveal about intelligence itself. Understanding how a single cell develops into a highly organized brain may help scientists answer some of the deepest questions about the mind.
"The brain somehow makes us intelligent," Kerstjens says. "How did it manage to accumulate this capability, not just over its developmental time, but over evolutionary time? This is one piece in that big puzzle."
