Treasure hunting for rare cells in the developing human brain

November 16, 2015

Being able to pinpoint and study the specific types of cells that help our brains develop is crucial to understand both how our brains work and what makes us uniquely human.

But with 86-billion neurons of various types and billions more supporting cells intermingled in a complex web, the human brain is a challenging place to conduct a hunt for a needle in a haystack.

Researchers at the Allen Institute were particularly interested in studying a small set of cells called radial glia: a rare type of cell that supports the growth of neurons during early human brain development. Radial glia can be picked out by their distinct shapes and locations, but their molecular makeup has been challenging to study since these cells are intermixed with very different cell types in the brain and so must be analyzed one cell at a time.

“In order to get at these cells, which are just one percent of the cells in the developing human cortex, we need to blindly analyze as many as 20,000 cells,” says Boaz Levi, Ph.D., Manager in In Vitro Human Cell Types at the Allen Institute for Brain Science.

This is because until now, scientists have only been able to gather gene expression information on living cells, as opposed to cells that have been fixed so that scientists can select them by the presence or absence of molecules present only inside the cell. But in research published this month in Nature Methods, Allen Institute researchers have pioneered a new technique that allows them to fix the cell first, sort only rare cells based on expression of certain intracellular markers, and sequence later.

“Instead of sequencing 20,000 cells, we were able to study the progenitor cells we were interested in by profiling just 200 cells,” says Levi.

By analyzing the data, Levi and his colleagues were able to make some interesting observations about radial glia, including defining the molecular differences and identifying new molecular markers for two subtypes of radial glia.  Interestingly, one class of these progenitors seems to have become much more abundant through evolution and may hold insights into how complex brains, such as those of primates, evolved.

“This new technique that allows us to measure gene expression from rare populations of cells where only intracellular markers are known is exciting in part because it can have impact far beyond neuroscience,” says Levi. “Many of the tissues that are the most difficult to study (such as primary human tissue) are also the ones that contain the cells you actually care about, so having a way to study them using fewer resources means we can ask many more interesting questions.”