From the BRAIN Director: The Great Unknown

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BRAIN Director, Dr. John Ngai

Imagine looking up on a clear night and instead of seeing the giant celestial smear that is the Milky Way, visualizing every individual star as a crystal-clear sparkle of light. That was my reaction 8 years ago when I laid eyes on the first data to emerge from the BRAIN Initiative Cell Census Consortium.

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Photo of Milky Way
Credit: John Ngai

That early work matured into the highly collaborative BRAIN Initiative Cell Census Network (BICCN) and led us to achieve a recent major BRAIN milestone: a census of the major cell types in the mouse, non-human primate, and human primary motor cortex. This fastidious “multi-modal” analysis involved cataloging cells based on their molecular signatures, anatomy, and physiological properties. Over time, we would learn that many cell types are remarkably similar across mammalian species, suggesting that subtle differences define species-level differences among brains.

As I wrote about recently in Cell and in this Director’s Corner, we are now ready to begin to catalog the constituent cell types in bigger brains, including healthy brains and those damaged or dysfunctional as in brain injury, neurological diseases, and neuropsychiatric disorders. Central to this research that will be conducted by the newly funded BRAIN Initiative Cell Atlas Network will be invention and application of new technologies as they emerge from the foundational BICCN work. The work will be painstaking – and exhilarating – as it addresses a few key challenges:

  • The human brain is 1,000 times larger than that of a mouse, creating significant challenges ranging from sample preparation to data analysis.
  • Humans are incredibly diverse – much more so than the inbred lab mice we usually study in controlled environments.
  • Brains grow up – even though the brain of a child is not that much smaller than the brain of an adult, we know there are vast differences that shape learning, memory, sensation, and emotions over time.

Another consideration: we don’t know what we don’t know. Whether and how a cell reveals its secrets to us as experimenters isn’t always straightforward. Take, for example, the excitatory intratelencephalic (IT) neurons studied in the motor cortex. Unlike other cortical neurons that show discrete differences from one another, cortical IT neurons look to be a continuum of cell types with continuous and correlated variation in gene expression, laminar position in the cortex, and physiological properties. Or do these cells in fact possess discrete identities that today’s state-of-the-art tools simply cannot discern?

The ongoing challenge will be to reveal the ground truth principles and nuances underlying cell diversity in mammalian brains, including those from non-human primates and humans. In time, we want to decipher the language spoken by and between cells upon which this diversity builds and sustains human thought, creativity, emotion, and pain.

The process of discovering the great unknown is what keeps me, and thousands of other scientists, headed back to the lab every day to do the hard work that ultimately becomes knowledge as we strive to learn the basis of what it means to be human.

Back in 2014, I was completely stunned by the clarity, beauty – and yes, complexity of the data. My somewhat fuzzy picture of the multitude of cell types suddenly came into sharper focus, and it was humbling just to imagine what lay further beneath the surface. Today, I am thrilled by how far we’ve come and the great opportunity we have to unlock the brain’s many secrets.

With respect and gratitude,

John Ngai, Ph.D.
Director, NIH BRAIN Initiative