CRACKing the Brain’s Cellular Code: An Interview With Professor Jerry Chen

Our world is awash with sensory information. Reach out and touch an object around you – it could be hot, cold, sharp soft, rough or smooth – and know that your brain is processing a dizzying array of information in that simple action. We know our brain has layers of complexity rivaling that of our environment but unpicking that intricacy at a cellular level is a mammoth task. How do our genes, cells and electrical impulses come together to decode the world around us?

At Boston University’s College of Arts & Sciences, Assistant Professor of biology Jerry Chen is trying to crack this code. Chen has published new research in Science that uncovers how the mouse brain processes the sense of touch at a cellular level using a technology called Comprehensive Readout of Activity and Cell type Markers, or CRACK. Chen’s findings could have important ramifications not only for our understanding of how our brains are wired, but for our ability to offer therapies for disorders where sensory processing is disrupted, such as autism spectrum disorder (ASD).

In this interview, we speak to Chen about his study’s aims, findings and implications.

What did you aim to study with your research? What made you want to examine this issue?

Jerry Chen (JC): Our lab is interested in studying the neural basis for perception and cognition. The brain is the most complex organ in the body. That complexity is partially defined by the fact that billions of the neurons in the brain are not all the same. There are hundreds of thousands of different types of neurons – serving different functions and carrying out different computations. To really understand how the brain operates, we need to deconstruct the brain down to its individual components and then start asking how these components interact during behavior.

Can you please explain the first-of-its-kind “neuron catalog” technology that contributed to this study – and its impact?

JC: Our collaborators from the Allen Institute for Brain Science had a goal of creating a “neuron catalog” by generating a census of all of the types of cells in the brain. This is part of a collective effort by several teams across multiple institutions.

The catalog only describes the molecular composition of the neurons but it doesn’t necessarily say anything about the function of the neurons or the computations they perform. The technology that my research team developed leverages this new information from the catalog, and adds the next layer of information, which is the activity patterns of the cells. It allows us to hone in and study the function of the cells in the catalog in a comprehensive manner. This is why we call it Comprehensive Readout of Activity and Cell type MarKers, or CRACK (ie. a pun on “cracking neural circuits”). Our CRACK technology will pave the way for a “catalog 2.0,” allowing researchers to collect both molecular and functional information about all of the cells in the brain.

How did you apply this technology within your study? 

JC: We applied the CRACK platform to study a specific part of the cortex involved with our perception of touch. We looked at how the different neurons from the catalog process information and talk to other neurons when an animal touches objects in their environment. We also looked at how the neurons adapt when the environment changes.

How significant is the advent of spatial transcriptomics for our understanding of the brain?

JC: Spatial transcriptomics is a very powerful tool to investigate not only the brain, but any tissue or organ in the body. Five to ten years ago, we were limited in only being able to see how a few genes were expressed in the brain at a time. We had to piecemeal the information together across different samples. Now, with the newest spatial transcriptomic technologies, we’re able to see how hundreds or even thousands of genes are expressed in a single sample. This reveals new relationships in how patterns of genes in neurons relate to their function that we weren’t able to capture before.  

What did the findings reveal?

JC: When you’re perceiving the world around you, your brain does a combination of processing the stimuli that makes up the scene – but it also tries to fill information based on what you’ve learned in the past to help you interpret what you’re sensing. For example, let’s say you’re rummaging through a bag feeling around for your car keys. Your brain has learned what keys feel like and so it’s filling in information as you are feeling objects of different textures or shapes to guide your search. However, there are times when you feel something, like a sharp edge, that really jumps out and tells you that you’re on the right track and that you’ve maybe found your keys. Our findings essentially uncover that there is a dedicated circuit composed of specific cells in the catalog that we call “hub cells.” These cells help to alert the brain that you’ve come across a salient feature that needs to be investigated further.

In the current study, you examined 11 different cell types. How long will it take to profile all the cortex’s cell types?

JC: The 11 cell types that we looked at constitute more than 300 potential cell types that have been discovered as part of a cell type “atlas.” Going off of the atlas analogy, you can think of cell types as “cities” that are part of “countries” that are part of “continents.” I think it’s fair to say that our understanding of cell types has historically been on the level of continents. Most of the research over the past two decades has been focused on the continent-level, occasionally zooming to countries – but we haven’t really zoomed into the level of cities until now. With this in mind, it’s hard to say how long it will take be able for us to understand all of the cities that exist in the atlas. However, we now have the ability to look at cities – and we can look at many different cities at the same time. Ultimately, the takeaway is that the rate at which we can profile all the cell types will definitely accelerate.

What was the most surprising finding?

JC: A surprising finding is that the “hub cells,” that we identified to be important for “feature detection,” also respond in interesting ways when your environment changes. There are a certain set of genes that are known to be important for learning and adaptability, that can go up or down depending on changing environments. We found that those genes are always “on” in hub cells, which goes against some current principles. When environments change, these cells respond by trying to compensate for these changes. We think this could be a way for the circuit to “remember” or “not forget” how to process information in the old environment.

How experience-agnostic are “hub cells” and how do they catalog the vast array of sensory experiences in our world?

JC: We’re looking at these hub cells in adult animals. There is some evidence that suggests that the hub cells may have accumulated sensory experiences early during development as the animal was experiencing the world for the first time. Potentially other cell types are responding to newer experiences, but these hub cells may be there to “not forget” those early life experiences.

How translatable are these findings to the human brain?

JC: A recent study compared some of the cell types we reported in the mouse with those found in humans. There were some similarities in some of the cell types that we looked at. However, it appears that the cell types in humans have continued to evolve and diversify. What this means is that our genomes can have a strong influence on how the circuits in the brain are organized, which may result in specialized functions described in our study. 

What is the significance of these findings?

JC: Our findings have relevance for a range of neurological disorders such as stroke, to neuropsychiatric diseases such as Autism Spectrum Disorder, where an individual’s sense of perception can be altered. Rather than viewing the brain as a homogenous piece of tissue, understanding which specific cell types are the most relevant will allow us to develop treatments that can be highly targeted. This marks exciting progress toward directly treating the underlying cause of specific symptoms – while also potentially avoiding unwanted side effects from other therapeutics and interventions.

What do you hope to study next? 

JC: There are a lot of directions that we’re going in based on our new technology and findings. The idea of dedicated circuits for neuronal plasticity composed of specific cell types in the catalog – or the surprise finding in our study – is especially intriguing. This is one area that we’re following up on; we’re specifically looking at potentially similar types of circuits in other parts of the brain and how they function both during learning and memory, and across time.

Jerry Chen was speaking to Molly Gluck, Assistant Director, public relations at Boston University and Ruairi J Mackenzie Senior Science Writer at Technology Networks.