Sophie Brown

4th year graduate student Sophie Brown

Graduate Student

Sophie Brown

Author: 
Joshua Speiser

Sophie Brown is a 4th year graduate student working in the Borton lab

Carney Institute (CI): Tell us a little about yourself. 

Sophie Brown (SB): I grew up in Santa Fe, New Mexico, surrounded by a big, loving family where there was always a lot going on! I moved to California to pursue an undergraduate degree in Bioengineering at the University of California, San Diego. My experience at UCSD was exciting…it set me on a path to understanding and appreciating the world of engineering concepts and tools. Importantly, that path included how these tools could be applied to study and interface with the brain. I was hooked.

When I was ten years old my wonderful aunt was diagnosed with ALS.  As the disease stole her ability to speak and move, the frustration I felt for her was consuming. I wanted SO much to help her.  She was so present in our lives: cognitively “there” and yet, the disease attacked her nervous system relentlessly. I remember thinking to myself, “there must be some way to connect her thoughts to a device to help her communicate and move?” I look back on those moments as a kid and realize my passion grew powerfully from something very tangible; I wanted to help. And at UCSD I found that biomedical engineering and neurodegenerative disease research held the key.  

Applying to master’s programs was an important step and I was ultimately drawn to Brown for the pioneering research happening here in the field of neuroengineering. People like John Donoghue, Leigh Hochberg, and David Borton were (and are) doing groundbreaking work, developing neurotechnologies that can interface with the central nervous system to help restore movement and sensation to individuals suffering from paralysis. I was eager to be a part of that world which gave meaning to my curiosity about the brain by actually helping to find answers to the questions I had been asking since I was a kid.  

CI: Tell us about your research.  

SB: My graduate research really began with an investigation of the dynamic cellular crosstalk and intricate mechanisms that take place at the device-tissue interface. In particular, I was working to improve our understanding of microglia. As the key immune cells in the brain, microglia can drive acute and chronic neuroinflammatory reactions in the neural tissue that surrounds an implanted device. Ultimately these reactions can lead to instability of the device-tissue interface and compromise the fidelity of implanted devices such as stimulating or recording electrodes, which can be implanted in the brain to communicate with neurons.

By the end of my master’s program, I was not quite ready to say goodbye to research here at Brown. The challenges of my research only motivated me further and over the course of my master’s degree, I developed new and exciting questions about microglia and their many enigmatic roles in health and disease. Since then, I’ve spent the last four years in the Ph.D. program trying to parse out some answers. And I think a real catalyst moment for my research was when my advisor professor David Borton encouraged me to reach out to professor Alvin Huang of the microbiology, cell biology and biochemistry department here at Brown. Not only did this meeting with professor Huang help to solidify my research plans to explore human microglia, it really initiated what would become an exciting collaborative project between professor Huang and Prof. Borton’s lab which is centered on developing new tools to study human microglia biology in Alzheimer's disease (AD).  

Using human induced pluripotent stem cell (iPSC) technologies out of professor Huang’s lab and a three-dimensional primary cortical “microtissue” model out of professor Borton’s lab, I am working to create a hybrid in vitro model to study cell-type specific effects of AD-risk factors, such as the APOE genotype, on human microglia biology. Microglia are a highly dynamic cell type that can rapidly shift cell states. In other words, they can change their morphology, function and gene expression patterns in response to the culture environment. Studying human iPSC-derived microglia, or iMG as we call them, in a dish is inherently tricky because they often do not fully recapitulate human microglia that you would find in the brain.  To really dig in and decipher the roles of human microglia in the context of Alzheimer’s disease, we needed to come up with a three-dimensional cell culture system that allows us to effectively study human iMG and probe specific cell mechanisms in a physiologically relevant or “brain-like” environment. In limited ways, the concept of combining human iMG and a 3D culture system is somewhat similar to that of an organoid. You may have heard of “brain organoids,” which are 3D cultures of human iPSCs that can mimic the structure and function of the human brain.

CI: Do these organoids effectively mimic the human system?  

SB: That's a great question and I think the field itself is still figuring that out. Unfortunately, because microglia originate from a different germ layer in comparison to neuronal and other glial cells, they are not easily incorporated into brain organoids. All of this is to say that organoids have not proven very useful for studying human iMG and thus is a major motivation of our work; that is to create an effective 3D culture system compatible with iMG. But the fact that brain organoids can model the developmental trajectory, adopt cellular architecture similar to what you'd find in the developing human brain, and can even be derived in a patient-specific manner makes them an incredible tool for studying complex mechanisms in human health and disease.

CI: Is this work related to the 2023-24 graduate award you received? 

SB: Yes, very much so. We know that the e4 allele of the APOE gene (APOE4)  is one of the strongest genetic risk factors for sporadic AD and that it is highly expressed by glial cell populations in the brain. But what we don’t know is the exact mechanisms by which the APOE4 genotype affects microglia function in the brain. The Carney graduate award has expanded my work in characterizing how APOE4 affects iMG functionality within our 3D brain-like microtissue environment. 

As an example, one of the many functions of microglia is to maintain the synaptic environment by pruning away excess synapses. This happens naturally in the developing brain but is also thought to occur during aging and in disease. Whether or not APOE4 affects this particular mechanism and contributes to AD pathogenesis is still unclear. It is an example of one such behavior or aspect of microglia functionality that I am investigating in this 3D iMG-microtissue culture system. This work is really about applying interdisciplinary methods and experimental techniques.  We are utilizing molecular biology assays, human iPSC technology, RNA-sequencing, and fluorescent live-imaging developed in both the Huang and Borton labs to validate the use of this 3D iMG-microtissue culture system for investigating the cell-type specific effects of the APOE4 genotype on microglia functionality.

CI: Recent advances in Alzheimer's disease research, including new therapeutics, have many feeling that we’re finally turning a corner on the battle against the disease. Are you optimistic as well?  

SB: Yes, definitely optimistic. I feel we are much closer now than we were even just five years ago. I think there has really been an effort within the field, and certainly here on Brown's campus, to better understand the different pathologies, how they arise, and even how they interact to drive disease progression. I think in the end, it's never going to be a single target or single therapy answer. It is going to be a multi-pronged, multidisciplinary approach to really answer the big questions and ultimately drive successful therapeutic interventions. 

CI: You’ve noted the interdisciplinary nature of your experience here at Brown. Tell us more about that. 

SB: I think it’s safe to say I would not be where I am today without interdisciplinary collaboration. Not to sound cheesy but I’m not sure I would have had this same type of opportunity to explore such exciting science without an institute like Carney or the Center for Alzheimer’s Disease Research. They bring together an interdisciplinary environment that has been critical to my research and growth as a graduate student. My research has expanded greatly because of the collaboration between the labs of professor Borton and professor Huang, both Carney affiliate faculty. Bridging the disciplines of both these labs while working to establish this investigative 3D iMG-microtissue project has added new depth to my growing and complex role as a researcher in both the realms of neuroengineering and neurobiology. 

CI: Looking ahead, what do you hope to be doing in five years' time? 

SB: I hope that in five years I will be furthering this research in whatever capacity I can. I'm not entirely sure what my next role will be, but trust it will likely involve further exploring glia-neuron interactions and the dynamic roles of microglia across the neurodegenerative disease landscape. My hope is that much of what I’ve learned in this work along with the tools I’ve developed will ultimately find broad utility in addressing the array of other neurodegenerative diseases and neurological conditions. I have been so fulfilled by this research and continue to be excited by the questions that constantly swirl in my head about glial cells and their roles in health and disease. I am certain I will continue to chase that feeling for the next ninety years, at least.