Sophia Shi: Decoding the role of sugar molecules in brain aging and neurodegenerative diseases

Could you give us a glimpse into your personal history, emphasizing the pivotal moments that first kindled your passion for science?

Growing up, I enjoyed doing a lot of puzzles, brain games, and crafts. I discovered early on that I had a knack for math and pattern recognition, and I still enjoy these types of games today. In school, I gravitated toward STEM subjects and found myself often wondering how people made the discoveries we were learning about. Whether it was the structure of DNA or physics equations that govern our natural world, I was captivated by the process of discovery and the pursuit of a deeper understanding of the world around us. Biology interested me because of its potential for immediate impact on human health and well-being. I started college as a biology major at Cornell University but soon found that my chemistry courses enabled me to understand processes at a much more fundamental level and provided powerful tools for manipulating biological systems. I decided to double major in Chemistry and Biology and sought out diverse research opportunities to develop a breadth of technical skills and conceptual frameworks. This interdisciplinary training enabled me to approach problems from multiple perspectives—a mindset I continue to value deeply. I found research to be incredibly fun and fulfilling. It combines my enjoyment of problem-solving, hands-on experimentation, and the thrill of discovery and creation. It reminds me of the joy I felt solving puzzles as a kid, but now with far more complex problems and real-world impact.

Please share with us what initially piqued your interest in your favorite research or professional focus area.

I have been fascinated by post-translational modifications (PTMs) ever since I first learned about them in high school. Early on, we are often taught about the central dogma of biology, where DNA is transcribed into RNA, which is then translated into proteins. People often think of proteins as the central machinery that carries out many of our biological functions, from signaling cascades to enzymatic reactions. However, most proteins are modified after translation by PTMs—diverse chemical modifications that can dramatically alter a protein's structure, function, and fate. The idea that a small chemical group, such as a hydroxyl group (−OH, ∼17 Da) or a phosphate group (−PO₃²⁻, ∼79 Da), could completely transform the behavior of a protein thousands of times larger in mass was mind-blowing to me. I became intrigued by the elegance and complexity of these modifications: how they are added, how they are regulated, and how these small changes could drive biological processes.

We would like to know more about your career trajectory leading up to your current role. What defining moments channeled you toward this opportunity?

I have been fortunate to have had many outstanding teachers and research mentors throughout high school and college who believed in me and encouraged me to pursue a career in science early on. All of those experiences in class and the lab led me to pursue a Ph.D. and a career in academic research. When I began graduate school, I knew I wanted to understand how post-translational modifications influence protein function and biology. I joined Dr. Carolyn Bertozzi's lab for my first rotation, where I was introduced to the fascinating world of glycosylation. Later, I found an important biological context where these modifications were understudied in the mechanisms of brain aging and neurodegeneration in Dr. Tony Wyss-Coray's lab. Bridging the distinct expertise of these two labs allowed me to approach longstanding biological questions from a new interdisciplinary perspective. Dr. Bertozzi and Dr. Wyss-Coray were exceptional research advisors who gave me the encouragement, freedom, and guidance to pursue questions that deeply interested me. I am incredibly grateful for their support.

A pivotal moment in my young research journey occurred in 2023, when I received the David S. Miller Young Scientist Award at the Cerebral Vascular Biology Conference in Uppsala, Sweden, recognizing the most promising research presented by a young scientist in the field of brain barriers research. It was my first year attending and presenting at scientific conferences, and I did not personally know anyone going into the conference. The experience of connecting with researchers in my field, who were incredibly welcoming and interested in the same topics, and receiving recognition from highly respected scientists in our field was profoundly encouraging. It gave me a strong sense of belonging to the broader scientific community. Another major milestone was the recent publication of one of our key stories (Shi. S.M., et al. Nature 2025), which opened up new opportunities to engage with scientists and the public around research that is deeply meaningful to me.

I am now preparing to launch my independent research lab at the Rowland Institute at Harvard University immediately following my doctoral training. I am incredibly excited to build a fantastic team and execute a research program focused on decoding the molecular logic of glycans in the brain and developing new treatment strategies for brain aging and neurodegenerative diseases.

What is a decision or choice that seemed like a mistake at the time but ended up being valuable or transformative for your career or life?

During graduate school, I assumed the responsibility of independently managing our lab's liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics workflow for approximately a year after a senior student graduated. The instrument was notoriously temperamental, and I found myself spending an inordinate amount of time performing troubleshooting and maintenance, often late at night or on weekends alone. At times, the work felt all-consuming, and I questioned whether the effort and frustration were worthwhile, especially as they diverted attention from my primary research. Nevertheless, despite these challenges, the experience was profoundly transformative. I was grateful to support lab members and collaborators in generating rich proteomic datasets that propelled multiple research projects forward and contributed to their journeys of discovery. In the process, I developed greater scientific breadth, deepened my understanding of proteomics, and cultivated higher levels of patience, technical problem-solving skills, and fortitude. While I am now quite content to leave the instrument upkeep and operation to dedicated specialists, the deep insights into mass spectrometry-based proteomics I gained are indispensable. They will be foundational in my research program moving forward.

What habits and values did you develop during your academic studies or subsequent postdoctoral experiences that you uphold within your research environment?

Reserving early mornings for focused work like writing, revising, and deep thinking. Meticulous planning of experiments and tasks each day. Collaborating with really smart, friendly, and supportive people and seeking out feedback routinely.

Please tell us more about your current scholarly focal points within your chosen field of science.

My current research centers on understanding how glycans modulate physiological function in the brain and how their dysregulation contributes to dysfunction and disease. Glycosylation is one of the most structurally complex and understudied forms of post-translational modification. It plays essential roles in virtually all cell surface processes, including cell signaling, adhesion, and morphology. My early work and work from others have shown that glycans become aberrant in disease states and can profoundly rewire biological systems. My lab aims to investigate how these modifications shape brain resilience and vulnerability, with the ultimate goal of leveraging these insights to develop new therapeutic strategies for neurological and neurodegenerative diseases.

What impact do you hope to achieve in your field by focusing on specific research topics?

My lab aims to uncover new insights into the mechanisms underlying healthy brain function and disease by decoding the molecular logic of glycans in the brain. My long-term goal is for our work to deepen the field's understanding of glycosylation as a central regulator of brain biology and to position glycoscience as a key frontier in neurodegeneration research. It is an exciting area of research to be in, where fundamental molecular questions intersect with urgent biomedical challenges, and I am thrilled to contribute to this emerging field.

What do you most enjoy in your capacity as an academic or research rising star?

I enjoy the freedom to pursue the scientific questions that truly excite me and to craft a research program deeply rooted in curiosity and purpose. Being able to build a team around a shared vision and invest fully in discovery at this stage of my career is a rare and deeply fulfilling opportunity.

At Genomic Press, we prioritize fostering research endeavors based solely on their inherent merit, uninfluenced by geography or the researchers' personal or demographic traits. Are there particular cultural facets within the scientific community that warrant transformative scrutiny, or is there a cause within science that you feel strongly devoted to?

I believe in empowering individuals who may not have had access to opportunities in science or considered research a viable career path. It is easy to feel isolated or like you do not belong in science, especially without early exposure or role models. I believe in building systems that actively identify and elevate promising individuals from different backgrounds, enabling more people to make meaningful contributions to scientific discovery and innovation. Science communication, outreach, and mentorship are core goals of mine as a principal investigator. Some of the most pivotal moments in my journey came from mentors who supported me long before I had a clear sense of direction. It is both a responsibility and a privilege to pay that forward. Within my lab, I strive to foster a culture rooted in intellectual curiosity, rigorous thinking, effective scientific communication, and kindness towards all—values that I hope will ripple outward and contribute to a more inclusive and vibrant scientific community.

Outside professional confines, how do you prefer to allocate your leisure moments, or conversely, in what manner would you envision spending these moments given a choice?

I really enjoy running, playing tennis, swimming, learning new skills, and spending time with friends and family.

What is your most marked characteristic?¹

Thoughtful and driven.

Among your talents, which one(s) give(s) you a competitive edge?

Deep focus, creative problem-solving, kindness.

If you could change one thing about yourself, what would it be?

Employing systems of organization more.

What is your current state of mind?

Optimistic and grateful.

What is your idea of perfect happiness?

Doing the things you enjoy in life.

When and where were you happiest? And why were so happy then?

It's hard to list just one and compare it to different life stages, but here are a few—Christmas mornings, marrying my partner, and perhaps now.

What is your greatest fear?

Fear itself (!).

What is your greatest regret?

I do not have regrets. I always make the best decisions with the information I have at the time and strive to lead with kindness. As long as I have acted with integrity and good intent, I find it hard to regret the outcome. Regardless of how things turn out, every experience is something to learn from.

What are you most proud of?

The whole journey.

What do you consider your greatest achievement?

Receiving the opportunity to start my independent research lab as a Rowland Fellow and Principal Investigator.

What or who is your greatest passion?

Creating and spending time with the people I love.

What is your favorite occupation (or activity)?

Running outdoors with a nice view, tied with swimming in the ocean.

What is your greatest extravagance?

A nice pair of running shoes and dessert.

What is your most treasured possession?

Cards and gifts that family and friends have given me.

Where would you most like to live?

Somewhere near the ocean or mountains and close to family.

What is the quality you most admire in people?

Those who balance brilliance and humility.

What is the trait you most dislike in people?

Unkindness.

What do you consider the most overrated virtue?

Certainty.

What do you most value in your friends?

Support.

Which living person do you most admire?

My PhD advisors, Carolyn Bertozzi and Tony Wyss-Coray. They are wonderful people and leaders.

Who are your heroes in real life?

My mom and dad.

If you could have dinner with any historical figure, who would it be and why?

Edwin H. Land. In addition to founding the Rowland Institute, he was the founder of the Polaroid Corporation, a hero to Steve Jobs, and one of the most prolific inventors of the 20^th century. I would love to learn more about the vision he had for the Institute, science, and humanity, as well as the advice he would offer to scientists today. Marie Curie is a very close second for her brilliance, persistence, and lasting impact on science and society.

Who are your favorite writers?

I do not have a favorite writer, but I enjoy reading biographies and other nonfiction.

Who are your heroes of fiction?

In my youth, Fa Mulan and John Keating of the Dead Poets Society—for their courage, principled defiance of norms, strong sense of purpose, and compassion for others.

What aphorism or motto best encapsulates your life philosophy?

Live as if you were to die tomorrow. Learn as if you were to live forever.

(Attributed to Mahatma Gandhi).²