What achievement are you most proud of, as a scientist or mentor?
As a scientist, starting from my postdoc and continuing in my own lab, we have helped redefine the role of the lysosome. Historically, it was considered a “boring organelle,” just the endpoint of degradation—a cellular trash can. But we’ve demonstrated that the lysosome is actually a sophisticated signaling center. We now call it the “metabolic computer” of the cell because it integrates information from other organelles and nutrient signals, particularly through mTOR kinase. The lysosome and mTOR communicate to make key metabolic decisions, balancing anabolism and catabolism. This has far-reaching implications for various cell types, including neurons, immune cells, and cancer cells.
One discovery I’m particularly proud of is identifying cholesterol as a major regulator of mTORC1. We’ve made several important findings about how cholesterol regulates mTORC1, the conditions under which this regulation occurs, and how cholesterol is sensed at the lysosome. We discovered LYCHOS, a strong candidate for a cholesterol sensor. Our work also has significant disease implications—imbalanced cholesterol can dysregulate mTOR, contributing to neurodegeneration and cancer. These are very active research directions in my lab, and we continue to expand on them.As a mentor, the greatest satisfaction for any PI is seeing lab members grow and find their path, whether in science or another field. It has been especially rewarding to mentor undergraduate and master’s students, many of whom decided to pursue PhDs after working with us. I’ve had 15 master’s students from Germany, the Netherlands, and other institutions, who all chose to continue their studies and get PhD after their time in my lab. That tells me we did something right! Several of my PhD students have gone on to postdocs or industry roles, and postdocs have become faculty. For instance, Regina Shieen is now a faculty member at UT Southwestern, Chun-Yan Lim is leading a lab in Guangzhou, China, and Aakriti Jain, a recent postdoc, is currently on the job market. So it is nice to see that there is a trend in the lab that people mature, prosper and do well.
You also co-founded a company. Can you talk about that journey?
Yes! The company is called Frontier Medicines, and it focuses on oncology. We use advanced chemistry to target and block proteins that are traditionally considered “undruggable,” particularly those involved in cancer. This approach allows us to tackle major oncogenic drivers like KRAS.
The company came about almost by chance. I had always dreamed of starting a biotech company, and the Bay Area makes it easier because of the strong venture capital (VC) ecosystem. In 2019, I was collaborating with Dan Nomura, a chemical biologist, to develop new inhibitors for the mTOR pathway. I was thinking about cancer applications, and we combined my biology expertise with his chemistry expertise. We found an investor who believed in the idea, and from there, we pitched it to multiple investors. Eventually, we secured Series A funding, which provided the initial capital to launch the company.
From that point on, the company took on a life of its own. I don’t run it day-to-day; they have their own leadership team. In fact, I initially tried to convince them to focus on mTOR, but they decided to prioritize KRAS instead. And you know that is great. I contribute of course and I advise them. But this worked quite great for me because this could lead to medicines that help people. For example, we have a program that is starting a phase II clinical trial, which has been exciting.
One of the most rewarding aspects has been working with biotech and pharmaceutical scientists. They are extremely rigorous—there’s no tolerance for “nice stories” or findings that aren’t solid. Everything must be reproducible, mechanistically understood, and actionable. That reality check has been an enriching experience.
What are the most exciting projects currently underway in your lab, and what are the “big questions” you are trying to answer? We have three major directions:
Tissue-Specific Regulation of mTOR – mTORC1 is a critical central kinase, yet we only know a handful of the stimuli that regulate its activity—primarily amino acids, lipids, and sugars. But there must be many other biological molecules that influence mTORC1. We believe these regulators vary by tissue, meaning that immune cells, liver, muscle, and brain cells each have unique mTOR signals. We are developing pipelines to uncover these tissue-specific regulatory mechanism. Our ultimate key goal is to find the sensor for certain metabolites and understand how the sensor communicates that information to the machinery of the cell.
Inter-organelle communication of Lysosome – The lysosome communicates with different organelles and through these communications, not only it regulates other organelles, but it also receives for example lipids to repair itself upon damage. These communicatations may be related to mTOR but possibly through independent mechanisms to maintain its own integrity. This is especially relevant in neurodegenerative diseases, where lysosomal dysfunction is a key feature.
Drug Discovery Targeting the mTOR Pathway – While mTORC1 is crucial in various diseases, the current drugs targeting it, such as rapamycin, are incomplete or have limitations. We are developing highly specific assays to identify small-molecule inhibitors or activators to control distinct parts of the mTORC1 pathway, with potential applications in metabolic diseases, cancer, and neurodegenerative disorders.
If you could design the perfect tool or technology to answer a major open question in cellular metabolism/lysosome biology, what would it be?
One major challenge in cell biology is predictive power—we don’t always know if a model will hold true across different conditions. Could we use machine learning and computational modeling to analyze massive datasets (protein-protein interactions, metabolic pathways) and determine which findings are universal versus context-specific? That would greatly enhance reproducibility in biology. We are very good at doing experiments and coming up with models, but to understand how true these are, is another story. Integrating more bioinformatics and computer science will help with that.
Another critical need is better in-cell biochemical sensors. Right now, techniques like imaging and biochemistry provide different perspectives, but they don’t always integrate well. Imagine a fluorescent sensor that could report on phosphorylation events or metabolite levels in real-time, inside the living cell, without disrupting it. Some tools exist, but they’re not very robust or widely applicable. Improving these would be a game-changer. And I think the technology is becoming more and more possible, using more with chemistry and chemical biology.
I read that you decided to become a scientist at the age of 6! Have you ever doubted this goal, faced a major setback, or been tempted by another exciting career path?
Never! And I will never be! Which is a good and a bad thing. I remember when I was in elementary school, probably 6 or 7, I decided to go to America, I wanted to be a scientist. And I liked the idea of studying diseases, because my parents are medical doctors. And to me what was exciting was to discover something fundamental about what was causing disease. So, I never doubted that.Of course, I’ve had tough times, like everyone does—moments where things weren’t going as planned, or I felt unsure about my research direction. But the overall goal never wavered. The only downside is that I don’t see myself doing anything else. Hopefully, I can keep doing science for as long as possible because it’s what makes me happy every day.
What was the biggest culture shock you had when you came here?
The food! As an Italian, that was a big adjustment.
And what do you think of New Haven pizza? The traditional Pepe’s and Sally’s I was never a big fan, but I love Bar pizza because they are not trying to make it Italian, it is an American pizza, but it is delicious!
What advice do you have for young scientists?
Find your passion and follow it—wherever it leads. Science can take you into academia, drug discovery, consulting, venture capital, even fashion! But in all cases, a PhD equips you with resilience, creativity, and troubleshooting skills that are valuable in any field.
Stay humble—don’t expect the world to revolve around you. Learn from others, take responsibility, and be open to feedback.
And always share ideas. Collaboration and communication are far more beneficial than working in isolation.
How do you enjoy spending your free time outside of lab?
I love to cook—it’s a creative outlet with immediate rewards. I also stay active with sports to keep my mind and body balanced. I also love traveling: When I travel for a conference, I always try to extend the trip to explore new places and friends.
If you could have dinner with any scientist (living or dead), who would it be and why?
Rita Levi-Montalcini. Not only did she discover nerve growth factor, which is one of the foundational principles of brain development and health, but she was also a deeply ethical person. Despite facing immense challenges as a woman in science over 50 years ago and living through some of the darkest moments in modern history, she never lost sight of the bigger picture.
She understood not just the importance of scientific discovery, but also its humanistic value—how science can bring people together, advance society, and promote empathy and understanding.
Unfortunately, I never had the chance to meet her, but I’ve spoken with several people who knew her, and they all say she was phenomenon.
And what would you ask her?
I would ask her, “Where do you think science is going?”. Because even toward the end of her life, she had remarkable foresight. She could identify the biggest challenges ahead and articulate how we might come to understand something as complex as the brain. I think she would have incredibly insightful answers.