Research in Focus: Nan-Kai Wang, MD, PhD

Nan‑Kai Wang, MD, PhD, is a physician-scientist whose work probes one of the fundamental questions in vision science: how cells in the eye lose the energy required to survive. His research specializes in mitochondria—the “powerhouses” of the cell—focusing on how inherited blinding diseases, such as retinitis pigmentosa and optic nerve degeneration, occur when these energy systems fail. Using advanced genetic tools and custom-designed disease models, Dr. Wang and his team investigate how specific genetic mutations disrupt the eye’s delicate energy balance, why certain ocular cell types are uniquely vulnerable to energy shortages while others endure, and ultimately develop targeted, patient-specific therapies to prevent vision loss through mitochondrial reprogramming.

In his recent Science Advances publication, “Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy,” Dr. Wang and his colleagues reveal a key metabolic dimension of optic nerve degeneration, offering new insight into how mitochondrial dysfunction and energy imbalance may drive vision loss. The study advances our understanding of how Autosomal Dominant Optic Atrophy (ADOA) progresses and lays important groundwork for future drug development.

This moment coincides with a pivotal transition in Dr. Wang’s career. After serving as an Assistant Professor at Columbia, he has returned to Taiwan to take on a new role as Associate Professor at Chang Gung Memorial Hospital, Linkou Medical Center, in Taoyuan, where he also serves as the Director of Medical Education of the Department of Ophthalmology. There, he brings together bench research, clinical care, and mentorship within one of Asia’s leading medical centers. In this interview, we speak with Dr. Wang about the scientific journey behind his latest findings, the questions that continue to drive his work, and how this new chapter in his career shapes his vision for the future of translational ophthalmic research.

How does your paper “Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy” tie into the overall mission of your lab?

Our laboratory focuses on the "powerhouses" of the cell—the mitochondria. A core question we strive to answer is whether we can rescue vision by "reprogramming" these cellular powerhouses. We want to know why certain cells in the eye are uniquely vulnerable to energy shortages while others survive, and ultimately, how we can use that knowledge to develop targeted, patient-specific therapies to prevent vision loss.

This recent publication is a perfect example of our mission in action. Autosomal Dominant Optic Atrophy (ADOA) is a disease that gradually destroys the optic nerve. For this study, we created a specialized model that mimics the exact genetic mutation found in a human patient. By doing this, we were able to prove that the disease is driven by a severe energy imbalance and oxidative stress. Most importantly, it showed that when we step in and correct that metabolic balance, we can successfully protect the optic nerve cells from dying.

What were the key biological insight(s) from this paper?

Think of the genetic mutation in ADOA as causing a severe, localized power failure. The mutation creates an unstable protein that cripples the mitochondria, limiting their ability to generate energy while simultaneously producing toxic stress. We discovered that when this power failure happens, other cells in the eye can quickly switch to "backup generators" (alternative energy pathways). However, the cells of the optic nerve lack this flexibility. Because they cannot adapt to the energy deficit, they run out of power and degenerate.

Previous research models mostly used a different type of mutation than what is typically seen in the clinic. We introduced the first model featuring a "missense" variant, which is the most common mutation type in actual ADOA patients. Because of this, we were able to show that the disease is driven by a simple shortage of functional protein. Furthermore, by using advanced mapping technologies, we pinpointed exactly where and why the energy failure happens cell by cell, giving us a much clearer target for future drugs.

What inspired you to collaborate with your co-authors on this paper? How important was collaboration to the success of this project?

During my time at Columbia, I quickly realized that no single laboratory can master every state-of-the-art technology. Whenever our projects required a specialized technique to answer a difficult question, I made it a point to reach out directly to the principal investigators and scientists who pioneered those methods in their own published papers.

This proactive approach blossomed into a fantastic, multi-institutional collaboration. For this study alone, we partnered with a group from UCLA for specialized mitochondrial bioenergetics (RIFS and HyFS), researchers at CUNY for spatial metabolomics and super-resolution microscopy, and teams in Taiwan—specifically Chang Gung University for spatial transcriptomics and National Tsing Hua University for advanced electron microscopy. I am incredibly proud of how these diverse groups came together to form one powerhouse team.

It was absolutely essential. No single laboratory has the tools to simultaneously generate a patient-specific genetic model, map millions of data points across single cells, and execute targeted mitochondrial gene therapies. This breakthrough was only possible through the seamless cooperation of our domestic and international research partners.

You recently moved from an Assistant Professorship at Columbia University to an Associate Professorship at Chang Gung Memorial Hospital. How has this change affected or influenced your research?

This transition has fundamentally shifted my day-to-day focus, but in a deeply inspiring way. While I was at Columbia University, I devoted more than 80% of my time directly to basic research. Now, at Chang Gung Memorial Hospital, I devote about 80% of my time to clinical practice—such as seeing patients and performing vitreoretinal surgeries—while also conducting research.

As a physician-scientist, I absolutely love clinical practice. It is incredibly rewarding to receive immediate appreciation from patients when I can help figure out what is going on with their eyes and restore their vision from cataracts and retinal diseases. Furthermore, my patients and their unique conditions serve as my greatest inspiration. When you spend the majority of your time in the clinic and the operating room, the urgency of finding cures becomes intensely personal. Seeing patients struggle with vision loss—and having the privilege to sometimes restore it—directly inspires the specific questions I ask back in the lab. It shifted my priority from purely understanding the basic science to rapidly translating those discoveries into real-world treatments. Today, every animal model we develop and every mechanism we study is directly tied to the goal of curing the patients I see in my exam chair.

Unavoidably, this shift means I have less time to personally conduct basic research at the lab bench in Taiwan. However, I bridge this gap by actively collaborating with my colleagues here in Taiwan and with my team back at Columbia, allowing us to continue working on these critical projects together seamlessly.

How do you envision your research program evolving in Chang Gung’s clinical and research environment?

I envision our program becoming a premier hub for precision ophthalmic medicine. By leveraging the clinical environment here, we can rapidly take the molecular discoveries we make in the lab and translate them into targeted screening and personalized treatments for our patients. It is the ideal setting for large-scale genetic studies and, eventually, advanced clinical trials.

To support this goal, I also see our program evolving into a highly collaborative research hub. While the concentration of in-house research resources differs from what is available at Columbia, Taiwan has a fantastic ecosystem of state-of-the-art technologies spread across its various premier institutes. My strategy is to replicate the highly successful collaborative model I utilized at Columbia. By building a strong, multidisciplinary team and actively partnering with leading experts across different technological fields throughout Taiwan, we can tap into a powerful national network to continue driving our cutting-edge research forward.

What advice would you give to early-career scientists interested in advancing their careers?

First, embrace collaboration. As I’ve learned from working across different institutions and continents, no one can solve these complex blinding diseases alone; you need to build a strong, multidisciplinary team. Second, never lose sight of your "why." Whether you are pipetting at a lab bench or examining a patient, let the people affected by these diseases be your ultimate inspiration. Understanding exactly how a condition impacts a person in the real world is the key to designing therapies that actually work. Finally, be adaptable—do not be afraid to learn a new technique or step outside your specific field to find the answer to a stubborn problem.

What are the next major questions your lab is pursuing following this study?

Following our success in protecting optic nerve cells by boosting their energy balance in ADOA, we want to know just how far we can take this "power restore" strategy. We have created new models for other genetic mutations, such as the SSBP1 gene, which is also linked to mitochondrial dysfunction. Our next major question is whether we can use these targeted metabolic therapies to successfully rescue vision across a much wider spectrum of inherited blinding diseases. Ultimately, our goal is to bring these cutting-edge treatments from the lab to our patients through our new precision medicine programs.

Any last words?

This breakthrough research was made possible through the generous support of several organizations. We are deeply grateful for funding from the National Eye Institute of the National Institutes of Health (Award Numbers R01EY031354, R21EY037007, and 5P30EY019007), Gerstner Fund, Vagelos College of Physicians & Surgeons (VP&S) Grants, the United Mitochondrial Disease Foundation, and an Unrestricted Grant to the Department of Ophthalmology at Columbia University from Research to Prevent Blindness.

I would also like to specifically acknowledge Dr. Chyuan-Sheng (Victor) Lin, who generated the critical OPA1 mouse model, and Dr. Stephen Tsang, who provided the conditional MitoLbNOX mice. Furthermore, science is a team effort, and I want to express my profound gratitude to all my co-authors and collaborators. A very special thanks goes to Dr. Eugene Yu-Chuan Kang, our postdoctoral scientist and the first author of this paper, whose dedication and hard work were the driving force behind this study.

Additionally, I extend my deepest personal gratitude to Professor Stanley Chang, whose invaluable guidance helped us secure crucial support from Gerstner Philanthropies. Quite simply, without this specific funding, these essential mouse models, Professor Chang's belief in our work, and the tireless efforts of Dr. Kang and our entire collaborative team, we would not have been able to achieve these results and bring this vital project to the finish line.