Can you share a bit of your background?
I am a second generation Taiwanese American, born and raised in rural south Texas. Life was an interesting merger of enrooting industrial raw plastics, aluminum and petrol companies on a provincial backdrop of cash crop and livestock farming. Apart from exploring the backwoods and the occasional outfall of storm drains, I remember growing up having my nose from time-to-time stuck against the TV watching science channels, while I jotted down notes only so I could proudly impress friends and teachers. This self-satisfying exercise eventually grew to genuine curiosity for the complexity of God’s creations, including the organization and the function of the human body, and an appreciation of how the general laws of life seem to govern the known and unknown alike. I remember also reading autobiographies, memorizing the life of historical figures, unwitting looking for a roadmap to life and fed off quotes (‘advices’) they left behind. The quote, ‘stupid questions are the only ones not asked’ was probably the most instructional. Melded with my innate stubbornness that was forever opposed to imposed boundaries and assumed limitations by others, I guess it makes sense that life has led me into biomedical research, where scientists continuously push the frontiers, and bring Sci-Fi to life so to help others through applications like medicine. I will be the first in the family to be a physician, and the first to be a scientist.
I began research during my undergraduate years at Washington University in St. Louis, where I also began my intimate journey with medicine and became interested in addressing socioeconomic disparities and medical gaps through healthcare. In this last decade as a student, I have explored research areas that address cardiac tissue repair though the development of injectable gels at Drexel University College of Medicine and built cartilage tissue for addressing nasal and joint repair at the University of California San Diego. More recently, at UNT Systems College of Pharmacy, I use human pluripotent stem cells (hPSCs) to form complex 3D structures known as human ‘mini-brains’ (or cerebral organoids) that closely captures the developmental process and tissue organization of the human brain. By using a particular kind of hPSCs called human induced pluripotent stem cells (hiPSC) – ones converted from a person’s own mature cells, reverted back to an embryonic-like stage, and then trained to become virtually any cells in the human body– we build these human mini-brains and use them to study disease development that’s specific to an individual.
Why did you decide to get into research?
I think, in short, “it called me”. It’s become more apparent to me now that it takes a certain personality to be drawn into biomedical research. For example, I’ve been warned that the research path, where it takes you in life, and even making discoveries in science is inevitably uncertain; things more often than not don’t go the way you want. This may sound scary but that’s life. In research, however, we consciously increase the occasions that we head-butt the uncertain. Oddly, I find this thrilling. I also find the fundamental need to ask questions, fulfilling, and being more often wrong that right quite motivating. Research means that equipped with some known truths, I can explore unknown territories, and eventually unravel the intricacies of life and understand its entwinement with disease. Ultimately though, there are the applications of research, which is where I think the fun begins. From fun cerebral summersaults, it’s during the transition from ‘knowing’ to ‘using’ facts and knowledge that the very practical part of me is satisfied. For me, it is important that what I do has tangible impact on life. So what keeps me going in research is knowing that one day what I study can be wielded by myself or someone else and applied in bedside medicine to impact health and others.
Being a clinician-in-training, I believe comprehensive experience and training in research is also paramount. Having clinical sensitivity to symptoms and attention to new clinical guidelines, I believe, is no longer exhaustive enough for handling patient’s lives at the front line of medicine. In the constantly changing climate of the clinic, with new drugs and guidelines pouring in each day and people being diverse and responsive to treatment in their own way, the ability to ask ‘why’, test hypotheses (via diagnostics), and reason from basic sciences down to the level of cell, is needed. Because of this, I am certain that at the end of my research training with my mentor, Dr. Yu-chieh Wang, I will be closer to the sufficiency I think is required for me to think critically. Through research, I hope to explore uncharted areas of medicine, and hopefully coming up with new solutions for our patients in the future.
Why did you choose NGLY1?
That’s a very good question. First, NGLY1 deficiency is a rare genetic disease where NGLY1, just one gene in a person’s genome, is mutated. Since this cause was only recently identified, there is currently no effective treatment. And besides that cause, very little else is known about the disease. Without knowing how the disease progresses or why certain symptoms happen, the development of therapeutic approaches is slow. The disease shows us just how important NGLY1 is for human life. NGLY1 has a critical role in the many cells that make up our bodies, such that without it, these cells can’t successfully initiate the process to recycle cellular junk. I study NGLY1 to understand this importance, which I think the disease itself makes a point to highlight, but also so that we might come up with an effective and safe approach for treating patients with NGLY1 deficiency. Occasionally, I’ve also had that same question you ask directed to me by others with the intention of doubly meaning: how important really is this disease? This alludes to the sentiment that because a disease is less common, its impact on people is less, or perhaps, that the importance of what is found has less significance and translation for the clinic. In the history of biomedical research, though, there have been numerous cases where our understanding of more-widespread diseases came from studying ones that are caused by a single gene mutation. Further, with over 7,000 rare diseases and 350 million people affected worldwide, more people are affected than cancer and AIDs patients combined, making rare diseases not really rare at all. In studying NGLY1 deficiency we may discover that NGLY1, or the insights we discover from studying NGLY1, may be important to understanding and treating those more-common diseases (e.g., neurodegenerative disorders like Alzheimer’s and Parkinson’s disease), since NGLY1 deficiency seems to share similar cellular features like the aggregation of damaging misfolded proteins. The current NGLY1 research study I am working on provides my lab mates and me with opportunities to comprehensively understand NGLY1 and its implications in multiple diseases.
I also chose to study NGLY1 deficiency because it appeals to me as a future physician. The struggles that patients with NGLY1 deficiency and families go through is real, unfortunate, and deeply exposes the imperfect sides of medicine. As patients with NGLY1 deficiency show us, just the route to diagnosis is arduous, taking five to seven years, typically with visits up to eight different physicians, and two-to-three misdiagnoses. From diagnosis to treatment, patients with rare diseases take on a windy, long, and often a disappointing road ending with no FDA approved drug or cure. In Dr. Yu-chieh Wang’s lab we want to increase the efficiency and the speed to treatment for NGLY1 deficiency, and hope to do so through using a NGLY1 patient’s own cells and developing and screening through treatments based on patient-specific responses. My mentor and I share a belief that something rare doesn’t mean it is not important. We want to bring greater attention to rare disease communities, for patients with NGLY1 deficiency, and help as many patients as we can with our studies. Personally, in studying NGLY1 and following how the disease was discovered, the NGLY1 story is also a continuous reminder and lesson to me on how novel technologies (e.g. whole exome sequencing) can be utilized in the clinic to speedily arrive at accurate diagnosis, and suggestion that it is also time to utilize the power of the personalized approach to understanding disease in order to tailor treatments.
What do you hope will come out of your research?
Like most researchers in the biomedical field, I hope to see that my research findings, one day, will positively influence many people’s lives. Being practical at the same time, I also realize that there is still a long way to go for coming up with useful strategies to alleviate the impact of NGLY1 deficiency or cure patients, since we just began to learn more about this newly identified genetic disorder. However, I also hope and believe that our on-going efforts using cutting-edge tools and creative approaches to study NGLY1 will bridge us to the day when NGLY1 deficiency can be effectively managed. In addition, I expect that my study will shed light on the potential involvement of NGLY1 dysregulation in other types of human disease and help to raise the awareness of the necessity and value for investing in orphan (or rare) disease research. At the personal level, I anticipate that my research training based on the NGLY1 study will provide me with a sturdy foundation to continuously working at the interface of clinical practice and translational research as a physician scientist. Perhaps, this will also lead to my larger dream to fashion disease understanding and treatment around an individual, moving away from the current all-size-fit-all approach. For families that might be dealing with NGLY1 deficiency or a rare disease, I hope that they are inspired knowing that people are working on solving the disease they face, and that our studying the disease helps highlight NGLY1 and its history, so that families will be further empowered to fight for their children just like how the Mights and Wilseys had, before their efforts ultimately helped researchers and clinicians discover NGLY1 deficiency. In the end, it’s true that we are all in the fight together.
What excites you about the work you are doing in research? NGLY1?
In Dr. Yu-chieh Wang’s lab, we’re taking a very unique approach to studying NGLY1 deficiency. Since many of the symptoms NGLY1 deficiency patients exhibit during their development can be related to trouble in how neurons talk to each other, we decided to look into these work horses of the brain and designed a way to determine how early brain development in these patients would look like using what is called human mini-brains. From human induced pluripotent stem cells (hiPSCs), which are cells we bring back to the embryonic-like stage by the reversion of a patient’s skin cell, we get patient cells that can mimic and be used to study an individual’s disease. I assemble these blank canvas-like hiPSC cells in a ball, and with a clean start I instruct and guide them down a particular path. Then, I watch how these balls go through the many stages of growth and maturation in a process that’s based much on their own accord and eventually organize into different brain regions. This process recaptures many of the same events that naturally occur as the human brain would develop in the womb, but finally allows scientists and clinicians to see, dissect and physically examine what was previously not possible without introducing unintended harm to a mother or baby. Using the cells from a NGLY1 patient, we’re able to become familiar with what happens in the NGLY1 deficiency brain as the disease takes its toll. The more impressive piece is that we’re able to do this in mass. By generating hundreds of these mini-brains at a time, and studying this process over and over again for a number of times, we enhance the ability to gather meaningful information about a disease, what it does, and why it happens. Currently, we study NGLY1 deficiency from the DNA to the protein, all the way up to how those building blocks influence brain tissue organization and communication through electrical signals. At each step of the way, NGLY1 deficiency may change the way things normally work, and so at each of these steps it offers us different ways in how therapeutic intervention may be developed. We’re now pulling in all the data from our months of studies, so pretty soon we will know more about the backstory of disease than we ever have. With hundreds of mini-brains built from NGLY1 patient cells, we could also soon test collections of therapeutics at a massive and efficient scale.