Q&A with Wyatt Yue, Ph.D.
January 20, 2026
Dr. Wyatt Yue is a Professor and the Chair of Structural Biology at Newcastle University Biosciences Institute and a member of the APBD Research Foundation’s Scientific and Medical Advisory Board. Dr. Yue’s laboratory uses biochemistry, structural biology, and chemistry techniques to understand how genetic mutations lead to metabolic disease and identify disease targets for the development of small molecule therapies to treat diseases, like APBD.
Dr. Yue received a 2024 Million Dollar Bike Ride grant titled "Development of Glycogen Synthase Inhibitors for APBD". His grant expands upon his 2021 project to evaluate oral therapies for APBD that are aimed at controlling glycogen synthase activity.
We interviewed Dr. Yue recently to give you a chance to learn more about him and his innovative APBD research.
Q: What inspired you to pursue this field of research?
Dr. Yue: I have always wanted to make a difference in whatever I do in life. I learnt through my university degree in Biochemistry that a research career involves experimenting with new concepts and bringing them into discoveries. I realized that this is a very meaningful way to make a difference and have been drawn to it ever since. The notion of applying our expertise in the shapes of enzymes (structural biology) to create a new treatment in the clinic one day is a strong motivation.
Dr. Wyatt Yue, Newcastle University
Q: What excites you about rare disease research?
Dr. Yue: It has been inspiring being a part of the rare disease ecosystem, in the unprecedented, opportune moment in time that is now. There are three developments in the field that excite me. First, I'm excited by the phenomenal advances in many therapeutic modalities, be they small molecules, gene therapy, or ASO. Rare disease is the field where we should go all in and try out everything. Second, I’m fascinated by approaches to speed up the drug development process, including the growing importance of drug repurposing, phenotypic screening, and patient-derived iPS cells (a type of stem cell). Third, while academia continues to play a key role in translating discovery research to clinics, I welcome the emerging and growing industry presence in the rare disease arena, particularly startup and biotech that are driving technology platforms, including AI machine learning.
Q: How did you approach designing this project?
Dr. Yue: Our approach can be likened to a manufacturing conveyor belt. In APBD, the glycogen manufacturing factory inside the body has a problematic worker (glycogen branching enzyme) in the middle of the conveyer belt. As a result, the glycogen that is formed is often in the wrong shape, can no longer function well, and unfortunately will build up as clumps. Our approach is to turn to the earlier worker (glycogen synthase) in the conveyor belt of the glycogen factory and make them slow down their part of the manufacturing process. In doing so, the body will make less glycogen and prevent the buildup of clumps. Our task is, therefore, to design small molecules (inhibitors) that could target glycogen synthase and slow down its work.
Q: How is the research progressing so far?
Dr. Yue: We have built a strong partnership team at Newcastle University for this project, with expertise in structural biology, medicinal chemistry, and computational chemistry. In addition, we have been collaborating with colleagues at University of Zurich towards high-throughput screening. We have made good progress towards the project goals in identifying small molecules that could target the glycogen synthase enzyme.
Q: Have there been any challenges with the project?
Dr. Yue: Research is often full of unexpected surprises, some presenting as challenges. One example is the variability of experiment outcomes from repeating the same approaches – in synthesizing compounds, growing cells, taking reading measurements. This is part and parcel to biological research, and it is important that we as researchers take notice of these variations and account for them in our interpretation.
Q: What has surprised you about the discoveries from your lab and their impact?
Dr. Yue: Over the years, I have come to appreciate that an enzyme is a highly dynamic concept, which changes its own shape all the time as it functions and as it malfunctions. I am surprised by the plasticity of an enzyme in ‘shape-shifting’, impressed by all the emerging technologies to capture these changes, and excited by the potential of exploiting them in new drug discovery.
Q: Your research builds on prior work, supported by a 2021 MDBR grant, investigating glycogen synthase inhibitors for APBD. Can you tell us why this is an important area for APBD research?
Dr. Yue: We are very grateful to MDBR and APBDRF for awarding us this grant for the second time. This has hugely enabled us to continue the work that we started in the 2021 project, building from a very good foundation of our knowhow in the features of the enzyme, in the experimental setup, and in troubleshooting the different processes.
The importance of looking at glycogen synthase inhibitors as treatment for APBD is in expanding the ways in which treating APBD can be approached. When we think of genetic diseases, our first thought is to treat the gene or the protein that has the mutation -- in the case of APBD, glycogen branching enzyme. However, reducing glycogen synthase activity to balance the reduced glycogen branching enzyme in APBD is another way to approach treatment and could, potentially, work for other glycogen storage disorders. This approach of targeting other enzymes within the same pathway of the mutated gene, often known as substrate reduction therapy, has proven success in several metabolic disorders, and is the central focus of my team's various drug discovery programs.
Q: Your research has implications for several glycogen storage disorders that impact different steps of glycogen metabolism. Tell us why. What is needed to build momentum?
Dr. Yue: There are other glycogen storage disorders which affect another worker(s) in the manufacturing conveyor belt, leading to similar problematic buildup in the process. Therefore, slowing down glycogen synthase, which is a worker early on in the manufacturing process steps, could offer potential rescue to these other disorders. It is important that we look at the other disease systems as early as we can, to ensure cross-applicability of a potential treatment.
Q: What are your next steps for this project?
Dr. Yue: As mentioned, we have made good progress in identifying new molecules that target glycogen synthase. We are currently increasing our confidence in these molecules, by determining how tightly they target the enzyme, and how well they function to slow down the enzyme, so that we can further optimize these properties that are key to future drug development.
Thank you, Dr. Yue. We wish you much success on behalf of our community!