CI: Tell us a little bit about yourself.  

Tongyin Zheng (TZ): I am originally from a small city called Guilin in the south of China. I studied chemistry as an undergrad at Nankai University and worked in a few labs during that time. I then pursued a Ph.D. at Syracuse University where I met my advisor, Carlos Castañeda. One of the things he showed me was how powerful nuclear magnetic resonance can be in structural biology studies.   

Together, we looked at a family of proteins called the Ubiquilins which undergo a fascinating biophysical process called phase separation, wherein the protein is in solution but - if you have enough of it or if you have binding partners - it can form these little droplets within water. Mutations of these proteins can lead to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). The Ubiquilins and their association with ALS was a new area of research at the time and about which we published a few papers.   

I have personal experience with neurodegenerative diseases. Both my grandmothers suffer from dementia, and I’ve seen first-hand how devastating neurodegenerative diseases can be. This has really motivated me to find a cure for these diseases, or at least contribute to a better understanding of them. I'm also really drawn to intricate things, and neuroscience is probably the pinnacle of intricacy in human systems. There are so many players: proteins, RNA, small molecules and peptides that can all influence how neurons work. And oftentimes very small, seemingly unimportant perturbations in the system can lead to devastating results. We now know that phase separation is a very important aspect of neuron functions and also that dysfunction of this system can lead to neurodegenerative diseases.  

I wanted to continue my research in this field after I got my Ph.D., and that led me to the lab of Nicolas Fawzi, who studies the fundamental physics of protein phase separation at the atomic level resolution; essentially investigating the forces that drive phase separation. This is super cool because the tools that he uses are unique, and so are the skills that he has to look at things at such a level.  

CI: Tell us more about this research.   

TZ: We’re looking at this protein called fused in sarcoma, or you can call it FUS for short. Fus is an RNA binding protein that undergoes phase separation by itself and with RNA. Researchers have found that mutations in this protein can cause ALS and other neurodegenerative diseases. But no one really knows how this happens. Furthermore, no one really knows how phase separation is involved in the normal function of this protein. So, we’re trying to understand the functional role of FUS phase separation first and then the dysfunctional aspect of this process that can cause disease.   

My study is looking at the FUS phase separation with RNA. On an atomic level of resolution, we’re trying to understand the molecular forces that mediate the interaction between the FUS protein and RNA in phase separation, how the structures of FUS and RNA molecules can change upon binding, upon phase separation, and how mutations in FUS will change that interaction.  

Usually, when you think about protein RNA interaction, you think about the electrostatic interaction between positively charged amino acids and the negatively charged RNA backbone. That's a big aspect of the interaction there, but also between base and certain amino acid types. But what we've found is there are other amino acid types that can also get involved in the interaction in phase separation. Our findings open up the possibilities of more complex interactions and new ways that RNA and proteins can coexist within these condensed, concentrated environments.  

CI: Tell us about your experimental design.  

TZ: The experiment most of the time involves purifying the protein and making protein constructs with different parts of the protein, with and without mutations. We then look at the protein in the NMR tube. What’s especially exciting about this research is that we can look at the specific chemical environments of each individual amino acid within the protein. We can then form our hypotheses and test them by making mutations to the protein or introducing binding partners such as RNA. We also use other biochemical and biophysical assays such as circular dichroism, disseminated intravascular coagulation or fluorescence microscopy, looking at the shape and the transition from these nice little droplets to aggregates. We track the time span that it takes for that transition.   

CI: In 2023, you received the Judith and Jean Pape Adams Postdoctoral Award which supports a postdoctoral researcher studying ALS or other neurodegenerative diseases. How has that recognition dovetailed with your current research?    

TZ: It was great to receive the award as it really gave me a certain degree of freedom to independently look at the things that I wanted to study. Specifically, the funding has supported me during a particularly important period of my research. Receiving this recognition has also given me confidence that my excitement and dedication are well-placed, and that I am making a meaningful contribution to the research community. 

CI: Where do you see this research going in the near future?  

TZ: What we are finding now is that understanding the physical forces that underlie phase separation can lead to the types of therapeutic development that target these biochemical assemblies and their transition to aggregates. So, if we can prevent this aggregation, we may be able to prevent specific types of neurodegenerative diseases.   

While we are not directly testing this idea, companies are already trying to do that by using small-molecule drugs that may be directed to specific parts of the brain. A big challenge, of course, is to make these things less toxic and easier to administer. Using this technology, we may be able to address and abate some of the most challenging neurodegenerative diseases.  

CI: After you finish your postdoctoral work, where do you hope to go next?   

TZ: I really hope that I can become an independent researcher in the future as a PI, ideally somewhere in a research institute. At the same time, I can see myself continuing to do neurodegenerative disease related research in the future as well. It’s what inspires me, drives me and pushes me to do my best workday in and out.