December 17, 2018
Meet Makoto Saito
Makoto Saito is a PhD student in the group of Patrick Matthias, which is well-known for studies on histone deacetylases (HDACs). In his recent work published in Nature Chemical Biology, Makoto identified deacetylation by HDAC6 of disordered protein domains as an important determinant for phase separation and granules formation.
Q: How did you come to study phase separation?
The group of Patrick Matthias had been studying HDACs for a while. A former member of our group found an unexpected relationship between the histone deacetylase HDAC6 and stress granules: she discovered the deacetylase activity of HDAC6 to be important for formation of stress granules and published this evidence in 2007. However, back then the mechanism underlying this correlation was not clear. When I joined the lab five years ago, I decided to address this gap for my PhD project. I analyzed all HDAC6 substrates to see if any of them was directly related to stress granules formation. Indeed, I could demonstrate that a novel substrate, the RNA helicase DDX3X, efficiently undergoes liquid-liquid phase separation upon deacetylation by HDAC6 in a structurally disordered region, which leads to stress granules maturation; this is the answer to the 10-year-old mystery of the HDAC6 role in stress granules formation.
Q: What do you think are the main applications of your study?
Stress granules formation has been related to neurodegenerative diseases like Amyotrophic Lateral Sclerosis, Alzheimer’s and Parkinson’s disease. HDAC6 was already known to be important in these diseases but it was difficult to target because its exact function was unclear. My study shows the possibility that phase separation, mediated by HDAC6, is a key factor for the development of diseases. Moreover, phase separation is involved in several other biological processes, like nuclear bodies formation, transcription and synaptic vesicle clustering. It will be interesting in the future to look at how these processes are affected by HDACs.
Q: Did you face difficult moments or obstacles during your project? What keeps you motivated despite the daily challenges of research?
It is quite usual to encounter hard times while doing research. I had used up six lab notebooks with tons of negative data by the time I had my first thesis committee meeting! [after 1.5 years.] But I persevered, because I was aware that I was still enjoying the question behind the experiments. I think breakthroughs in science require an intrinsic curiosity about nature and a huge amount of passion. I admire and strive to become one of those scientists who can stay entirely devoted and concentrated on their research. When I am tired or frustrated, it motivates me to remind myself that I am helping people, albeit indirectly: the applications of my research can contribute to save people’s lives in the future.
Q: Your PhD studies are coming to an end. What are your plans for the future?
I want to continue my career in academia and I am looking for a postdoc position in Europe or in the US. I want to keep studying molecular mechanisms related to diseases that are hard to treat, such as cancer and neurodegenerative diseases. At the same time, I am particularly fascinated by technological advances in the fields of chemical and synthetic biology, which could be exploited for innovative therapeutics. Thus, I also hope that I can develop tools to modify the biological systems in order to fix pathological malfunctions.
Q: You are Japanese. What brought you to do your PhD at the FMI and how are you enjoying life in Switzerland?
I was born, grew up and lived in Tokyo for 24 years. At the end of my Master’s studies, I was really curious to go abroad and experience a different culture. I applied to several universities in Europe and in the US. I eventually chose the FMI because it is very well funded and provides a robust, supportive program that allows students to fully concentrate on cutting-edge scientific questions. I had heard that my current mentor Prof. Patrick Matthias gave graduate students plenty of freedom to pursue their scientific interests, and I thought this was a good environment to help me develop as an independent researcher. I am very satisfied with my experience at the FMI and in Switzerland. I have the impression that Swiss researchers are less under pressure than Japanese ones in their everyday job. I appreciate the collaborative, relaxed atmosphere at the FMI, which ensures a high quality of life while favoring an impressive scientific productivity. Without this excellent research environment I could not have succeeded in my work. Nonetheless, I really miss ramen!