An Interview with Dr. Huaiying Zhang

Dr. Huaiying Zhang is an Eberly Family Assistant Professor in the Department of Biological Sciences at Carnegie Mellon University, with a courtesy appointment in the Department of Chemical Engineering and Physics. Her research focuses on the functional significance of phase transitions in cells, particularly in the context of cancer. By developing chem-optogenetic tools, she explores how liquid condensates influence telomere DNA synthesis in cancer cells, aiming to understand the mechanisms that support cellular immortality. In this exclusive interview, Dr. Zhang unveils her passion for engineering synthetic organelles to manipulate biomolecular condensation, enhancing our understanding of cellular processes such as the cell cycle and apoptosis.

Q: How did you embark on your career in science? Could you tell us about your journey and the motivations behind your choices?

A: Indeed, my journey into science wasn’t a straightforward one. Initially, I was drawn to the practicality and tangible outcomes of engineering, leading me to pursue a Ph.D. in chemical engineering. I was captivated by the idea of creating and building solutions that could have a real-world impact. However, as I delved deeper into my studies, I discovered a profound fascination with the fundamental principles underlying natural phenomena. The allure of uncovering the hidden mechanisms that govern the world around us proved irresistible. This newfound passion for scientific exploration led me to pursue graduate studies and eventually transition into the captivating realm of cell biology during my postdoctoral research.

Q: That’s a remarkable shift! What was it like transitioning into a new field?

A: The transition was both exhilarating and challenging. It was akin to embarking on a grand adventure, navigating uncharted territories with a steep learning curve and a new language to master. The sheer volume of knowledge to absorb was initially overwhelming. However, the thrill of discovery and the boundless possibilities of biology fueled my determination. I embraced the challenge, immersing myself in the literature, attending conferences, and engaging in countless discussions with colleagues. The support and encouragement of my mentors and peers were instrumental in my successful transition.

Q: Your current research focuses on biomolecular condensates, a relatively new and exciting field. What sparked your interest in this area?

A: My fascination with condensates began while investigating a protein that formed intriguing high-order assemblies within cells. Initially, we explored whether these assemblies were amyloids, but they weren’t. This led us to investigate the possibility of them being biomolecular condensates. Through meticulous experimentation, combining techniques such as fluorescence microscopy, protein engineering, and biophysical assays, we confirmed the presence of droplets formed between protein and RNA. This revelation opened the door to a captivating new world of research, and I haven’t looked back since.

Q: It seems your background in chemical engineering has played a significant role in your research. How does it contribute to your understanding of biomolecular condensates?

A: My training in chemical engineering has been invaluable. The principles of colloidal science and polymer physics that I learned during my PhD have provided a strong foundation for understanding the physical chemistry underlying the formation of biomolecular condensates. Concepts such as phase separation, interfacial tension, and nucleation kinetics have direct relevance to condensate behaviour. This interdisciplinary perspective allows me to bridge the gap between the molecular and cellular levels, providing a unique vantage point for exploring the complexities of condensate formation and function.

Q: Are there any past or current scientists who have inspired you and shaped your scientific philosophy?

A: I’ve been fortunate to have had exceptional mentors throughout my career. My two postdoctoral advisors, Dr. Amy Gladfelter and Dr. Michael Lampson have been particularly influential. Dr. Gladfelter, who welcomed me into the world of biology, embodies a spirit of boundless curiosity and an unwavering belief in the potential of science. Her passion and open-mindedness have been a constant source of inspiration. Dr. Lampson, a brilliant scientist and mentor, has taught me the importance of rigorous experimentation, critical thinking, and effective communication. These mentors have not only shaped my scientific approach but have also instilled in me the importance of fostering a supportive and intellectually stimulating lab environment that encourages growth, collaboration, and the pursuit of knowledge.

Q: What are some of the significant challenges in condensate research, and what specific challenges do your lab aim to address? What breakthroughs do you foresee in this field in the coming years?

A: Condensate research is a rapidly evolving field with numerous challenges and opportunities. A central challenge lies in deciphering the diverse functions and emergent properties of these membraneless organelles. My lab is particularly interested in condensates involved in cancer, as they present unique therapeutic targets. Cancer cells exhibit distinct dependencies on condensates, and targeting their formation or dynamics could disrupt critical cellular processes without harming healthy cells. We employ a multidisciplinary approach, encompassing techniques such as live-cell imaging, protein engineering, and the creation of synthetic condensates, to gain a deeper understanding of their functions and develop potential therapeutic strategies.

Image: Droplets  (green) in  a human cell nucleus (purple)

Q: Could you elaborate on your recent manuscript, “TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells”? Do you think telomeres dynamically form condensates through phase separation and are quadruplexes and shelterins involved?

A: Our research focused on understanding how specific proteins are concentrated at precise locations within the cell, a fundamental question in cell biology. We used TERRA, a long noncoding RNA transcribed from telomeres, as a model to explore its role in concentrating proteins at these chromosomal ends. By knocking down TERRA, we identified LSD1, a lysine-specific demethylase, as a protein whose localization to telomeres is dependent on TERRA. We further discovered that LSD1 binds to TERRA in a G-quadruplex-dependent manner, leading to phase separation and the subsequent concentration of both TERRA and LSD1 at telomeres. This positive feedback loop facilitates the redistribution of TERRA from its transcription sites to other telomeres, providing a novel mechanism for protein recruitment and telomere maintenance in ALT cancer cells, which rely on alternative lengthening of telomeres (ALT) for survival.

While LSD1 interacts with histone modifiers, it does not specifically interact with the shelterin complex, which plays a crucial role in telomere protection. It’s worth noting that LSD1 is found in other genomic regions as well. However, in ALT cancer cells with mutated ATRX, the chromatin environment at telomeres is altered, enabling the enrichment of LSD1.

Our findings suggest that telomeres can indeed dynamically form condensates through phase separation, and G-quadruplex structures within TERRA likely contribute to this process. However, the involvement of shelterin proteins in telomere condensate formation remains an open question and an area of active investigation in our lab.

Q: Could you tell us about your research group and your philosophy on training and mentoring young scientists?

A: Our group is a vibrant and diverse collective, with members hailing from various backgrounds, including chemical engineering, physics, and biology. I’m deeply committed to fostering an interdisciplinary environment where everyone can learn and grow together. We actively collaborate with chemists, physicists, and cancer biologists, creating a rich tapestry of knowledge exchange and opportunities for cross-disciplinary learning. Additionally, we hold regular journal clubs where we delve into papers from different fields, expanding our horizons and encouraging intellectual curiosity.

My mentorship philosophy centres on empowering students to develop a multidisciplinary approach and a lifelong learning mindset. I want them to acquire problem-solving skills that transcend the boundaries of any single discipline. I encourage them to be bold, embrace new techniques, and continuously evolve as scientists. I believe in providing them with the freedom to explore their own ideas while offering guidance and support along the way.

Q: In the realm of microscopy, what type of microscopy is your favourite, and why? What has been your most exciting observation so far?

A: I’m captivated by the magic of time-lapse and fast imaging. Witnessing the dynamic dance of cellular processes in real-time, especially in 3D or 4D, is simply mesmerizing. It’s like peering into a hidden world, observing the intricate choreography of molecules and organelles as they carry out their vital functions. Lightsheet microscopy is my ultimate aspiration, as it would enable us to delve even deeper into the intricate world of cellular interactions and movements, capturing the dynamic processes in unprecedented detail.

Q: Achieving success in science often requires long hours. How do you maintain a work-life balance?

A: Work-life balance is a continuous balancing act. I try to prioritize based on the most pressing needs at any given time. While it’s a constant juggle, I believe that both work and personal life are integral to a fulfilling existence. The balance may fluctuate depending on the stage of one’s career, but ultimately, work and life intertwine and enrich each other. I find that engaging in hobbies and spending time with loved ones helps me recharge and maintain perspective.

Q: What advice would you offer to young scientists and investigators interested in cell biology and microscopy?

A: My advice is simple: follow your passion with unwavering determination. Don’t let fear or self-doubt hinder your pursuit of knowledge. Embrace the power of microscopy, an indispensable tool for studying condensates and observing the dynamic symphony of cellular life. Be open to interdisciplinary collaborations, as they can lead to unexpected breakthroughs and broaden your scientific horizons. Most importantly, never lose your sense of wonder and curiosity.

Q: Have you faced any specific challenges as an Asian researcher working abroad? How can the field of cell biology become more inclusive?

A: I’ve encountered various challenges, from the simple act of people correctly pronouncing my name to navigating cultural nuances in communication. These experiences underscore the need for greater inclusivity in science. Recognizing and valuing the diverse perspectives and communication styles of scientists from all backgrounds is essential for creating a truly welcoming and supportive scientific community.

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