Focus Interview with Evgeny Zatulovskiy | Department of Biochemistry

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It's great to welcome Evgeny Zatulovskiy back to Cambridge as a group leader in the Department. We asked him about his background and his plans for research in the new lab.

Question 1. Tell us about your background and how you came to study biochemistry.

I was initially trained as a physicist, drawn to the beauty of mathematical formulas that can describe and predict the world around us. During my university studies, I read Erwin Schrödinger’s book “What is Life?”, which examines life from a physicist's perspective. This sparked my fascination about using mathematical and physical approaches to understand and predict the laws of life. After earning a Master’s degree in biophysics from the Polytechnical Institute in St Petersburg, Russia, I joined the MRC Laboratory of Molecular Biology (LMB) in Cambridge for my PhD. There, under the mentorship of Rob Kay and under the influence of many other inspiring colleagues, I delved deeply into cell biology and biochemistry. My postdoctoral work in Jan Skotheim’s systems biology laboratory at Stanford University allowed me to blend my knowledge of mathematics, physics, and cell biology to develop an interdisciplinary, quantitative approach to understanding how cells make a decision to divide and how different biophysical and biochemical stimuli influence cell behaviours.

Question 2. What led you to focus on cell size regulation?

I was very interested in how basic physics principles impact the behaviours of living systems. In this context, the mystery of cell size regulation sounded like a perfect topic for me. While size is probably the most obvious and fundamental property of any cell in nature, we know surprisingly little about how and why it is tightly regulated in our tissues. Cell types in our body differ in size by multiple orders of magnitude – for example, the volume of sperm and blood cells, which need to move through tight spaces, is on the order of 100 cubic microns, while heart muscle cells, which need to produce high forces, are 100 times larger, and oocytes are 300 times larger than even muscle cells. At the same time, cells of the same type are incredibly uniform in size within healthy tissues, while diseases and ageing are often associated with size deregulation. Nevertheless, cell size has been largely neglected by cell biology studies so far. While the cell size homeostasis is a century-old observation, we know very little about how it affects cell physiology, and we are only starting to understand how cells sense and regulate their size. Latest advances in gene editing, quantitative imaging, proteomics, and single-cell techniques now provide unprecedented opportunities to explore the molecular aspects of cell size regulation, which is why I am excited to study this field.

Question 3. Explain the main research questions your group is seeking to answer.

The overarching goal of our research is to understand HOW and WHY animal cells tightly control their size. This is not as trivial a question as it may sound. To maintain cell size homeostasis, cells must measure their own size and use this information to adjust their behaviours. For instance, if a cell grows too large, it must either slow its mass accumulation rate, or divide into two smaller cells. We are working to uncover the molecular mechanisms that allow cells to sense their size and transmit this information to the signalling pathways that regulate growth and division. Additionally, we are investigating why maintaining the correct size is crucial—specifically, how changes in cell size impact cellular functions.

Question 4. Are there any important collaborations with other research groups?

We currently have a fruitful collaboration with Prof Lars Steinmetz's lab at the European Molecular Biology Laboratory (EMBL) in Germany, where we combine their expertise in imaging-based cell sorting and CRISPR-knockout library screening with our knowledge of cell biology and live-cell imaging. Together, we are exploring how cellular organelles scale with cell size and why, for example, the nucleus always maintains a fixed fraction of the cell volume in a given cell type.

Another promising collaboration is with the laboratories of Dr Ali Shariati in California and Dr Jette Lengefeld in Finland, who are experts in embryonic stem cells and hematopoietic stem cells, respectively. Together we aim to mechanistically understand how cell size biases stem cell fate decisions do divide, differentiate, or maintain pluripotency, and why an increase in cell size leads to the loss of potency and onset of ageing in stem cells.

Question 5. How are your group using state-of-the-art quantitative techniques?

We use highly-quantitative mass spectrometry to detect subtle changes in the concentrations of hundreds of crucial proteins as cells grow in size, which allows us to predict how cell size affects cell behaviours. This approach is complemented by CRISPR-based fluorescent tagging of key proteins, timelapse quantitative live-cell microscopy, and other single-cell methods, such as flow cytometry, to observe biochemical and physiological changes in real-time as cells grow and divide.

Question 6. With the centenary in mind this year, what synergies does your group's work have with past research in the Department?

The Department has historically been at the forefront of gene expression research and has greatly contributed to our understanding of how biochemical processes determine cell physiology. My research, which aims to understand the mechanisms through which cell size differentially modulates the expression of numerous important genes to modulate cellular behaviours, certainly aligns with and benefits from the pioneering approaches and techniques developed by current and former Department members.

Question 7. How does your research contribute to the advancement of medicine and curing disease?

Although our research primarily focuses on fundamental questions of cell biology and aims to understand the basic principles of life, it has the potential to offer insights into how our organs and tissues function normally and what happens in cases of disease and ageing. For example, in healthy tissues, cells are highly uniform in size, whereas in cancers, cell size is often deregulated, and the aggressiveness of tumours correlates with cell size heterogeneity. We do not yet understand how this heterogeneity mechanistically contributes to key features of cancer cells—their uncontrolled division, genomic instability, and cell motility leading to metastasis. By understanding how cell size affects cancer cell properties, we might be able to design more efficient treatment strategies for cancer.

Another example is the connection between cell size and cellular ageing: as we age, our cells tend to increase in size, and this increase is correlated with enhanced senescence (also known as cellular ageing), inflammation, and loss of stem cell potency. We aim to mechanistically understand this process and explore how cell size might affect the sensitivity of cells to treatments used to improve cell and tissue function, or to eliminate abnormal cells.

Question 8. What are your future plans for expansion and tackling new research questions?

Nearly all published studies investigating mammalian cell size regulation have been performed on cell lines grown in artificial culture conditions. Although such in vitro experimental systems provide a good starting point for understanding basic phenomena related to size control, they cannot reproduce the tissue and organ contexts that impose additional layers of cell size regulation in vivo. Therefore, to comprehensively understand how cell size is controlled within living tissues, we plan to use more physiologically relevant experimental systems that can shed light on additional layers of cell size regulation within real tissues and organs. This approach will allow us to understand how cell and organ size control mechanisms are coordinated during organ development and regeneration, and how miscommunications between these mechanisms contribute to tumorigenesis. The mouse liver is an excellent model system to study these phenomena. On one hand, the liver demonstrates unique regenerative abilities and robust organ-size control—surgical removal of part of the mouse liver induces hepatocyte enlargement that restores the organ to its original size. On the other hand, cell-size control limits the degree of hepatocyte hypertrophy: their size rarely increases by more than 30%. Using this system, we can begin addressing questions of cell and organ size regulation in vivo.

Another exciting direction for me is to understand how dynamic changes in cell size during early development affect stem cell potency, cell fate decisions, and cell differentiation programs in embryos. By revealing these connections, we will be able to better understand the principles that govern embryo development and tissue regeneration.