First person – Emmet Francis Free

Emmet Francis

How would you explain the main findings of your paper in lay terms?

Practically every cell in our bodies has an intrinsic 24-h, or circadian, rhythm. These rhythms persist even when cells are cultured outside the body, manifesting as 24-h oscillations in gene expression. Recent experiments with mammalian cells have shown that mechanical cues, such as the stiffness of the surface a cell interacts with, can significantly alter circadian oscillations. Although many mathematical models of circadian rhythms exist, most do not explore this potential overlap between cell mechanobiology and the expression of circadian genes. In this paper, we developed a mathematical model that integrates a cell's response to mechanical cues (mechanotransduction) with its intrinsic circadian clock. Our simulations show that increased mechanical activation − for instance, through interactions with stiffer surfaces − can change the period and amplitude of circadian oscillations. Furthermore, our model suggests that such high levels of mechanical activation can eliminate circadian oscillations altogether in certain cases. This has possible implications for diseases associated with changes in the mechanical properties of cells and tissues, such as atherosclerosis or certain cancers. Our findings are also relevant to certain tissues that experience large amounts of strain, such as skeletal muscle during exercise.

Were there any specific challenges associated with this project? If so, how did you overcome them?

I came into this project with no background in circadian biology and found myself somewhat intimidated by the large body of literature associated with the molecular details of the mammalian circadian clock. However, several key modeling papers, as well as a pivotal textbook by Alfred Goldbeter, one of the foundational researchers in mathematical models of biochemical oscillations, helped me come to terms with the field. I quickly realized that the cell's circadian clock can be mathematically described as a system with time-delayed negative feedback, which helped inform my choice to model the system using delay differential equations (DDEs). These equations presented a further challenge as I had not previously used DDEs in any of my research. However, I found it an exciting mathematical topic to dive into, one that could well be useful in my future work.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

Early in the project, Dr Rangamani and I admired colorful plots known as kymographs featured in one of the primary experimental papers we reference, from Abenza and colleagues in the Journal of Cell Biology. These plots showed variation in the time-dependent expression of a key circadian protein, REV-ERBα, within populations of cells. This had me thinking back to population-level modeling approaches I encountered during my time as a PhD student at the University of California (UC) Davis. This work, led by Dr Eleonora Grandi and Dr Colleen Clancy, modeled the variation in behavior among populations of cardiomyocytes by assuming that each cell had slightly different sets of parameters (e.g. rate constants) governing their signaling dynamics. I realized that we could take the same tactic here, allowing us to reproduce the experimental variability in circadian oscillations (see our kymographs in the included figure). The true eureka moment came when I recognized that the variation in parameters could be directly informed by estimating distributions for each parameter using Bayesian parameter estimation approaches recently explored by a graduate student in our lab, Nate Linden. The success of this approach showed me that opportunities abound to integrate different computational techniques I encounter across different bodies of literature.

Why did you choose Journal of Cell Science for your paper?

The main experimental work we drew from in this paper was published in Journal of Cell Science (Xiong et al., 2022). This immediately drew us to JCS for our computational investigation of circadian rhythms and mechanotransduction. Beyond this, I have long appreciated JCS's willingness to publish both experimental and computational work in cell biology. In the end, we appreciated the ease and transparency of JCS’s review process and journal staff were very helpful at each step along the way to publication.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

My current advisor, Dr Padmini Rangamani, boldly suggested the idea for this project after finding a couple preprints that suggested mechanotransduction and circadian rhythms were tightly linked. Although we each had experience in the field of mechanotransduction, neither of us had published on circadian rhythms previously. Dr Rangamani pointed me to researchers at the Center for Circadian Biology (CCB) at UC San Diego, where I was able to present a preliminary version of this work at a workshop. I received crucial feedback and guidance from members of the CCB that helped inform my completion of this project and have opened up opportunities for future projects in the Rangamani lab.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

When I was working on my undergraduate degree in Biomedical Engineering at UC Davis, I decided to seek opportunities to gain scientific research experience. After reaching out to several professors, I connected with Dr Volkmar Heinrich, whose research focuses on the biophysics of human immune cells. At the time, I was not very familiar with the idea that one could use physics to understand cellular behavior. This piqued my interest and motivated me as I started conducting hands-on experiments with immune cells, carefully observing phagocytosis, the process by which white blood cells consume pathogenic particles. I began exploring the intersection between Ca²⁺ signaling and cell deformations during phagocytosis, which led to my current passion for understanding the tight coupling between cell signaling and cell mechanics. Without those days spent observing cells in action, I doubt I would have my current conviction to pursue a career in scientific research.

Who are your role models in science? Why?

One of my main role models is my current advisor, Dr Padmini Rangamani. Her diversity of research interests, dedication to collaborating with experimental researchers to keep our theoretical work grounded and pure excitement to answer questions in biophysics all motivate me to continue working hard and enjoying my research. More broadly speaking, I draw inspiration from many other researchers who engage in truly interdisciplinary work. Dr David Odde's (University of Minnesota) willingness to integrate experimental biology and computational approaches, and even bring in an artistic flair in his collaboration with the Theatre Arts and Dance Department, motivates some of my scientific aspirations. Beyond my own field, I find the theoretical physicist Dr Sean Carroll's work to be a compelling example of interdisciplinarity. His ability to merge careful philosophical considerations with physics and mathematics is remarkable. Furthermore, his weekly podcast interviewing researchers across many different fields reminds me how important it is to talk to and learn from people who study topics entirely outside my realm of research.

What's next for you?

I am currently continuing my position as a postdoctoral researcher with Dr Rangamani. In addition to expanding this project on mechanotransduction and circadian rhythms, one of my main focuses has been on developing and utilizing custom software to simulate the spatiotemporal behavior of cell signaling networks. This software, called SMART (Spatiotemporal Modelling Algorithms for Reaction and Transport), is an important tool for addressing new research questions in mechanobiology. Soon, I will begin applying for assistant professorships. In my research lab, I plan to apply computational techniques to understand the intersection between cell signaling and cell mechanics, particularly in the context of human immune cells.

Tell us something interesting about yourself that wouldn't be on your CV

I enjoy playing music in my free time, especially playing guitar and singing, or playing the piano if one is available. In graduate school, my wife and I teamed up with some grad student friends to form a band. Although we lacked a drummer, we still had fun covering songs by an eclectic set of artists, from Weezer to Stray Cats to the Eagles. Currently, I love going out to open mics in San Diego to play some songs of my own and to hear from other local artists.