We continue our series on inspirational female scientists by interviewing Dr. Elizabeth Chen. Elizabeth leads a research group at Johns Hopkins University that explores the basis of cell-cell fusion. Pushing a traditionally genetics-only system to examine molecular machinery and biophysical inputs, her work has opened the black box of how cells fuse together in context, such as the making of multinucleate cells in muscle.

We asked Elizabeth to tell us about her science and how she got to where she is today.

Marie Bao: What does your lab focus on?

Elizabeth Chen: My laboratory studies the molecular and cellular mechanisms underlying cell-cell fusion, a fundamental process in the conception, development, and physiology of multicellular organisms. We address this question using myoblast fusion in Drosophila as a starting point, where we can combine diverse approaches such as forward genetic screens, biochemistry, biophysics, live imaging, super-resolution microscopy, and electron microscopy. We have identified several evolutionarily conserved components of the signaling cascade controlling myoblast fusion and elucidated a key function of the actin cytoskeleton in the fusion process.

Our research led to the unexpected discovery that myoblast fusion is an asymmetric, invasive process mediated by actin-propelled membrane protrusions from one cell (invading cell) into the apposing fusion partner (receiving cell). These invasive protrusions trigger a mechanosensory response in the receiving cell by activating its cortical actomyosin network. It is the interplay between the pushing force from the invading cell and the resisting force from the receiving cell that brings the two cell membranes into close proximity to facilitate fusogen engagement and membrane fusion.

Based on these insights, we were able to reconstitute cell-cell fusion in a generic nonfusogenic cell line. We believe that actin-based membrane protrusions represent a general mechanism of cell-cell fusion, since they have now been reported in the fusion of nonmuscle cell types. We are currently focused on identifying transmembrane proteins that mediate the final steps of the cell membrane fusion reaction. We are also exploring the role of lipids and mechanotransduction in cell-cell fusion, as well as studying myoblast fusion in muscle development and regeneration in vertebrates.

MB: Tell us about your favorite paper or project from your career.

EC: I feel attached to all the papers I have published, but my favorite one has to be Sens et al. (2010), published in the Journal of Cell Biology. In this study, we identified a surprising asymmetry at the myoblast fusion site, which we call a fusogenic synapse, and provided a new conceptual framework to think about cell-cell fusion. Prior to this work, it was thought that cell-cell fusion was a symmetrical process in which two fusion partners contributed equally. However, our initial analysis of actin polymerization in myoblast fusion did not support this view, since the bulk of the actin-enriched structure at the site of fusion appeared to be localized to one of the two cells. Fortunately, we followed up this initial observation with careful cell biological and electron microscopy studies.

From these studies, we were able to demonstrate unambiguously that the actin-enriched structure is only generated in one cell, which propelled finger-like protrusions to invade the neighboring fusion partner to promote fusion. This is an important finding, since it brought a new foundation to investigate the mechanisms of cell-cell fusion. It is on this foundation that we followed up with reconstitution of cell-cell fusion in nonfusogenic cells and the discovery of a mechanosensory response in the receiving fusion partner.

MB: Who has inspired you?

EC: In my childhood, I read a biography of Madame [Marie] Curie and was greatly inspired. Her passion toward making discoveries, her intense focus on research, her persistence in times of difficulties, and even her moderate lifestyle all made an indelible impression on me. Years later, what she said still sounds so inspiring: "Life is not easy for any of us. We must have perseverance and above all confidence in ourselves. We must believe that we are gifted for something and that this thing must be attained."

MB: What key factors contributed to your success?

EC: I always have a strong desire to make discoveries and understand more about ourselves and about the world around us. My graduate school mentor Bruce Baker at Stanford taught me to identify important biological questions and use whatever tools are needed to solve the problem. He did not work in a so-called "hot" field, but made fundamental discoveries of an alternative splicing cascade controlling sexual development. This had a strong influence on me, instilling in me a desire to explore uncharted territories.

When I joined Bruce's lab, he suggested three potential thesis projects to me. Two of them were within the main scope of the lab, and the third one was to open up a completely new research area. Being a green and adventurous graduate student, I chose the third project without any hesitation. Little did I know what I had gotten myself into! There were moments in the beginning when I completely lost sight of my direction and felt that I could never figure anything out. But with Bruce’s encouragement and faith in me, I put the “fear” aside, submerged myself in literature, and eventually came up with tractable directions. I owe my thanks to Bruce for giving me all the freedom to explore and no pressure to produce, which made graduate school a very enjoyable experience.

Apparently the thrill of exploration is addictive. For my postdoctoral studies, I also wanted to identify an important but poorly understood problem to pursue. I became interested in cell-cell fusion, since it is such an indispensible process, yet, at the time, it was pretty much a black box. I interviewed with Eric Olson and really liked his lab at UT Southwestern. Although Eric has a mouse muscle lab, I proposed to him that I would like to study myoblast fusion using Drosophila genetics. This was again a risky project, since there was no guarantee that I would find anything interesting. But to my delight, Eric simply said that it was a great idea and told me to "just go ahead and do it." He was so enthusiastic about my project that, after a week in his lab, he asked me if I had gotten a fusion mutant. And after I eventually got my first fusion mutant, months later, he emailed me in the middle of the night telling me how excited he was! This level of enthusiasm and support is so uplifting for a budding young scientist, for which I will always be extremely grateful.

Since I established my own lab at Hopkins, I have been very fortunate to work day in and day out with an amazing group of people, who are passionate, creative, and rigorous. It is a wonderful pleasure to share the journey of exploration and the thrill of discovery with them!

MB: Do you think you encountered any extra hurdles as a female scientist?

EC: For sure, especially as a female scientist who has a family with two kids. On one hand, my kids are the most precious things in my life, but on the other hand, they do take an enormous amount of time and energy to care for. I think that there are no other ways to strike a work/life balance than having a great support system at home. I have been very fortunate to have my parents helping me along the way. I also have an extremely supportive husband, who does great work in and out of the house.

MB: Any words of advice for more junior scientists (male and female)?

EC: When I had a small setback in Eric’s lab, he gave me a postcard that had this on it: "Once the destination is set, it does not matter if the road is long and uneven." I would encourage a junior scientist to follow your star, be fearless, and not to give up easily. In addition, I would suggest finding mentors who have faith in you and who are really interested in and supportive of what you would like to pursue.

MB: If you were not a scientist, what would your alternative career/life choice be?

EC: I love nature. I guess if I were not a scientist, I would probably like to work in a beautiful national park.