Cell scientist to watch – Shashank Shekhar

Shashank Shekhar

What inspired you to become a scientist?

There wasn't a specific moment when I decided to pursue science. My parents had very different careers – my father was a geneticist running a research lab in India and my mother was an economist. I remember visiting my father's office as a kid and listening to his conversations with students while I sat drawing in the corner. Watching him doing experiments left a lasting experience on me and likely influenced my choice to pursue science. In India, excelling in high school often led to careers in engineering or medicine. For 6 months, I took extra classes to prepare for the Indian Institutes of Technology (IITs) entrance exam, but quickly realized engineering wasn't for me. Middle school-level biology, with its focus on drawing things like beaks and claws of birds and memorization didn't appeal to me either. However, I really liked physics. My father encouraged me, predicting that physicists would play a crucial role in future breakthroughs in biology. His foresight in the late 1990s deepened my appreciation for physics, leading me to study it full time.

Afterwards, I applied for a master's program in nanoscience and had the opportunity to study at two universities in two different countries: applied physics (nanoscience) in Delft and Leiden, and molecular bioengineering in Dresden. Living and studying abroad was a wonderful experience. While in Delft and Leiden, I attended a workshop called ‘Biology for physicists’, organized by Nynke Dekker and Herman Spaink at the Lorentz Center in Leiden. During the workshop, a speaker presented a video by cell biologist Julie Theriot, showing how bacteria inside a mammalian cell are propelled forward by actin comet tails. As a physicist who hadn't explored biology in depth, I was fascinated by how actin could drive such movement. This moment was a turning point for me. I reached out to one of my professors at TU Delft, Marileen Dogterom, to ask about scientists who worked on actin. She directed me to Marie-France Carlier at CNRS in Paris. After several unanswered emails, I called her to express my interest in working in her lab. Initially, she said there was no space, but after I persistently followed up, she agreed to accommodate me for a summer. That experience in her lab solidified my decision to do research.

How did you choose what to do and where to go for your PhD?

I applied for various fellowships and programmes, including the Marie Curie programme called Immunanomap. My future advisor, Vinod Subramaniam at the University of Twente, came across my application and invited me for an interview. His lab was developing optical and magnetic tools as well as new microscopes to explore biological questions. I really liked the lab and its projects, especially because most of the members were physicists who had transitioned into biology, which played a major role in my decision. My project focused on studying phagocytosis using magnetic tweezers. We replaced pathogens being engulfed with magnetic particles and applied force to prevent the phagosome's movement towards the nucleus, a process known as centripetal transport, which was thought to be essential for pathogen degradation. We discovered that although this delayed phagosome maturation, once the maturation began, it proceeded at the same rate. This finding is significant because it might explain how pathogens like the tuberculosis bacteria can remain dormant in the body for a lifetime, hiding within stalled phagosomes in immune cells. My PhD work demonstrated the importance of phagosomal transport – preventing it can delay the entire phagosome maturation process.

Following your PhD in The Netherlands, you moved to France to do a post-doc with Marie-France Carlier. What prompted this move?

During my PhD, I developed a strong curiosity about management consulting. So, immediately after, I joined a professional services firm called KPMG to work in their operations and strategy group. In just 6 months, I worked on a wide range of topics, from chemicals and chocolate to oil and gas. However, I quickly realized how much I missed science and research. Around that time, my PhD paper had just been published in the Biophysical Journal, and I received an email from Marie-France Carlier informing me about her recently awarded European Research Council (ERC) grant. She asked if I wanted to return to her lab for a postdoc position. I interviewed, got the job, and it marked a significant transition in my career.

I found that Marie-France was truly a force of nature. Her enthusiasm for science and passion for asking the big questions left a lasting impression on me. During my PhD, I had focused on building tools without being deeply attached to specific research questions. In Marie-France's lab, the emphasis was entirely on the questions, and we used tools to find the answers. That approach has stayed with me ever since. I often tell my students, “Don't worry whether you are a physicist, chemist or biologist – if you are excited by the question you are working on, it will keep you engaged and driven”. In Marie-France's lab, I worked on actin networks. In cells, there are two types of actin networks – branched and linear. My research question was to determine how these two networks function together. Can one network be made from the other, or are they formed independently in cells? It was a challenging project. A pivotal moment occurred when I accidentally added a capping protein to an experiment containing the elongating protein formin, which should have protected the elongating filament end from binding the capping protein. To our surprise, the filaments stopped growing. This unexpected result challenged conventional wisdom, revealing that multiple regulatory proteins could simultaneously occupy the barbed end of an actin filament. We shifted our focus to understanding how these proteins interact and we uncovered a fascinating new story. Another major achievement in her lab was solving the 70-year-old question of how actin filaments depolymerize. This experience has defined my career: revisiting so-called ‘settled’ questions in biology and challenging existing principles. If you have solid evidence and present it convincingly, people will eventually come around. This mindset has shaped my work ever since – I enjoy revisiting old questions with new technologies, diving deep into areas once thought to be resolved.

Afterwards, you moved to the US for a second postdoc. Why?

There were many reasons behind my decision. While working in Marie-France's lab, we were working on a project in parallel with Bruce Goode and Jeff Gelles, and eventually coordinated the publication of our papers. Afterwards, Jeff invited me to work in his lab for a few years until I felt ready to apply for a Principal investigator (PI) position. Jeff was an expert in single-molecule imaging, and I was eager to learn this approach. Additionally, my wife was working in the pharmaceutical industry, and the Boston and New Jersey areas – both pharma hubs – offered great opportunities. Initially, we planned to stay for just a couple of years and then return to Europe. However, many people told me that once you go to the United States, you rarely come back – and they were right, we ended up staying. I chose to work with Bruce Goode, a leader in the field of actin, Jeff Gelles, an expert in single-molecule work, and Jané Kondev, a theoretical physicist at Brandeis University. It turned out to be the best decision of my life!

International moves are part of the career of many scientists. You have worked in several different countries. Tell us more about your experience as a global nomad?

I recently did the math and realized that I've lived in 25 different houses across six different countries: India, The Netherlands, the UK, Germany, France and the USA. I think I've been a nomad all my life. Even in India, where each region has its own language and culture, we moved frequently as a family, and I had to adapt wherever we lived. In France, I learned enough French to navigate daily life, and the same with Dutch in The Netherlands. My wife holds both German and French nationalities, which helped me interact with the society around me, but I always knew our stay was temporary. This transient lifestyle has been a constant throughout my career, likely influenced by my parents, who also moved frequently for their jobs. That sense of always being on the move has stayed with me. I often tell people that when I lived in the Netherlands, boarding a KLM plane and hearing ‘Dames en Heren’ (ladies and gentlemen) made me feel like I was going home. The same happened when I lived in France hearing ‘Mesdames et Messieurs’ on an Air France flight. This nomadic lifestyle excites me; it keeps me motivated. There is always an itch to ask, “What's next?”. Maybe that will fade with age, but I'm not even sure I want it to because it's part of who I am. My wife is the same way. Our daughter even has four different passports! This reminds me how global our family is.

You were jointly mentored by Bruce Goode, Jeff Gelles and Jané Kondev. What have you learnt from this experience that you use in your approach to mentoring your own lab members?

To be honest, I wouldn't recommend having multiple mentors very early in your career (i.e. in graduate school) because it can lead to conflicting guidance and cause you to feel lost among different PIs. However, during my second postdoc at Brandeis University, I was already established in my field and greatly benefited from having multiple mentors. I spent most of my time with Bruce, a geneticist with whom I shared a passion for actin. He encouraged me to think beyond biochemistry and consider broader cellular processes. Jeff taught me to critically evaluate my data, and Jané inspired me to contemplate the big questions. Each mentor offered something unique, making their combined guidance invaluable. Bruce often discussed grants, funding, teaching and lab management with me, showing me that being a PI involves much more than just science. This experience gave me a close-up view of a PI's role, which I now try to share with my students. Another impactful mentor was Jim Bear at the University of North Carolina at Chapel Hill. We met at a Gordon conference before I started my lab, and he generously offered to meet with me over Zoom to discuss my progress. These conversations turned into regular meetings and evolved into collaborative projects, significantly shaping my independent career.

What are the main research questions that your lab addresses?

Broadly, three questions define my lab's research focus. First, we aim to understand how proteins work together to generate forces within a cell and explore how these forces, in turn, affect biochemistry. Cells can sense forces in their environment, but how is this force transduced from the outside to the inside? In the past 5–10 years, we have begun to appreciate that actin filaments can both generate and sense forces. We know that filaments in stress fibers persist for minutes, whereas those in the lamellipodium exist for only seconds, despite being composed of the same actin. One hypothesis is that filaments in stress fibers are under tension from myosin pulling on them, which might prevent binding of the protein responsible for severing and breaking them down. Conversely, filaments in the lamellipodium are not under tension, suggesting that mechanical forces within the filament could influence biochemical interactions. Second, we are exploring how actin-binding proteins work together to regulate actin assembly and disassembly. Recently, we discovered that the actin polymerase formin, the blocker capping protein (CP), and the actin depolymerase twinfilin can all simultaneously bind to the same site on a filament. In another study, we found that although cofilin and cyclase-associated protein (CAP) individually produce a 5-fold acceleration of depolymerization, together they achieve a 300-fold acceleration, which more closely matches what occurs in cells. The third question in my lab involves challenging the long-standing belief that the pointed ends of actin filaments can't grow – a concept known as the ‘treadmilling dogma’. Since the mid-1980s, it has been accepted that barbed ends grow while pointed ends depolymerize. Until recently, no one had observed an actin filament growing from its pointed end under cytosol-mimicking conditions. However, in collaboration with Dmitri Kudryashov's lab, we have now discovered the first-ever mechanism that supports growth at the pointed end. We are currently investigating the rules governing pointed end growth, which is exciting, as it involves challenging and redefining this dogma.

What challenges did you face when you started your own lab and how are the challenges that you're facing now different?

I started my lab in August 2020, during the SARS-CoV-2 pandemic. While the pandemic itself presented significant challenges, one advantage was that lower expectations made any progress feel substantial. One major obstacle was navigating a new role without fully understanding all its responsibilities. Unlike most jobs, where you build on existing skills, starting as a PI requires applying your expertise while learning an entirely new set of skills. With few colleagues in my department focusing on my research area, finding someone who understood my needs was difficult. However, my training with Bruce Goode proved invaluable and in retrospect, I was better prepared than many peers who started their labs around the same time. Recruitment has been another major challenge. Identifying the right candidates and managing diverse personalities often proves difficult. Each individual has unique motivations and career goals, requiring tailored approaches to motivation and mentorship. Balancing teaching and research took effort, but once we published our first paper, it marked a turning point. Publishing was crucial not only for the lab's success but also for my own confidence. The positive feedback on our papers from the scientific community, including respected senior figures, confirmed that we had established ourselves as a research group.

Are you still doing experiments yourself?

I'm not at the bench as much as I would like, but I believe it's important to supervise new lab members and monitor their progress. I make a point of working closely with newcomers, particularly rotation students. For instance, I try to dedicate full days to working with rotation students, especially when they are learning new techniques. Microscopy is a passion of mine, so I prefer to be hands-on with experiments that require it. When I first started, I was familiar with every instrument in the lab and how each one worked. However, with the recent addition of a new microscope, I find myself not fully understanding how it operates, which is a new experience for me. Recently, we were on a tight schedule for a project, and I had the opportunity to assist with the actual experiments. I was particularly proud that in one of our recent papers, I personally ran all the gels for a binding assay! Typically, the author contributions section might read ‘Shashank supervised research and secured funding’, but this time I could say ‘Shashank also performed experiments’, which was very gratifying. I aim to stay as hands-on as possible for as long as I can, though I recognize that this will likely change over time.

Your publication record reveals that you collaborate frequently. What is your advice on establishing good collaborations?

Collaborations have always been significant for me. When transitioning from a physics background to biology during my PhD, I worked with collaborators like cell biologist Alessandra Cambi and immunologist Carl Figdor at Radboud University in The Netherlands. This early exposure demonstrated the power of collaboration. I've been fortunate to work with collaborators who bring new and exciting questions to the table, often leading me into new research areas. However, this comes with a risk – new questions outside my focus area can dilute my efforts. As a new lab, it's tempting to pursue what seems like an ‘easy’ paper, but side projects can quickly consume time and resources that would be better spent on ongoing lab projects. Collaborations, while valuable, are a double-edged sword. As a new PI, you must learn to choose your partners carefully. Over time, I've learned that collaborations need to be organic. My advice to new PIs is to accept collaborations only if they align with projects in your lab. The pressure and temptation to say yes can be strong, especially when approached by senior colleagues, but overcommitting can detract from your primary research goals. A balanced approach is key – collaborations bring new ideas and questions, but one needs to be strategic about which ones to pursue.

How do you get the most out of the meetings you attend, particularly in the early stages of your career?

Meetings are incredibly important, which is why I'm strongly opposed to shifting all meetings to Zoom. Although virtual meetings can facilitate connections across the globe, the power of face-to-face meetings lies in forming connections that go beyond casual greetings or random emails. When you meet someone in person, get to know them and build trust over time, they are much more likely to support you in the future. After all, we humans are social animals! Before attending meetings, I make a list of people I need to talk to – not just to say hello, but to have meaningful conversations and discuss specific projects. Without this approach, meetings can pass in a blur of brief interactions, and one risks spending days without achieving much. This is especially crucial at large conferences like the American Society for Cell Biology (ASCB) annual meeting, where the sheer scale can be overwhelming. Being organized helps ensure that you don't miss out on valuable opportunities. Engaging with the community at these meetings is vital. Science isn't just about discoveries; it's also about the people who make those discoveries.

If you could change one thing in academia, what would it be?

Emails. I'm sure anyone who knows me and is reading this will immediately recognize that I'm really bad at responding to them. I want to write the perfect email, which often leads me to postpone replying, and more often than not the email just gets forgotten. I wish we could rely less on emails – I would much prefer to have a quick phone call or text than deal with the endless back and forth of emails. Another pet peeve of mine is worrying about major instruments breaking down. I never thought I'd have to worry about that, but it's one of my biggest nightmares. In Europe, where I spent part of my career, major instruments were usually owned by the Institute and shared between many labs. But in the USA, at least in my department, it's different – labs tend to manage and be responsible for their own major equipment. As a PI, you need to ensure that you have service contracts and that everything is properly maintained. Aside from that, my other frustrations are the usual ones that come with academia – lots of meetings and administrative tasks. But I think everyone deals with those. It's just part of the job, and you do that part so you can focus on the work you really want to do.

Could you tell us an interesting fact about yourself that people wouldn't know by looking at your CV?

When I was a graduate student and postdoc, I used to go horseback riding and fly sailplanes. Gliding was something I immensely enjoyed. There is a quote attributed to Leonardo da Vinci that says, “Once you've flown, you will walk the earth with your eyes turned skyward, for there you have been, and there you will long to return”. The funny thing is, he had never actually flown, but he imagined how it might feel, and I think this quote captures it perfectly. I still feel that way. Even now, when I see planes, I think about how much fun it would be to get back into the air. I hope I can return to horseback riding and gliding at some point because I'm still passionate about those things. Recently, we took our daughter for a riding lesson and my wife suggested I get back into it too. I do want to return to my hobbies because, otherwise, this job can become all-encompassing. Recently, a senior professor named Emil Reisler, who is close to retirement, said to me out of the blue, “What about hobbies? You need to have hobbies because you need something else to keep you going”. I think we don't appreciate that early in our careers, but now I'm starting to – hopefully.

Shashank Shekhar was interviewed by Sara Morais da Silva, Reviews Editor for Journal of Cell Science.