Cell scientist to watch – Francesca Bottanelli Free

Francesca Bottanelli

How and when did you first become interested in science?

I don't remember exactly when I first became interested in science during my childhood. I have vivid memories from high school, being terrible at subjects like Latin, philosophy and history, where you had to memorise a lot, and being much more drawn to subjects that pushed me to think critically, like maths and science. This was also around the time of the genetically modified organism boom in the late 1990s. There was an excitement about modifying organisms and understanding plant molecular mechanisms, which led me to pursue plant biotechnology at university. I remember clearly taking a course on membrane organisation in plants, about vesicles and organelles, which I absolutely loved. One of my lecturers (Sandro Vitale) ran a lab that focused on intracellular trafficking in plants, and his class was the one I enjoyed the most. That class inspired me to apply for an Erasmus scholarship. Sandro knew Jürgen Denecke (University of Leeds, UK), and there were already a few Italians working in Jürgen's lab. That course and those connections really set my path, and I chose to do my Master's thesis in Jürgen's lab.

How did you choose to do your PhD on the late secretory pathway in plant cells with Jürgen Denecke?

I've stayed true to that early interest in live-cell microscopy. I loved the topic and the research so much that I stayed on to do my PhD. I never went back! I was still interested in intracellular organisation and microscopy, and that's what Jürgen was working on. My PhD project was somewhat of a continuation of my Master's work. During my PhD, I studied the function of Rab proteins in plants. It's funny because now we're starting to work again on some of the themes from my PhD, like Rab GTPases. I guess I've always loved GTPases!

Following your PhD in Leeds, you moved to Yale School of Medicine to join James Rothman's lab as a postdoc. What prompted this move?

I really wanted to continue working on intracellular trafficking and communication, so I applied to several well-known labs in the USA. It was a difficult decision to be far from my family, but I was driven by the desire to experience research in a well-funded environment like the USA. I had several interviews, but the opportunity in Jim Rothman's lab (Yale School of Medicine, USA) stood out. It involved a Wellcome Trust-funded collaborative project with Joerg Bewersdorf (a microscopy developer I closely worked with at Yale University, USA), Derek Toomre (Yale University), Alanna Schepartz (University of California, Berkeley, USA), Martin Booth (University of Oxford, UK), Sean Munro (MRC Laboratory of Molecular Biology, UK) and Daniel St Johnston (University of Cambridge, UK) that aimed at pushing the boundaries of super-resolution microscopy for biological discovery. As someone with a deep love for microscopy, I was immediately hooked. It felt like a dream to be one of the first people in the world using cutting-edge microscopes. That's how I ended up in Jim's lab in the Cell Biology Department at Yale, which is one of the best places in the world for membrane biology. It's a fantastic, collaborative environment where everyone is scientifically engaged, with a strong sense of community and social activities that bring people together. Yale was an exceptional place to do a postdoc. Jim was great at helping me see the big picture. He taught me to think broadly and gave me a lot of independence early on, which was very helpful when I later started my own lab. In the early days of super-resolution microscopy, I focused heavily on method development with Joerg's lab. Our goal was to adapt these techniques for live-cell imaging. That meant figuring out how to label proteins of interest with organic dyes that had specific photochemical properties, which was a real challenge at the time. Once we overcame those technical hurdles, we were able to start using these advanced imaging techniques to study intracellular organisation at a resolution of just tens of nanometres. That led to some surprising findings about how cells organise and communicate. We were at the intersection of biology, chemistry and physics – working on probe development, instrument calibration and identifying the right biological questions. I even learned enough optics to align our own microscopes, adjusting laser paths to ensure proper setup. It took a while for things to get off the ground, but that period of early technological development, paired with my own growth in scientific independence, shaped me profoundly as a scientist.

In 2018, you moved to Germany to start your own lab at the Freie Universität Berlin. What challenges did you face when starting your lab that you didn't expect?

I was in Jim's lab from 2011 to 2018, but that's a bit of a long story because my husband and I were both looking for faculty positions during that time. It took a while for the stars to align. It's that classic ‘two-body problem’, something many people in academia can relate to. I always saw it as a strength: hiring both of us could have been a great advantage for any institution. But it involved about two years of going back and forth between the USA and Europe, doing interviews, getting offers in one place but not the other, and then wondering ‘Now what?’ My husband decided that academia wasn't for him anymore and became a patent lawyer, so he was happy to follow me wherever the right opportunity came up. Eventually, we ended up in Berlin, where I was offered a great scientific environment, so that's where we settled. On the scientific side, the transition wasn't too difficult. I had a lot of ideas, and finally, I had more hands to help bring them to life. Thanks to the independence I had already experienced in Jim's lab, I felt well prepared to take ownership of my research. But there were challenges I hadn't anticipated. Like many new group leaders, I quickly realised that we're trained to do experiments but not to handle all the other responsibilities that come with running a lab. Suddenly, there's admin, personnel management and budgets – things you're just thrown into with little preparation. In Germany, you need to be aware of many rules, regulations and procedures, but the system does work. Once you understand the system, things do fall into place. Also, one of my biggest concerns was making sure my team would be supported for the full duration of their contracts. That means constantly writing grants, though to be honest, that's something I enjoy. I really like writing grants. And then, of course, there was the language barrier. German regulations, contracts and legal documents are all still in German, which made things quite tough in the beginning. Thankfully, I had a lot of help. And Berlin is a very international city, so the cultural adjustment wasn't too shocking.

How are the challenges you're facing now different from when you first started your lab?

Well, the first challenge is having tenure. That's always in the background, and it adds a layer of uncertainty. On a positive note, I've never really struggled to recruit people; the real limitation has been funding. I've had excellent candidates but not enough money to support everyone I would've liked to bring in. I think the nature of our work, using cutting-edge techniques, makes the lab appealing. Even in the early days, I was able to attract great PhD students. In the early years, it's all about survival. Then, once you publish your first few strong papers, you feel like, ‘Okay, I'm in. Things will be fine now.’ But then comes the next level of challenge. I remember a colleague visited a few months ago and said something that really stuck with me: “Now it's time to think about what you'll do in the next 20 years.” You need to start thinking on a higher level: what is the core question or vision that will drive this lab for the next two decades? That's a big and exciting challenge. Early on, people advise you to stick to safe, solid projects, things that are likely to work within a couple of years and lead to publishable results. But now, I feel I'm finally in a position where I can start thinking long-term.

Did you have any mentors that helped you in your career?

The Yale Cell Biology community was amazing. All the professors would show up at the monthly happy hour, and you could just chat with them – they were always open to giving career advice, life advice or scientific feedback. It was a really supportive environment. The same is true here in Berlin. I'm surrounded by great colleagues. For example, my colleague Helge Ewers is just downstairs, his door is always open. I can walk into his office at any time to vent about something or ask for advice. There are also many others who are incredibly helpful, like Volker Haucke, Robin Hiesinger and Andrew Plested, who are always willing to sit down, brainstorm ideas for grants, read through my proposals and provide honest feedback. Throughout my career, I've been lucky to keep meeting people who are just genuinely supportive.

What is your approach to mentorship with your lab members?

Since I receive so much support from all sides, I try to pay it forward and do the same for others. With everyone in my lab, I make a point to discuss their career goals early and help them navigate the decision-making process, because I think that's one of the hardest parts. Some have asked to stay on in the lab after their PhD, and while I'd love to keep them for longer, I encourage them to move on to a strong postdoc lab that suits their goals. Now, I try to help them understand that from the moment they start a PhD or postdoc, the so-called ‘academic clock’ starts ticking. There are windows: four years for this grant, seven years for that one, ten years for another. And once those windows close, you're no longer eligible. Frankly, I wish academia didn't work like that. For example, the Emmy Noether Programme (funded by Deutsche Forschungsgemeinschaft, Germany) requires you to apply within four years of obtaining your PhD. That's a very tight window, especially considering that science often takes time. I don't like how constrained it is, but I want to make sure my lab members have the best possible shot.

What are the main research questions that your lab addresses?

The common thread across all our research is the use of CRISPR to endogenously tag proteins and track them in unperturbed cells. Some might call it descriptive science; I prefer to think of it as uncovering the true dynamics of cellular processes as they naturally unfold. About half of the lab focuses on intracellular membrane trafficking, particularly the mechanisms of import and export from the Golgi. This interest began during my time in Jim's lab, where I became fascinated by the function of small GTPases, especially the ARF family. There are six ARFs in mammals, and they are structurally almost identical. We combine CRISPR and super-resolution microscopy to look at the intracellular localisation of several ARFs. Surprisingly, despite their similarities, they localise to distinct regions within the cell. This unexpected finding raised many new questions. For example, ARF1, one of the best-characterised ARFs, is classically thought to mediate clathrin-coated vesicle budding from the Golgi to endosomes. But what we observe instead are long tubular structures detaching from the Golgi, with clathrin associated not just with vesicles but with an entire tubular–vesicular compartment. This compartment undergoes a transition: it sheds its ARF1 coat and acquires a Rab11 identity, marking it as a recycling endosome. This identity shift appears to drive the polarisation of transport. Work by Margaret (Scottie) Robinson (Cambridge Institute for Medical Research, UK) and Ben Glick (University of Chicago, USA) supports this model of compartment maturation, rather than vesicle shuttling, driving forward trafficking. In this view, vesicles primarily serve a quality control role, retrieving cargo that should remain in the Golgi. We've now tagged over 120 trafficking-related proteins using CRISPR, giving us a powerful toolkit to study various aspects of the secretory and endocytic pathways.

The other half of our lab works on immune cell biology. We often joke that we became ‘accidental immunologists’, a description I actually love. Our entry into the field came through a collaborative grant led by Zhao Wenting (Nanyang Technological University, Singapore) and Xiaolei Su (Yale University). The project investigates how signalling proteins are organised on the plasma membrane of immune cells. One of our current projects focuses on the role of actin-rich protrusions in immune signalling. While these structures are well known for their role in cell migration, their contribution to immune signalling is still debated. Some studies suggest that T cells concentrate signalling proteins at the tips of these protrusions, potentially enhancing signal transduction. We are using CRISPR and live-cell imaging to study how endogenous signalling proteins dynamically arrange themselves in these actin-rich structures and across the plasma membrane during immune synapse formation and activation. We're currently starting to combine our interests in intracellular organisation and immune cell biology, as we suspect that GTPase-driven cascades can also regulate the spatial distribution of signalling proteins in immune cells. This is especially relevant for processes like antigen presentation and major histocompatibility complex trafficking.

Are you still doing experiments yourself?

I've recently started doing experiments again. When I first started the lab, my daughter was born just a few months later, and then my son came along two and a half years ago. So, for a while, life outside the lab was a bit unpredictable. But now that things are a bit more stable, daycare drop-offs are more reliable and the chances of an emergency call are lower, I can start experiments without disrupting the lab or annoying everyone by suddenly disappearing. I especially enjoy doing the more exploratory or higher-risk experiments myself, like pilot experiments for grant ideas or the early steps in generating new cell lines. If something works, I can hand it over to someone in the lab to take it further. I also still help supervise Master's students during their internships, and I stay quite hands-on with troubleshooting, especially when it comes to CRISPR, molecular cloning and, of course, imaging. So yes, I still know how to use the microscopes, I still get into the wet lab, and I stay actively involved in the experimental side of things.

Your publication record reveals that you are a very collaborative person. What is your advice on establishing good collaborations?

Because our lab is so tech-driven, we receive many collaboration requests. Over time, I've learned the importance of saying no when necessary to protect my team's time and ensure we stay focused on our core projects. For me, the key to successful collaborations is honest, early communication. I always try to have an upfront conversation to set clear expectations from the start. And most importantly, I always try to be the kind of collaborator I would want to work with: responsive, communicative and respectful of others' contributions. I make sure to provide feedback on what we've done, and I appreciate it when others do the same. Our lab is still relatively small – we're just four PhD students and one postdoc – so I have to be selective. We're well connected, so we sometimes get ‘easy’ collaborations like: “Hey, I made this probe, can you check where it localises in your cells?” These are often quick and straightforward. But then there are the larger, more intensive collaborations that require significant contributions from both sides. That's the kind of long-term, high-investment collaboration where alignment and trust are crucial. In short, my advice is to communicate clearly, set expectations early and protect your team's time.

What do you think is needed to help more women and underrepresented researchers take up leadership positions in science?

Re-entry programs for those who take career breaks are essential, because re-entry support is crucial. Sure, if you take parental leave, you might get a one-year extension, but what about the five years when you don't sleep? That needs to be considered. As a young parent, you're living in a fog way longer than the official extension covers. You might need time, encouragement and proper support to really get back into the rhythm of things. Also, running ‘women in leadership’ workshops teaching women to be leaders isn't going to magically fix the deeper structural problems. What we really need is to normalise having a family while running a lab. A lot of people feel discouraged because they don't see role models doing both, and they start to believe it's not possible. Therefore, structural support is critical. If you have less time for research and teaching, someone should help with the admin load. Having a lab manager, or even just someone to share the operational burden, allows you to focus on what really counts in evaluations, which is your scientific output. For example, funding 50% of the salary of a technician who can step in during parental leave would be extremely helpful. It ensures that the lab doesn't grind to a halt while you're away. Ultimately, it comes down to more money that needs to be invested into the system to make it fair and sustainable.

How do you achieve work–life balance as a parent?

I've always been a very organised person, but becoming a parent has made me even more organised. I think that's how I've managed to achieve some kind of work–life balance. I'm usually ahead of my deadlines, which still surprises me. For example, I applied for a grant with a deadline of mid-January, and by the end of November, I already had a full draft of my proposal. That was very intentional because I wanted to spend Christmas with my family and my kids, not writing a grant for weeks straight. So that really pushed me to stay on top of things. Of course, there are times when work becomes more intense, and during those periods I'll catch up in the evenings after the kids are in bed. Sometimes that means long nights, but it doesn't happen often. Also, my husband is my rock: he's always supportive and readily takes over responsibilities for the kids from me. I remember seeing a post on X a few years ago where a scientist shared a photo of herself holding her children and wrote that it was probably the last time she would ever carry them. That really stuck with me. I don't want to grow old with regrets, thinking ‘I was writing that grant instead of spending time with my children.’ I think that's one of the most common regrets, because kids grow up so fast, and you miss so much if you're not careful. So, I try to keep that thought in the back of my mind. Time spent with your children isn't a distraction or a waste, it's essential.

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

I would change how we define and use academic age. It really discourages people with non-linear academic paths. As I mentioned earlier, I didn't have a perfectly planned-out career, and if someone hadn't taken a chance on me at a key moment, I might not be here having this conversation. This idea that the clock is always ticking, for grant applications, fellowships or awards, puts people who've taken career breaks, or followed different paths, at a real disadvantage. I think people should be evaluated in the context of their academic journey, rather than according to rigid timelines. Of course, I understand it's difficult because we all want objective ways to assess productivity and success. But maybe we need to rethink how we define excellence and find better ways to recognise diverse experiences and contributions.

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

This always makes people laugh, especially my lab, who are still trying to uncover the full story! Until I started my PhD, I played guitar in an all-girl punk rock band. We played gigs around Milan, and there are still some videos floating around on YouTube (no, I won't tell you the band name!). For the first few months of my PhD, I even flew back to Italy a couple of times to play shows, but eventually, I had to admit that I couldn't keep doing both, and I had to focus on my PhD. Nowadays, I still play guitar occasionally, both electric and a bit of acoustic, and I try to play the ukulele with my kids, singing children's songs. My dream is to start a band here in Berlin like the ‘Membrane Band’ in Paris, which is a group of membrane biologists, including Franck Perez, who plays drums. That would be the ultimate science/music combo: performing at conferences!

Francesca Bottanelli was interviewed by Sara Morais da Silva, Reviews Editor at Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.