Interview with Agnese Loda

• Could you start by telling us a bit about yourself and your journey to Institut Imagine?

My scientific journey started in Italy, in Pavia, where I studied Biology. I then moved to the Netherlands for my Master’s studies in Rotterdam, where I focused on  human genetics. 

It is in Rotterdam that I discovered my curiosity for epigenetics and developmental biology and I decided to join the lab of Prof. Joost Gribnau for my PhD, where I started to work on the epigenetic process of X-chromosome inactivation. That was the start – and I never stopped!

While studying how one of the two X chromosomes is almost completely turned off in female mammals, I became very much fascinated by a subset of X-linked genes that are the exception to the rule. We call these genes 'escapees' because they resist X inactivation and remain active on the X chromosome that is otherwise inactivated.

To study these genes, I joined the lab of Prof. Edith Heard for my postdoc, first at the Institut Curie in Paris, and then at the EMBL, in Heidelberg. Since then, I’ve been focused on figuring out how these “escapees” stay active on the inactivated X chromosome. We’ve learned a lot, but there’s still much more to uncover!

My postdoc work provided the basis to start my lab at Institut Imagine, where I aim to move from understanding how escapees are regulated to exploring why escape from X-inactivation matters, both during development and throughout life. 

• Could you explain it to someone who’s outside of your field?

Females and males differ in their sex chromosomes: females have two Xs, males one X and one Y. X-chromosome inactivation balances this difference, as having a double dose of X-linked genes in females would not be compatible with life. However,  escapees remain active on both X chromosomes, and what is becoming more and more clear is that the increased or reduced dosage of these genes play a key role in shaping sex differences. This occurs in different contexts, including sex-biased disease predisposition.

Studying these genes has therefore important implications for women health and will also help us to explain why certain diseases affect men and women differently, which is an increasingly important question for public health.

In my lab, we’ll explore how these escapee genes are regulated and what is their function during development, to understand how they might contribute to sex differences that can affect normal embryo development. For example we want to understand whether the sex chromosomes explains differences in how the placenta develops and functions in pregnancies with male or female babies. If we can understand the molecular basis of sex-specific traits, we will learn how the baby’s sex can influence pregnancy outcomes and ultimately why some complications or developmental conditions can affect one sex more often, sometimes with lifelong effects. 

• What has been the most defining moment in your scientific career so far?

I would say it was towards the end of my postdoc when I took a step back to bring together everything I had learned – all the ideas and notes I have been collecting - to develop a strategy for the kind of science I wanted to explore moving forward. That was very exciting. This is when I realized that I really wanted to go ahead. The support and encouragement of both my mentors and peers with whom I always discuss my ideas was a fundamental part of the process. 

• What specifically attracted you to Institut Imagine? And what made you choose us over other opportunities?

Institut Imagine gives me the rare opportunity to transform my fundamental research into new translational projects that have a more direct impact on patient care through close collaborations with clinical researchers. This will be a complete new adventure for me and I am excited to see what someone with my background can contribute to such an environment. 

• If you could solve one major challenge in rare genetic diseases, what would it be and why?

A big challenge in disorders caused by sex chromosome aneuploidies is understanding why patients with the same aneuploidy show very variable clinical features. I’d love to understand how X-linked gene dosage and sex-specific molecular mechanisms drive the diverse phenotypes observed in these disorders.

• Where do you see your research making the biggest impact in the next five years? And how will this benefit patients and families?

The impact of my lab’s research will be at multiple levels. First, we will unveil the fundamental mechanisms that tightly control the regulation of X-linked genes expression during development, and how variations in the dosage of these genes contribute to sex differences that affect pregnancy outcomes. At the same time, our work has the potential to discover new targets that may be possibly modulated to improve sex-biased pregnancy complications in the longer term, with direct relevance for human reproductive medicine. 

• What excites you the most about the collaborative environment at Imagine? And are there any specific teams or projects that you’re eager to work with?

What I love most is that science is more fun - and more powerful - when we do it together! Working across disciplines brings fresh perspectives, sparks new ideas, and helps us tackle questions we couldn’t solve on our own. 

There is plenty of synergies that I foresee at Imagine, from teams working on gene regulation, chromatin dynamics and developmental disorders in different contexts to clinical researchers and gynecologists to study sex differences in the human placenta. My lab will also benefit from a secondary affiliation with the Developmental and Stem Cell Biology department of the neighbouring Institut Pasteur, to boost the scientific synergies around early development and pregnancy health in different contexts. I am very happy to be able to join a broad community of fantastic scientists to tackle different exciting questions. 

• What first sparked your interest in science? Was there a particular moment or a person that inspired you when you were younger?

I didn’t consider science until the end of high school, I actually wanted to be an architect. Then a new teacher shared her research experience, and her passion completely changed my perspective. Since then I’ve been incredibly fortunate to have encountered very generous and caring mentors who always guided and supported me – and still do. 

• How do you stay motivated when research gets challenging or results don’t come as you expect them to?

This is the hardest part – to stay motivated when a project isn’t going as planned, which happens most of the time! What helps me is reading really good science, not necessarily in my field, just things I find exciting. It reminds me why I love research and triggers me to figure out new ways to understand cool things.

• Outside of the lab, what do you enjoy doing? How do you recharge?

I recharge mostly by spending time with my family, my two daughters and my partner, they are the very best! Whenever I can, I also travel for a weekend with my old friends – who are spread all over Europe and beyond -  those moments with family and friends really recharge me.

• If you could have dinner with any scientist, living or dead, who would it be and why?

It would be Mary Lyon, who discovered X chromosome inactivation! 

• If you had to describe your research philosophy in one sentence, what would it be?

I’d say my research is driven by curiosity, care, collaboration, and fun!

• What message would you like to share with the Imagine community as you join us in January?

I want to start by thanking everyone at Imagine for being so welcoming. This is an exciting phase of my career as I take this step toward independence, and I feel very lucky to be joining such a supportive and nurturing community. I am truly excited to get started!