One Year In: Miguel Leung reflects on his first year as a group leader at the Hubrecht Institute

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A year after starting his lab at the Hubrecht Institute, we asked Miguel Leung to reflect on building his discovery-driven lab. His group uses structural biology to study reproduction and microbial diversity at atomic resolution by starting with the deceptively simple question: what does it look like?

Tell us about your journey since joining last year. What path brought you to the Hubrecht Institute?

I grew up in the Philippines and studied molecular biology and biotechnology for my bachelor’s degree at the University of the Philippines-Diliman. A PhD opportunity took me to the UK, where I trained in classical structural biology at the University of Oxford, working on protein biochemistry and later cryo-electron microscopy. After that, I followed one of my PhD supervisors to Utrecht University for my postdoc. When the opportunity at the Hubrecht came up, I wasn’t sure it would be a good fit since my work is quite different from the institute’s main focus. But a year in, I see that the differences are a strength. It’s allowed me to think more broadly about where structural biology can make an impact.

What attracted you to the Hubrecht Institute?

The size and the culture. It’s small enough to get to know almost everyone, and that creates a real sense of community. I appreciate that group leaders all work on very different topics. It’s good to be somewhere without too many structural biology groups right next door, so scientific conversations stretch me beyond my usual community. The culture is very open: if you have a new idea and can make a case for it, people will support you, even if it’s a little unconventional. And with no heavy teaching load, there’s more freedom to focus on research.

What is your research focus?

At its core, my lab asks one simple question: what does it look like? For us, that means down to the atomic level. We use structural biology, especially cryo-electron microscopy, to study protein complexes that are very hard to access with other methods. Structural biology is the field of biology that’s concerned with looking at the three-dimensional architecture of molecules. Instead of starting with a hypothesis, we start by looking.

With cryo-EM at high enough resolution, we can even see amino acid side chains and essentially determine a protein’s sequence from structure alone. The field sometimes calls this visual proteomics. For systems that are hard to manipulate genetically, like gametes or protists, our “structure-first” approach can flip the script and uncover completely unexpected proteins embedded in the architecture. For this reason, resolution is very important to us: think of it like wrapping cling film around an object. The tighter you wrap, the more detail you see.

What key questions are you aiming to address?

Our overall aim is to use structural biology techniques to characterize poorly studied protein complexes. Right now, we have two main interests. One is early development: moving beyond sperm, which I worked on as a postdoc, into oocytes and early embryos. These systems are crucial for life, but very difficult to manipulate genetically, making them good targets for our approach. The other is cytoskeletal diversity in microbial eukaryotes, or protists, which show extraordinary variation in their cytoskeletal structures. They come in many mostly unicellular forms such as algae, amoebae, and flagellates. They inhabit soil and water, and some live as parasites that can cause disease. They’re ecologically and medically important, but we know very little about their molecular biology.

Across both areas, the theme is the same: how are core building blocks of the cell, like microtubules and actin, modified by interacting proteins to generate such a variety of specialized forms and functions?

When do you consider a finding to be interesting?

For me, something is exciting when I can actually get a structure of it. Cryo-EM freezes samples so quickly that ice doesn’t crystallize, letting us image them directly without stains or fixatives. The trade-off is that we get noisy data, since biological materials scatter electrons poorly. We solve this by averaging many copies of the same object, which works best when the sample is abundant and ordered. That’s why it’s exciting to put a new sample in the microscope and see that order appear. It feels like going on a research expedition, but with the microscope.

The Leung Group in front of the Hubrecht Institute

How have you found settling in over the past year?

It’s been fun and a little terrifying. The biggest change has been shifting from working independently to being responsible for a team. I used to disappear into the data and come back with a structure or a draft paper. Now, there are people relying on me every day. Within months, we went from one technician to a postdoc, a PhD student, and now two more students have started. A highlight has been seeing the group take shape and sharing that sense of curiosity as we explore together. I hope to pass on intuition for the whole workflow to my team members: how to steer sample preparation and data collection when there are countless variables at play.

The main challenge for me has been to keep my focus. With so many fascinating systems out there, it’s tempting to look at everything. But resources are finite, so I must carefully consider when to pursue a lead and when to let it go.

What keeps you going on the stressful days?

I always remind myself how much of a privilege it is to do science at this level. Many talented people never get the chance, so I feel lucky and want to use these resources to pursue things I genuinely believe in. On tough days, that perspective helps: this job is unpredictable by design, unlike a regular office job, and that’s what makes fundamental research so unique. Here, we can explore the unknown.

Alongside discovery, there’s a quieter but equally important side of our work: developing new workflows and technical improvements in sample preparation, microscopy, and computation. Those advances are essential because they let us look at things people haven’t seen before. Bring us an interesting sample; we’ll figure out how to see it clearly. If we can make the workflows robust, others can use them too, especially for “atypical” organisms where standard recipes don’t work.

If you weren’t a researcher, what might you be doing instead?

Probably something still connected to biodiversity. My childhood dream was to become a paleontologist, but now I could imagine being a field biologist or working in a museum. I’ve always loved the diversity of life, and in a way, my research is just another way of exploring that. Only now I’m doing it at the atomic scale.