Martijn Verdoes - Interview

Always on the lookout to learn something new, Martijn Verdoes has steadily expanded his horizons. Working from a basis in organic synthesis, he has gradually added a whole array of biological techniques to his portfolio. With a recent ERC Starting Grant and the first ICI Tenure Track under his belt, he is now all set to tackle a range of interesting research ideas. “I don’t believe in a magic bullet when it comes to a complex disease like cancer. We need multiple lines of attack.” 

When you started in early 2013 as a postdoc in Carl Figdor’s group in Nijmegen, the ICI was just getting off the ground. Did that influence where you decided to do your research?

It did, but not as you might think. Before moving to Nijmegen, I was a postdoc at the Stanford School of Medicine with Matt Bogyo. After almost four years there, my girlfriend and I decided to move back to the Netherlands. She interviewed for a position at the chemistry department in Nijmegen, so I started orienting myself there as well. The research in Carl Figdor’s Tumor Immunology department got me interested and Carl granted me thirty minutes of his time. That turned into a two hour conversation. Anticipating the possibility of the ICI being funded, Carl was looking for a chemist to expand the group. I happened to be in the right place at the right time. It really was lucky timing.

You started out as a chemist with a classic focus: organic synthesis. Now, you’re working in an immunology group within a medical center. How did biology cross your scientific path?

During my studies, I hugely enjoyed puzzling around with chemistry and trying new things, but most of the time, your compounds end up in a freezer and that’s the end of the story. But then I went to Hidde Ploegh’s group at Harvard Medical School for a student internship. That was my first experience of applying chemistry to biological study. From that moment on, I knew I wanted to work on biological questions. Back in Leiden, I started my PhD research in Hermen Overkleeft’s bioorganic synthesis group. I was one of the first to bring biology into the lab there - doing cell cultures and all that. But I wanted to explore further and also test my compounds in preclinical models. My move towards biology has been a gradual process of discovering new possibilities and trying to take new steps.

And the move to Stanford was motivated by further expanding the biological part of your research?

(Laughs) When I was reviewing my options for my NWO Rubicon application to go abroad, I wasn’t only focusing on the science to be honest. From my time with the Ploegh-lab, I knew that the East Coast environment was pretty competitive and that the weather didn’t really suit me – with very hot summers and really cold winters. So, spending a few years with a renowned research group at one of the best universities in the US in relaxed and comfortable Northern California sounded very attractive.

Was it a good move?

Yes, it was a great environment to work and live.

What did you work on?

I focused on quenched fluorescent activity-based probes (qABPs) to investigate a specific group of proteases, the cysteine cathepsins. These are linked to the regulation of antigen presentation, matrix degradation and cell motility. In tumors (as well as in inflamed tissues) protease activity is high, making the cysteine cathepsins useful targets for our probes. The probes mimic the cathepsins’ substrates, but instead of the usual peptide bond, they contain an electrophilic trap. As a result, the cathepsin gets stuck. By ensuring that the quenching group is also the leaving group, binding the cathepsin makes the fluorescent dye visible. You get to see the trapped cathepsin. The approach worked out really well, but it immediately got me thinking about the underlying biology. What caused all that protease activity in the tumor?

…and what did you discover?

Measurements with FACS (fluorescent activity-based cell sorting) revealed that our probe was specifically switched on one type of macrophage called M2. We know that tumors can recruit immune cells to work on their behalf. One of the tumor’s strategies is to lure macrophage precursor cells, manipulate them and then put them to work, for example in degradation of cellular matrices to create room for new blood vessels. Tumors are very good at creating their own beneficial microenvironment with immunosuppressive conditions.

2015 was a very successful year; you obtained an ERC Starting Grant and were selected as the first ICI Tenure Track recipient. What are your plans now?

I strongly believe in a combined strategy of stimulating and evoking a tumor-specific immune response while simultaneously breaking down the tumor’s immunosuppressive barrier. We are working, for example, on targeting tumor antigens at dendritic cells as a vaccine approach. Another important topic is the checkpoint inhibitors. These compounds interfere with the communication lines that tumors use to inhibit T-cells. The checkpoint inhibitors reactivate T-cells to do their proper job. Checkpoint inhibitors are already used in the clinic, but often they generate autoimmune responses as well. What if we were able to make the checkpoint inhibitor work only in a very specific manner? Then, we might avoid autoimmunity. Furthermore, I plan to continue my work on the ‘bad’ macrophages; can we find a way to manipulate them and turn them into the good guys again?

That’s a lot of work on a range of topics.

I don’t believe we’ll find a magic bullet for treating a complex disease like cancer. We’ll need multiple lines of attack. After a year spent largely on writing proposals, I now have the time and, most importantly, the resources to really get going with all these ideas.

Finally, about the ICI - can a large initiative like this, involving multiple parties, really be effective?

When large sums are at stake you often see that on paper a proposal sounds fantastic, revolutionary and innovative. However, as soon as the money is secured, everyone just goes back to minding their own business. But with the ICI I don’t see that at all. This community clearly has a collaborative attitude, and the combined PhD projects are a great example. We are now training true chemical-immunologists. This exchange between disciplines is very fruitful and we can all stimulate it. We must push chemists towards doing biological experiments and motivate biologists to dive into the chemistry.

This interview was first published in ICI bulletin 2, in April 2016.