Hermen Overkleeft - Interview

A new institute, new research challenges, new partnerships and new discoveries lying ahead: it all calls for a newsletter. The ICI Bulletin will be published twice a year and will focus on the people behind the science. Each issue will feature a number of regular items, including an interview with two PhD students on their joint project, a column by a scientist who may or may be not affiliated to ICI, a portrait of a partner organisation and an opening interview with a leading researcher from the chemical immunology field. In this first issue of the ICI Bulletin, Hermen Overkleeft, professor of Bio-organic Synthesis at Leiden University and principal investigator within ICI, kicks off. 

Hermen Overkleeft is one the initiators and driving forces behind ICI. He goes more deeply into proteasome inhibitors, creating crossovers and the joy of designing a molecule.

Your research field is bio-organic synthesis. What made you take the leap to immunology?

“To me, it is not a leap. I am interested in finding chemical solutions to biological problems, which also includes questions related to the immune system. In my lab, we have been working on the chemistry of the immune system for a long time. When the Gravitation Programme was announced, I wanted to submit a proposal related to chemical biology. Sjaak Neefjes (who I already knew) was thinking about submitting an immunology proposal, and combining the two seemed a logical step; immunology covers almost all aspects of molecular and cell biology and the chemistry involved is very broad. Moreover, we have a number of internationally renowned immunology research groups in the Netherlands. Together, Sjaak and I started building a consortium, which developed into the Institute for Chemical Immunology.”

The core team consists of six scientists. Who does what?

“Carl Figdor and Ton Schumacher are the ‘real’ immunologists, but both also have a strong link to chemistry in their research. Piet Gros is the expert on structural chemistry, Albert Heck takes care of the analytical chemistry part, I am the organic chemist in the team and Sjaak actually knows his way around all these fields. Although we all have different backgrounds, we share an interest in translating immunological phenomena into chemical structures and vice versa.”

Looking at these immunological phenomena as an organic chemist, what will be your research focus within the ICI?

“One of the topics we are working on concerns proteasome inhibitors. There are two types of proteasomes, which both degrade proteins into smaller peptides. The constitutive proteasome acts primarily as a garbage disposal unit. The immunoproteasome plays a role in class I antigen presentation; it degrades proteins present on viruses and presents the peptides to the major histocompatibility complex (MHC). The combined proteasome has six different binding activities and my goal is to create highly specific chemical knock-outs for each separate activity. By silencing one activity, we can get a detailed view of what happens to the peptides that normally would be presented as epitopes by this particular part of the proteasome. Where do these peptides go now? Such studies are very relevant to increase our understanding of auto-immune diseases. We will also use this approach to learn more about the role of post-translational modification (PTM) in peptides. Does that influence the actions of the proteasome? Are PTMs linked to auto-immune diseases? We have almost completed our toolbox of proteasome inhibitors. These will be used by Albert Heck’s group to perform mass spectrometry experiments using their collection of MHC class I epitopes. Hopefully this will reveal exactly which oligopeptides end up on the antigen-presenting cells.”

What led you to this topic? What bigger questions do you want to answer?

“I don’t have big, abstract questions and to be honest, I don’t believe such questions make any sense. That is far too much of a reductionist approach to science.

Fair enough, but then why did you decide to work on chemical biology? Being an organic chemist by training, you could have chosen a variety of chemical specialisations.

“This may sound like an easy answer, but I got into it by chance. You can find beauty in nature on many levels and during my studies, my supervisor taught me to see the beauty of nature on the molecular level. I was intrigued by how you can use chemistry to impact biological processes and by the fact that sometimes the chemical approach turns out to be much simpler than nature’s solution. Examining a process from a chemical perspective can really teach you a lot about what is actually happening. Besides that, I still very much enjoy designing and creating a molecule with a specific functionality. That is in essence what we do: designing molecules that can perform certain tasks.”

The ICI covers such a broad range of scientific disciplines, how do you find enough common ground?

“Organising the PhD projects as joint operations in which a student with a chemistry background collaborates with another who’s worked on immunology is a deliberate choice to stimulate cohesion and interaction. We also organise meetings along different research lines, for example bringing together everyone who works on bioconjugates or all researchers working on rheumatoid arthritis. This leads to crossovers, as all the participants fit into at least two subgroups. This way we create many opportunities for scientists to meet each other in different settings and with different areas in common. That will surely help to get a dynamic and tight-knit community off the ground.”

This interview was first published in ICI bulletin 1, in October 2015.