Using Mass Spec to Rewrite Textbooks

Tell me a bit about your work at the Netherlands Proteomics Centre.
 

The Netherlands Proteomics Centre is one of the largest mass spectrometry labs in Europe, and I’m currently heading up a team of around 60 people. We have pretty much every size and style of MS instrument you can think of – more than 20 different models of instruments from various vendors. Some are better for protein analysis, some for peptide analysis and others for studying protein complexes. We’re a diverse bunch of people – with 19 different nationalities represented – but we’re also diverse in terms of our academic backgrounds. Many in our team are analytical chemists, but we also have biochemists, immunologists, engineers, bioinformaticians and programmers. I’m proud to be at the helm of this group – though all 60 are not directly supervised by me of course. We have assistant and associate professors each with their own interests and research topics – but we still form one big cohesive group to keep up the facilities and expertise here at Utrecht University. 

And what are the main areas you work in?
 

Again, it’s pretty diverse. At the broader level, I’d say there are two main spaces we work in: i) technology innovation and ii) fundamental knowledge in biology and medicine. On the one hand, we work to develop better tools for MS – or try to do things that have never been done before with MS, whether that’s intact protein analysis, crosslinking MS, or the analysis of post-translational modifications. Here, we may work closely with vendors to help them improve their instruments or ask them to implement certain useful features. 

On the other hand, we work on basic research questions in science, like cell signaling events or immune responses. And that means the application aspect of our work is quite broad. One exciting area at the moment (for me at least) is measuring the proteomes of single cells. Why do certain cells react differently to different drugs or changes in the environment? Here, the sensitivity of mass spectrometers is something we are really keen to develop. It’s also extremely exciting to see both our group and others making single-molecule measurements by MS. We are now developing tools to make this even easier and to ensure the technology is more accessible.

What drives you?
 

I’m a mass spectrometrist at heart. So I’m driven by a (perhaps naïve) view that MS can answer all sorts of questions in biology. I’m constantly asking, what’s the next big question we can answer with MS? Is there a question we never even thought about answering with MS? Outside of MS, I’d say what really drives me is a yearning to understand how life works. There’s so much we don’t yet understand – but whenever we do understand something new it seems all the more beautiful. 

Where did your initial thirst for all things MS come from?
 

Honestly, I don’t know. I never woke up as an eight year old kid and said, I want to work in proteomics! It’s something that has developed naturally by being presented with chances and challenges – and by making decisions. I trained as a physical chemist – I was more interested in how atoms worked and how chemical bonds were formed. After making a few decisions about my career, I entered the field of analytical chemistry; initially, I wasn’t even sure how interesting it would be! At the time, I was more intrigued by physical chemistry – possibly because there seemed to be too many unanswered questions in biology. But over the years, the ability to get real-world data has really taken off in biology – and I think that triggered my move into these fields. People often ask me if I’m a biochemist or an analytical scientist or an immunologist… Basically, I’m MS-based – but I want my expertise to be useful across almost every field. 

Would you say you’ve been successful in your career?
 

I think it’s always tough to measure your own success. What I’m most proud of is watching young people come into our group, get trained up, grow and mature, and then leave to do their own thing. They often go on to become experts in industry or academia and become very successful in the next step of their career – it’s great to see what they’ve all achieved over the years. And I guess that’s one way of measuring success. 

And if you can change the textbook – on biology or immunology say – then that’s also a real success. Going against the grain and making a significant contribution to our understanding of how the world works is truly amazing. We’ve been lucky enough to make these sorts of contributions – we’ve shown that posttranslational modifications of proteins, such as phosphorylation and glycosylation, are way more diverse and complicated than what was traditionally believed in the textbooks. We’ve also recently shown that, contrary to popular belief, the human body makes a limited repertoire of antibodies that are abundantly present in our blood to fight invading pathogens. [You read more on this story and how it impacts our understanding of COVID-19 in this article). 

What type of leader are you?
 

That’s a great question – but possibly one you would rather have other people answer for you! I’ve learnt over the years that you often have a view of yourself that is different to how other people view you. That said, I’d like to think I’m a motivator who encourages creativity. I’m also a connector – I like people with different expertise and backgrounds to work together. I try to foster a creative atmosphere where we try to get the best out of everyone. That’s my job as a leader.

What are the areas you are most excited about?
 

I think we all hope – and expect – MS to play an even bigger role in personalized healthcare moving forward. I don’t know exactly what that role will be, but already we’ve seen how MS is used to analyze biomarkers. There’s the example of heel-prick testing in babies for metabolic diseases. Soon, we should be able to expect MS to be used for personalized diagnostics and to monitor the health of individuals. There are then bigger questions to be answered around whether we want this and how useful it will be… I see it as our job to show whether it can be done first. I actually think it will be very useful; for example, personalized proteome profiling can help us understand whether a certain therapy will work for an individual. It can then also help you understand how altering the treatment alters the response. In the future, I think we’ll be able to use MS to not only monitor disease, but to monitor healthy people as well. 

Any advice for those taking their first steps in the field?
 

I think the danger with young scientists is that they read something in the literature and they conclude that it has already been studied so there’s no need to question it anymore. If you do this too much, you find always reasons not to do an experiment. Of course, I’m not saying don’t read the papers – just don’t be put off. I hate to be told that someone isn’t going to perform a certain experiment because either everyone says it won’t work or it’s been done already. Some of my best findings have come from doing things people supposedly “had done already!”, but we observed a complete different outcome or mechanism. The great thing about MS is that – unless your instrument stops working – an experiment can never fail in my eyes. You’re always collecting data, so even if it disproves your hypothesis, it doesn’t matter. What is it telling you? 

It’s good to have goals and plans, but don’t be too rigid. Stay creative and remember that not everything will go exactly to plan. Always be ready for the unexpected. And be sure to take the chances that come your way – and then make the most of them.