Protein Protagonist

What was your route into proteomics?

I originally trained as a physical chemist but gained experience in mass spectrometry (MS) during my PhD. But my route into proteomics started when I joined the University of Warwick as a senior research fellow in around 1995. I was working on biomolecular MS – looking at intact peptides and proteins – and even though I was a newcomer to molecular biology, I soon realized that it had enormous potential and decided to stay in the field. I’m not sure it was even called proteomics back then...

What are you working on at the moment?

For ten years or so, my group has had two focal points: i) developing new fragmentation techniques and new separation techniques for shotgun or peptide-centric proteomics, and ii) developing tools for structural biology – mostly by native MS and hydrogen deuterium exchange (HDX) MS. The aim has always been to bring these two areas closer together and now feels like the right time.

What are the biggest challenges in the field right now?

I think one of the big questions or challenges is: can we really understand how all these molecular players work together to regulate the whole system? Every simple question has a complicated answer. All the protein, DNA, and metabolites are all entwined with each other. We are getting very good at generating high-quality data, but we still don’t know what to make of it from a biological standpoint – and that’s very frustrating. I hope that by measuring more or by answering more hypothesis-driven questions, we can get a better understanding. Everyone knows that systems biology is essential, but no one really knows how to do it!

What do you think the answer is?

A simple answer that is not a simple answer! Though I certainly think more and better bioinformatics is important, we need to ask the right questions and to do the right experiments. I am humble; human biology is very fine tuned and I think the questions we ask and the experiments we do are still way too simple compared to the complexity of how a cell in a human being solves a particular problem.

Do you agree that proteomics hasn’t delivered on its early promises?

Yes and no. Ten or fifteen years ago, there was this hype about proteins being simple biomarkers for diseases, and in clinical proteomics, the hype has never been fulfilled. However, the hype was not introduced by core proteomics people, but rather by those who saw an opportunity. It’s the same today, I think. We are likely to hear bold claims about CRISPR from some quarters, for example, while core researchers will remain excited but modest about what can be achieved. What has proteomics delivered? Well, it has fundamentally changed how we look at molecular and cellular biology.

You’re a strong believer in collaboration...

It’s the way science should be. In the past (and maybe still), science has been too ego-centric, when it should be problem-centric. There are many scientists who want to do everything and take all the credit. But you can’t do everything by yourself anymore, and certainly not to the same degree as when you work with experts in other fields. Moreover, collaboration essentially means free learning!

What drives you?

I’ll try not to get too philosophical, but I would say curiosity drives me. I am really happy if we see something that no one else has ever seen. The feeling that you reached a new level of understanding – that excites me very much. It’s a little bit like being the first man on the moon – exploring new territories. In that sense, I’m very technology driven. Maybe you’d like to hear that I want to cure cancer or something – and of course I would love to do that – but I believe we understand so little about how life is organized that my biggest contribution comes from improving technologies so that we can better look at life and how it works.

What advice do you give young people coming into the field?

I tell them that it is one of the most exciting areas to work in! And I always tell them to go off the beaten track and try to be creative. Sometimes you can start with a naive idea and go with it because you don’t know all the details, and find something new. When people read all the literature, it can actually stop them from being creative... But it’s a fine line.

What would you like to achieve in the next few years?

Ultimately, I’d like to sit on top of a protein in the cell and see what it’s communicating, how it’s behaving, how it’s influenced by its environment. I’d like to see how that protein operates, and if it’s similar to how a human being operates in society. I’m pretty sure proteomics is going to be part of getting there, but we also need other technologies. If we could gain that insight – even for one protein – then I’ll be able to say, “That’s the dream I’ve had for 20 years – and now I’m pretty sure we’re there.”