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The Big Challenge… With Theo Alexandrov

With the ever-increasing potential of new technology and the exponential growth of the life sciences field, researchers are always running into new problems to solve. In this interview series, we get scientists’ opinions on the ‘Big Challenge’ in their field and the steps being taken to address it. From new and unique hurdles to fresh takes on common problems, we dive into the complexities of the research landscape.

In this interview, we chat to Theo Alexandrov (Group leader at European Molecular Biology Laboratory (EMBL)) about the ‘big challenge’ in metabolomics, particularly regarding the latest single-cell and spatial methodologies.

FLG: Can you tell us about your background and role?

Theo: Absolutely. My name is Theodore, I go by Theo, and I work at EMBL, the European Molecular Biology Laboratory, which is an amazing place to work. It is an inter-governmental organisation for life sciences in Europe, you can think of it as like CERN, but for molecular biology. So, we have a very vibrant place to work, and I’m leading a research team that mainly develops methods and technologies for spatial and single-cell metabolomics. I also work in a metabolomics core facility, which is much more routine, but it was very useful for me to learn the basics and the inside-outs of metabolomics. This is because it’s actually not my background. On top of this, I’m also a scientific lead at the Bio-Innovation Institute in Copenhagen, Denmark, where we are incubating a startup in single-cell metabolomics.

My background is computational. My PhD was in mathematics and statistics. I then went to Germany for a postdoc in a city called Bremen. You might not have heard of it, and not many people have, other than for the Town Musicians of Bremen fairy tale. Surprisingly, this is actually the world capital for mass spectrometry. Two out of five major mass-spec vendors have R&D departments there, which I didn’t know then. My first postdoc was on econometrics on predicting transactions for MasterCard. Then someone approached me from the Bruker mass spec company – ‘can you do some machine learning predictions for something called mass spectra?’ That’s how I got into mass spectrometry. It was computational first but then I was asking myself – ‘why do we need these mass spectra?’ And the answer was metabolomics, because metabolomics uses mass spectrometry to get a read out about small molecules. Back then it was an up and coming technology and I went to UCSD to learn it. I got hosted by Pieter Dorrestein and learned a bunch from him and his team. This is how I transitioned more and more towards metabolomics and molecular questions and molecular biology.

FLG: What would you say is the big challenge in your field?

Theo: The next challenge for metabolomics is in data interpretation. In metabolomics, in terms of detection, we have amazing technologies already, in terms of hardware and instruments. We can do a lot of things, but in terms of interpretation, metabolism and metabolic pathways are inherently very complex. Metabolites are building blocks and energy sources, but the same molecules can play signalling roles. There are also many unknown roles of metabolites. Lately, the Rutter lab has published a paper in Nature Cell Biology showing how metabolites have unstudied roles, in particular in controlling the activity of enzymes in their pathways and also enzymes throughout the whole metabolism. This kicked off the discussion of ‘metabo-verse’, a universe of all the small molecules with diverse functions and roles.

FLG: Why should people care about this challenge?

Theo: We do not have the databases of roles and functions for metabolites, similar to how we have them for genes and for proteins. There is work to be done to create these catalogues of their functions and associations with cell types. I think these databases will eventually explain the roles and contain all the biochemical molecular functions of the molecules. That will be a big breakthrough, but this is our current challenge.

FLG: What is being done to tackle the issue, or what should be done to tackle the issue?  

Theo: First of all, we lack robust protocols, particularly in single-cell and spatial, that are accessible for scientists who are not from analytical chemistry labs. We’ll have impact with this technology only when it will be accessible by biologists and by clinical scientists. Over the last years, it started happening with spatial metabolomics when  a number of biology labs installed their first imaging mass spectrometer. However, we’re not there yet. Once this happens, they will create bigger opportunities. For this to work, we need to have better instrumentation, we need to have robust protocols, which are relatively easy to execute, we need to have user friendly software, which is not for geniuses in mass spectrometry.

On top of this, we need to have databases that this software can tap into to enhance data interpretation. And, in particular, we need to link to other omics, because metabolomics is not an ultimate tool, it is orthogonal and complementary to other omics. Obviously, to have a biological or medical conclusion or a decision for drug development, one needs to use all the tools, and have metabolomics in your portfolio. There should be more to be done to link metabolomics with other omics tools that will help achieve much bigger impact.

FLG: What is your advice to people breaking into the field?

Theo: My personal advice for early career scientists, and this was absolutely transformational for me, is to find a person with whom you can actually talk about your research: your “metabolomics buddy”. This field has a different language, and it is very challenging and complicated. So, find someone who can help you learn the metabolomics language to make an impact in your own way in no time.