It was a hot Summer day in the last week of August 2018 when I was walking towards the Fortezza da Bassa conference center in Florence, Italy. My appetite for lunch was only just satisfied upon eating my favorite sandwich from Caffé degli Innocenti, a cute café which I passed every day that week on my way to and from the conference center. With a stomach filled with pane, mozzarella and pomodoro, I was longing for my daily fix of post-lunch espresso which I planned to score at the coffee corner inside the Fortezza. This espresso needed to keep me focused during the upcoming keynote lecture which I had been looking forward to ever since I studied the conference’s program book. But I was unlucky that day (when it comes to coffee), people were queuing up for fresh coffee at the coffee corner, and I needed to make a decision right away: option A. do I go for fresh coffee and stay focused during the full lecture minus the first few minutes; or option B. do I arrive in time but risk hitting an after-dinner dip? It felt like an important decision at that moment, so I gave myself a minute to think, while in the meantime taking a place at the back of the queue which would be helpful in case I would go for option A. Well, I did not need that minute after all as I came to my senses more quickly. The answer was so simple and obvious, but I was probably too high on the Tuscan warmth and the Florentine cuisine to comprehend that the keynote lecture itself would keep me focused from start to finish.
Before I continue, it might be relevant to explain why I was at this conference and why I was drawn to this particular keynote lecture. At that time, I was near the end of my 4-year PhD research project, and I was proud to present a poster featuring our latest results during this conference, which, by the way, was the 12th International Mass Spectrometry Conference. Mass spectrometry, or MS, take center stage in both my PhD project and this conference, so it made sense for me to be in Florence that week.
Obviously, I understand that most people think about a disabling disease when they see the abbreviation MS; however, MS in my work refers to an analytical technique which I would like to introduce briefly in the following sentences. Basically, MS instruments are very sensitive balances which you can use to simultaneously measure several compounds at the molecular level. These instruments typically consist of three different parts: an ionization part, a separation part, and a detection part. Compounds that enter a mass spectrometer first need to become charged, which we refer to as ‘ionization’, as they otherwise cannot be measured. In the second part of the instrument, these charged compounds can be separated from each other based on differences in their weight/mass. Subsequently, the separated compounds go to the detection part of the instrument where they generate an electric signal which is recorded by a computer. In most MS instruments, the detection part contains a metal plate, and compounds crash into this plate which leads to a signal. OK, I will stop here and I shall keep in mind that my simplification of the principle of MS is probably still pretty vague and difficult to understand. For now, please keep in mind that you can take a mixture of compounds and simultaneously ‘weigh’ the different compounds using a mass spectrometer (typically in less than a second, by the way).
An MS instrument can do a lot, but there are also a lot of things that MS is not great at. For example, it is possible to separate a mixture of only a handful of compounds in one analysis, but this will not be feasible when we have a mixture of thousands of different compounds, which would be the case if we study human samples such as blood. For such complex samples, researchers typically place an additional analytical instrument in front of the MS with the aim of pre-separating the mixture before MS analysis. The mixture is thereby split into several fractions which are then analyzed one by one using MS. This coupling of analytical techniques allows us to analyze the challenging complex mixtures with MS which was previously impossible when we used MS alone. However, this opportunity comes at the price of prolonged analysis times, which may be an issue in industry where time equals money or in medical laboratories that need to report to doctors today’s lab results preferably by yesterday (I tend to exaggerate a bit sometimes, so please keep that in mind when reading my texts).
Another challenge for MS instruments is posed by compounds that have a different structure but have the same mass and thereby reach the detector plate at the same time. In order to discriminate between such compounds, we need another ‘dimension’ of separation which may, for example, be offered by placing an additional analytical instrument in front of the MS, as is discussed above. Moreover, some MS instruments contain a special module inside which is based on so-called ‘ion mobility’. This module could offer the desired extra dimension of separation without coming at the price of a (substantial) prolongation of analysis time. In order to explain the concept of ion mobility, please take a moment to visualize a cylinder, which represents the ion mobility module, as well as a ‘cloud’ of compounds, which represent the freshly ionized compounds, that move from one side of the cylinder to the other. If this movement takes place under vacuum conditions, the space inside the cylinder is filled with……well, nothing at all. The cloud will thus move from one side to the other without experiencing any obstructions and delays. As a result, different compounds that are present in the cloud will not be separated from each other in the cylinder under these conditions. However, if we fill the cylinder with, for example, a little bit of gas, compounds will now be slowed down inside the cylinder as they bump into the gas molecules. The extent of a compound’s delay is determined by its three-dimensional shape, which you could compare with air resistance and aerodynamics in cycling.
To illustrate this more vividly, just imagine that we have two different road bikes which we want to separate from each other: a lightweight climber’s bike and an aerodynamic time trial bike. In this hypothetical situation, Tom Dumoulin, a former Giro d’Italia winner, will help us out, and he will ride these bikes at a constant power of 400 watts up the famous Passo dello Stelvio in Italy. Aerodynamics do play a role on such a steep course, but not as substantial as compared to the benefit of weight savings. Therefore, the total weight of rider plus bike will be the lowest in case of the lightweight climber’s bike, and we can expect Tom to set the fastest time with this bike when he attacks this heavyweight mountain. So, we separate the bikes based on their weight, just like we do with MS. However, with the advancing technologies and owing to the fact that there is a strict minimal weight for road bikes in professional cycling competitions, we can expect that we will soon reach the point that climber’s bikes and time trial bikes can all be manufactured at that same minimal weight. Sending Tom up the Stelvio is thus likely not the ideal way of separating these bikes, so we will now ask him to drive the bikes on a flat road, with fierce headwind of course, at 400 watts for exactly an hour. What we can expect in this situation, is that Tom tries to find the most aerodynamic position on both bikes, which will be far more effective in case of the time trial bike as this bike was designed for this purpose. His frontal area is expected to be lower when he rides this bike, he will thus be slowed down by the air to a lesser extent, and he will ultimately complete a larger distance in one hour of cycling as compared to when he rides the climber’s bike. So in this case, the bikes are separated based on three-dimensional structure, just like we do with ion mobility.
OK, I can imagine that my lengthy explanations of MS, ion mobility, and cycling made you tired, so let us go back to warm and beautiful Florence and imagine me walking around the poster exhibition area with a tasty pistachio gelato. (By the way, please do not worry about my dietary preferences that week and keep in mind that I brought my running shoes along and ran 34 km in total during my 6-day stay in Florence) So, I am walking around, enjoying my Italian treat, and I am looking for a poster of a group from Geneva which reported on the application of ion mobility-MS for fast blood analysis of hemoglobin, which is the protein in red blood cells that transports oxygen through our bodies. After finding and subsequently studying this poster, I got really enthusiastic by the presented work, and I was even a bit jealous as we did not have such instrument in our lab in Groningen back then. At that moment, I believed (and I still do) that this technique holds great potential, and I was convinced that I needed to learn to apply it as this would help me in my future career. So, I made a photo of the poster and decided to study the work further when I would be back in the Netherlands. In addition, I wanted to visit the lecture of the professor who supervised this research project, and this professor (coincidentally?) happened to be the one whose lecture was on top of my to-attend list that week. Needles to say, I am referring to the lecture of my coffee-dilemma.
As you can imagine, I had pretty high expectations when I arrived in Fortezza’s plenary hall (in time) to witness a prominent professor talking science for 40 minutes. I was likely a bit grumpy due to missing out my post-lunch espresso when the professor started talking, but my sad face quickly transformed into a happy face. Afterwards, I did stay in the room for the remaining four lectures, but I do not remember what these were about. I was thinking about a strategy to become a postdoctoral researcher in Geneva. I really wanted to continue my academic career over there, and this was the time to start drafting the blueprints for my future academic career.
I can go on for hours and tell you that I was not brave enough to isolate this professor during the conference’s gala dinner so I could introduce myself to him or that I was totally distracted in the week after the conference, during which my partner and me were enjoying some peace and rest in the Morvan regional park in France. Instead, I will fast-forward to Mid-October 2018 when my PhD supervisor and me went to Geneva to meet with this professor over there. During our 2-day visit, the professor and my PhD supervisor discussed options for a collaboration between Groningen and Geneva, and the three of us furthermore aimed to find out whether there was a mutual interest in me potentially joining the lab in Geneva. Well, I can tell you that there was definitely a ‘click’, and in only a few hours we came up with some great ideas for potential projects. Eventually, we agreed that I would write our ideas down into multiple grant proposals which could give me the opportunity to move to Geneva, when funded of course. This is exactly what I did in the following months, and with the help of them, but also of so many others, I was able to apply for several research funds. The decisions for all these grants are expected in the Spring of 2019 which brings us to the present, which is a very exciting present for me as you can imagine…
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