Nicklas Österlund is doing his PhD at the Department of Biochemistry and Biophysics and will defend his dissertation in January (2023). Nicklas’ research is about proteins that do not form stable folded states but clump together over time into large insoluble aggregates. Such aggregation is associated, for example, with Alzheimer's disease, where plaque (largely consisting of the peptide amyloid-beta) can be observed in the patient's brain. The amyloid beta peptide will spontaneously begin to clump over time in an aqueous solution, and it is possible to follow the aggregation process in these basic in vitro experiments as well as how the process is affected by various added molecules that may be of cellular or therapeutic relevance.

Nicklas studies the smallest aggregates, which consist of only a few amyloid-beta peptides. These "oligomers" are today considered to be the most toxic aggregates, they are suspected of being able to act as small pores in biological membranes and cause uncontrolled leakage into the cell. An experimental problem is that the oligomers are extremely few in a normal aqueous solution in a test tube, the oligomer state is only a few percent in the peptide mixture. Many measurement methods have problems with this since they only measure the average of all states, which makes it very difficult to study the small toxic needle in the large peptide haystack. Nicklas has therefore worked a lot with mass spectrometry in his project, a method where each individual molecular state gives its own signal, its own peak in the spectrum. In this way, they have been able to study individual oligomeric aggregates and how their stability is affected by being in a membrane environment. They have also been able to study how specific oligomers are affected by chaperone proteins, which naturally protect us against protein aggregation in the cell.

Unfortunately, the molecular background to Alzheimer's disease is still not fully understood, and there currently are no effective drugs available. Research has shown that it is very likely that protein aggregation plays a role, but it has been difficult to transfer promising results on this from in vitro studies to the bedside. Molecules that stop aggregation in test tubes have rarely shown any major effect in drugs against the disease. Nicklas believes that the reason for this could be that basic research mostly has focused on the formation of the large and more stable aggregates that are the end product of the clumping of peptides. The methodology that recently has been developed to study the small oligomers can hopefully contribute with new angles of approach that can lead to a better understanding of the underlying molecular processes in the disease. This is important basic research that can form the basis for the development of better therapies in the future, says Nicklas.

Why did you choose to do a PhD in biophysics, and why did you want to focus on clumped peptides in particular?

I was very interested in mechanistic explanations for different things when I started studying chemistry, so I thought physical chemistry was fantastic! My first encounter with biophysics was already during a lecture in the first course of the bachelor's program: Basic Chemistry. Arnold Maliniak (Professor of Physical Chemistry) explained thermodynamic free energy and Boltzmann distribution and stated that these concepts applied to everything, including the folding of proteins. This was very exciting and new for me since physical chemistry and thermodynamics usually revolves around fairly simple and boring systems such as gas that is moving pistons and alike. I then realized that even complex life systems are governed by the same basic physical principles, which was super cool! Biology is super fascinating, especially all the complex and effective chemistry that nature does so much better than we humans could ever do in the lab. However, learning biochemistry is sometimes a little too much memorization sometimes for me. So, the combination of satisfactory mechanistic explanation models and cool biological systems is a perfect combination!

But the path is not always straight. I stumbled upon analytical chemistry and mass spectrometry at the end of my bachelor's degree by chance, which also was a fun field with exciting applications. But I always thought that I would return to the biological world in some way. So, when Leopold Ilag at analytical chemistry told me that he had a collaborative project underway with Astrid Gräslund at biophysics, it felt like it was made for me, and it therefore became my master's thesis. I have worked on applying my methodological knowledge in mass spectrometry and the physical chemical research to protein aggregation since then. It turned out to be a very good combination, and also shows that you never know what knowledge and combinations of knowledge you can use in the future!

Read more about Nicklas’ research here!

Nicklas with the mass spectrometer.