Neurodegenerative disease research using NMR: an interview with Christian Griesinger

Interview conducted by Will Soutter, M.Sc.

Christian Griesinger, director of the NMR-based Structural Biology department at the Max-Planck Institute for Biophysical Chemistry, talks about his research into neurodegenerative diseases using NMR to examine the dynamics of disordered proteins.

Could you give us an introduction to the research areas your group is interested in?

Our main interest is in intrinsically disordered proteins, and their role in neurodegeneration. We have interests in the basic physical questions about the dynamics of proteins, and about membrane proteins that are involved in signal transduction in bacteria, as well as on small molecules.

Since we have a lot of other structural biology techniques at our institute, such as EPR spectroscopy headed by Marina Bennati’s group, we also do a lot of work on hybrid methods, not only with EPR but also with electron microscopy, with modelling, and so on.

Could you share some of the most recent results of your research?

We have recently characterized the dynamics of soluble proteins in great detail. At the moment we are exploring their kinetics, as well as their functional importance. One of our most recent achievements is the introduction of some new techniques in order to measure the dynamics of proteins on faster timescales than was previously possible.

Another of our current projects is in a more applied field, in neurodegeneration, where we are trying to characterize the influence of intrinsically disordered proteins that aggregate and lead to diseases like Alzheimer’s disease, Parkinson’s disease, type II diabetes, and also Creuzfeldt-Jacob disease. We have had some great results from this project - we have been able to characterize structural transitions between monomeric, oligomeric, and fibreless states in these proteins, and even influence and divert aggregation pathways using a small molecule.

The molecule we developed is currently in preclinical trials, and hopefully we will be able to move into clinical tests in humans at some point.

Would you say that NMR is moving towards being a tool in directly applicable biomedical research, as well as in more fundamental studies?

We are working on many systems – like signal transduction in bacteria, as I mentioned – where our work is more on the basic mechanisms, and we don’t really know where it might lead to.

The neurodegeneration work is the most advanced project we are doing at the moment, and that clearly has a direct impact on biomedical research. However, NMR was not really the driving force here, because the molecule was found using fluorescence-based assay, then with blind chemistry. NMR’s role in this work is to actually go back to the basics, to work out the biophysical reason for the effect that we observe. So we are always grounded in that fundamental research, even when the overall aim is very application-focused.

I should also mention that, since I am working at the Max Planck Institute, and Max Planck once said that basic understanding has to precede applications, we believe that academic groups should work on fundamental science first, with the applications in biomedicine and other fields always following on from that.

When we think about translating our work into the field of biomedicine, and having an impact on the health and living standards of people, this can either be immediate, or it can be more indirect. For example, I think one very important thing that we can do as an academic group is to teach people, to help them gain a profile of knowledge and experience that industry maybe does not have – industry whose responsibility is to produce molecules, treatments, or devices, which improve human health and lengthen life. If we can do a good job of attracting people to the field, educating them well, and releasing them to pharmaceutical industries or device manufacturers, I think there is a real importance to that kind of activity as well.

Importance of instrumentation

Everything we do is based on instrumentation, coupled with the ideas that people have. The instruments are the tools we use, and the better the tools, the more effectively our ideas can be implemented.
For example, 20 years ago we could imagine pulse sequences which we simply weren’t capable of, because the instrumentation had features – with respect to stability, setting the phases, making the power levels constant and so on – that would just not allow it to be done.
Instrumentation is the basis of our work. It is also the basis of a lot of the money we spend, because the instrumentation we need is very expensive – so expensive in fact, that one has to be not only a genius in finding new experiments and applying them to the samples, but also in finding the funding for the instruments! So far, at least in Europe, people in our field have been pretty successful at this – I read that the Science Foundation in Germany has spent more money on NMR than on any other technique.
Fundamentally, without the NMR instruments, we could not do our research – it is the core of our work.

What technological developments would push your research forward?

As an NMR spectroscopist, I can only say we need better sensitivity, and better resolution. For the whole time I’ve been working in NMR, this has been the guiding desire of anyone you talk to

I remember when I first got my own spectrometer in 1990, the sensitivity was 600:1 on a 600MHz spectrometer. Now on our 900MHz spectrometer at Max-Planck, we have a sensitivity close to 10,000:1. So the sensitivity is really decisive in our research in terms of what we can do. Developments like dynamic nuclear polarization (DNP), and techniques like proton detection in liquid state NMR at high speeds are incredibly useful as well.

In general, as long as there is no field-dependent line broadening, it makes a lot of sense to go to the highest field possible. Bruker has always been a great partner, and I am very fortunate to have secured funding for a 1.2GHz system that will hopefully come at about the end of 2016, providing there are no problems with production.

NMR is not the only technique that is important to us – for example, we have a collaboration with a group doing AFM, which is a nice complimentary technique to NMR. I was really pleased to find out that Bruker produce AFMs as well. I think if we could see more developments between the different parts of the company would be extremely helpful to see for our research, and for future projects.

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