Seeing red: investigating blood components via neutron scattering

High-quality neutron and X-ray data acquired using red blood cells HAVE allowed researchers to establish a universal theoretical description of cell membranes

In every cell of our bodies, a myriad of chemical reactions takes place which allow us to breathe, move and think. To protect their interior, cells are surrounded by a protective layer of fatty molecules (lipid membranes). These membranes are inherently complex, given the chemical diversity of their building blocks - the lipid molecules. They are rendered even more complex due to the additional presence of so-called membrane proteins. Amongst other tasks, these are responsible for an exchange of carefully selected small particles such as ions and water between the cell and its environment, which allows the cells to function properly.

Defects in cell membranes can have serious consequences. For example, red blood cells which fail to assume their well-known bi-concave disc shape due to an inherited structural defect in their membrane are destroyed by the immune system. This causes a condition known as spherocytosis, which can lead to symptoms such as breathlessness, fatigue and general malaise in those affected. In order to understand such clinically relevant phenomena and to optimise their treatments, a detailed investigation of the structural and functional properties of cell membranes and their constituents is essential.

Due to their non-invasive nature and their ability to probe multiple length scales, neutron scattering methods are excellent tools for studies of such intricate systems. Once the experimental data are obtained, mathematical modelling is the next step to obtain a detailed representation of the structures and processes studied. This step can often be tricky, especially in systems as complex as lipid membranes and their proteins. A close collaboration between theoreticians and experimentalists is key to optimising the process of modelling.

An article just published in the Journal of Applied Crystallography describes such a successful collaboration between scientists from Forschungszentrum Jülich (FZJ, Germany), the University of Liège (Belgium) and the ILL. “Given their fundamental role in the human body, we felt inspired to perform a detailed study of the structure and dynamics of red blood cell membranes and the proteins they contain”, says Andreas Stadler from FZJ, principal investigator of the project. The team used a specific experimental protocol to empty red blood cells of their contents. In this way, they obtained intact and functional red blood cell membranes, which allowed for precise, targeted experiments. These were performed on the small-angle scattering instrument D22 at the ILL as well as on KWS-X at FRM-II in Garching (Germany) to reveal structural aspects of the membranes. Insights into membrane dynamics were obtained via experiments on the neutron spin-echo spectrometer IN15 at the ILL. “Due to its exceptionally high energy- (and therefore time-) resolution, neutron spin echo is ideally suited for studying complex dynamics of biological membranes”, says Orsolya Czakkel, Instrument Responsible of IN15.

Using these results, Cédric Gommes – a physicist with the Funds for Scientific Research (FNRS, Belgium) based at the University of Liège – developed a mathematical tool which makes it possible to obtain 3D models of any protein-membrane system from neutron and X-ray scattering data. “In our approach, the proteins are represented by cylinder-like structures intersecting with the membrane, which itself is represented by deformed sheets”, explains Gommes. “Our model can also describe proteins which pass through an arbitrarily chosen fraction of a membrane or which are partially hidden within the membrane and partially protrude into the cellular environment.”

The model developed by Gommes is therefore highly adaptable and widely applicable to membrane-protein complexes, of which there are numerous examples in nature. Crucially, the model can be easily extended to describe, e.g., channel-like proteins which play essential roles in cellular metabolism and signalling. In addition, by optimising experimental parameters of energy-resolved techniques such as neutron spin echo, detailed insights into the dynamics of both membrane and proteins can be obtained.

“Even though we focused on red blood cells in this project, our model can be applied to many different types of cell membranes and their proteins”, emphasises Andreas Stadler. “The combination of theory and experiment highlights how powerful such interdisciplinary collaborations are in producing frameworks for the benefit of the scattering community and for advancing biomedical science.”