Protein fingerprinting in minutes

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Massenspektrometrie. Foto: Arne Sattler/Charité

New technology identifies COVID-19 biomarkers in the shortest possible time

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Berlin, 25.03.2021 – Faster and cheaper than an ordinary blood count: researchers at Charité – Universitätsmedizin Berlin and the Francis Crick Institute have developed the technology of mass spectrometry so that thousands of proteins in a sample can be measured within a few minutes. The research team demonstrates the potential of the technique by analysing the blood plasma of COVID-19 sufferers: Using the new technology, they identified eleven previously unknown proteins that indicate the severity of the disease. The study is published in the journal Nature Biotechnology*.

At any given time, thousands of different proteins are active in the human body: they give it its structure and enable vital reactions. Even when the body reacts to external influences such as pathogens or drugs, it increases or decreases the activity of different proteins. The detailed pattern of proteins in cells, tissues or blood samples – the so-called proteome – can therefore help researchers to better understand diseases or to make statements about diagnoses and the course of diseases. In order to obtain such a „protein fingerprint“, scientists use mass spectrometry, which until now, however, has been very time-consuming and cost-intensive. The new mass spectrometric technology „Scanning SWATH“ now promises a remedy: developed by a team led by Prof. Dr. Markus Ralser, Director of the Institute of Biochemistry at Charité, it is much faster and cheaper than previous methods and allows the measurement of several hundred samples per day.

„To speed up the technology, we have changed the electric fields in the mass spectrometer. This generates extremely complex data that a human can no longer analyse,“ explains Prof. Ralser, who is also Einstein Professor and group leader at the Francis Crick Institute in London. „That is why we have developed computer algorithms based on neural networks that extract the necessary biological information from the data. This allows us to determine thousands of proteins in parallel and reduces the measurement time many times over. Encouragingly, the method is also more accurate.“

The potential applications for this high-throughput technology are manifold: from basic research to the large-scale search for effective drugs to the identification of biological characteristics (biomarkers) that can be used to assess the individual risk of patients. The research group demonstrated that the technique is suitable for the latter in their study using the example of COVID-19. To do this, the team analysed the blood plasma of 30 patients with COVID-19 symptoms of varying severity who were hospitalised at the Charité and compared the protein patterns with those of 15 healthy individuals. The measurement of a single sample took only a few minutes.

In this way, the scientists identified a total of 54 proteins whose concentration in the blood was increased or decreased depending on the severity of the COVID-19 disease. Forty-three of these had already been linked to the severity of the disease in previous studies; however, for eleven of the proteins, this connection had not been known before. Several of these previously unknown proteins are part of the immune system’s response to pathogens, which also increases the tendency to clot. „So with our new method, we have discovered protein fingerprints in blood samples in a very short time, which we can now use to classify COVID-19 sufferers according to the severity of their disease,“ says Dr Christoph Messner, one of the first authors of the study and a scientist at the Institute of Biochemistry at Charité and the Francis Crick Institute. „Such an objective assessment can be very valuable, as patients sometimes overestimate their state of health. However, in order to be able to use mass spectrometric analysis as standard for the classification of COVID-19 sufferers, the technique must be further developed into a diagnostic test. In the future, it might also be possible to use a rapid analysis of the protein pattern to make statements about the probable course of COVID-19. We have already collected first promising results in this regard, but further studies are still needed before it can be used routinely.“

Prof. Ralser is convinced that the mass spectrometric examination of the blood could complement the classic blood count in the future: „Determining the proteome now costs less than a large blood count. By determining many thousands of proteins simultaneously, a proteome analysis additionally provides much more information. I therefore see great potential in a widespread application, for example for the early detection of diseases. In our studies, we will therefore continue to work towards such an application of proteome technology.“

*Messner CB et al. Ultra-fast proteomics with scanning SWATH. Nat Biotech 2021. doi: 10.1038/s41587-021-00860-4

About the study

The work was carried out in collaboration with the University of Cambridge in the UK, Chalmers University of Technology in Sweden, the Bernhardt Nocht Institute for Tropical Medicine in Hamburg and SCIEX, a Canadian manufacturer of mass spectrometers.

Mass spectrometry

Mass spectrometry is a technical method for analysing the mass of molecules and atoms. The substance to be analysed is transferred into a gas phase and then ionised. The resulting ions are strongly accelerated with the help of an electric field and sorted in the analysis unit of the mass spectrometer according to the ratio of their mass to their charge. The mass spectrum of a substance provides information about its molecular composition. Therefore, mass spectrometry is suitable for the identification, characterisation and quantification of a variety of biomolecules, such as proteins, metabolites, sugars and fats, which behave differently depending on the clinical picture and the individual.

Study platform for research into COVID-19 at the Charité The basis for generating the data now published was the Pa-COVID-19 study platform. Pa-COVID-19 is the central longitudinal register study for COVID-19 patients at the Charité. It aims to investigate COVID-19 patients clinically and molecularly quickly and comprehensively in order to identify individual risk factors for severe forms of progression as well as prognostic biomarkers and therapeutic approaches.

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