11 May 2021

New method provides unprecedented insight into the biology of cells and disease

PROTEOMICS

Researchers have developed a method for identifying distinct cell states by using proteomic profiles, thereby ensuring that tissue can be very accurately characterized to assist in making clinical decisions.

Deep visual proteomics concept

Researchers from the University of Copenhagen and the Max Planck Institute of Biochemistry in Germany have developed a method to examine cells much more precisely and thus improve researchers’ and doctors’ insight into the mechanisms of disease.

Researchers use deep visual proteomics (DVP) to identify the disease-specific protein signatures of cells in a tissue sample and then study their protein landscape in depth. This can provide doctors more in-depth understanding of various diseases and possibly identify drugs that might help.

“When doctors today diagnose cancer, they examine the cells under a microscope or examine the concentration of dozens of proteins. By contrast, DVP examines thousands of proteins, providing unprecedented insight into what might have gone wrong in the cells and caused the disease,” explains the leader of the DVP project, Matthias Mann, Professor, also from the Novo Nordisk Foundation Center for Protein Research.

The research, which has not yet been published in a peer-reviewed journal, is available through BioRxiv.

Doctors currently only have access to a fraction of the knowledge on disease

Proteins play a key role in all diseases. Cells express themselves through proteins, and imbalances in the ratios between proteins are often closely associated with diseases such as cancer, cardiovascular disease and metabolic diseases.

When doctors need to determine whether a person has cancer, they examine a tissue sample visually to find specific morphological features but also use molecular biological methods (tissue or blood test) to identify cancer-specific changes.

Doctors can perform both examinations and compare the visible and invisible characteristics to enable diagnosis. However, this only scratches the surface.

“Think of an iceberg. The morphological features of the cell such as the shape comprise the visible part of the iceberg. However, the molecular profile or protein landscape is like the rest of the iceberg hidden beneath the surface. Doctors cannot treat an ill person properly by only visually inspecting the tip of the iceberg. We need the full picture,” explains the researcher leading the development of DVP, Andreas Mund, Associate Professor, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

Using lasers and artificial intelligence to dissect tissue samples

DVP reveals the whole iceberg.

The researchers take a high-resolution microscopy image of a tissue sample. Then artificial intelligence categorizes the sample into the different types of cells based on morphology and dissects them out of the sample by using a computer-controlled laser. The cells are isolated so that a novel ultrasensitive proteomics procedure can analyse the ratios of all the proteins in the sample.

This provides researchers with an unprecedented level of detail for understanding which protein landscapes characterize healthy and diseased tissue – and the differences.

“This has never been done before in an unbiased way at the protein level. We have taken the best of two worlds – high-resolution microscopy and mass spectrometry-based protein research – and developed a method that is 100 times more sensitive than any previous method,” says Matthias Mann.

Tools for doctors

Andreas Mund explains that as knowledge about how proteins are expressed in various diseases increases, DVP might help doctors tailor special individualized courses of treatment and might help to predict the disease trajectory and how each person will react to a given treatment.

A doctor would take a tissue sample and send it for review. DVP reports on anything unusual and proposes the optimal treatment approach.

For example, people might have the same type of cancer, but they may require different types of treatment based on their unique molecular profile.

“We have worked very closely with clinicians and pathologists to develop a tool that can complement and extend their daily workflow. This is a proof of concept, and we are working hard to make this available as soon as possible,” says Andreas Mund.

Helping researchers to identify new drug targets

In addition to helping doctors better understand various diseases, DVP can also contribute substantially to research and development of drug treatment strategies.

DVP can advance knowledge about diseases by mapping how they are expressed through proteins, which will give doctors much greater insight into the signalling pathways involved.

Knowledge about the signalling pathways and dysfunction in the cells can also be used to identify new targets for treatment. Most drugs target proteins in the cells.

Greater insight into how the body’s many thousands of proteins behave during a given disease can enable the pharmaceutical industry to discover new targets for developing drugs.

“With DVP, we are closing the gap between clinicians, pathologists and researchers and the enormous quantity of data about the protein landscapes of disease. We are still working to make this tool available to more and more people,” concludes Andreas Mund.

Written by Kristian Sjøgren - sciencenews.dk.