3D Maps shed new Light on Complex Systems

A team of scientists from Helmholtz Munich, the LMU University Hospital and the Ludwig-Maximilians Universität München (LMU) have found a way of using of standard antibodies to map whole bodies of mice using fluorescent markers, especially useful for studies of body-wide structures such as the nervous system. The wildDISCO method enables creation of detailed three-dimensional maps of normal and diseased structures in no longer living mammalian bodies by perfusion of the blood vasculature followed by optical clearing of the animal and light-sheet fluorescence microscopy. The scientists detect a fluorescence signal where a specific antibody is bound to the structure, molecule, or cell of interest and then advanced computational tools will pin-point all the specific locations where a molecule of interest is present throughout the body. 

A crucial factor for the success of this project was finding a way to uniformly distribute a fairly large antibody homogeneously throughout every cell of an animal. A team led by Professor Ali Ertürk identified a specific compound which enhances cell membrane permeability and facilitates deep and even penetration of standard antibodies without aggregation.

Ali Ertürk explains the vision behind the project: “Knowing where each protein is expressed in the body is essential for developing a comprehensive understanding of how the body works and what goes wrong in complex diseases”. 

Using wildDISCO, the researchers were able to create detailed maps of cellular structures leading to entire mouse body atlases, focusing on the nervous system, lymphatic vessels, blood vessels and immune cells. Having already discovered that the gut microbiome plays a significant role in the development of the enteric nervous system using this approach, the researchers have also mapped tumour-associated lymphoid structures (TLS) in relation to breast cancer spread which will provide insights into how these structures affect the immune response to tumours. 

These high-resolution images have also been made available as online atlases. First authors Dr. Hongcheng Mai and Dr. Jie Luo from the Ertürk lab at Helmholtz Munich emphasize the benefits of whole-body atlases: "Our online atlases have already generated data for published papers. Other scientists have obtained critical data from our atlases, saving time, resources and reducing animal use."

The Helmholtz Munich team are now working to enhance wildDISCO's capabilities and envision that in the future the technology could allow for the simultaneous use of numerous antibodies, for example in the modeling of multiple-complex systems together. The large-scale imaging data obtained could also be useful for the training of artificial intelligence (AI) algorithms, which thrive on large data sets.

The team is committed to harnessing the power of AI to simulate complex biological systems, with the ultimate goal of understanding diseases and developing new treatments more efficiently via computational predictions without the need for further animal experiments.

Mai and Luo et al. (2023): Whole-body cellular mapping in mouse using standard IgG antibodies. Nature Biotechnology. DOI: 10.1038/s41587-023-01846-0

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