miniature chips

Four times as much information per cell

Scientists from the BIH at Charité and the MDC have teamed up with U.S. and Japanese researchers to take single-cell analysis to a new level. They combined methods for determining mRNA levels and DNA accessibility with those used for detecting proteins and mutations in mitochondrial DNA, they report in “Nature Biotechnology”.

Joint press release by BIH in the Charité and MDC

These days single-cell analysis is primarily associated with determining the messenger RNA (mRNA) profile of individual cells. These messenger molecules transmit information from the genome in the cell nucleus – the DNA – into the cytoplasm, where the mRNA is translated into protein. The amount and composition of mRNA may thereby vary across different types of cells. For example, cells of the nervous system require different proteins than liver cells, meaning they also read (or transcribe) different genes from DNA into mRNA.

“However, a picture of a cell based on its mRNA profile alone is incomplete,” explains Dr. Leif S. Ludwig, head of the Emmy Noether Junior Research Group “Stem Cell Dynamics and Mitochondrial Genomics” at the Berlin Institute of Health (BIH) at Charité and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). He is one of the lead authors and part of the joint Focus Area “Single Cell Approaches for Personalized Medicine,” which is carried by the BIH at Charité co-founded with the MDC and the Charité – Universitätsmedizin Berlin. “Not all mRNA molecules are necessarily translated 1:1 into proteins, and the amount of mRNA cannot be readily measured for every gene,” explains Leif S. Ludwig. “The ability to simultaneously quantify proteins provides a more comprehensive picture of what is happening in the cell.”

Understanding why the cell transcribes some genes more often

In collaboration with colleagues from the United States and Japan, the scientists determined not only the mRNA and protein profiles but also the “accessibility” of the DNA in individual cells. This is because the genetic material of the cell is tightly packed into a complex structure called chromatin: sites where the chromatin is less tightly packed can be more easily transcribed into mRNA, while very tightly packed sites are hardly ever used for transcription. “This enables us to assess how the DNA structure is related to the amount of mRNA, and as a result we can better understand why some genes are transcribed more often than others,” says Leif S. Ludwig, a trained biochemist and physician.

Schematic of the workflow and the modality capture enabled by DOGMA-seq.

With his group, which is based at the Berlin Institute of Medical Systems Biology (BIMSB) of the MDC, he is also studying the DNA of mitochondria – the “power plants” of the cell – which have their own genome. They are, for example, investigating how changes in mitochondrial DNA contribute to human diseases. “So it made sense for us to include mitochondrial DNA in the single-cell analysis,” explains Leif S. Ludwig. This enabled the scientists to be the first in the world to examine four modalities simultaneously at the single cell level. This ability is also of uttermost importance from a medical perspective. “For example, the more comprehensively we can analyze cancer cells, the better we can understand what goes wrong inside these cells – which will in turn facilitate the precise tailoring of treatment strategies,” he says.

Dr. Ludwig is pursuing the clinical application of his findings together with his clinical partners, Professors Lars Bullinger and Ulrich Keller, the Directors of the Department of Hematology, Oncology and Tumor Immunology at Charité Campus Virchow-Klinikum (CVK) and Charité Campus Benjamin Franklin (CBF), respectively.

Text: Stefanie Seltmann, BIH

 

Literature

E. P. Mimitou et al. (2021): „Scalable, multimodal profiling of chromatin accessibility, gene expression and protein levels in single cells“. Nature Biotechnology, DOI:  10.1038/s41587-021-00927-2

 

Further information


Contacts

Dr. Stefanie Seltmann
Head Communication & Marketing
Berlin Institute of Health (BIH) at Charité
+49 30 450 54 3019
stefanie.seltmann@bih-charite.de

Jana Schlütter
Communications

Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
+49 30 9406 2121
jana.schluetter@mdc-berlin.de oder presse@mdc-berlin.de

 

About the Berlin Institute of Health (BIH) at the Charité

 

The mission of the Berlin Institute of Health (BIH) is medical translation: transferring biomedical research findings into novel approaches to personalized prediction, prevention, diagnostics and therapies and, conversely, using clinical observations to develop new research ideas. The aim is to deliver relevant medical benefits to patients and the population at large. As the translational research unit within Charité, the BIH is also committed to establishing a comprehensive translational ecosystem – one that places emphasis on a system-wide understanding of health and disease and that promotes change in the biomedical translational research culture. The BIH was founded in 2013 and is funded 90 percent by the Federal Ministry of Education and Research (BMBF) and 10 percent by the State of Berlin. The founding institutions, Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), were independent, member entities within the BIH until 2020. Since 2021 the BIH has been integrated into Charité as the so-called third pillar. The MDC is now the Privileged Partner of the BIH.

 

Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)

 

The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) is one of the world’s leading biomedical research institutions. Max Delbrück, a Berlin native, was a Nobel laureate and one of the founders of molecular biology. At the MDC’s locations in Berlin-Buch and Mitte, researchers from some 60 countries analyze the human system – investigating the biological foundations of life from its most elementary building blocks to systems-wide mechanisms. By understanding what regulates or disrupts the dynamic equilibrium in a cell, an organ, or the entire body, we can prevent diseases, diagnose them earlier, and stop their progression with tailored therapies. Patients should benefit as soon as possible from basic research discoveries. The MDC therefore supports spin-off creation and participates in collaborative networks. It works in close partnership with Charité – Universitätsmedizin Berlin in the jointly run Experimental and Clinical Research Center (ECRC ), the Berlin Institute of Health (BIH) at Charité, and the German Center for Cardiovascular Research (DZHK). Founded in 1992, the MDC today employs 1,600 people and is funded 90 percent by the German federal government and 10 percent by the State of Berlin.