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Prof. Dr. Leonhard Möckl

  • Professorship for Nano-optical Imaging
  • Associated Group Leader
  • Room A.3.428
  • Phone +49 9131 7133115
  • Email
  • Head of research group Physical Glycosciences

Leonhard Möckl studied Chemistry and Biochemistry at LMU Munich. He obtained his PhD in 2015 with a thesis on the role of the glycocalyx in membrane protein organization. In 2016, he joined the lab of W.E. Moerner at Stanford University, where he used single-molecule techniques to investigate the glycocalyx and furthermore developed deep-learning based approaches for single-molecule studies. In 2020, he joined the MPL as an independent group leader. Since 2024, he holds the professorship for Nano-optical Imaging at FAU, located at the newly established CITABLE.

In his free time, he loves to read, to play the piano, to hike, and to play volleyball.

2020

Super-resolution Microscopy with Single Molecules in Biology and Beyond–Essentials, Current Trends, and Future Challenges

Leonhard Möckl, W. E. Moerner

Journal of the American Chemical Society 142 (42) 17828-17844 (2020) | Journal | PDF

Single-molecule super-resolution microscopy has developed from a specialized technique into one of the most versatile and powerful imaging methods of the nanoscale over the past two decades. In this perspective, we provide a brief overview of the historical development of the field, the fundamental concepts, the methodology required to obtain maximum quantitative information, and the current state of the art. Then, we will discuss emerging perspectives and areas where innovation and further improvement are needed. Despite the tremendous progress, the full potential of single-molecule super-resolution microscopy is yet to be realized, which will be enabled by the research ahead of us.

Metabolic precision labeling enables selective probing of O-linked N-acetylgalactosamine glycosylation

Marjoke F. Debets, Omur Y. Tastan, Simon P. Wisnovsky, Stacy A. Malaker, Nikolaos Angelis, Leonhard Möckl, Junwon Choi, Helen Flynn, Lauren J. S. Wagner, et al.

Proceedings of the National Academy of Sciences of the United States of America 117 (41) 25293-25301 (2020) | Journal | PDF

Protein glycosylation events that happen early in the secretory pathway are often dysregulated during tumorigenesis. These events can be probed, in principle, by monosaccharides with bioorthogonal tags that would ideally be specific for distinct glycan subtypes. However, metabolic interconversion into other monosaccharides drastically reduces such specificity in the living cell. Here, we use a structure-based design process to develop the monosaccharide probe N-(S)-azidopropionylgalactosamine (GalNAzMe) that is specific for cancer-relevant Ser/Thr(O)–linked N-acetylgalactosamine (GalNAc) glycosylation. By virtue of a branched N-acylamide side chain, GalNAzMe is not interconverted by epimerization to the corresponding N-acetylglucosamine analog by the epimerase N-acetylgalactosamine–4-epimerase (GALE) like conventional GalNAc–based probes. GalNAzMe enters O-GalNAc glycosylation but does not enter other major cell surface glycan types including Asn(N)-linked glycans. We transfect cells with the engineered pyrophosphorylase mut-AGX1 to biosynthesize the nucleotide-sugar donor uridine diphosphate (UDP)-GalNAzMe from a sugar-1-phosphate precursor. Tagged with a bioorthogonal azide group, GalNAzMe serves as an O-glycan–specific reporter in superresolution microscopy, chemical glycoproteomics, a genome-wide CRISPR-knockout (CRISPR-KO) screen, and imaging of intestinal organoids. Additional ectopic expression of an engineered glycosyltransferase, “bump-and-hole” (BH)–GalNAc-T2, boosts labeling in a programmable fashion by increasing incorporation of GalNAzMe into the cell surface glycoproteome. Alleviating the need for GALE-KO cells in metabolic labeling experiments, GalNAzMe is a precision tool that allows a detailed view into the biology of a major type of cancer-relevant protein glycosylation.

From small Beginnings to steep Ascent The Fraunhofer Society

Jürgen Evers, Christiane Herzog, Leonhard Möckl

Chemie in unserer Zeit (2020) | Journal

The Fraunhofer-Gesellschaft (FhG) was founded by the Secretary of the Baverian Ministry of Economics, Hugo Geiger. He intended to create a research organisation that should unite science and economics to foster applied research. The new institution was named after Joseph von Fraunhofer, a hint to its intended orientation as Fraunhofer was both an ingenious scientist and a successful businessman. His inventions were developed into products which were sold all over the word. The FhG as new organisation would become the third pillar of German Research next to the Max-Planck-Society (MPG) and the German Research Foundation (DFG), but initially, the MPG and the DFG caused some problems for the newly founded FhG. However, when the German Ministry for Research guaranteed funding, the FhG quickly rose to international recognition.

Supersensitive Multifluorophore RNA-FISH for Early Virus Detection and Flow-FISH by Using Click Chemistry

Nada Raddaoui, Stefano Croce, Florian Geiger, Alexander Borodavka, Leonhard Möckl, Samuele Stazzoni, Bastien Viverge, Christoph Braeuchle, Thomas Frischmuth, et al.

ChemBioChem 21 (15) 2214-2218 (2020) | Journal | PDF

The reliable detection of transcription events through the quantification of the corresponding mRNA is of paramount importance for the diagnostics of infections and diseases. The quantification and localization analysis of the transcripts of a particular gene allows disease states to be characterized more directly compared to an analysis on the transcriptome wide level. This is particularly needed for the early detection of virus infections as now required for emergent viral diseases, e. g. Covid-19. In situ mRNA analysis, however, is a formidable challenge and currently performed with sets of single-fluorophore-containing oligonucleotide probes that hybridize to the mRNA in question. Often a large number of probe strands (>30) are required to get a reliable signal. The more oligonucleotide probes are used, however, the higher the potential off-target binding effects that create background noise. Here, we used click chemistry and alkyne-modified DNA oligonucleotides to prepare multiple-fluorophore-containing probes. We found that these multiple-dye probes allow reliable detection and direct visualization of mRNA with only a very small number (5-10) of probe strands. The new method enabled the in situ detection of viral transcripts as early as 4 hours after infection.

The Emerging Role of the Mammalian Glycocalyx in Functional Membrane Organization and Immune System Regulation

Leonhard Möckl

Frontiers in Cell and Developmental Biology 8 253 (2020) | Journal | PDF

All cells in the human body are covered by a dense layer of sugars and the proteins and lipids to which they are attached, collectively termed the "glycocalyx." For decades, the organization of the glycocalyx and its interplay with the cellular state have remained enigmatic. This changed in recent years. Latest research has shown that the glycocalyx is an organelle of vital significance, actively involved in and functionally relevant for various cellular processes, that can be directly targeted in therapeutic contexts. This review gives a brief introduction into glycocalyx biology and describes the specific challenges glycocalyx research faces. Then, the traditional view of the role of the glycocalyx is discussed before several recent breakthroughs in glycocalyx research are surveyed. These results exemplify a currently unfolding bigger picture about the role of the glycocalyx as a fundamental cellular agent.

Deep learning in single-molecule microscopy: fundamentals, caveats, and recent developments [Invited]

Leonhard Möckl, Anish R. Roy, W. E. Moerner

Biomedical Optics Express 11 (3) 1633-1661 (2020) | Journal | PDF

Deep learning-based data analysis methods have gained considerable attention in all fields of science over the last decade. In recent years, this trend has reached the single-molecule community. In this review, we will survey significant contributions of the application of deep learning in single-molecule imaging experiments. Additionally, we will describe the historical events that led to the development of modern deep learning methods, summarize the fundamental concepts of deep learning, and highlight the importance of proper data composition for accurate, unbiased results. (C) 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

Accurate and rapid background estimation in single-molecule localization microscopy using the deep neural network BGnet

Leonhard Möckl, Anish R. Roy, Petar N. Petrov, W. E. Moerner

Proceedings of the National Academy of Sciences of the United States of America 117 (1) 60-67 (2020) | Journal | PDF

Background fluorescence, especially when it exhibits undesired spatial features, is a primary factor for reduced image quality in optical microscopy. Structured background is particularly detrimental when analyzing single-molecule images for 3-dimensional localization microscopy or single-molecule tracking. Here, we introduce BGnet, a deep neural network with a U-net-type architecture, as a general method to rapidly estimate the background underlying the image of a point source with excellent accuracy, even when point-spread function (PSF) engineering is in use to create complex PSF shapes. We trained BGnet to extract the background from images of various PSFs and show that the identification is accurate for a wide range of different interfering background structures constructed from many spatial frequencies. Furthermore, we demonstrate that the obtained background-corrected PSF images, for both simulated and experimental data, lead to a substantial improvement in localization precision. Finally, we verify that structured background estimation with BGnet results in higher quality of superresolution reconstructions of biological structures.

Here you can download Leonhard's CV.

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