WELCOME TO THE SVEN KLUMPE LAB
In our group, we combine technical development in cryo-focused ion beam milling (cryo-FIB) and cryo-electron tomography (cryo-ET) with biological applications to address questions in cellular structural biology.
Using cryo-FIB milling, we generate thin sections of biological samples that are subsequently imaged in a transmission electron microscope at different tilt angles. The resulting projections of the cellular material can be reconstructed similar to computed tomography widespread in biomedical applications. These approaches allow to generate three dimensional reconstructions of the cellular environment that reveal membrane architecture and the ‘molecular sociology’ of protein complexes. Through computational analyses, the macromolecules identified in these tomograms can be extracted, averaged and, in favorable cases, even resolved to high resolutions below 1 nm, revealing secondary structure. These technologies recently allowed us to study the cellular structural biology of a transposon or “jumping gene”, the copia retrotransposon.
Transposable elements (TEs) are a diverse group of mobile genetic elements that can autonomously replicate and insert themselves into new genomic locations. TEs are widespread in organisms across the tree of life, frequently constituting a substantial proportion of their host genomes. In mammals, for instance, TEs account for approximately 25-75% of the genome, with humans reaching ~50%, and in some plant species, TEs can comprise up to 85% of the genome. A subclass of TEs, the long terminal repeat (LTR) retrotransposons of which the copia retrotransposon is a member, transpose via an RNA intermediate and are evolutionarily related to retroviruses. If not kept in check, TEs pose a severe threat to genome integrity and intricate defense mechanisms have evolved to protect metazoan germline genomes from this immanent threat by transcriptional and post-transcriptional regulation. Currently, we are fascinated by the cell biological mechanisms that drive the replication cycle and, thus, evolutionary success of TEs. How do retrotransposons reach the germline genome to generate new insertions? What drives the sex-specificity observed for TEs? And how do TEs make their way into the genome in the first place? To that end, we use the model system Drosophila melanogaster as well as other model systems to study TEs in their respective niches during gametogenesis, the generation of sperm and egg.
Vision
Our vision is to enable structural biology in the multicellular context to uncover the cell biological mechanisms driving a range of biological processes.
Mission
We aim to understand the structural diversity of retroelements and the molecular determinants that lead to their specific host interactions and, thus, drive the TE’s replication cycles within their host niche.
In a constant race of host defense factors against transposable elements, we want to understand the cell biological mechanisms that allow mobile genetic elements to navigate the genome and drive evolution. Long-term, we want to develop cryo-ET workflows in a pursuit to democratize in situ structural biology techniques to enable the broadest community to benefit from the molecular resolution imaging that this technology can achieve.
Approach
In addition to the specific biological questions on transposon biology, we strive to make new discoveries by developing and improving methodology, hardware, and open-source software in cryo-FIB milling to enable new experimental approaches and widen the sample spectrum in cryo-ET. Recent work in the field by us and others has opened up the world of tissue biology to the cellular structural biologist. By employing micromanipulation methods to extract material from large vitreously frozen multicellular organisms and tissues, a process referred to as lift-out, we are able to zoom into the cellular ultrastructure of tissues at molecular resolution.
Moving forward, we aim to leverage our developed approaches to investigate the cellular structural biology of germ cells, with a particular focus on the architecture and interactions of LTR retrotransposons within them. By preserving native cellular environments at near-atomic resolution, these techniques will enable us to uncover key structural insights into retrotransposon activity, regulation, and their impact on germline integrity.
Impact
Overcoming technical limitations that have prevented the elucidation of the nanoscale mechanisms of genome defense, gametogenesis, and retrotransposon replication cycles, we aim to advance the fundamental understanding of essential biological events that ensure the faithful inheritance of genomes into the next generation. Beyond fundamental research, our discoveries could inform studies in reproductive biology and biotechnology, with potential applications in infertility research and gene delivery strategies.
Selected Publications
Klumpe, S., Senti, KA., Beck, F (...) Beck, M., Plitzko, JM. (2025). In-cell structure and snapshots of copia retrotransposons in intact tissue by cryo-ET. Cell.
McCafferty, CL., Klumpe, S., Amaro, RE (...) Collinson, L., Engel, BD. (2024). Integrating cellular electron microscopy with multimodal data to explore biology across space and time. Cell. 187(3):563-584
Schiøtz, OH., Kaiser, CJO., Klumpe, S (...) Thompson, C., Plitzko, JM. (2024). Serial Lift-Out: sampling the molecular anatomy of whole organisms. Nat Methods. 21(9):1684-1692
Klumpe, S., Fung, HK., Goetz, SK (...) Plitzko, JM., Mahamid, J. (2021). A modular platform for automated cryo-FIB workflows. Elife. 10
Erdmann, PS., Hou, Z., Klumpe, S (...) Plitzko, JM., Baumeister, W. (2021). In situ cryo-electron tomography reveals gradient organization of ribosome biogenesis in intact nucleoli. Nat Commun. 12(1):5364