Press releases – 2023

Bees, wasps and ants belong to the Hymenoptera order and inject a whole cocktail of venomous ingredients when they sting. Despite their tremendous ecological and economic importance, little was previously known about the origins of their venom. Through extensive genomic studies, a team of researchers led by Dr. Björn von Reumont from Goethe University Frankfurt has now discovered that typical venomous components were already present in the earliest ancestors of Hymenoptera and must therefore have evolved before the stingers of bees and other insects. What's more, and contrary to previous assumptions, the gene for the venom melittin is found solely in bees. 

Venoms have developed in many animal groups independently of each other. One group that has many venomous species is Hymenoptera, an insect order that also includes aculeates (stinging insects) such as bees, wasps and ants. Hymenoptera is very species-rich, with over 6,000 species of bees alone. And yet, despite the great ecological and economic importance of hymenopterans, very little is known about the evolutionary development of their venoms.

By means of comparative genomics, researchers led by Dr. Björn von Reumont, who is currently a visiting scientist in the Applied Bioinformatics Working Group at the Institute for Cell Biology & Neuroscience of Goethe University Frankfurt, have now examined systematically and for the first time how the most important components of the venom of bees and other hymenopteran taxa developed in the course of evolution. The toxins are complex mixtures composed of small proteins (peptides) and a few large proteins and enzymes. Stinging insects actively inject this poisonous cocktail into their prey or attackers with the help of a special sting apparatus. 

In the first step, the researchers identified which of the peptides and proteins in the venom were most prevalent in hymenopterans. To do this, they drew on information from protein databases, although this was sparse. In addition, they analyzed the proteins in the venoms of two wild bee species – the violet carpenter bee (Xylocopa violacea) and the great-banded furrow-bee (Halictus scabiosae) – as well as of the honeybee (Apis mellifera). They found the same 12 “families" of peptides and proteins in all the hymenopteran venoms analyzed. These are evidently a “common ingredient" in these venom cocktails. 

In collaboration with colleagues from the Leibniz Institute for the Analysis of Biodiversity Change (LIB), the Technical University of Munich (TUM) and the LOEWE Center for Translational Biodiversity Genomics (LOEWE TBG), the research team then searched for the genes of these 12 peptide and protein families in the genome of 32 hymenopteran taxa, including sweat bees and stingless bees, but also wasps and ants such as the notorious fire ant (Solenopsis invicta). The differences in these genes, in some cases only the exchange of single letters of the genetic code, helped the scientists to determine the relationship between the genes of different species and later – with the help of artificial intelligence and machine learning – to compile a lineage of the venom genes. 

The surprising result was that many of the venom genes analyzed are present in all hymenopterans. Evidently the common ancestor of all hymenopteran taxa already possessed these genes. “This makes it highly probable that hymenopterans are venomous as an entire group," concludes von Reumont. “For other groups, such as Toxicofera, which includes snakes, anguids (lizards) and iguania, science is still debating whether the venoms can be traced back to a common ancestor or whether they evolved separately." 

Within Hymenoptera, only the stinging insects – bees, wasps and ants – have an actual stinger to administer the venom. The evolutionary old parasitic sawflies, by contrast, use their ovipositor along with their eggs to inject substances that alter their host plant's physiology: The sirex wood wasp (Sirex noctilio), for example, not only introduces a fungus into the plant, which facilitates the colonization of the wood by its larvae, but also its own poisonous cocktail with the venom proteins examined in the study. The purpose of these proteins is to create suitable conditions in the plant for the larvae. “This means that the sirex wood wasp can also be classified as venomous," says von Reumont. 

New venom components in bees are the gene for the peptide melittin and genes for representatives of the newly described protein family anthophilin-1. The fact that melittin is encoded by just one single gene came as a surprise to the researchers, as von Reumont explains: “Not only are there many different variants of melittin, but the peptide also accounts for up to 60 percent of the dry weight of bee venom. That is why science previously assumed that there must be many gene copies. We were able to disprove this quite clearly." Because they found the melittin gene only in bees, the researchers also invalidated the hypothesis that it belongs to a group of venom genes postulated for stinging insects called aculeatoxins. Von Reumont is convinced: “This shows us once again that genome data are the only way to draw meaningful conclusions about the evolution of venom genes." 

The Frankfurt study is the first one to show for an entire insect group with around one million species where venom genes originated and how they have developed. It provides a starting point for tracing the evolution of venom genes in the ancestors of Hymenoptera as well as specializations within the group. However, to be able to perform comparative genomics on a large scale, analysis methods for the partly very large protein families must first be automated. 

Publication: Ivan Koludarov, Mariana Velasque, Tobias Senoner, Thomas Timm, Carola Greve, Alexander Ben Hamadou, Deepak Kumar Gupta, Günter Lochnit, Michael Heinzinger, Andreas Vilcinskas, Rosalyn Gloag, Brock A. Harpur, Lars Podsiadlowski, Burkhard Rost, Timothy N. W. Jackson, Sebastien Dutertre, Eckart Stolle, Björn M. von Reumont: Prevalent bee venom genes evolved before the aculeate stinger and eusociality. BMC Biology, (2023) https://doi.org/10.1186/s12915-023-01656-5 

Picture download:
https://www.uni-frankfurt.de/146271865 

Caption: Components of the venom cocktail used by wild bees such as the Banded Mud-Bee (Megachile ericetorum) are evolutionarily older than their sting. Photo: Björn von Reumont 

Further information
Dr. Björn M. von Reumont
Visiting Scientist in the Applied Bioinformatics Working Group/Professor Ingo Ebersberger
Goethe University Frankfurt
Tel. +49(0)151-61997924
bmvr@reumont.net
http://www.venom-evolution.de 

Twitter/X: @BReumont @goetheuni @LOEWE_TBG @Leibniz_LIB @TU_Muenchen

Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de.

Each year, around 13,000 people in Germany are diagnosed with leukemia, of which up to half die from the disease despite intensive chemotherapy. Beyond that, therapies have severe side effects: In particular, they inhibit the formation of normal blood cells. In a preclinical study, a team from the Department of Pediatrics at Goethe University Frankfurt has tested a novel therapy based on a therapeutic RNA. Through the treatment, the laboratory animals survived significantly longer than their untreated counterparts. The hope now is that this leukemia-specific therapy will be able to support existing chemotherapies in the future. 

Each year, about 13,000 people in Deutschland are diagnosed with leukemia, an umbrella term that encompasses various forms of blood cancer. Among those affected are also many children and adolescents under 15 years of age. A common and very aggressive form of leukemia in adults is acute myeloid leukemia (AML). In AML, blood cells in the early stages – the stem cells and the precursor cells that develop out of them – transform. AML is the second most common form of leukemia in children, accounting for around four percent of all malignant diseases in childhood and adolescence. Despite treatment with intensive chemotherapy, only between 20 and 50 percent survive the first five years after diagnosis and treatment; half or more relapse and die. Furthermore, these intensive therapies have severe side effects: In particular, they damage the stem cells that form new blood. There is therefore an urgent need to develop new therapies tailored specifically to AML. 

Researchers led by Professor Jan-Henning Klusmann from the Department of Pediatrics and Professor Dirk Heckl from the Institute for Experimental Pediatric Hematology and Oncology at Goethe University Frankfurt have now tested such a leukemia-specific therapy in animal experiments. They used a therapeutic RNA molecule packaged in lipid nanoparticles to treat animals with leukemia. “By packaging it in lipid nanoparticles, we have in principle applied the same technique that was used for COVID-19 immunization," explains Klusmann. “The lipid nanoparticles transport the therapeutic RNA into the blood cells." 

The therapeutic RNA miR-193b was already described in 2018 as having a protective effect against cancer. In healthy cells, miR-193b slows down signaling pathways that are only activated for cell proliferation and which the stem cell otherwise hardly uses. That is why miR-193b is referred to as a tumor suppressor. In AML cells, however, miR-193b is not present in sufficient amounts and therefore unable to fulfil its task as a tumor suppressor. “Scientists have been testing active substances for many years that act as inhibitors and intervene in these signaling pathways used by AML cells," says Heckl. “The problem is that such substances only ever attack one component, whereas miR-193b acts on all levels of the signaling pathway. This stops the division of the abnormal cells very efficiently and causes the leukemia cells to die off quickly." Another advantage of therapeutic RNAs is that they do not damage the stem cells of the hematopoietic system, unlike conventional chemotherapies, because they are not dependent on the suppressed signaling pathways. 

All the laboratory animals tolerated the treatment with the nanoparticles containing the active substance well, and the leukemia cells were successfully fought off, as Klusmann summarizes: “We were able to significantly extend survival time in all the animals we treated, and some were even cured." What is particularly encouraging is that miR-193b worked in all the AML subtypes tested: The scientists examined four different types of cancer cells in their trials, including one common in people with Down syndrome. “In the past, noncoding RNAs and their genes were regarded as junk DNA," explains Klusmann. “Now we have developed a therapy based on this 'junk' that promises a new and very specific treatment option for myeloid leukemia." The hope is that this therapy can support chemotherapies in the future so that they do not have to be so intensive. 

Publication: Hasan Issa, Raj Bhayadia, Robert Winkler, Laura Elise Swart, Dirk Heckl, Jan-Henning Klusmann: Preclinical testing of miRNA-193b-3p mimic in acute myeloid leukemias. Leukemia 37, 1583 (2023) https://doi.org/10.1038/s41375-023-01937-6 

Further information
Professor Jan-Henning Klusmann
Director Department of Pediatrics and Adolescent Medicine
University Hospital Frankfurt
Tel: +49 (0)69 6301-5094
E-Mail: kkjm.direktor@gmail.com
www.leukemia-research.de 

Professor Dirk Heckl
Institute for Experimental Pediatric Hematology and Oncology
Goethe University Frankfurt
E-Mail: d.heckl@kinderkrebsstiftung-frankfurt.de

Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de.

Society is changing and housing with it. A joint research training group of Goethe University Frankfurt and Bauhaus-Universität Weimar will investigate this connection scientifically. 

Goethe University Frankfurt and Bauhaus-Universität Weimar have secured more than €7 million in funding from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) for the joint research training group on "Societal Transformation and Spatial Materialization of Housing". Starting in fall 2024, young researchers at Weimar and Frankfurt will conduct interdisciplinary research on the current housing provision. 

Housing is a basic human need and fundamentally important to both individual and social development. It also reflects epochal upheavals and processes of social change. Creating more socially just housing is a central and major challenge of contemporary urban development. 

Given that tomorrow's built environment is shaped by today's social developments, the research training group focuses on changes in the living environment caused by social conflicts, ecological demands or digitalization processes, asking, for example, what challenges, problems, contradictions and conflicts this poses for housing. And how does this built-up living environment in turn influence future social developments, or how should it shape them? 

Sebastian Schipper, who is the research training group's deputy spokesperson and Professor of Geographical Urban Research at Goethe University Frankfurt, explains: "The work being produced by the group will focus on the tense relationship between social transformation and the built-up residential environment. The aim is to develop research perspectives with which questions of housing, its transformation and its future can be systematically researched from a social and structural-spatial perspective." 

The research training group brings together specialist expertise from Goethe University Frankfurt and Bauhaus-Universität Weimar: On the one hand, the consortium includes experts from Weimar, who take a planning and engineering or design-related perspective on housing, and, on the other, professors from Frankfurt, who research housing primarily from a social science and humanities perspective. 

Up to 36 doctoral theses on housing issues can be completed over the entire nine-year funding period. For the research training group's first, five-year funding phase, Bauhaus-Universität Weimar and Goethe University Frankfurt will receive a total of €7.2 million from the DFG. As the main applicant, Bauhaus-Universität Weimar will initially act as the group's spokesperson. The other cooperation partners are Darmstadt-based Institute for Housing and Environment – Institut Wohnen und Umwelt GmbH (IWU), Frankfurt University of Applied Sciences (UAS), Klassik-Stiftung Weimar, Stiftung Baukultur Thüringen and Bundesverband für Wohnen und Stadtentwicklung e.V. (federal association for housing and urban development). 

The DFG press release is available at
https://www.dfg.de/en/service/press/press_releases/2023/press_release_no_45/index.html 

Two images for download: https://www.uni-frankfurt.de/145231130 

Caption: "Three rooms, kitchen, hallway, bathroom". Exhibition on the teaching research project at Bauhaus-Universität Weimar under the direction of Prof. Verena von Beckerath and Prof. Dr. Barbara Schönig, February 2018. Photo: Andrew Alberts 

Further information
Prof. Dr. Sebastian Schipper
Professor for Geographical Urban Research
Institute for Human Geography
Goethe University Frankfurt
Tel.: +49 (0)69 798-35165
E-Mail s.schipper@geo.uni-frankfurt.de
Homepage https://www.uni-frankfurt.de/129754253/Prof__Dr__Sebastian_Schipper

Editor: Dr. Anke Sauter, Science Editor, PR & Communication Office, Tel: +49 (0)69 798-13066, Fax: +49 (0) 69 798-763 12531, sauter@pvw.uni-frankfurt.de

Dr. Christian Münch from Goethe University Frankfurt's Institute of Biochemistry II has been awarded the European Research Council's (ERC) prestigious Consolidator Grant to conduct further research into a mechanism he discovered, which the cell uses to operate its recycling system. The research funding consists of two million euros provided over the next five years. The mechanism, which Münch has named "autoxitus", could serve as a novel communication pathway between neighboring cells and play a role in viral infections and neurodegenerative diseases. 

Congratulating the biochemist, Goethe University President Prof. Enrico Schleiff said: "Dr. Christian Münch is an outstanding scientist, who has now succeeded for the second time in asserting himself in the highly competitive ERC grant selection process. As in the past, his research project on 'autoxitus', too, will yield fundamental and groundbreaking insights into the interplay between metabolism and signaling in the cell. That is because with his program, Münch demonstrates the courage to take scientific risks – something we at Goethe University greatly appreciate and encourage, because such projects truly advance our knowledge, and thereby constitute the absolutely necessary prerequisite for innovation and transfer. This ERC grant once again illustrates just how successful we are in attracting excellent young talent to Goethe University." 

As part of his new research project, Dr. Christian Münch is investigating a new type of degradation process through which the cell maintains a finely tuned balance for its constant synthesis of diverse substances and organelles. As part of the so-called autophagy, the cell encloses components that are no longer required with membrane vesicles, within which these components are broken down. However, as part of the "autoxitus" degradation pathway discovered by Münch, the contents of these membrane vesicles are transported out of the cell. One of Münch's research questions is whether the cell can use this to signal to its neighbors that it is in a state of stress, caused, for example, by a viral infection or a neurodegenerative disease. 

Christian Münch completed his doctorate at the University of Cambridge and worked as a postdoctoral researcher at Harvard Medical School. He has served as head of the Department of Quantitative Proteomics at Goethe University Frankfurt's Institute of Biochemistry II since 2016. His research focuses on cellular stress responses to misfolded proteins in the cell's power plants (mitochondria) as well as on infections and diseases, all with a view towards understanding how the entire cell system reacts to stress. For his work, he has already received an ERC Starting Grant, an Emmy Noether grant and a number of awards. Münch is an EMBO Young Investigator and a steering committee member in the Federal Ministry of Education and Research's Cluster4Future Proxidrugs, the Collaborative Research Center 1177 on selective autophagy, the Fraunhofer High-Performance Center TheraNova, and the Goethe University-led EMTHERA (Emerging Therapeutics) research cluster initiative. 

The European Research Council's ERC Consolidator Grant supports excellent, promising scientists whose working group is in the consolidation phase. The grant is intended to enable them to expand their own field of research and conduct visionary, basic research. With a funding volume of up to two million euros for five years, the Consolidator Grant is one of the most highly endowed individual funding measures in the European Union. 

Links:
SFB 1177: Molecular and Functional Characterization of Selective Autophagy
https://www.sfb1177.de/
Proxidrugs: Innovative therapies for human diseases: Targeted degradation as a new mode of action for drugs
https://www.proxidrugs.de
TheraNova: High-Performance Center Innovative Therapeutics
https://www.fraunhofer.de/en/institutes/cooperation/high-performance-centers/theranova.html
EMTHERA: Emerging Therapeutics
https://www.emthera.de/ 

Image for download: https://www.puk.uni-frankfurt.de/93374838 

Caption: Dr. Christian Münch, Goethe University Frankfurt. Photo: Uwe Dettmar 

Further information
Dr. Christian Münch
Head of the Emmy Noether Group – Protein-Quality Control and Quantitative Proteomics
Institute of Biochemistry II
Goethe University Frankfurt
Tel.: +49 (0)69 6301-3715
ch.muench@em.uni-frankfurt.de
https://pqc.biochem2.de

Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de

Leukemia is the most common type of cancer in children. Treatment involves intensive chemotherapy, which has severe side effects due to its non-specific mode of action. A team from the Department of Pediatrics and the Institute for Experimental Pediatric Hematology and Oncology at Goethe University Frankfurt has now discovered a site in the DNA of cancer cells that is essential for leukemia cells to survive. Cancer cells in which the gene encoded at this site was modified experimentally died off. The gene locus thus constitutes a promising target for an alternative therapy in the future. 

The term 'leukemia' encompasses various forms of blood cancer, including acute myeloid leukemia (AML). In AML, blood cells in the early stages – the stem cells and the precursor cells that develop out of them – degenerate. AML is the second most common leukemia in children, accounting for around four percent of all malignant diseases in childhood and adolescence. Despite intensive chemotherapy, only around half of those affected survive without relapsing. About one third of children are dependent on a stem cell donation. Since non-specific chemotherapies have severe side effects, there is an urgent need to find new and specific therapy approaches. 

A team led by Jan-Henning Klusmann from the Department of Pediatrics and Dirk Heckl from the Institute for Experimental Pediatric Hematology and Oncology at Goethe University Frankfurt has now discovered an unusual “Achilles heel" in AML cells. For their study, which has now been published, they looked at a specific group of nucleic acids in leukemia cells: noncoding RNAs. Just like regular messenger RNAs (mRNAs), these are produced through gene transcription. However, unlike mRNAs, noncoding RNAs are not translated into proteins but instead often assume regulatory functions, for example in cell growth and cell division. A typical characteristic of cancer cells is a massive disruption of regulatory processes. This makes noncoding RNAs an interesting starting point in the fight against cancer. 

Against this background, the researchers led by Klusmann and Heckl wanted to know more about the role of noncoding RNAs in AML cells. For this purpose, they compiled a kind of inventory of these molecules in cancer cells taken from sick children and compared the resulting pattern with that of healthy blood stem cells. AML cells differentially expressed almost 500 noncoding RNAs in comparison to healthy cells – an indication that they could perform an important function in cancer cells. To validate this, the researchers turned off every single one of these RNA molecules by preventing the coding gene in the genome from being read. The most distinct effect they found was for the gene MYNRL15: Cancer cells in which this gene was turned off lost their ability to replicate indefinitely and died off. 

Surprisingly, however, it was not the absence of noncoding RNAs that was responsible for this effect, as Klusmann comments: “The regulatory function we observed is due to the MYNRL15 gene itself." The team was able to show that destroying the gene altered the spatial organization of the chromatin, i.e. the three-dimensional structure of the genome. “This led to the deactivation of genes that AML cells need for survival," says Klusmann. This offers a new and unforeseen possibility for fighting leukemia. 

What is significant against this background is the fact that the inhibitory effect triggered by the modified MYNRL15 gene could be observed in different AML cell lines. These cells originated both from children as well as adults and included various subtypes of the disease – among them one common in people with Down syndrome. “The fact that all the leukemias we studied were dependent on this gene locus tells us it must be important," concludes Klusmann. The researchers now hope that the cancer cells' dependence on MYNRL15 can be used to develop a specific gene therapy. “In our study, we systematically examined noncoding RNAs and their genes in AML cells for the first time, and in the process we identified a gene locus that constitutes a promising target for developing a therapy in the future," says Klusmann, summing up. 

Publication: Michelle Ng, Lonneke Verboon, Hasan Issa, Raj Bhayadia, Marit Willemijn Vermunt, Robert Winkler, Leah Schüler, Oriol Alejo, Konstantin Schuschel, Eniko Regenyi, Dorit Borchert, Michael Heuser, Dirk Reinhardt, Marie-Laure Yaspo, Dirk Heckl, Jan-Henning Klusmann: Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15. iScience 26, 107844 (2023) https://doi.org/10.1016/j.isci.2023.107844 

Further Information:
Professor Jan-Henning Klusmann
Director
Department of Pediatrics
University Hospital Frankfurt
Tel.: +49 69 6301-5094
kkjm.direktor@gmail.com
www.leukemia-research.de 

Professor Dirk Heckl
Institute for Experimental Pediatric Hematology and Oncology
Goethe University Frankfurt
d.heckl@kinderkrebsstiftung-frankfurt.de

Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de