© Anton Windfelder
Insects represent invaluable models for medical research, offering unique insights into biological mechanisms leading to potential breakthroughs in biomedical research. By actively researching the pathological, physiological, and biochemical aspects of insects (especially lepidopterans), we contribute to unlocking their potential as alternative models for understanding diseases, drug development, and therapeutic interventions.
Here are some current projects we are working on:
Caterpillars as a replacement for mammalian models in preclinical research
© Anton Windfelder
Inflammation research is becoming more ethical and economical: caterpillars help to understand gut inflammation and enable the faster and more efficient development of new therapies. Insects, like caterpillars, suffer from the same or related diseases as humans because 75 % of genes associated with human illness are also present in insects. Consequently, caterpillars like the tobacco hornworm can be used as a model organism, improving the understanding of diseases and helping to test and develop new therapies or diagnostic tools. A team around Anton G. Windfelder, a zoologist at the University of Giessen and from the Fraunhofer IME, Germany, are reporting the alternative use of caterpillars to study chronic inflammatory bowel diseases in Nature Communications. "Inflammatory diseases of the alimentary tract affect millions of people worldwide, and the incidence of chronic inflammatory bowel diseases is rising globally," says Dr. Windfelder. "The gut innate immunity and the organization of the intestinal epithelium of tobacco hornworm larvae are comparable to those of mammals. However, in contrast to other insects such as Drosophila, the fruit fly, caterpillars of Manduca setxa are large enough for medical imaging." Together with national and international cooperation partners from Düsseldorf, Germany, and New York, USA, Anton G. Windfelder and his team developed an innovative and unique imaging platform. "We use medical imaging modalities like computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) to characterize a gut inflammation in M. sexta." "Intestinal inflammation in M. sexta is diagnosed using contrast media and tracers such as FDG," says Dr. Windfelder. "This is in analogy to the diagnosis of gut inflammation in humans." Anti-inflammatory medications such as cortisone, used in acute flares of human chronic inflammatory bowel disease, also show a significant reduction in gut inflammation in the larvae of the tobacco hornworm. The advantage of the imaging platform is that multiple animals are studied simultaneously. In contrast to traditional methods, the animals stay alive and survive. "The animals tolerate the anesthesia and imaging very well and can continue to live after the experiments." With the publication mentioned, Windfelder and his team want to draw attention to the successful alternative use of insects in early preclinical research. "Of course, insects like Manduca cannot fully replace mice and rats.” Windfelder adds. "Evidence from cell culture is often not reproducible in in-vivo systems like mice," Windfelder says. "Here, insects like Manduca can help identify promising new targets or therapies worth further investigating in traditional mouse models." This would speed up research and make it more affordable. In this way, researchers could significantly reduce the use of classic laboratory animals and thus contribute substantially to animal welfare. Publikation Anton G. Windfelder, Frank H. H. Müller, Benedict Mc Larney, Michael Hentschel, Anna Christina Böhringer, Christoph-Rüdiger von Bredow, Florian H. Leinberger, Marian Kampschulte, Lorenz Maier, Yvette M. von Bredow, Vera Flocke, Hans Merzendorfer, Gabriele A. Krombach, Andreas Vilcinskas, Jan Grimm, Tina E. Trenczek & Ulrich Flögel: High-throughput Screening of Caterpillars as a Platform to Study Host-microbe Interactions and Enteric Immunity. Nature Communications 2022 DOI: 10.1038/s41467-022-34865-7
New ways in teaching and research through virtual reality and micro-computed tomography
© Anton Windfelder
Life is three-dimensional. But traditional methods such as light microscopy can only capture life in two dimensions. That's why researchers led by Giessen biologist Anton Windfelder are breaking new ground by using micro-computed tomography (µCT) to visualize complex anatomical structures inside insects. The team has discovered several previously unknown anatomical structures in the guts of the tobacco hornworm (Manduca sexta). The results have now been published in the international journal iScience (Cell Press). Based on the µCT data, the researchers have created three-dimensional computer models that will also be used in teaching at Justus Liebig University Giessen. Students will be able to explore and thus better understand the complex anatomical relationships inside insects using virtual reality. The American tobacco hornworm is an important model organism in biomedical research. Since many areas of the innate immune system of the gut are comparable between mammals and insects such as Manduca sexta, the team led by Anton Windfelder of the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and Justus Liebig University in Giessen, Germany, has established the tobacco hornworm as a model for chronic inflammatory bowel disease. "We use imaging techniques from radiology such as clinical computed tomography to test new drugs against chronic intestinal diseases in Manduca. This eliminates the need for unnecessary experiments with mice," said Prof. Gabriele Krombach, director of the Department of Diagnostic and Interventional Radiology, who was involved in the study. "The 3D atlas now presented helps us with anatomical orientation within the animals. Ultimately, we measure how much contrast agent is deposited in the intestinal wall of the tobacco hornworms. The more contrast agent, the more severe the inflammation. In this way, we can check whether new drugs help with intestinal inflammation," says Windfelder. The team also succeeded in calculating the larvae's intestinal volume. This revealed that the animals have roughly the same intestinal volume as a laboratory mouse. Thus, fed active ingredients can reach about the same concentration as in the intestine of a mouse. However, the data also provide important insights into the structure of digestive organs in insects. "We were particularly surprised by the complexity of the hindgut," said Prof. Andreas Vilcinskas, institute branch chief at Fraunhofer IME in Giessen, who was also involved in the study. "Previous microscopic analyses could only insufficiently depict the complexity of the fold pattern of the hindgut. It is possible that the surface enlargement produced by the complex hexagonal fold pattern is related to the water resorption of the hindgut," Vilcinskas said. The hexagonal pattern runs throughout the midgut and hindgut. Such an analysis would be unthinkable using traditional light microscopy. The new anatomical findings will also be incorporated directly into teaching. Starting this semester, Dr. Anton Windfelder, who played a leading role in the study, will offer the subject "Experimental Radiology and Nuclear Medicine" and, starting next semester, the course "Alternative Animal Models in Medical Research" at the Department of Medicine at Justus Liebig University Giessen. "Human medicine students can be introduced to insect anatomy and learn about the potential of insects as alternative animal models for early preclinical research," Windfelder said. Artificial reality, or virtual reality (VR), is a technology through which users can interact with virtual objects. For example, this technology makes it possible to fly through the gut of tobacco hawkmoths. "I could only dream of this as a student" said Windfelder. "But since not every department has VR headsets, we produced high-quality video sequences." Interested parties can download these videos under the article "A Quantitative Micro-Tomographic Gut Atlas of the Lepidopteran Model Insect Manduca sexta" published on the iScience homepage. "We hope this will help us get more students interested in experimental radiology and working with insects." Publikation Windfelder AG, Steinbart J, Flögel U, Scherberich J, Kampschulte M, Krombach GA, Vilcinskas A. A quantitative micro-tomographic gut atlas of the lepidopteran model insect Manduca sexta. iScience. 2023 Jun 16;26(6).
Manduca sexta is an alternative in vivo model for testing new innovative imaging agents in Radiology.
© Anton Windfelder
Polymer scientists around Olga Koshkina and Timo Rheinberger from the University of Twente have developed a new phosphorus-based polymer that could be used as a new contrast agent for magnetic resonance imaging (MRI). Most current MRI contrast agents rely on the toxic element gadolinium. Instead, Koshkina and her colleagues explored biodegradable phosphorus MRI contrast agents as a more eco-friendly option. Phosphorus is promising as an alternative element for MR imaging due to its natural stability, with the only naturally occurring stable isotope, 31P, being both spin-active and highly biocompatible. Phosphate esters are integral components of key biomolecules such as DNA, RNA, and ATP. However, the biocompatibility of phosphorus, which arises from its prevalence in biomolecules, also presents challenges for MRI. These biomolecules generate substantial background noise, and phosphorus has inherently lower sensitivity compared to hydrogen or fluorine. Therefore, the researchers employed various chemical techniques to create phosphorus-based polymers capable of standing out from background signals. They selected phosphonate monomers with unique MRI signatures by incorporating distinctive side chains. Combining two different monomers into gradient copolymers allowed them to fine-tune the polymers' magnetic relaxation time and their ability to form phosphorus-rich nanoparticles that remained in the body long enough for valuable imaging. For in vivo testing, the researchers teamed up with Anton Windfelder from the Fraunhofer Institute for Molecular Biology and Applied Ecology IME in Giessen (Germany) and tested the capabilities of their new imaging agent by injecting it into tobacco hornworms (Manduca sexta). Unnecessary, expensive and ethically controversial experiments with mice could thus be prevented. The new agent showed up as a vivid and clear contrast against the background and persisted in the hemolymph (equivalent to blood in invertebrates) for over 24 hours, indicating its potential for targeted imaging. Furthermore, they observed degradation products of the polymer in the caterpillars' feces, confirming its natural breakdown. The researchers have demonstrated the use of insect larvae like M. sexta as an alternative animal model for the in vivo research of new imaging agents and showed the potential of phosphorus-based polymers as contrast agents. Publicatio: Koshkina O, Rheinberger T, Flocke V, Windfelder A, Bouvain P, Hamelmann NM, Paulusse JM, Gojzewski H, Flögel U, Wurm FR. Biodegradable polyphosphoester micelles act as both background-free 31P magnetic resonance imaging agents and drug nanocarriers. Nature Communications. 2023 Jul 19;14(1):4351.