Why do we need animal experiments?
The biology of the human body is highly complex. Different organs, cell types, signalling and hormone systems are interconnected in an infinite number of feedback loops. We do not yet understand the functions of these different structures and how they interact, and so in many areas we are still in our infancy. It is true that individual processes of a living organism can indeed be studied in isolation. But only on a living organism can the specific interactions between organs, cells and cell components be studied. An immune response, for example, with its many components, cells and soluble constituents that travel through the body and interact with each other in a temporally and spatially staggered manner, cannot be replicated in an in-vitro experiment on cell cultures.
The complexity of biological systems such as the immune system, our metabolism or the epigenetic regulation of genes can be approached in many small steps, depending on the question. Non-animal methods such as lab-on-a-chip techniques, organoids (structures created from cell cultures that mimic individual organ functions) or computer models can also yield important findings. However, at a certain point, every research project comes to the question of what the processes in the living organism actually look like - and how they react when one tries to modulate a certain part of them. Here, work with laboratory animals becomes indispensable in order to gain reliable insights into the complex interaction of genetic and biochemical processes in both healthy and diseased bodies. Often, only comparative studies in different animal species lead to new insights. This is why basic research is dependent on animal experiments.
Findings from our research with animals
Human females have two copies of the X chromosome with over 1,000 genes. Human males, on the other hand, have only one copy and instead have a gene-poor Y chromosome. This chromosomal imbalance is also found in many other species in the animal kingdom. However, it is vital to "balance" these differences in order to achieve the same "gene dose" in both sexes. Whereas human and mouse females shut down one of their X chromosomes, in fruit flies it instead the male that does the work. An epigenetic factor called the MSL complex binds to the single male X chromosome and hyperactivates it.
Insights into these processes and the molecules involved not only help to understand the mechanisms of dosage compensation in flies, mice and humans, but also contribute significantly to a better understanding of gene regulation in general. For example, studies from the Institute's basic research were central to deciphering the molecular biological cause of a rare disease in which affected children suffer from severe developmental delays.
We are more than the sum of our genes. Epigenetic mechanisms, which are altered by environmental influences such as diet, disease or our lifestyle, take on an important role in controlling our genetic make-up by switching genes on or off. For a long time it was questionable whether this epigenetic information, which accumulates in our cells throughout life, can cross the boundary of generations and be passed on to children or even grandchildren. Researchers at the MPI were able to show with the help of Drosophila that not only the inherited DNA itself, but also inherited epigenetic instructions contribute to the regulation of gene expression in the offspring.
An epigenetic modification called H3K27me3 is thus not only transmitted to the offspring through the maternal germline, but also controls a finely tuned mechanism required for genome activation during early embryogenesis of the fly.
Obesity and flies
Scientists at the MPI were able to show that fruit flies inherit changes in their metabolism from father to son. A sugary feast before mating can thus have consequences for a fruit fly and its offspring: The fly offspring then become more susceptible to obesity. The diet of the fathers activates genes that can change the genetic make-up epigenetically. These changes are inherited and control the activity of genes for fat metabolism in the next generation.
The researchers have also found a similar gene network in humans and mice that increases susceptibility to obesity. For this purpose, data from studies on Pima Indians - a tribe of North American natives whose members often suffer from obesity - and identical twins were analysed. According to this, overweight humans have the same gene signature as fruit flies. The susceptibility to high body weight thus also increases in humans when certain genes are epigenetically altered.
Swarming behaviour of cells of the innate immune response
Using the mouse as a model organism, scientists at our institute are investigating the functioning of the innate immune system. This is the first line of defence with an effective arsenal of cellular weapons when, for example, bacteria invade and damage the body.
Using special imaging techniques, but also genetic studies on mice, new insights could be gained into how different immune cells coordinate their behaviour at the site of an inflammation. The researchers deciphered the signals that cause phagocytes to join together in large swarms to attack pathogens in infected tissue.
Fate of blood stem cells
At the Institute, scientists research the molecular and functional properties of blood stem cells, so-called haematopoietic stem cells (HSCs). By combining different molecular biological analysis methods such as metabolomics and epigenomics with functional in vivo and in vitro approaches, the researchers aim to understand which mechansims and signalling substances control the development of stem cells and other progenitor cells. The studies, which focus on signalling substances such as vitamin A metabolites, can help to improve the treatment of blood diseases and leukaemias in the future.
A special focus is on the unique potential of blood stem cells to supply the body with fresh blood cells for life. "This extraordinary ability of haematopoietic stem cells is protected by the fact that some of them enter a very deep dormant state when they are not needed. We want to understand the regulatory networks involved in maintaining this resting state," says Nina Cabezas-Wallscheid. Since disturbances of this mechanism can lead to diseases of the blood system, the research from Freiburg also contributes to the development of basic principles for new therapeutic approaches for blood diseases.
Epigeneticists at the Institute research the molecular basis of the regulation of genes. With a better understanding of how and under which conditions genes are activated or not, it will not only be possible to develop new starting points for drugs in the future, but possibly also to realise therapies that can take into account individual genetic and epigenetic conditions of patients.
Researchers at the Institute have studied genetically modified mice that have only one copy of the Trim28 gene. Although the animals are genetically identical, their body weight varies enormously: they are either normal weight or suffer from overweight, there are no intermediate stages. Responsible for this unusual weight distribution is a network of genes whose activity is controlled epigenetically. Since epigenetic processes react sensitively to environmental stimuli, the scientists therefore want to find out whether a change in diet, stress minimisation or even medication can influence the gene switch accordingly and permanently change it from overweight to normal weight.
Malfunction of blood stem cells in cancer
Studies at our Institute are using zebrafish to explore haematopoietic stem cells and other precursors of our blood cells to better understand disorders of haematopoiesis in humans. A research group was thus able to determine the role of the transcription factor HLX in leukaemia in more detail. HLX functions like a molecular light switch that can turn genes on and off, and is often over-activated in patients with acute myeloid leukaemia (AML). In complementary experiments in zebrafish and human cell lines, the researchers found that an over-activated HLX switch primarily influences metabolic genes in the cells that lead to misregulation and blockage during cell differentiation.
Thus, the study results also provide indications for future therapeutic approaches. This is because the metabolic pathways regulated by the transcription factor can be influenced by drugs. In cell culture, experiments succeeded in significantly reducing the survival rate of degenerated cancer cells.
Structural principles of acquired immunity
Researchers at MPI-IE use the zebrafish as a model organism in their research into the genetic basis of the immune system. Using a comparative approach, they analyse genes, cell types and lymphoid organs from different species to identify the design principles of adaptive immunity that are common to all vertebrates.
Besides zebrafish, this includes lancelets, lampreys, mice and, of course, humans. Among other things, these studies produced impressive real-time images of T cell development in living zebrafish embryos: starting with the formation of the thymic anlage, through the immigration of the cells from the bone marrow, to the stage at which the finished T cells were released from the thymus.
Overall, the genetic basis of thymopoiesis, i.e. the maturation and development of T cells, in vertebrates will be investigated with the help of zebrafish and other species. This is because a better understanding of evolutionary developmental steps of the genetic networks that regulate the development and function of the immune system can elucidate the design principles of the vertebrate immune system. The research helps to better understand disorders of the immune response.