Biomedical Research Uncovers the Mechanisms Behind Rare Genetic Diseases and offers hope for novel therapies
Freiburg, 31/03/2025
Researchers at the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies at the University of Freiburg are investigating fundamental biological processes that are crucial for, among other things, the healthy development of the immune system and organs.
Under the theme “Healthy beginnings, hopeful futures”, World Health Day 2025 highlights ways to improve newborn health. A healthy start in life is not guaranteed for all children. Genetic factors can present serious health challenges early in development.
Two researchers provide insights into their work
Dr. Miriam Schmidts studies the molecular mechanisms of rare inherited diseases, particularly ciliopathies – genetic disorders that affect cilia function and can disrupt early organ development.
Professor Dr. Stephan Ehl investigates monogenic immune disorders and their impact on key immune signalling pathways. His research provides valuable insights into immune cell regulation and the balance between immune defence and autoimmunity.
This research is vital for understanding immune and developmental disorders at the molecular level. It lays the foundation for more targeted diagnostic and therapeutic approaches.
Dr. Miriam Schmidts, Center for Paediatrics and Adolescent Medicine, University Medical Center Freiburg
Miriam Schmidts, your research focuses on the genetic causes of ciliopathies and their impact on cell communication. What role do cilia play, and why is their function important for a healthy body?
Cilia are hair-like projections that extend from the surface of most human cells. They act like antennae, receiving and transmitting signals – both into the cell, such as towards the nucleus, and outward to neighbouring cells. Signals can be transmitted between nearby cells or over longer distances through tissues or the bloodstream. Disruption of cilia function can impair this signalling process and, as early as the embryonic stage, lead to developmental abnormalities.
Cilia clearly play an important role in developmental processes. What are the consequences of cilia dysfunction for organ development, and which signalling pathways are the focus of your research?
For a fertilised egg to develop into a fully-formed human, each cell must constantly know what role it plays and which organ or tissue it will contribute to. Although all cells carry the same DNA, different genes are activated depending on the cell type. This controlled gene expression determines cell identity and ensures proper organ development. My lab focuses particularly on the Hedgehog signalling pathway. Disruption of this pathway – often caused by defective cilia – can alter gene expression and cell identity. As a result, affected cells may fail to perform their intended function, impairing organ development. This disruption can lead to conditions such as polydactyly (extra fingers or toes), skeletal dysplasia with shortened limb bones and ribs, kidney cysts, cleft palate, or central nervous system abnormalities. Our genetic research has shown that mutations in genes responsible for protein transport in cilia cause these malformations. Depending on which protein is affected, the severity and type of developmental issues can vary.
The World Health Day 2025 theme highlights the importance of a healthy start in life. Why do some patients with genetic defects have milder symptoms than others, and what new treatment approaches might arise from this?
Using kidney and cartilage organoid models, we investigate how genetic changes affecting cilia proteins impact cell differentiation and identity. This research helps explain why some patients develop severe organ damage, while others with similar defects remain stable into old age. With CRISPR/Cas genome editing and base editing techniques, we can replicate individual genetic mutations to predict the likely progression of a patient’s condition. This enables families to better plan medical care and daily life. We also hope that improved understanding of these signalling disruptions will lead to new drug therapies. Since kidney and retinal diseases often progress slowly, delaying their onset or slowing progression would greatly improve patients’ quality of life. Recent advances in gene therapy, particularly for retinal conditions, offer additional hope that similar approaches may one day benefit ciliopathy patients as well.
Does your research also provide insights relevant to other signalling pathways, developmental processes, or diseases?
Our primary goal is to understand how genetic mutations affect cell identity and differentiation in kidney and cartilage cells – and to develop targeted therapies from these insights. The proteins affected in our patients usually retain some function rather than being completely inactivated. Traditional gene knockout methods – which disable entire genes – typically result in complete loss of the cilium structure, making it difficult to study the roles of individual components. However, the mutations observed in our patients impair specific cilia functions without destroying the entire structure. This provides unique opportunities to investigate individual cilia components in detail. Our analyses of transport processes and signal transmission have also provided insights that may be relevant for conditions such as osteoarthritis, skeletal disorders, and certain kidney diseases.
A healthy start in life requires not only intact organ development but also a well-functioning immune system. While Dr Miriam Schmidts focuses on genetic developmental disorders, Professor Dr. Stephan Ehl studies genetic defects in the immune system that can lead to severe illnesses early in life.
Professor Dr. Stephan Ehl, Center for Chronic Immunodeficiency, University Medical Center Freiburg
Stephan Ehl, what biological mechanisms are you investigating in monogenic immune disorders, and what new insights have emerged regarding immune regulation?
As a paediatrician, I focus on children with inadequate or excessive immune responses. When genetic analysis reveals a defect in a signalling protein, we examine whether this amplifies or weakens immune signals. We use cell models to study how these changes affect immune cell behaviour and to test potential medications. Insights from rare genetic disorders often provide valuable clues for developing new treatments – including therapies for more common autoimmune diseases.
Why are these mechanisms particularly important for early immune development, and what processes are crucial to this?
A healthy immune system must both recognise pathogens and mount a rapid defence by activating and multiplying immune cells. Equally important is the system’s ability to limit this response to prevent excessive immune activity. Negative feedback mechanisms, which operate both inside and outside immune cells, prevent immune responses from spiralling out of control. If immune activation is impaired, severe infections may result. Conversely, if immune regulation fails, this can trigger chronic inflammation or autoimmune diseases, often as early as infancy.
Your research on SOCS1 insufficiency investigates genetic influences on immune signalling pathways. What role does signal transmission play in autoimmune processes, and what mechanisms have you identified?
Cytokines – the immune system’s messenger molecules – transmit information between immune cells. When cytokines bind to cell receptors, they trigger signals that regulate gene activity in the nucleus. The JAK/STAT pathway is particularly important in this process. This communication system activates Janus kinases (JAKs), which in turn control STAT proteins that regulate key immune genes. Over 30 different cytokines use this pathway. The SOCS1 molecule acts as a natural brake in this system, preventing excessive immune responses. Our current research shows that a SOCS1 deficiency – caused by genetic mutations – can result in uncontrolled cytokine signalling and excessive immune cell activation. This dysregulation can trigger over 30 different autoimmune conditions, often with multiple conditions affecting the same patient. Interestingly, only 60% of individuals with SOCS1 mutations develop symptoms, and 60% of those affected are women. This suggests that additional environmental or genetic factors are involved – a key focus of our ongoing research.
How does immunological research contribute to understanding congenital immune deficiencies and autoimmune diseases, and what treatment approaches arise from this?
Without fundamental immunological research, we would lack the knowledge framework to interpret rare genetic conditions. By understanding how specific mutations alter protein function, we can develop targeted therapies. For example, our research into SOCS1 insufficiency enabled us to introduce JAK inhibitors – drugs that selectively block excessive immune signalling. Previously, SOCS1 patients were treated with high-dose corticosteroids and other broad immunosuppressants, often causing severe side effects. In contrast, the new JAK inhibitor therapy offers targeted treatment and has provided new hope for patients who had long endured serious symptoms.