Technology Network Precision Organoid Engineering for Multi-Organ Interaction Studies (POEM)

The in-depth understanding of disease mechanisms requires research in clinically relevant and reproducible models, to uncover routes towards treatment of organ dysfunction such as cardiovascular disease, neurological disorders or cancer. Human organoid models are increasingly gaining predictive value in drug approval ("FDA Modernization act 2.0"), and human cell-derived organoid and assembloid research offers attractive avenues towards patient-specific diagnostics and new personalized treatment options. Current challenges, however, derive from incomplete representation of cellular complexity using existing patient-derived (stem) cell protocols, the inability to induce necessary differentiation and maturation, and the lack of multi-organ models to approximate in vivo organ-organ interactions. Further, heterogeneity, low complexity, immaturity and reproducibility in organoids, limitations in the materials supporting tissue growth, such as mouse-derived Matrigel, lack of perfusion and lengthy maturation processes required for modeling adult human tissues impose substantial limitations in reliable models. Therefore, novel, synthetic, and automated organ-on-a-chip approaches with high-throughput capabilities are needed to provide an in-depth understanding of disease mechanisms and reproducibly testable therapeutic avenues via organ-on-a-chip. The POEM PIs aim to develop novel bio-engineering approaches to build and interrogate organoids and (multi-)organ assembloids and to combine these with machine-learning enhanced automatized and parallelized screening to provide tailored disease models with unprecedented reproducibility as well as new mechanistic insight. Reproducible and cost-efficient, engineering-based clinically relevant disease model systems will be developed through a cross-disciplinary program to contribute to 3R and high-quality standards for non-animal drug testing.

The participating scientists are experts in organoid / assembloid, microtissue and organ biology, including for clinically relevant questions, bio-engineering, microfluidic lab-on-chip design, integrated photonics and machine learning.

The Backs group studies cardiovascular diseases and discovered lipid droplet- associated proteins as essential cardioprotective components to control pathological gene expression in systolic heart failure and in cardiometabolic disease. The group pioneered a mouse model for stress-induced Takotsubo syndrome, leading to a clinical trial testing of Cyclosporin A. The group’s insights are advancing heart tissue engineering and therapeutics, therapeutic exploitation within the startup Revier Therapeutics is underway.

The Boutros and Ebert groups established a high-throughput workflow for creating organoid cultures from gastrointestinal cancer patients, including patient recruitment, biopsy, and organoid propagation. They developed a drug profiling pipeline for these PDO models, enabling the testing of over 500 compounds, assessing viability and morphological changes. Their research, including a PDO biobank, explores MEK inhibition, Wnt activity, and gene signatures related to stemness and cancer relapse. 

The Dobreva group studies cardiovascular progenitor specification, expansion, and differentiation into various cardiac cell types, which foster the further development and optimization of organoids that faithfully recapitulate in vivo cardiogenesis. Using these in vitro systems, the group also explores how genes and environmental cues collaborate to shape cardiovascular development and function. The group’s research delves into the interplay of genes, environmental factors, and epigenetic mechanisms like nuclear lamins and RNF20, in influencing cell fate and aging.

The Freichel group focuses on ion channels within cellular membranes and acidic organelles, studying their impact on Ca²⁺ signaling in the cardiovascular system and their role in diseases like arrhythmias and cardiac remodeling, for which therapeutic approaches are currently exploited in the group’s Spin-Off „CalTIC“. The group’s work includes developing genome editing techniques for precise DNA insertion into the mouse genome, supporting preclinical disease models. They are establishing a Genome Engineering platform with support from the Health + Life Science Alliance Heidelberg Mannheim.

The Kuner group focuses on chronic pain mechanisms, uncovering key molecular pathways in sensory neuron dysfunction and brain circuitry. They explore cancer pain through bilateral interactions between tumor cells and sensory neurons, revealing neurodevelopmental mechanisms as causative, such as Wnt, VEGF and semaphorin- plexin signaling. Their findings serve as a basis for ongoing work on patient-derived tumor organoids, cultured alone or together with sensory neuron organoids to understand how tumor cells invade and exploit sensory nerves for metastasis, nutrition and shelter from chemotherapy. 

Katrin Schrenk-Siemens specializes in producing functional human pluripotent stem cell-derived peripheral and central neurons, focusing on nociceptor-like sensory neurons expressing TRPV1. Recent findings show these neurons form synapses with CNS-like glutamatergic neurons, mirroring in vivo interactions. Schrenk-Siemens utilizes microfluidic devices to study neuron and glia interactions under various conditions.

The Mall group leverages stem cell and cell fate engineering to explore human development and diseases, notably through neuronal reprogramming. Their pioneering human stem cell model for autism, linked to MYT1L mutations, has identified potential treatments currently tested in patients. Their use of CRISPR and organoids illuminates neurodevelopmental disorders and tumor-neuron interactions, emphasizing the clinical potential of their human disease models.

The Melde and Fischer groups have developed new technologies for the use of ultrasound to enable the in-situ trapping and manipulation of particles and cells using acoustic fields, and their groups have recently demonstrated the first compact assembly of 3D structures using holographic sound field techniques. The groups are internationally known for the invention of the acoustic hologram. Another recognized expertise lies in the field of microsystems and nanorobotics.

The Pernice group investigates nanophotonic circuitry, photonic computing, and quantum photonics, marking significant advances in brain-inspired optical computing and machine learning. Operating cutting-edge nanomanufacturing facilities, the group pioneered hybrid photonic architectures, including innovative 2D-3D integration techniques and biohybrid architectures.

The Selhuber-Unkel group specializes in biophysics and biomaterials, focusing on controlling 3D cell cultures through two-photon laser printing, mechanical stimulation, force microscopy, and nanoindentation. They excel in manipulating cancer spheroids and organoids with precise, dynamic changes, employing switchable microfluidic systems and microactuating materials for targeted interventions in 3D cell environments.

The Wittbrodt group is internationally leading in CRISPR-based genome engineering, developing high-performance Cas9 protein modifications, precise nucleotide changes, advanced base-editing, and large DNA insertions to model human patient alleles, generate reporters, and drive genetic effectors.