Personalized Medicine and Drug Development – Lauschke-lab

Background

The number of successful drug development projects has stagnated for decades, despite major breakthroughs in chemistry, molecular biology and genetics. Unreliable target identification and poor translatability of preclinical results have been identified as major causes of failure. To improve predictions of clinical efficacy and safety, interest has shifted from conventional 2D cultures to organotypic and microphysiological culture methods in which human cells can retain physiologically and functionally relevant phenotypes for extended periods of time. The Lauschke lab develops 3D cell culture models of primary human tissues and microfluidic devices for the discovery and development. By interfacing these systems with high-throughput screening, we aim to develop novel drug candidates for a variety of indications, including NASH, type 2 diabetes, COVID-19 and hemorrhagic fevers.

In addition, we integrate population-scale genomics with machine learning to optimize pharmacogenomic drug response predictions and facilitate the implementation of NGS in personalized medicine and precision public health.

Projects

Bioengineering of 3D primary human tissue models

We develop and characterize long-term stable 3D human tissue models of liver, pancreas, adipose tissue and skeletal muscle. Importantly, we exclusively use patient-derived cells, i.e. no cell lines or stem cells, and integration of histological, transcriptomic, proteomic and metabolomic signatures demonstrates that the tissue models feature mature phenotypes that facilitate improved result translation. A main area of our interests is the integration of different cell types (endothelial cells, immune cells, etc.) and the functional characterization of cell-cell interactions in both health and disease.

Micro and Nanofabrication for biomedical applications

Using state-of-the-art cleanroom tools, we leverage nanofabrication technologies for their implementation in biomedicine. Uniquely, we have established a novel nanofabrication platform, termed Nano Reaction Injection Molding (NanoRIM) for the rapid, versatile and cost-effective fabrication of polymer micro- and nanodevices. We further utilize micro- and nanopatterned surfaces to study the interaction of human cells with surface topographies.

We employ diverse materials, including polymers and inorganics, such as silicon and glass, with appropriate surface treatment for different biomedical applications. Specifically, we develop platforms for pharmacological and toxicological applications using materials with minimal drug absorption.

Development of microfluidic multi-organ co-culture chips

In the field of drug development and discovery, the poor predictive accuracy of preclinical models due to pronounced species differences has led to a high rate of project attrition. The co-culturing of human cells from different tissues and the subsequent tissue-tissue interaction in perfused microfluidic devices have shown great potential to tackle this problem in ex vivo.

By integrating our custom-designed microfluidic systems with 3D human tissue models, we have developed microphysiological organ-on-a-chip platforms with superior function that allow to mimic tissue-tissue interactions. Specifically, we integrate human 3D tissue models of liver, pancreas, adipose tissue and skeletal muscle, and utilize this platform as a model of integrative glycemic control.

Monitoring of intracellular signal transduction in primary human tissues

We monitor signaling of G protein-coupled receptors (GPCRs) and other signal transduction events in primary human tissue models using highly sensitive and selective bioluminescence resonance energy transfer (BRET)-based biosensors. The obtained information sheds new light on the functional selectivity and subcellular signaling of important signaling cascades without the need to overexpress the receptors. Employing such biosensor-based approaches to map signaling events in fine detail holds great promise for our understanding of drug efficacy and side effects. Combining these tools with patient-derived material will provide much needed insight into the intra- and inter-patient variability of drug action and offers the potential to develop better and more targeted therapies.

Hepatic spheroids as model system for liver regeneration

Strikingly, during spheroid aggregation stages, hepatocytes first dedifferentiate, followed by rapid redifferentiation, providing an ideal ex vivo experimental paradigm to study the full spectrum of differentiation state changes that occur in vivo during liver regeneration. Besides extending our mechanistic understanding, this finding opened possibilities for the development of therapeutic approaches as a substitute for orthotopic liver transplantations. We work on the establishment of protocols in which hepatocytes isolated from patients proliferate and, after cells sufficiently multiplied, are induced to redifferentiate into functional hepatocytes using our 3D spheroid culture system. Furthermore, we investigate the molecular mechanisms underlying liver hypertrophy and develop drug candidates that improve hepatocyte proliferation.

Evaluation of the importance of rare genetic variants on hepatic metabolism and drug response

Genetic variants primarily in drug and metabolite transporters, phase I and phase II drug metabolizing enzymes and nuclear receptors can influence drug response by modulating drug absorption, distribution, metabolism and excretion (ADME). Importantly, while in the past decades an ever-growing arsenal of genetic variants with demonstrated impacts on human drug response has been identified in these pharmacogenes, a substantial fraction of the heritable variability in drug response remains unexplained. Rare genetic variants that only occur in very few individuals and are hence missed in genome-wide association studies have been proposed to contribute to this missing heritability.

We integrate data from recent population-wide Next-Generation Sequencing (NGS) projects to quantify the extent of genetic variability in pharmacogenes on a population level and, using an arsenal of in silico techniques, quantify the impact on hepatic metabolism and pharmacokinetics and -dynamics.