The overarching research goal in the Mayer Lab is to apply our passion for biophysics towards improving human health. We do so by contributing to the molecular understanding of disease, developing sensitive diagnostic assays and sensors, as well as characterizing individual protein molecules for applications in biomarker detection, routine protein analysis, personalized medicine, and proteomics. To this end, we often take inspiration from nature to develop biophysical assays, methods, and tools that enable molecular-scale interrogations with unprecedented information content, sensitivity, and speed.
For instance, we are interested in the role of misfolded proteins in damaging the membranes of nerve cells. This damage is thought to contribute to neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Prion disease. One challenge is that misfolded proteins aggregate and from particles in all sizes and shapes. This heterogeneity renders established analytical techniques inadequate for characterizing these samples. What is worse, the size and shape of these protein aggregates influence their propensity to damage membranes and to kill neurons – aggregates of intermediate size are more toxic than smaller and larger ones. We are developing single molecule tools for rapid characterization of protein aggregates in solution and, based on the ensuing insight, we are exploring the role of different aggregates on membrane damage and neurotoxicity, taking advantage of recent breakthroughs in electrical and optical characterization of the membrane potential of hundreds of living nerve cells in parallel.
Another research focus explores the effect of transmembrane voltage on membrane proteins that are typically not thought to respond to electric fields. Examples of such proteins are the ATP-driven transport proteins responsible for resistance of cancer cells to chemotherapy. These proteins recognize anti-cancer drugs and pump them out of cancer cells, contributing to failure of cancer therapy. To interrogate these efflux pumps, the challenge lies in developing assays that maintain defined membrane potentials in live cells over long periods and distinguish between active efflux activity by these proteins and artifacts such as leaks through their membranes. Our ultimate goal in this research is to monitor the activity of transport proteins on a single molecule level to better understand the effect of pharmaceutical compounds and drug candidates on these efflux pumps.
The Mayer lab also applies the dynamic behavior of single molecules in electric fields to develop ultra-sensitive, multi-dimensional analyses of proteins in mixtures. Electric fields induce drag and torque on proteins, which are related to the protein’s charge and dipole moment. Examining the passage of proteins through pores that are on the size scale of the proteins themselves, makes it possible to measure, simultaneously and in real time, the size, shape, charge, dipole, an rotational diffusion coefficient of single proteins or protein aggregates. Furthermore, the nanoscale sensing zone inside such a nanopore transiently separates individual proteins from other macromolecules in solution, making it possible to interpret the acquired signal in a mixture. This approach is amenable to studying conformational dynamics of single proteins in solution. Ultimately, we envision that this five-dimensional fingerprinting of proteins will compete with established ensemble approaches of one- and two-dimensional protein analyses. We propose that characterizing, identifying, and counting individual proteins has the potential to impact routine protein analysis, biomarker detection, structural biology, and proteomics.
Research in our group is multidisciplinary and collaborative. For instance, we work with computational experts to apply molecular dynamics simulations and advanced statistical methods for data analysis and interpretation. We also interact closely with experts in physical organic chemistry to synthesize tailor-made proteins and small molecules that enable systematic studies of protein and lipid function in living systems. In this context, we are particularly interested in solutions to biological problems and challenges that evolved in extremophile organisms. These life forms thrive in solutions of concentrated salts and acids or at temperatures of 100°C. Apart from our desire to understand the survival strategies of these organisms, we apply the resulting insight to develop autonomic and robust sensor materials that mimic the signal amplification and power generation of living systems.