UNIverse - Public Research Portal
Profile Photo

Prof. Dr. Michael Nash

Department of Chemistry
Profiles & Affiliations

Projects & Collaborations

13 found
Show per page
Project cover

MechanoBody

Research Project  | 1 Project Members

Directing nanoscale particles to strongly adhere to cancer cells and tissues under hydrodynamic flow in vivo is a challenging biophysical problem with important clinical implications. A common approach uses antibodies conjugated to nanoparticles to impart binding specificity, however, when exposed to mechanical shear stress antibodies are known to unbind at extremely low forces (<150 pN)1-3. This problem can occur even when antibodies are selected for high-affinity (e.g., KD < 1 nM) interactions at equilibrium. The goal of this research is therefore to engineer artificial binding proteins that form mechanically stable complexes with their target ligands for applications in nanoparticle-based drug delivery and bioimaging. I will focus on non-antibody (nAb) binding scaffolds (e.g., anticalin, affibody and DARPin) that will be optimized through two disparate yet complementary approaches: (1) geometrics and (2) genetics. By mechanically enhancing binding interactions, I will pioneer a new paradigm in the molecular engineering field called 'MechanoBodies' that will enable enhanced labelling and cargo delivery to cells under high shear stress.

Project cover

Exploring Sequence-Function Landscapes of Therapeutic Enzymes using Single-Cell Hydrogel Encapsulation and Deep Sequencing

Research Project  | 3 Project Members

The pharmaceutical industry is rapidly transitioning from small molecule therapeutics towards biologics. Among the various classes of biologics under development, therapeutic enzymes are gaining attention as molecular entities that can catalyze specific chemical reactions in the body to achieve a therapeutic effect. Therapeutic enzymes can be delivered systemically as full proteins or incorporated into gene therapies to transduce target cells with specific functionality in vivo. In these envisioned applications, understanding sequence-function relationships of therapeutic enzymes will play a crucial role. There is therefore an urgent need for improved methods for molecular analysis and enhancement of therapeutic enzymes. Naturally occurring enzyme sequences are typically not suitable as biopharmaceuticals due to general lack of stability, developability, and/or activity. In this context, molecular enhancement by improvement of colloidal stability, catalytic turnover rate, substrate binding affinity, and/or sensitivity to environmental conditions are essential steps in enabling therapeutic enzymes to reach their full potential. The establishment of rapid design, build, test, and learn (DBTL) cycles and the analysis of large-scale sequence-function relationships for therapeutic enzymes will be crucial for the advancement of leading therapeutic strategies.The Nash Lab at the University of Basel/ETH Zurich focuses on engineering and biophysics of artificial biomolecular systems. We recently developed an ultrahigh throughput enzyme screening strategy that outperforms multi-well robotic assays and automation by several orders of magnitude. We are now able to screen genetic libraries of catalytic enzymes using a one-pot reaction followed by fluorescence activated cell sorting (FACS). Our system is based on localized enzyme-triggered polymerization of a hydrogel capsule around individual yeast cells. Our goal is to utilize the ultrahigh throughput nature of this system to analyze sequence-function landscapes of enzymes on an unprecedented scale.

Project cover

CatchGel - Catch Bond Cross-linked Hydrogels

Research Project  | 1 Project Members

Exploiting Nature's architectures for the development of responsive materials has long been a high impact area of research. However, Nature's exquisite design is rarely equalled in synthetic systems and the unique mechanical behaviour of certain bacterial and cellular adhesins, and their receptor-ligand (RL) complexes, is no exception. The adhesive properties of these RL complexes are of particular interest in the development of mechanically adaptable materials. The observed increase in adhesive strength at low tensile force (catch bonds), followed by a decrease at higher shear stress (slip bonds), could lead to classes of materials with extraordinary mechanical properties. By transplanting these RL complexes into polymeric networks, materials with truly variable mechanical properties with respect to applied stress could be developed. While catch bonds have been observed in both cellular and bacterial RL complexes, bacterial systems are of particular interest in the planned research. The potential of the receptor unit to adhere both environmental bacteria and the adhesin ligand, should impart the newly developed materials with the ability to self-clean when developed in cooperation with anti-bacterial polymers. Mechanical modulation, combined with self- cleaning properties, is infinitely applicable in the biomedical materials field. However, these goals are filled with limitations, which the current research plans to overcome. The complexity of intermolecular interactions in biological systems, further complicated by the size of adhesin proteins, make understanding and manipulating interactions extremely difficult. The planned research aims to break down the complexity of transferring behaviour from biological molecules into macroscale materials by investigating the intramolecular interactions across a range of length scales as the research progresses from the molecular to the macroscale. This should be achieved by combining single molecule analysis techniques, particularly single molecule force spectroscopy (SMFS), with chemical modification strategies, macroscale materials characterisation and supramolecular polymer chemistry. Examining how properties change as environmental complexity increases will allow more accurate development and manipulation of responsive biomimetic materials and greater understanding of the nano-macroscale relationships of complex multiphase systems. The objective of the proposed research is to obtain polymeric hydrogels whose assembly is controlled by RL complexes derived from bacterial adhesins and their substrates. In achieving this, a fundamental understanding of bacterial RL complexes and their behaviour as the complexity of their environment increases from biological molecules to synthetic macroscale materials will be gained.