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.

Molecular Systems Engineering is a National Centre of Competence in Research (NCCR) funded by the Swiss National Science Foundation (SNSF), and headed by the University of Basel and the ETH Zurich. This NCCR combines expertise from chemistry, biology, physics, bioinformatics, and engineering. The overreaching aim is to develop tools and devices to monitor and manipulate off-equilibrium (bio)chemical systems. These may find applications in the synthesis of high added-value products, as innovative diagnostic tools and for the restoration of a desired cellular or organ function.

The NCCR Molecular Systems Engineering combines competences from life sciences, chemistry, physics, biology, bioinformatics and engineering sciences. More than 100 researchers and support personnel distributed into four work packages and 31 projects work together to address systems engineering challenges by integrating novel chemical and biological modules into molecular factories and cellular systems for the production of high added-value chemicals and applications in medical diagnostics and treatment. Molecular systems engineering relies on the combination of both chemical- and biological modules. In this approach, complex dynamic phenomena emerge as the result of the integration of molecular modules designed to interact in a programmed way with their complex environment. In this manner, it should be possible to create molecular factories and cellular systems whose properties are more than the sum of the attributes of the individual modules. The commitments of the leading houses, the University of Basel and ETH Zurich, also include new (joint) professorships, and extensive training of a new generation of scientists and technologists, leading to a long-term paradigm shift in molecular sciences and a new structure of the Swiss research landscape.