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Chemical Reaction Networks: signal amplification, spatiotemporal control, and materials

Periodic Reporting for period 1 - CReaNet (Chemical Reaction Networks: signal amplification, spatiotemporal control, and materials)

Reporting period: 2019-04-01 to 2021-03-31

This European Training Network (ETN) entitled “Chemical Reaction Networks: Signal amplification, spatiotemporal control, and materials” (CReaNet) will train 15 bright early-stage researchers (ESRs) on the emerging topic of chemical reaction networks (CRNs). It brings together six excellent academic research groups and four awardwinning non-academic beneficiaries that will prepare the students using a training-through-research philosophy, and will let them acquire intersectoral (i.e. academic and industrial) experience. Physical Chemistry, Biochemistry, Physics, and Engineering are all of key importance in CReaNet, guaranteeing a highly multidisciplinary education of our ESRs.

CReaNet is the action to break down existing barriers between the academic and non-academic sectors to realise the full potential of research for the benefit of the economy and society. The Network will promote close collaboration and exchange of intellectual resources between the sectors, which will provide pathways to ensure immediate commercialisation of any new technology or materials developed by the Network. In addition, our programme will strengthen the collaborative links on CRNs and dynamic materials to provide Europe with a competitive advantage, taking the lead in Systems Chemistry and non-equilibrium materials, while at the same time training ESRs to be competitive at the frontier of this emerging research field, and become future leaders with career opportunities in the public and private sector.

The long-term scientific goal of CReaNet is to develop biocompatible Chemical Reaction Networks (CRNs) for signal amplification and novel (bio)materials. To this end we will study CRNs in homogeneous environments, then add diffusion to the CRNs to yield spatiotemporal behaviour, and finally, integrate CRNs into materials to obtain life-like properties.
To push the frontiers of CRN-based autonomous and dynamic materials of we have assembled a team of beneficiaries with complementary skills in synthesis and self-assembly (TU Delft, ALU-FR, WEIZMANN, UNISTRA), microfluidics (ELVESYS, CHALMERS, UNISTRA), mathematical modelling (USFD), surface science (IBM), and detection (NANOT, NFI). The proposed research is developed along three highly intertwined lines, represented by three WP (Fig. 1), where CRNs are always at the basis:

• In WP1 we use CRNs in homogeneous environments, so only the chemical kinetics are of importance to get so-called emergent temporal properties such as oscillations, bistability or ultrasensitivity.

•In WP2 we add diffusion and localised chemical modifications to the CRNs leading to systems with spatiotemporal behaviour, due to reaction–diffusion instabilities.

• In WP3 we combine CRNs, diffusion, and supramolecular systems to result in a novel class of biomaterials with (chemo)mechanochemical properties, similar to those found in a living system such as for example the actin-based cytoskeleton.
In the first project phase, the CReaNet consortium performed detailed screening and recruiting process to find 15 excellent PhD candidates to be employed in the project as early-stage researchers (ESRs). To each ESR one of the beneficiaries has been assigned as a supervisor. ESRs will carry out research on the individual projects within specific WP.

ESR1.1 CRN in core-shell microbeads for ultrasensitive chemical amplification
Lead: NFI

ESR1.2 Zeroth–order ultrasensitivity in a kemptide phosphorylation/dephosphorylation CRN

ESR1.3 Simulations of CRNs for signal detection and amplification
Lead: USFD

ESR1.4 Cascading CRN to achieve surface acoustic wave detected ELISA

ESR2.1 Spatiotemporal control over CRNs using coupled on-chip µCSTRs

ESR2.2 Spatiotemporal reaction control using connected liposomes

ESR2.3 Photopatterned spatiotemporal enzymatic cascade reactions
Lead: ALU-FR

ESR2.4 Modelling of spatiotemporal instabilities in biocatalytic CRNs with feedback
Lead: USFD

ESR2.5 Altering CRNs with photoresponsive nanoparticles

ESR2.6 Reaction cascades coupled to surface-chemical nanoscale patterns
Lead: IBM

ESR3.1 Supramolecular materials with feedback control of CRNs
Lead: TU Delft

ESR3.2 Supramolecular gels controlled by phosphorylation/dephosphorylation CRNs

ESR3.3 Transient pH-profiles and hydrogels through engineered chemo-mechanical feedback
Lead: ALU-FR

ESR3.4 Triggered catalysts to make responsive active materials
Lead: TU Delft

ESR3.5 Active materials fuelled by carbon dioxide
CRNs are ubiquitous in biochemical systems and serve a range of complex biological functions such as signaling, protein synthesis, and homeostasis. Such CRNs operate necessarily in dissipative non-equilibrium states and are orchestrated by feedback loops. CRNs are often sustained by the consumption of chemical energy (e.g. ATP or GTP hydrolysis) dissipated in the form of heat, and have non-zero (cycle) fluxes. Since CRNs operate far-from-equilibrium, they can give rise to instabilities that result in complex emergent behavior such as oscillations, multistability, ultrasensitivity, amplification, excitability, quorum sensing, and pattern formation. Recently, a bottom-up approach is ongoing in the field of synthetic biology, where minimal functions are being reproduced in vitro using CRNs consisting of natural building blocks. CReaNet takes an approach in that biocompatible CRNs will be developed with tuneable positive/negative feedback mechanisms that allow the desired function to be programmed a priori. This approach will provide the design tools to develop novel and improved (bio)materials, with unprecedented functionalities.
The CReNet will strengthen Europe’s innovation capacity by establishing a critical mass of scientists in an emerging area of research with knowledge currently scattered across Europe. The Network brings together a diverse team of people with diverse expertise united under the common, strategically relevant technology theme of chemical reaction networks. Despite the diversity, their research interests overlap to allow for productive collaborations and synergy, which is required for the challenges of the proposed research. The Network has a broad scope and ambitious goals; hence, previously non-interacting partners have been included to elevate the research in this field to the next level, and define the state of the art. The outlined objectives can only be reached through the concerted efforts of the critical mass of researchers that will become possible by the establishment of this ETN. Moreover, through a conceptually structured yet operationally flexible framework for research, training, and professional development, this Network will provide a unique professional profile to a new generation of young scientists, which will enable them to successfully compete for the most attractive employment opportunities in the academic and non-academic sectors, and provide inspiration for entrepreneurial activities. The Network unites leading EU scientists in the fields of (bio)chemistry, biophysics, nanoscience, analytical theory, and microfluidics who have the goal to push the boundaries of the current state-of-the-art, and in this process teach their approaches, methods, and reflections to the ESRs, involve them actively, and provide them with a challenging atmosphere.
Fig.1. Overview of CReaNet: Goals, WPs, participants, and secondments