ERC FUNDED PROJECTS

Dietary fibres are recognized for their health promoting properties; nevertheless, many of the physicochemical mechanisms behind these effects remain poorly understood. While it is understood that dietary fibres can associate with small molecules influencing, both positively or negatively their absorption, the molecular mechanism, by which these associations take place, have yet to be elucidated We propose a study of the binding in soluble dietary fibres at a molecular level to establish binding constants for various fibres and nutritionally relevant ligands. The interactions between fibres and target compounds may be quite weak, but still have a major impact on the bioavailability. To gain insight to the binding mechanisms at a level of detail that has not earlier been achieved, we will apply novel combinations of analytical techniques (MS, NMR, EPR) and both natural as well as synthetic probes to elucidate the associations in these complexes from macromolecular to atomic level. Glucans, xyloglucans and galactomannans will serve as model soluble fibres, representative of real food systems, allowing us to determine their binding constants with nutritionally relevant micronutrients, such as monosaccharides, bile acids, and metals. Furthermore, we will examine supramolecular interactions between fibre strands to evaluate possible contribution of several fibre strands to the micronutrient associations. At the atomic level, we will use complementary spectroscopies to identify the functional groups and atoms involved in the bonds between fibres and the ligands. The proposal describes a unique approach to quantify binding of small molecules by dietary fibres, which can be translated to polysaccharide interactions with ligands in a broad range of biological systems and disciplines. The findings from this study may further allow us to predictably utilize fibres in functional foods, which can have far-reaching consequences in human nutrition, and thereby also public health.

1 500 000 €

Start date: 2016-04-01, End date: 2021-03-31

As nature’s first bioengineers, bacteriophages have evolved to modify, adapt and control their bacterial hosts through billions of years of interactions. Indeed, like modern synthetic biologists aspire to do, bacteriophages already evade bacterial silencing of their xenogeneic DNA, subvert host gene expression, and co-opt both the central and peripheral metabolisms of their hosts. Studying these key insights from a molecular systems biology perspective, inspired us to develop these evolutionary fully-adapted phage mechanisms as a next-level layer of synthetic biology tools. Thus, BIONICbacteria will provide conceptual novel synthetic biology tools that allow direct manipulation of specific protein activity, post-translational modifications, RNA stability, and metabolite concentrations. The goal of BIONICbacteria is to pioneer an unconventional way to perform synthetic biology, tapping an unlimited source of novel phage tools genetic circuits and phage modulators. To achieve these goals, we will apply and develop state-of-the-art technologies in molecular microbiology and focus on three principal aims: (1) To exploit new phage-encoded genetic circuits as synthetic biology parts and as intricate biotechnological chassis. (2) To build synthetic phage modulators (SPMs) as novel payloads to directly impact the bacterial metabolism in a targeted manner. (3) To create designer bacteria by integrating SPMs-containing circuits into bacterial strains as proof-of-concepts for applications in industrial fermentations and vaccine design. This proposed “plug-in” approach of evolutionary-adapted synthetic modules, will allow us to domesticate Pseudomonas strains in radically new ways. By building proofs-of-concept for applications in industrial fermentations and vaccine development, we address key problem in these areas with potentially high-gain solutions for society and industry.

1 998 750 €

Start date: 2019-09-01, End date: 2024-08-31

The rapidly changing climate puts commonly used crop plants under strong pressure. It is therefore essential to develop novel breeding technologies to rapidly enhance crops to better withstand newly emerging stresses. Interestingly, a clear link between transposable elements (TEs), crop improvement and varietal diversification exists. Furthermore, in recent years the importance of (TEs) in evolution and adaptation to stresses has been recognized. However the use of TEs in crop breeding is currently very limited because it is not possible to control TE mobility. My research group has identified a novel highly conserved epigenetic silencing mechanism that represses the activity of TEs in Arabidopsis. We also found drugs capable of inhibiting this mechanism. Because these drugs target highly conserved enzymes we were able to show that our drug treatment is also effective in rice. We are therefore able to produce TE bursts in a controlled manner in virtually any plant. We can thus, for the first time, generate and study TE bursts in crop plants in real time. More importantly, we found that the accumulation of novel insertions of a heat-stress inducible TE produced plants that, at a high frequency, were more resistant to heat stress. This suggests that the stress that was initially applied to activate a specific TE in the parent, lead to an improved tolerance to that specific stress in the progeny of that plant in a very straight-forward manner. In this project I propose to accelerate plant breeding by testing and implementing a revolutionary TE-directed crop improvement technology. For that I plan to 1. Mobilize TEs in crop plants using selected stresses 2. Using these mobilized stress-responsive TEs breed novel crop plants resistant to those selected stresses and 3. Study the genetic and epigenetic impact of TE mobilization on host genomes. This project will have a broad impact on crop improvement and on the basic understanding of the evolutionary importance of TEs.

1 965 625 €

Start date: 2017-06-01, End date: 2022-05-31

Finely orchestrated protein activities are at the heart of the most fundamental cellular processes. The rational and structure-based design of novel functional proteins holds the promise to revolutionize many important aspects in biology, medicine and biotechnology. Computational protein design has led the way on rational protein engineering, however many of these designed proteins were solely focused on structural accuracy and completely impaired of function. DeNovoImmunoDesign proposes novel computational design strategies centered on the exploration of de novo protein topologies and the use of structural flexibility with the ultimate goal of designing functional proteins. The proposed methodologies aim to solve a prevalent problem in computational design that relates to the lack of optimal design templates for the optimization of function. By expanding beyond the known protein structural space, our approaches represent new paradigms on the design of de novo functional proteins. DeNovoImmunoDesign will leverage our new methodologies to design functional proteins with rational approaches for two crucial biomedical endeavors - vaccine design and cancer immunotherapy. Our strategy for vaccine design is to engineer structure-based epitope-focused immunogens to elicit potent neutralizing antibodies – a requirement for vaccine protection. The underlying basis of cancer immunotherapy is the inhibition of key protein-protein interactions - an arena where rational design is lagging. To meet this central need we will develop innovative approaches to design new protein binders for cancer immunotherapy applications. DeNovoImmunoDesign is a multidisciplinary proposal where computation is intertwined with experimentation (biochemistry, structural biology and immunology). Our unique competences and groundbreaking research have all the components to translate into transformative advances for both basic and applied biology through innovations in rational protein design.

1 695 489 €

Start date: 2017-03-01, End date: 2022-02-28