ERC FUNDED PROJECTS

Demand for biofuels and other biologically derived commodities is growing worldwide as efforts increase to reduce reliance on fossil fuels and to limit climate change. Most commercial approaches rely on fermentations of organic matter with its inherent problems in producing CO2 and being in conflict with the food supply of humans. These problems are avoided if CO2 can be used as feedstock. Autotrophic organisms can fix CO2 by producing chemicals that are used as building blocks for the synthesis of cellular components (Biomass). Acetate-forming bacteria (acetogens) do neither require light nor oxygen for this and they can be used in bioreactors to reduce CO2 with hydrogen gas, carbon monoxide or an organic substrate. Gas fermentation using these bacteria has already been realized on an industrial level in two pre-commercial 100,000 gal/yr demonstration facilities to produce fuel ethanol from abundant waste gas resources (by LanzaTech). Acetogens can metabolise a wide variety of substrates that could be used for the production of biocommodities. However, their broad use to produce biofuels and platform chemicals from substrates other than gases or together with gases is hampered by our very limited knowledge about their metabolism and ability to use different substrates simultaneously. Nearly nothing is known about regulatory processes involved in substrate utilization or product formation but this is an absolute requirement for metabolic engineering approaches. The aim of this project is to provide this basic knowledge about metabolic routes in the acetogenic model strain Acetobacterium woodii and their regulation. We will unravel the function of “organelles” found in this bacterium and explore their potential as bio-nanoreactors for the production of biocommodities and pave the road for the industrial use of A. woodii in energy (hydrogen) storage. Thus, this project creates cutting-edge opportunities for the development of biosustainable technologies in Europe.

2 497 140 €

Start date: 2017-10-01, End date: 2022-09-30

During the last decade, the principles of biomineralization have increasingly attracted multidisciplinary scientific attention, not only because they touch the interface between the organic/inorganic world but also because they offer fascinating bioinspired solutions to notorious problems in the fields of biotechnology and medicine. However, only one group of animals has the necessary genetic/enzymatic toolkit to control biomineralization: siliceous sponges (Porifera). Based on his pioneering discoveries in poriferan molecular biology and physiological chemistry, the PI has brought biosilicification into the focus of basic and applied research. Through multiple trendsetting approaches the molecular key components for the enzymatic synthesis of polymorphic siliceous skeletal elements in sponges have been elucidated and characterized. Subsequently, they have been employed to synthesize innovative composite materials in vitro. Nonetheless, knowledge of the functional mechanisms involved remains sketchy and harnessing biosilicification, beyond the in vitro synthesis of amorphous nanocomposites, is still impossible. Using a unique blend of cutting-edge techniques in molecular/structural biology, biochemistry, bioengineering, and material sciences, the PI approaches for the first time a comprehensive analysis of natural biomineralization, from gene to biomineral to hierarchically ordered structures of increasing complexity. The groundbreaking discoveries expected will be of extreme importance for understanding poriferan biosilicification. Concurrently, they will contribute to the development of innovative nano-biotechnological and -medical approaches that aim to elicit novel (biogenous) optical waveguide fibers and self-repairing inorganic-organic bone substitution materials.

2 183 600 €

Start date: 2011-06-01, End date: 2017-05-31

Brain tumors represent an extremely heterogeneous group of more than 100 different molecularly distinct diseases, many of which are still almost uniformly lethal despite five decades of clinical trials. In contrast to hematologic malignancies and carcinomas, the cell-of-origin for the vast majority of these entities is unknown. This knowledge gap currently precludes a comprehensive understanding of tumor biology and also limits translational exploitation (e.g., utilizing lineage targets for novel therapies and circulating brain tumor cells for liquid biopsies). The BRAIN-MATCH project represents an ambitious program to address this challenge and unmet medical need by taking an approach that (i) extensively utilizes existing molecular profiles of more than 30,000 brain tumor samples covering more than 100 different entities, publicly available single-cell sequencing data of normal brain regions, and bulk normal tissue data at different times of development across different species; (ii) generates unprecedented maps of normal human CNS development by using state-of-the art novel technologies; (iii) matches these molecular portraits of normal cell types with tumor datasets in order to identify specific cell-of-origin populations for individual tumor entities; and (iv) validates the most promising cell-of-origin populations and tumor-specific lineage and/or surface markers in vivo. The expected outputs of BRAIN-MATCH are four-fold: (i) delivery of an unprecedented atlas of human normal CNS development, which will also be of great relevance for diverse fields other than cancer; (ii) functional validation of at least three lineage targets; (iii) isolation and molecular characterization of circulating brain tumor cells from patients´ blood for at least five tumor entities; and (iv) generation of at least three novel mouse models of brain tumor entities for which currently no faithful models exist.

1 999 875 €

Start date: 2019-05-01, End date: 2024-04-30

It is now widely accepted that tumors are composed of heterogeneous population of cells, which contribute to many aspects of treatment resistance observed in clinic. Despite the acknowledgment of the tumor cell heterogeneity, little evidence was shown about complexity and dynamics of this heterogeneity in vivo, mainly because of lacking flexible genetic tools which allow sophisticated analysis in primary tumors. We recently developed a very efficient mouse somatic brain tumor model which have a full penetrance of high grade glioma development. Combination of this model with several transgenic mouse lines allow us to isolate and track different population of cells in primary tumors, most importantly, we also confirmed that this can be done on single cell level. Here I propose to use this set of valuable genetic tools to dissect the cellular heterogeneity in mouse gliomas. First we will perform several single cell lineage tracing experiment to demonstrate the contribution of brain tumor stem cell, tumor progenitors as well as the relatively differentiated cells, which will provide a complete data sets of clonal dynamics of different tumor cell types. Second we will further perform this tracing experiment with the presence of conventional chemotherapy. Third we will perform single cell RNA sequencing experiment to capture the molecular signature, which determines the cellular heterogeneity, discovered by single cell tracing. This result will be further validated by analysis of this molecular signatures in human primary tumors. We will also use our established in vivo target validation approach to manipulate the candidate molecular regulators to establish the functional correlation between molecular signature and phenotypic heterogeneity. This project will greatly improve our understanding of tumor heterogeneity, and possibly provide novel approaches and strategies of targeting human glioblastomas.

2 000 000 €

Start date: 2015-06-01, End date: 2020-05-31