ERC FUNDED PROJECTS

Today, our daily diet typically contains dozens of food additives (e.g. colours, emulsifiers, sweeteners: ~350 substances allowed on the EU market). Safety assessment is performed by health agencies to protect consumers against potential adverse effects of each additive, yet such an assessment is only based on current available evidence, i.e., for most additives, only in-vitro/in-vivo toxicological studies and exposure simulations. Meanwhile, the long-term health impact of additives intake and any potential ‘cocktail’ effects remain largely unknown and have become a source of serious concern. Growing evidence link the consumption of ultra-processed foods, containing numerous additives, to adverse health outcomes, in particular our recent results on cancer (Fiolet BMJ 2018). While most additives allowed in the EU are likely to be neutral for health and some may even be beneficial, recent animal and cell-based studies have suggested detrimental effects of several such compounds. In humans, data is lacking. No epidemiological study has ever assessed individual-level exposure to a wide range of food additives and its association with health, hampered by unsuited traditional dietary assessment tools facing the high additive content variability across commercial brands. Hence, a major breakthrough will come from the novel and unique tools I developed with my team, notably within the NutriNet-Santé cohort (n=164,000), collecting precise and repeated data on foods and beverages usually consumed, including names and brands of industrial products. With this unique resource, I propose a project at the forefront of international research to provide answers to a question of major importance for public health. Built as a combination of epidemiological studies and in-vitro/in-vivo experiments, this project will shed light on individual exposure to food additive 'cocktails' in relation to obesity, cancer, cardiovascular diseases and mortality, while depicting underlying mechanisms.

2 000 000 €

Start date: 2020-05-01, End date: 2025-04-30

Replacement of petrochemistry by bio-based processes is key to sustainable development and requires microbes equipped with novel-to-nature capabilities. The efficiency of such engineered microbes strongly depends on their native metabolic networks. However, aeons of evolution have optimized these networks for fitness in nature rather than for industrial performance. As a result, central metabolic networks are complex and encoded by mosaic microbial genomes in which genes, irrespective of their function, are scattered over the genome and chromosomes. This absence of a modular organization tremendously restricts genetic accessibility and presents a major hurdle for fundamental understanding and rational engineering of central metabolism. To conquer this limitation, I introduce the concept of ‘pathway swapping’, which will enable experimenters to remodel the core machinery of microbes at will. Using the yeast Saccharomyces cerevisiae, an industrial biotechnology work horse and model eukaryotic cell, I propose to design and construct a microbial chassis in which all genes encoding enzymes in central carbon metabolism are relocated to a specialized synthetic chromosome, from which they can be easily swapped by any – homologous or heterologous – synthetic pathway. This challenging and innovative project paves the way for a modular approach to engineering of central metabolism. Beyond providing a ground-breaking enabling technology, the ultimate goal of the pathway swapping technology is to address hitherto unanswered fundamental questions. Access to a sheer endless variety of configurations of central metabolism offers unique, new possibilities to study the fundamental design of metabolic pathways, the constraints that have shaped them and unifying principles for their structure and regulation. Moreover, this technology enables fast, combinatorial optimization studies on central metabolism to optimize its performance in biotechnological purposes.

2 149 718 €

Start date: 2015-09-01, End date: 2020-08-31

Our ability to predict adaptation and the response of populations to selection is limited. Solving this issue is a fundamental challenge of evolutionary ecology with implications for applied sciences such as conservation, and agronomy. Non genetic inheritance (NGI; e.g., ecological niche transmission) is suspected to play a foremost role in adaptive evolution but such hypothesis remains untested. Using quantitative genetics in wild plant populations, experimental evolution, and epigenetics, we will assess the role of NGI in the adaptive response to selection of plant populations. The ANGI project will follow the subsequent research program: (1) Using long-term survey data, we will measure natural selection in wild populations of Antirrhinum majus within its heterogeneous array of micro-habitats. We will calculate the fitness gain provided by multiple traits and stem elongation to plants growing in bushes where they compete for light. Stem elongation is known to depend on epigenetic variation. (2) Using a statistical approach that we developed, we will estimate the quantitative genetic and non genetic heritability of traits. (3) We will identify phenotypic changes caused by fitness that are based on genetic variation and NGI and assess their respective roles in adaptive evolution. (4) In controlled conditions, we will artificially select for increased stem elongation in clonal lineages, thereby excluding DNA variation. We will quantify the non genetic response to selection and test for a quantitative epigenetic signature of selection. (5) We will build on our results to generate an inclusive theory of genetic and non genetic natural selection. ANGI builds on a confirmed expertise in selection experiments, quantitative genetics and NGI. In addition, the availability of survey data provides a solid foundation for the achievement of this project. Our ambition is to shed light on original mechanisms underlying adaptation that are an alternative to genetic selection.

1 999 970 €

Start date: 2016-03-01, End date: 2022-02-28

The frightening increase in antibiotic drug resistance is threatening global healthcare as we know it. To this extent the World Health Organisation that has classes M. tuberculosis and Gram-negative nosocomial infections as the highest priority for novel R&D strategies. A major obstacle to drug discovery programs is to design inhibitors that can efficiently enter into bacteria. One such stealth strategy is exemplified by natural siderophore-antibiotics conjugates (sideromycins) that piggyback the bacterial iron acquisition machinery to enter bacteria. This Trojan-horse strategy has inspired the chemical synthesis of numerous sideromycin conjugates, with cefiderocol a current preclinical candidate. Despite the advances in this field, natural examples of sideromycins are still scarce, and finding new examples may provide further insight into siderophore antibiotic formation and delivery. ANTIBIOCLICKS will investigate a unique bioinspired conjugation chemistry that has been uncovered from a newly discovered natural sideromycin. This natural “click” chemistry is ideal for the coupling of catecholate containing siderophores (such as those of the WHO prioritised M. tuberculosis, A. baumannii, E. coli, P. aeruginosa and K. pneumonia) to antibiotics or other molecules. This project will aim to define the exact chemical mechanism behind this novel and surprisingly simple conjugation reaction, and use this unique and facile chemistry to generate a combinatorial library of siderophores with antibiotics and fluorophores. These products will subsequently be used to probe the exact mechanism of bacterial sideromycin uptake, potential intracellular decoupling and target engagement. Finally, the antibiotic and diagnostic potential of the generated siderophore conjugates will be evaluated. To this extent, ANTIBIOCLICKS will provide illuminating insight into new bioinspired conjugation chemistry, and evaluate its potential for novel bacterial therapeutics and diagnostics.

2 000 000 €

Start date: 2020-09-01, End date: 2025-08-31