ERC FUNDED PROJECTS

My proposal aims to take advantage of my ground-breaking finding that it is possible to mature, or activate, the [FeFe] hydrogenase enzyme (HydA) using synthetic mimics of its catalytic [2Fe] cofactor. (Berggren et al, Nature, 2013) We will now explore the chemistry and (bio-)technological potential of the enzyme using an interdisciplinary approach ranging from in vivo biochemical studies all the way to synthetic model chemistry. Hydrogenases catalyse the interconversion between protons and H2 with remarkable efficiency. Consequently, they are intensively studied as alternatives to Pt-catalysts for these reactions, and are arguably of high (bio-) technological importance in the light of a future “hydrogen society”. The project involves the preparation of novel “artificial” hydrogenases with the primary aim of designing spectroscopic model systems via modification(s) of the organometallic [2Fe] subsite. In parallel we will prepare in vitro loaded forms of the maturase HydF and study its interaction with apo-HydA in order to further elucidate the maturation process of HydA. Moreover we will develop the techniques necessary for in vivo application of the artificial activation concept, thereby paving the way for a multitude of studies including the reactivity of artificial hydrogenases inside a living cell, but also e.g. gain-of-function studies in combination with metabolomics and proteomics. Inspired by our work on the artificial maturation system we will also draw from our knowledge of Nature’s [FeS] cluster proteins in order to prepare a novel class of “miniaturized hydrogenases” combining synthetic [4Fe4S] binding oligopeptides with [2Fe] cofactor model compounds. Our interdisciplinary approach is particularly appealing as it not only provides further insight into hydrogenase chemistry and the maturation of metalloproteins, but also involves the development of novel tools and concepts applicable to the wider field of bioinorganic chemistry.

1 494 880 €

Start date: 2017-02-01, End date: 2022-01-31

Through smart technology, we are overwhelmed with new information. Does this unlimited access to knowledge make us smarter? One of the key challenges for modern societies is to understand how the brain assembles our rich inventory of knowledge. Here, I will test the hypothesis that newly acquired knowledge is represented in the hippocampal formation in neural concept spaces, which are based on the coding principles and representational structures of the neural machinery involved in spatial navigation. The key idea is that the brain’s navigation system provides the building blocks of a neural metric for knowledge. In this groundbreaking cognitive neuroscience framework, I will bridge and integrate principles from Nobel Prize awarded neurophysiology and concepts from cognitive science and philosophy. Partly building on my ERC-StG project in which I discovered the core neural mechanisms underlying reconfiguration, integration and scaling of memory networks, the aim of my proposal is two-fold: 1. I seek to decipher neural concept spaces and unravel the neural codes of a cognitive geometry for knowledge and its deformations. 2. I will provide a proof-of-principle framework for next-generation neurocognitive technology and neural user models for cognitive enhancement to edit memories and engineer knowledge. Novel ‘Wikipedia’ learning tasks will be combined with state-of-the-art pattern analyses of space-resolved fMRI and time-resolved MEG to map and quantify representational structures. I will further develop AI-inspired analyses and closed loop brain-computer interfaces to perturb and edit neural concept space. The integrative mission of my program, from cells to systems-level involvement in cognition and to technology, opens up the exciting possibility to lay the ground for redefining cognitive neuroscience of knowledge by unravelling the fundamental neural principles of a cognitive topography and to make critical translations to empower smart brains in a smart society.

2 000 000 €

Start date: 2017-05-01, End date: 2022-04-30

Mitochondria and mitochondrial function have gained increased attention within a wide range of clinical and scientific specialities, but exactly how mitochondria impact the rest of the cell is less well understood. Not only are mitochondria implicated in a range of rare genetic disorders, but dysfunction of mitochondria or reduced bioenergetic capacity has been associated with common diseases including cancer, heart failure, neurodegeneration and diabetes mellitus, as well as natural ageing. It is becoming increasingly clear that mitochondrial dysfunction is not only a downstream event in these conditions, but plays an important role in disease progression and pathology. S-adenosylmethionine (SAM) is the dominant methyl group donor within our cells, required for a diverse set of post-translational modifications, nucleotide methylations or the synthesis of co-factors and metabolites. Mitochondria play an important part in SAM synthesis, and mitochondrial function has recently been shown to influence cellular methylation. Approximately 30% of the cellular SAM pool is located within mitochondria, advocating a central role for mitochondria in cellular methylation. The advancements in genome sequencing techniques, unprecedented depth of modern mass spectrometry analyses and our possibility to efficiently generate model systems, provides a rare opportunity to comprehensively study the role of both SAM and mitochondria in health and disease. This project plan describes the genetic, molecular, metabolic and proteomic analysis of fruit fly and mouse models with mitochondrial dysfunction and disrupted intra-mitochondrial SAM levels to identify the mitochondrial methylome, its relevance towards other cellular functions and its impact on the epigenetic control of gene regulation. My extensive research on mitochondrial function, as well as working as a physician with patients suffering from inborn errors of metabolism gives me a unique perspective in this project.

1 499 999 €

Start date: 2017-04-01, End date: 2022-03-31