ERC FUNDED PROJECTS

Identifying risk factors for diseases that can be prevented or delayed by early intervention is of major importance, and numerous genetic, lifestyle, anthropometric and clinical risk factors were found for many different diseases. Another source of potentially pertinent disease risk factors is the human microbiome - the collective genome of trillions of bacteria, viruses, fungi, and parasites that reside in the human gut. However, very few microbiome disease markers were found to date. Here, we aim to develop risk prediction tools based on the human microbiome that predict the likelihood of an individual to develop a particular condition or disease within 5-10 years. We will use a cohort of >2200 individuals that my group previously assembled, for whom we have clinical profiles, gut microbiome data, and banked blood and stool samples. We will invite people 5-10 years after their initial recruitment time, profile disease status and blood markers, and develop algorithms for predicting 5-10 year onset of Type 2 diabetes, cardiovascular disease, and obesity, using microbiome data from recruitment time. To increase the likelihood of finding microbiome markers predictive of disease onset, we will develop novel experimental and computational methods for in-depth characterization of microbial gene function, the metabolites produced by the microbiome, the underexplored fungal microbiome members, and the interactions between the gut microbiota and the host adaptive immune system. We will then apply these methods to >2200 banked samples from cohort recruitment time and use the resulting data in devising our microbiome-based risk prediction tools. In themselves, these novel assays and their application to >2200 samples should greatly advance the microbiome field. If successful, our proposal will identify new disease risk factors and risk prediction tools based on the microbiome, paving the way towards using the microbiome in early disease detection and prevention.

2 500 000 €

Start date: 2019-03-01, End date: 2024-02-29

CRISPR-Cas systems are microbial defense systems that provide prokaryotes with acquired and heritable DNA-based immunity against selfish genetic elements, primarily viruses. However, the full scope of benefits that these systems can provide, as well as their costs remain unknown. Specifically, it is unclear whether the benefits against viral infection outweigh the continual costs incurred even in the absence of parasitic elements, and whether CRISPR-Cas systems affect microbial genome diversity in nature. Since CRISPR-Cas systems can impede lateral gene transfer, it is often assumed that they reduce genetic diversity. Conversely, our recent results suggest the exact opposite: that these systems generate a high level of genomic diversity within populations. We have recently combined genomics of environmental strains and experimental genetics to show that archaea frequently acquire CRISPR immune memory, known as spacers, from chromosomes of related species in the environment. The presence of these spacers reduces gene exchange between lineages, indicating that CRISPR-Cas contributes to diversification. We have also shown that such inter-species mating events induce the acquisition of spacers against a strain's own replicons, supporting a role for CRISPR-Cas systems in generating deletions in natural plasmids and unessential genomic loci, again increasing genome diversity within populations. Here we aim to test our hypothesis that CRISPR-Cas systems increase within-population diversity, and quantify their benefits to both cells and populations, using large-scale genomics and experimental evolution. We will explore how these systems alter the patterns of recombination within and between species, and explore the potential involvement of CRISPR-associated proteins in cellular DNA repair. This work will reveal the eco-evolutionary role of CRISPR-Cas systems in shaping microbial populations, and open new research avenues regarding additional roles beyond anti-viral defense

2 495 625 €

Start date: 2018-05-01, End date: 2023-04-30

Classical dendritic cells (cDCs) are leucocytes that play a key role in innate immunity as well as the initiation and regulation of T cell responses. cDCpoiesis starts with commitment of a bone marrow (BM) haematopoietic progenitor, known as the classical DC precursor (CDP), to the cDC lineage. CDPs then give rise to pre-cDCs that exit the BM via the blood and seed tissues to give rise to the two major types of fully-differentiated cDCs, the cDC1 and cDC2 subsets. The key parameters of cDCpoiesis are poorly understood. We propose to characterise the niche in which cDCs develop within the BM and to study how pre-cDCs seed tissues and establish local clones of differentiated cDC1 and cDC2. We further wish to ask how the activity of CDPs and pre-cDCs is altered following infection, inflammation or tissue damage. Finally, we want to know to what extent cDCpoiesis is affected by direct sensing of infection or cell damage by cDC precursors. All these objectives will be addressed in a mouse lineage tracing model in which cDC precursors are genetically labelled through the activity of a Cre recombinase driven by the Clec9a locus. These mice will be crossed to fluorescent protein reporter mice, including Confetti mice that allow for clonal analysis, and the appearance of labelled cDCs and cDC clones in tissues will be followed over time in the steady-state or after induction of infection or inflammation. The dependence of cDC precursor activity on specific pathogen and damage sensing pathways will be assessed by loss-of-function experiments. The interactions of cDC precursors with their BM niche will be analysed in steady-state or inflammatory conditions by visualising the cells in situ. Finally, the consequences of demand-driven cDCpoiesis for immunity will be assessed. The results from this project will lead to a greater understanding of the influence of environmental signals on cDCpoiesis and may have applications in the design of better vaccines and immunotherapies.

2 500 000 €

Start date: 2018-09-01, End date: 2023-08-31

Imagine if doctors could heal patients via remote control. Following simple injections into regions of the body, they could activate internal cells by an external bandage. In this way, they could remotely control the ways tissue heal. This Advanced grant sets out to understand, design and develop the mechano-nano-magnetic platform that will underpin this therapeutic strategy for the future – DYNACEUTICS. Key receptors have been identified such as ion channels, integrins and growth factors which respond to mechanical cues on the membrane and activate downstream pathways. How do we ‘bottle’ an agonist like a drug which can influence or regulate mechano-sensors on the membrane and can be controlled remotely? This project tackles this complex interdisciplinary question through breakthrough nanotechnologies. We aim to expand and develop a platform technology using magnetic particle tagging which will allow us to direct cells for therapeutic purposes. Specifically, we aim • to identify mechano-receptor binding sites on stem and mature cells which will enable remote activation of signalling pathways via magnetic fields, • to design and test magnetic particles with tailored tagging strategies using single cell through 3D human organoid models to in vivo disease models, • to tailor and design external remote control devices • to create clinically relevant treatment modalities for remote control healing. This proposal presents a unique opportunity to launch a new dynamic treatment platform, DYNACEUTICS, which we propose will extend the therapeutic horizon and provide a new form of remote controlled healing.

2 499 068 €

Start date: 2019-01-01, End date: 2023-12-31

Ultrafast laser material processing is approaching its limits in terms of ability to produce innovative materials with compositional and structural consistency. The main idea of this project is to remove barriers to product development and go beyond state-of-the-art by applying tailored and few-cycle laser pulses (FCLPs) for engineering of materials. In this project I will investigate the interaction between intense ultra-short light pulses and matter at or below the wavelength scale reaching states of matter found only deep planetary conditions.A key goal of the project is to exploit these extreme conditions for synthesising unique material phases with on-demand optical and electronic properties, and progress photonic devices with utilizing FCLP advantages: control over the bond scissoring density; efficient and highly localized energy deposition; seeding of self-organized nanostructures; manipulation of spatio-temporal coupling. Currently, a key limitation is plasma scattering that diminishes the performance of engineered materials. The question I will address is whether control of ultra-short pulses can lead to ways around this limitation. The control of self-organization process will revolutionize the field of data storage by achieving record high 100 TB/cm3 densities, high writing speed and practically unlimited lifetime. I will radically improve the performance of printed flat optics with perfected nanostructures engineered from nano- to macro-scale and capable of replacing conventional optics significantly advancing photonic devices used in high-resolution microscopy, consumer electronics, and high-power laser applications. I envisage obtaining exotic material phases such as metallic phases of silicon and tailored metallic nanoparticles in silicate glass. Hence this project will push the frontiers of laser material processing to unprecedented precision and will develop novel family of devices that will feed into the future of optics, electronics and computing

2 499 957 €

Start date: 2019-01-01, End date: 2024-06-30

The production of synthetic polymers with precisely defined monomer sequences – exact polymers, which I call “exactymers” – is highly challenging. Iterative synthesis, in which specific monomers are added one-at-a-time to the end of a growing polymer chain, affords exquisite control over the final sequence, but requires accurate purification of the growing polymer with each and every cycle. EXACTYMER will create new super-stable, ultra-selective nanomembranes, with high permeances, enabling rapid, repeated purifications, which will transform exactymer fabrication. Multiple growing polymer chains will be attached to a central hub molecule to create a macromolecular homostar with enhanced molecular size, promoting accurate separation of the growing exactymer from reaction debris via nanomembrane processing. Automation and engineering will enable rapid, accurate and precise cycles of exactymer chain growth. EXACTYMER objectives will be achieved through curiosity-driven research into (1) the creation of nanomembranes with exquisite molecular selectivity between growing homostars and monomer plus reaction debris; (2) advancing the chemistry of iterative synthesis by creating strategies for step-wise growth of polyethers, polysiloxanes, and polyesters, and side chain functionalised monomers of these species; (3) combining iterative chemistry and nanomembranes together in an automated homostar nanofiltration platform, and; (4) exploring the use of exactymers in healthcare, nanotechnology and information storage. EXACTYMER will undertake pioneering research at the boundaries of membrane technology, polymer synthesis, process engineering and nanotechnology. The most profound anticipated outcome is a new capability to produce synthetic polymers, over 20 monomers in length, with exactly defined monomer sequences to an unprecedented accuracy, at multi-gram scale. New scientific insights will derive from the properties and performances of these newly accessible molecules.

2 499 814 €

Start date: 2018-07-01, End date: 2023-06-30

H-unique will be the first multimodal automated interrogation of visible hand anatomy, through analysis and interpretation of human variation. It will be an interdisciplinary project, supported by anatomists, anthropologists, geneticists, bioinformaticians, image analysts and computer scientists. We will investigate inherent and acquired variation in search of uniqueness, as the hand retains and displays a multiplicity of anatomical variants formed by different aetiologies (genetics, development, environment, accident etc). Hard biometrics, such as fingerprints, are well understood and some soft biometrics are gaining traction within both biometric and forensic domains (e.g. superficial vein pattern, skin crease pattern, morphometry, scars, tattoos and pigmentation pattern). A combinatorial approach of soft and hard biometrics has not been previously attempted from images of the hand. We will pioneer the development of new methods that will release the full extent of variation locked within the visible anatomy of the human hand and reconstruct its discriminatory profile as a retro-engineered multimodal biometric. A significant step change is required in the science to both reliably and repeatably extract and compare anatomical information from large numbers of images especially when the hand is not in a standard position or when either the resolution or lighting in the image is not ideal. Large datasets are vital for this work to be legally admissible. Through citizen engagement with science, this research will collect images from over 5,000 participants, creating an active, open source, ground-truth dataset. It will examine and address the effects of variable image conditions on data extraction and will design algorithms that permit auto-pattern searching across large numbers of stored images of variable quality. This will provide a major novel breakthrough in the study of anatomical variation, with wide-ranging, interdisciplinary and transdisciplinary impact.

2 495 378 €

Start date: 2019-01-01, End date: 2023-12-31

Despite decades of intensive research, there is no agreement about the general scheme of perception: Is the external object a trigger for a brain-internal process (open-loop perception, OLP) or is the object included in brain dynamics during the entire perceptual process (closed-loop perception, CLP)? HOWPER is designed to provide a definite answer to this question in the cases of human touch and vision. What enables this critical test is our development of an explicit CLP hypothesis, which will be contrasted, via specific testable predictions, with the OLP scheme. In the event that CLP is validated, HOWPER will introduce a radical paradigm shift in the study of perception, since almost all current experiments are guided, implicitly or explicitly, by the OLP scheme. If OLP is confirmed, HOWPER will provide the first formal affirmation for its superiority over CLP. Our approach in this novel paradigm is based on a triangle of interactive efforts comprising theory, analytical experiments, and synthetic experiments. The theoretical effort (WP1) will be based on the core theoretical framework already developed in our lab. The analytical experiments (WP2) will involve human perceivers. The synthetic experiments (WP3) will be performed on synthesized artificial perceivers. The fourth WP will exploit our novel rat-machine hybrid model for testing the neural applicability of the insights gained in the other WPs, whereas the fifth WP will translate our insights into novel visual-to-tactile sensory substitution algorithms. HOWPER is expected to either revolutionize or significantly advance the field of human perception, to greatly improve visual to tactile sensory substitution approaches and to contribute novel biomimetic algorithms for autonomous robotic agents.

2 493 441 €

Start date: 2018-06-01, End date: 2023-11-30

The aim is to produce a complete evolutionary tree of tetrapods and use this to explore two core questions in macroevolution: the balance between innovation and external processes in driving the evolution of life; and, identifying the best model for morphological evolution. Biodiversity today is unbalanced, with a small number of highly successful groups, like birds and beetles, and many others of equal antiquity but with far fewer species. Why are those groups so successful – was it chance or do they have some remarkable adaptation(s)? The core of the project is to construct a complete evolutionary tree of all 30,000 living species of tetrapods (amphibians, reptiles, birds, mammals) and add the 10,000 fossil species; this will generate a database of key characters, the homologies, shared by major groups. The probability of different drivers of diversification will be tested, focusing on those key, highly successful groups (e.g. lizards, birds, neornithines, passerines, rodents) that show explosive evolution to very high species diversity. The proposal goes to the roots of macroevolutionary understanding, and encompasses key questions about origins and modern biodiversity. The project is ambitious, but is possible because of advances in knowledge of relationships of all key tetrapod groups based on phylogenomic and morphological data, increasing precision of geological dating, and the availability of a range of computational methods to construct large phylogenetic trees, to assess likelihood of trees, to explore innovation and evolutionary rates and models, and Bayesian modelling techniques that can map trait data onto large trees and evaluate multiple models of drivers and bias. A unique outcome will be the chance to explore waiting time between major morphological changes, assessing distribution and magnitude, and use this information to inform the construction of a meaningful model of morphological evolution for computational phylogenetics.

2 482 225 €

Start date: 2018-10-01, End date: 2024-03-31