ERC FUNDED PROJECTS

Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.

1 100 000 €

Start date: 2008-09-01, End date: 2014-04-30

I propose to pursue two emerging Force Microscopy techniques that allow measuring structural properties below the surface of the specimen. Whereas Force Microscopy (most commonly known under the name AFM) is usually limited to measuring the surface topography and surface properties of a specimen, I will demonstrate that Force Microscopy can achieve true 3D images of the structure of the cell nucleus. In Ultrasound Force Microscopy, an ultrasound wave is launched from below towards the surface of the specimen. After the sound waves interact with structures beneath the surface of the specimen, the local variations in the amplitude and phase shift of the ultrasonic surface motion is collected by the Force Microscopy tip. Previously, measured 2D maps of the surface response have shown that the surface response is sensitive to structures below the surface. In this project I will employ miniature AFM cantilevers and nanotube tips that I have already developed in my lab. This will allow me to quickly acquire many such 2D maps at a much wider range of ultrasound frequencies and from these 2D maps calculate the full 3D structure below the surface. I expect this technique to have a resolving power better than 10 nm in three dimensions as far as 2 microns below the surface. In parallel I will introduce a major improvement to a technique based on Nuclear Magnetic Resonance (NMR). Magnetic Resonance Force Microscopy measures the interaction of a rotating nuclear spin in the field gradient of a magnetic Force Microscopy tip. However, these forces are so small that they pose an enormous challenge. Miniature cantilevers and nanotube tips, in combination with additional innovations in the detection of the cantilever motion, can overcome this problem. I expect to be able to measure the combined signal of 100 proton spins or fewer, which will allow me to measure proton densities with a resolution of 5 nm, but possibly even with atomic resolution.

1 794 960 €

Start date: 2008-08-01, End date: 2013-07-31

I aim to develop an X-ray imaging technique capable of filming processes in 3D, with a temporal resolution several orders of magnitude faster than up-to-date 3D X-ray imaging techniques. The unique penetration power of X-rays allows us to study systems in their native environment. This property has led to the development of X-ray microtomography (µCT). µCT acquires 3D information, which determines the functionality and mechanical properties of nature, by rotating a sample with respect to the X-ray source. µCT is a crucial tool for several scientific disciplines such as physics, biology, and chemistry. Over the last decade, µCT has become a technique capable of not only recording 3D information but also filming dynamical processes. Several breakthroughs have made this possible: i) intense X-ray sources (synchrotron light sources), ii) efficient and fast X-ray detectors, and iii) fast 3D reconstruction algorithms. Despite all of these developments, the acquisition protocols remain unchanged, i.e., the sample is only rotated faster. This fast rotation introduces forces which may alter the studied dynamics and ultimately limit the achievable temporal resolution. My project is to establish an X-ray microscope that avoids the sample rotation, obtaining 3D information from a single X-ray flash by splitting it into nine-angularly resolved beams which illuminate the sample simultaneously. This approach, when implemented at intense X-ray sources such as synchrotron light sources and X-ray free-electron lasers, will allow the filming of natural processes with micrometer to nanometer resolution and resolve dynamics from microseconds to femtoseconds. To demonstrate its capabilities, I will study fundamental processes in cellulose fibers, a renewable biomaterial, which can replace fossil-based materials, such as plastics. This technique will open up the possibility to film dynamics in 3D to answer questions coming from industry and natural sciences at rates not accessible today.

1 999 213 €

Start date: 2021-03-01, End date: 2026-02-28

MAPs are polymer-based composites that respond to magnetic fields with large deformation or tuneable mechanical properties. I aim to apply heterogeneous 3D printed MAPs as modifiable substrates to support biological structures which can have their deformation state and stiffness controlled by the external application of magnetic stimuli. Such mechanical stimulation has an important role on biological structures leading to alterations in functional responses, morphological changes and activation of growth or healing processes. Current bottlenecks preventing progress in this field are a lack of: a) appropriate experimental methodologies to enable characterisation of the behaviour of these materials; b) fundamental theoretical underpinnings to support the design and application of these new materials. The first step is to undertake in depth characterisation and assessment of 4D printed MAPs to create a detailed understanding of the underlying physics controlling the interactions between the polymeric matrices and embedded magnetic particles during application of mechanical and/or magnetic loadings. I will then culture biological structures on the novel 4D printed MAPs to create a ‘designed’ biostructure with specified and controllable responses to a given magnetic stimulus. These novel biostructures will be assessed using three applications: a) astrocyte cellular networks, b) neuronal circuits and c) astrocyte-neuronal networks. The evaluation of cellular damage, morphological and physiological alterations will validate the performance of the new biostructures and also contribute new understanding to the effects of deformation and stiffness gradients during glial scarring on physiological functions of central nervous system cells. The resulting deep understanding of magneto-mechanics of MAPs and their further development for controllable stimulation devices, will enable the international consolidation of my research group within the mechanics and bioengineering fields.

1 499 625 €

Start date: 2021-01-01, End date: 2025-12-31