Project acronym 3DBrainStrom
Project Brain metastases: Deciphering tumor-stroma interactions in three dimensions for the rational design of nanomedicines
Researcher (PI) Ronit Satchi Fainaro
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors.
This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.
Summary
Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors.
This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.
Max ERC Funding
2 353 125 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym 3DCellPhase-
Project In situ Structural Analysis of Molecular Crowding and Phase Separation
Researcher (PI) Julia MAHAMID
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Call Details Starting Grant (StG), LS1, ERC-2017-STG
Summary This proposal brings together two fields in biology, namely the emerging field of phase-separated assemblies in cell biology and state-of-the-art cellular cryo-electron tomography, to advance our understanding on a fundamental, yet illusive, question: the molecular organization of the cytoplasm.
Eukaryotes organize their biochemical reactions into functionally distinct compartments. Intriguingly, many, if not most, cellular compartments are not membrane enclosed. Rather, they assemble dynamically by phase separation, typically triggered upon a specific event. Despite significant progress on reconstituting such liquid-like assemblies in vitro, we lack information as to whether these compartments in vivo are indeed amorphous liquids, or whether they exhibit structural features such as gels or fibers. My recent work on sample preparation of cells for cryo-electron tomography, including cryo-focused ion beam thinning, guided by 3D correlative fluorescence microscopy, shows that we can now prepare site-specific ‘electron-transparent windows’ in suitable eukaryotic systems, which allow direct examination of structural features of cellular compartments in their cellular context. Here, we will use these techniques to elucidate the structural principles and cytoplasmic environment driving the dynamic assembly of two phase-separated compartments: Stress granules, which are RNA bodies that form rapidly in the cytoplasm upon cellular stress, and centrosomes, which are sites of microtubule nucleation. We will combine these studies with a quantitative description of the crowded nature of cytoplasm and of its local variations, to provide a direct readout of the impact of excluded volume on molecular assembly in living cells. Taken together, these studies will provide fundamental insights into the structural basis by which cells form biochemical compartments.
Summary
This proposal brings together two fields in biology, namely the emerging field of phase-separated assemblies in cell biology and state-of-the-art cellular cryo-electron tomography, to advance our understanding on a fundamental, yet illusive, question: the molecular organization of the cytoplasm.
Eukaryotes organize their biochemical reactions into functionally distinct compartments. Intriguingly, many, if not most, cellular compartments are not membrane enclosed. Rather, they assemble dynamically by phase separation, typically triggered upon a specific event. Despite significant progress on reconstituting such liquid-like assemblies in vitro, we lack information as to whether these compartments in vivo are indeed amorphous liquids, or whether they exhibit structural features such as gels or fibers. My recent work on sample preparation of cells for cryo-electron tomography, including cryo-focused ion beam thinning, guided by 3D correlative fluorescence microscopy, shows that we can now prepare site-specific ‘electron-transparent windows’ in suitable eukaryotic systems, which allow direct examination of structural features of cellular compartments in their cellular context. Here, we will use these techniques to elucidate the structural principles and cytoplasmic environment driving the dynamic assembly of two phase-separated compartments: Stress granules, which are RNA bodies that form rapidly in the cytoplasm upon cellular stress, and centrosomes, which are sites of microtubule nucleation. We will combine these studies with a quantitative description of the crowded nature of cytoplasm and of its local variations, to provide a direct readout of the impact of excluded volume on molecular assembly in living cells. Taken together, these studies will provide fundamental insights into the structural basis by which cells form biochemical compartments.
Max ERC Funding
1 228 125 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym 3DEpi
Project Transgenerational epigenetic inheritance of chromatin states : the role of Polycomb and 3D chromosome architecture
Researcher (PI) Giacomo CAVALLI
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS2, ERC-2017-ADG
Summary Epigenetic inheritance entails transmission of phenotypic traits not encoded in the DNA sequence and, in the most extreme case, Transgenerational Epigenetic Inheritance (TEI) involves transmission of memory through multiple generations. Very little is known on the mechanisms governing TEI and this is the subject of the present proposal. By transiently enhancing long-range chromatin interactions, we recently established isogenic Drosophila epilines that carry stable alternative epialleles, defined by differential levels of the Polycomb-dependent H3K27me3 mark. Furthermore, we extended our paradigm to natural phenotypes. These are ideal systems to study the role of Polycomb group (PcG) proteins and other components in regulating nuclear organization and epigenetic inheritance of chromatin states. The present project conjugates genetics, epigenomics, imaging and molecular biology to reach three critical aims.
Aim 1: Analysis of the molecular mechanisms regulating Polycomb-mediated TEI. We will identify the DNA, protein and RNA components that trigger and maintain transgenerational chromatin inheritance as well as their mechanisms of action.
Aim 2: Role of 3D genome organization in the regulation of TEI. We will analyze the developmental dynamics of TEI-inducing long-range chromatin interactions, identify chromatin components mediating 3D chromatin contacts and characterize their function in the TEI process.
Aim 3: Identification of a broader role of TEI during development. TEI might reflect a normal role of PcG components in the transmission of parental chromatin onto the next embryonic generation. We will explore this possibility by establishing other TEI paradigms and by relating TEI to the normal PcG function in these systems and in normal development.
This research program will unravel the biological significance and the molecular underpinnings of TEI and lead the way towards establishing this area of research into a consolidated scientific discipline.
Summary
Epigenetic inheritance entails transmission of phenotypic traits not encoded in the DNA sequence and, in the most extreme case, Transgenerational Epigenetic Inheritance (TEI) involves transmission of memory through multiple generations. Very little is known on the mechanisms governing TEI and this is the subject of the present proposal. By transiently enhancing long-range chromatin interactions, we recently established isogenic Drosophila epilines that carry stable alternative epialleles, defined by differential levels of the Polycomb-dependent H3K27me3 mark. Furthermore, we extended our paradigm to natural phenotypes. These are ideal systems to study the role of Polycomb group (PcG) proteins and other components in regulating nuclear organization and epigenetic inheritance of chromatin states. The present project conjugates genetics, epigenomics, imaging and molecular biology to reach three critical aims.
Aim 1: Analysis of the molecular mechanisms regulating Polycomb-mediated TEI. We will identify the DNA, protein and RNA components that trigger and maintain transgenerational chromatin inheritance as well as their mechanisms of action.
Aim 2: Role of 3D genome organization in the regulation of TEI. We will analyze the developmental dynamics of TEI-inducing long-range chromatin interactions, identify chromatin components mediating 3D chromatin contacts and characterize their function in the TEI process.
Aim 3: Identification of a broader role of TEI during development. TEI might reflect a normal role of PcG components in the transmission of parental chromatin onto the next embryonic generation. We will explore this possibility by establishing other TEI paradigms and by relating TEI to the normal PcG function in these systems and in normal development.
This research program will unravel the biological significance and the molecular underpinnings of TEI and lead the way towards establishing this area of research into a consolidated scientific discipline.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym 3DICE
Project 3D Interstellar Chemo-physical Evolution
Researcher (PI) Valentine Wakelam
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), PE9, ERC-2013-StG
Summary At the end of their life, stars spread their inner material into the diffuse interstellar medium. This diffuse medium gets locally denser and form dark clouds (also called dense or molecular clouds) whose innermost part is shielded from the external UV field by the dust, allowing for molecules to grow and get more complex. Gravitational collapse occurs inside these dense clouds, forming protostars and their surrounding disks, and eventually planetary systems like (or unlike) our solar system. The formation and evolution of molecules, minerals, ices and organics from the diffuse medium to planetary bodies, their alteration or preservation throughout this cosmic chemical history set the initial conditions for building planets, atmospheres and possibly the first bricks of life. The current view of interstellar chemistry is based on fragmental works on key steps of the sequence that are observed. The objective of this proposal is to follow the fractionation of the elements between the gas-phase and the interstellar grains, from the most diffuse medium to protoplanetary disks, in order to constrain the chemical composition of the material in which planets are formed. The potential outcome of this project is to get a consistent and more accurate description of the chemical evolution of interstellar matter. To achieve this objective, I will improve our chemical model by adding new processes on grain surfaces relevant under the diffuse medium conditions. This upgraded gas-grain model will be coupled to 3D dynamical models of the formation of dense clouds from diffuse medium and of protoplanetary disks from dense clouds. The computed chemical composition will also be used with 3D radiative transfer codes to study the chemical tracers of the physics of protoplanetary disk formation. The robustness of the model predictions will be studied with sensitivity analyses. Finally, model results will be confronted to observations to address some of the current challenges.
Summary
At the end of their life, stars spread their inner material into the diffuse interstellar medium. This diffuse medium gets locally denser and form dark clouds (also called dense or molecular clouds) whose innermost part is shielded from the external UV field by the dust, allowing for molecules to grow and get more complex. Gravitational collapse occurs inside these dense clouds, forming protostars and their surrounding disks, and eventually planetary systems like (or unlike) our solar system. The formation and evolution of molecules, minerals, ices and organics from the diffuse medium to planetary bodies, their alteration or preservation throughout this cosmic chemical history set the initial conditions for building planets, atmospheres and possibly the first bricks of life. The current view of interstellar chemistry is based on fragmental works on key steps of the sequence that are observed. The objective of this proposal is to follow the fractionation of the elements between the gas-phase and the interstellar grains, from the most diffuse medium to protoplanetary disks, in order to constrain the chemical composition of the material in which planets are formed. The potential outcome of this project is to get a consistent and more accurate description of the chemical evolution of interstellar matter. To achieve this objective, I will improve our chemical model by adding new processes on grain surfaces relevant under the diffuse medium conditions. This upgraded gas-grain model will be coupled to 3D dynamical models of the formation of dense clouds from diffuse medium and of protoplanetary disks from dense clouds. The computed chemical composition will also be used with 3D radiative transfer codes to study the chemical tracers of the physics of protoplanetary disk formation. The robustness of the model predictions will be studied with sensitivity analyses. Finally, model results will be confronted to observations to address some of the current challenges.
Max ERC Funding
1 166 231 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym 3DIMAGE
Project 3D Imaging Across Lengthscales: From Atoms to Grains
Researcher (PI) Paul Anthony Midgley
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), PE4, ERC-2011-ADG_20110209
Summary "Understanding structure-property relationships across lengthscales is key to the design of functional and structural materials and devices. Moreover, the complexity of modern devices extends to three dimensions and as such 3D characterization is required across those lengthscales to provide a complete understanding and enable improvement in the material’s physical and chemical behaviour. 3D imaging and analysis from the atomic scale through to granular microstructure is proposed through the development of electron tomography using (S)TEM, and ‘dual beam’ SEM-FIB, techniques offering complementary approaches to 3D imaging across lengthscales stretching over 5 orders of magnitude.
We propose to extend tomography to include novel methods to determine atom positions in 3D with approaches incorporating new reconstruction algorithms, image processing and complementary nano-diffraction techniques. At the nanoscale, true 3D nano-metrology of morphology and composition is a key objective of the project, minimizing reconstruction and visualization artefacts. Mapping strain and optical properties in 3D are ambitious and exciting challenges that will yield new information at the nanoscale. Using the SEM-FIB, 3D ‘mesoscale’ structures will be revealed: morphology, crystallography and composition can be mapped simultaneously, with ~5nm resolution and over volumes too large to tackle by (S)TEM and too small for most x-ray techniques. In parallel, we will apply 3D imaging to a wide variety of key materials including heterogeneous catalysts, aerospace alloys, biomaterials, photovoltaic materials, and novel semiconductors.
We will collaborate with many departments in Cambridge and institutes worldwide. The personnel on the proposal will cover all aspects of the tomography proposed using high-end TEMs, including an aberration-corrected Titan, and a Helios dual beam. Importantly, a postdoc is dedicated to developing new algorithms for reconstruction, image and spectral processing."
Summary
"Understanding structure-property relationships across lengthscales is key to the design of functional and structural materials and devices. Moreover, the complexity of modern devices extends to three dimensions and as such 3D characterization is required across those lengthscales to provide a complete understanding and enable improvement in the material’s physical and chemical behaviour. 3D imaging and analysis from the atomic scale through to granular microstructure is proposed through the development of electron tomography using (S)TEM, and ‘dual beam’ SEM-FIB, techniques offering complementary approaches to 3D imaging across lengthscales stretching over 5 orders of magnitude.
We propose to extend tomography to include novel methods to determine atom positions in 3D with approaches incorporating new reconstruction algorithms, image processing and complementary nano-diffraction techniques. At the nanoscale, true 3D nano-metrology of morphology and composition is a key objective of the project, minimizing reconstruction and visualization artefacts. Mapping strain and optical properties in 3D are ambitious and exciting challenges that will yield new information at the nanoscale. Using the SEM-FIB, 3D ‘mesoscale’ structures will be revealed: morphology, crystallography and composition can be mapped simultaneously, with ~5nm resolution and over volumes too large to tackle by (S)TEM and too small for most x-ray techniques. In parallel, we will apply 3D imaging to a wide variety of key materials including heterogeneous catalysts, aerospace alloys, biomaterials, photovoltaic materials, and novel semiconductors.
We will collaborate with many departments in Cambridge and institutes worldwide. The personnel on the proposal will cover all aspects of the tomography proposed using high-end TEMs, including an aberration-corrected Titan, and a Helios dual beam. Importantly, a postdoc is dedicated to developing new algorithms for reconstruction, image and spectral processing."
Max ERC Funding
2 337 330 €
Duration
Start date: 2012-01-01, End date: 2017-12-31
Project acronym 3Dmaterials4Energy
Project Hierarchical Inorganic Nanomaterials as Next Generation Catalysts and Filters
Researcher (PI) Taleb Mokari
Host Institution (HI) BEN-GURION UNIVERSITY OF THE NEGEV
Call Details Proof of Concept (PoC), PC1, ERC-2016-PoC
Summary In the coming few decades, two major global grand challenges will continue to attract the attention of scientists and engineers in academia and industry: achieving clean water and clean energy. This PoC establishes the development of two prototypes, water oxidation catalyst and water purification filter, by creating inexpensive, abundant and versatile hierarchical structures of inorganic nanomaterials (HSINs).
The formation of HSINs has been one of the major obstacles toward achieving a technological progress in various applications. Presently, fabrication of well-defined 3-D structures can be achieved either by photo/electro lithography, assembly, 3D printing or template-mediated methods. Various structures with high quality/yield can be obtained through those techniques, however, these methods suffer from high cost, difficulty of fabrication of free-standing structures, and sometime the throughput is limited. On the other hand, the templated approaches usually are facile, low cost and offer several and complex structures in particular the ones obtained from nature.
Our invention is based on forming the HSINs using fossil templates from nature. We propose to harness the naturally designed morphologies of the fossil templates to rationally form hierarchical structures of nanomaterials. These structures have many advantageous, compared to the current state-of-the-art catalyst and filter, for example high surface area, high porosity, confined space (nano-reactor) and divers functionalities obtained by controlling the chemical composition of the inorganic material shell. Since these properties are important for achieving high performance, we propose HSINs as next generation water oxidation electrocatalyst and water purification filter.
Summary
In the coming few decades, two major global grand challenges will continue to attract the attention of scientists and engineers in academia and industry: achieving clean water and clean energy. This PoC establishes the development of two prototypes, water oxidation catalyst and water purification filter, by creating inexpensive, abundant and versatile hierarchical structures of inorganic nanomaterials (HSINs).
The formation of HSINs has been one of the major obstacles toward achieving a technological progress in various applications. Presently, fabrication of well-defined 3-D structures can be achieved either by photo/electro lithography, assembly, 3D printing or template-mediated methods. Various structures with high quality/yield can be obtained through those techniques, however, these methods suffer from high cost, difficulty of fabrication of free-standing structures, and sometime the throughput is limited. On the other hand, the templated approaches usually are facile, low cost and offer several and complex structures in particular the ones obtained from nature.
Our invention is based on forming the HSINs using fossil templates from nature. We propose to harness the naturally designed morphologies of the fossil templates to rationally form hierarchical structures of nanomaterials. These structures have many advantageous, compared to the current state-of-the-art catalyst and filter, for example high surface area, high porosity, confined space (nano-reactor) and divers functionalities obtained by controlling the chemical composition of the inorganic material shell. Since these properties are important for achieving high performance, we propose HSINs as next generation water oxidation electrocatalyst and water purification filter.
Max ERC Funding
150 000 €
Duration
Start date: 2017-03-01, End date: 2018-08-31
Project acronym 3DMOSHBOND
Project Three-Dimensional Mapping Of a Single Hydrogen Bond
Researcher (PI) Adam Marc SWEETMAN
Host Institution (HI) UNIVERSITY OF LEEDS
Call Details Starting Grant (StG), PE3, ERC-2017-STG
Summary All properties of matter are ultimately governed by the forces between single atoms, but our knowledge of interatomic, and intermolecular, potentials is often derived indirectly.
In 3DMOSHBOND, I outline a program of work designed to create a paradigm shift in the direct measurement of complex interatomic potentials via a fundamental reimagining of how atomic resolution imaging, and force measurement, techniques are applied.
To provide a clear proof of principle demonstration of the power of this concept, I propose to map the strength, shape and extent of single hydrogen bonding (H-bonding) interactions in 3D with sub-Angstrom precision. H-bonding is a key component governing intermolecular interactions, particularly for biologically important molecules. Despite its critical importance, H-bonding is relatively poorly understood, and the IUPAC definition of the H-bond was changed as recently as 2011- highlighting the relevance of a new means to engage with these fundamental interactions.
Hitherto unprecedented resolution and accuracy will be achieved via a creation of a novel layer of vertically oriented H-bonding molecules, functionalisation of the tip of a scanning probe microscope with a single complementary H-bonding molecule, and by complete characterisation of the position of all atoms in the junction. This will place two H-bonding groups “end on” and map the extent, and magnitude, of the H-bond with sub-Angstrom precision for a variety of systems. This investigation of the H-bond will present us with an unparalleled level of information regarding its properties.
Experimental results will be compared with ab initio density functional theory (DFT) simulations, to investigate the extent to which state-of-the-art simulations are able to reproduce the behaviour of the H-bonding interaction. The project will create a new generalised probe for the study of single atomic and molecular interactions.
Summary
All properties of matter are ultimately governed by the forces between single atoms, but our knowledge of interatomic, and intermolecular, potentials is often derived indirectly.
In 3DMOSHBOND, I outline a program of work designed to create a paradigm shift in the direct measurement of complex interatomic potentials via a fundamental reimagining of how atomic resolution imaging, and force measurement, techniques are applied.
To provide a clear proof of principle demonstration of the power of this concept, I propose to map the strength, shape and extent of single hydrogen bonding (H-bonding) interactions in 3D with sub-Angstrom precision. H-bonding is a key component governing intermolecular interactions, particularly for biologically important molecules. Despite its critical importance, H-bonding is relatively poorly understood, and the IUPAC definition of the H-bond was changed as recently as 2011- highlighting the relevance of a new means to engage with these fundamental interactions.
Hitherto unprecedented resolution and accuracy will be achieved via a creation of a novel layer of vertically oriented H-bonding molecules, functionalisation of the tip of a scanning probe microscope with a single complementary H-bonding molecule, and by complete characterisation of the position of all atoms in the junction. This will place two H-bonding groups “end on” and map the extent, and magnitude, of the H-bond with sub-Angstrom precision for a variety of systems. This investigation of the H-bond will present us with an unparalleled level of information regarding its properties.
Experimental results will be compared with ab initio density functional theory (DFT) simulations, to investigate the extent to which state-of-the-art simulations are able to reproduce the behaviour of the H-bonding interaction. The project will create a new generalised probe for the study of single atomic and molecular interactions.
Max ERC Funding
1 971 468 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym 3DNANOMECH
Project Three-dimensional molecular resolution mapping of soft matter-liquid interfaces
Researcher (PI) Ricardo Garcia
Host Institution (HI) AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Call Details Advanced Grant (AdG), PE4, ERC-2013-ADG
Summary Optical, electron and probe microscopes are enabling tools for discoveries and knowledge generation in nanoscale sicence and technology. High resolution –nanoscale or molecular-, noninvasive and label-free imaging of three-dimensional soft matter-liquid interfaces has not been achieved by any microscopy method.
Force microscopy (AFM) is considered the second most relevant advance in materials science since 1960. Despite its impressive range of applications, the technique has some key limitations. Force microscopy has not three dimensional depth. What lies above or in the subsurface is not readily characterized.
3DNanoMech proposes to design, build and operate a high speed force-based method for the three-dimensional characterization soft matter-liquid interfaces (3D AFM). The microscope will combine a detection method based on force perturbations, adaptive algorithms, high speed piezo actuators and quantitative-oriented multifrequency approaches. The development of the microscope cannot be separated from its applications: imaging the error-free DNA repair and to understand the relationship existing between the nanomechanical properties and the malignancy of cancer cells. Those problems encompass the different spatial –molecular-nano-mesoscopic- and time –milli to seconds- scales of the instrument.
In short, 3DNanoMech aims to image, map and measure with picoNewton, millisecond and angstrom resolution soft matter surfaces and interfaces in liquid. The long-term vision of 3DNanoMech is to replace models or computer animations of bimolecular-liquid interfaces by real time, molecular resolution maps of properties and processes.
Summary
Optical, electron and probe microscopes are enabling tools for discoveries and knowledge generation in nanoscale sicence and technology. High resolution –nanoscale or molecular-, noninvasive and label-free imaging of three-dimensional soft matter-liquid interfaces has not been achieved by any microscopy method.
Force microscopy (AFM) is considered the second most relevant advance in materials science since 1960. Despite its impressive range of applications, the technique has some key limitations. Force microscopy has not three dimensional depth. What lies above or in the subsurface is not readily characterized.
3DNanoMech proposes to design, build and operate a high speed force-based method for the three-dimensional characterization soft matter-liquid interfaces (3D AFM). The microscope will combine a detection method based on force perturbations, adaptive algorithms, high speed piezo actuators and quantitative-oriented multifrequency approaches. The development of the microscope cannot be separated from its applications: imaging the error-free DNA repair and to understand the relationship existing between the nanomechanical properties and the malignancy of cancer cells. Those problems encompass the different spatial –molecular-nano-mesoscopic- and time –milli to seconds- scales of the instrument.
In short, 3DNanoMech aims to image, map and measure with picoNewton, millisecond and angstrom resolution soft matter surfaces and interfaces in liquid. The long-term vision of 3DNanoMech is to replace models or computer animations of bimolecular-liquid interfaces by real time, molecular resolution maps of properties and processes.
Max ERC Funding
2 499 928 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym 3DPRINTEDOPTICS
Project 3D printed micro- and nano-optics for future integrated vision and endoscopy systems
Researcher (PI) Harald Giessen
Host Institution (HI) UNIVERSITAET STUTTGART
Call Details Proof of Concept (PoC), ERC-2019-PoC
Summary Optics is abundant in today’s world. Smartphone cameras, optical sensors for autonomous driving, virtual and augmented reality, medical imaging technology, and many more areas all require tailored optical sensors. In most cases, the optical sensors are still based on classical optical systems. For instance, high-end cameras or high-quality endoscopes still utilize classical glass optics. The related markets have sizes of several tens of billion USD and grow with double digit rates.
For all applications, size is the limiting factor. There is a tremendous demand for imaging capabilities using optics at sizes below 1 mm, with the quality of classical optics, i.e., correction of aberrations, extremely high transmission, and broadband operation. Key features include also zooming, focusing, and f-number variation, as well as customized fields of view to realize foveated imaging and multi-aperture, multi-lens systems. Ideally, such optical systems provide 180° field of view with simultaneous zooming capabilities.
Here, we propose a novel type of micro-optics that is extremely flexible, can be created at demand, possesses unprecedented functionality, and delivers solutions to problems that could not be solved before.
The basic building block at the heart of our problem solution is the use of 3D printed microoptics by femtosecond direct laser writing. This method has all features to fulfil the above-mentioned requirements: It takes only a day from the idea to concept, optical design and simulation, and to manufacturing and testing, i.e., to generate a working prototype.
Our method will create a new class of optical elements, which enable the smallest microscope objective in the world on the tip of an optical fiber with unprecedented imaging accuracy and functionality, such as focusing and zooming capability.
Summary
Optics is abundant in today’s world. Smartphone cameras, optical sensors for autonomous driving, virtual and augmented reality, medical imaging technology, and many more areas all require tailored optical sensors. In most cases, the optical sensors are still based on classical optical systems. For instance, high-end cameras or high-quality endoscopes still utilize classical glass optics. The related markets have sizes of several tens of billion USD and grow with double digit rates.
For all applications, size is the limiting factor. There is a tremendous demand for imaging capabilities using optics at sizes below 1 mm, with the quality of classical optics, i.e., correction of aberrations, extremely high transmission, and broadband operation. Key features include also zooming, focusing, and f-number variation, as well as customized fields of view to realize foveated imaging and multi-aperture, multi-lens systems. Ideally, such optical systems provide 180° field of view with simultaneous zooming capabilities.
Here, we propose a novel type of micro-optics that is extremely flexible, can be created at demand, possesses unprecedented functionality, and delivers solutions to problems that could not be solved before.
The basic building block at the heart of our problem solution is the use of 3D printed microoptics by femtosecond direct laser writing. This method has all features to fulfil the above-mentioned requirements: It takes only a day from the idea to concept, optical design and simulation, and to manufacturing and testing, i.e., to generate a working prototype.
Our method will create a new class of optical elements, which enable the smallest microscope objective in the world on the tip of an optical fiber with unprecedented imaging accuracy and functionality, such as focusing and zooming capability.
Max ERC Funding
150 000 €
Duration
Start date: 2019-06-01, End date: 2020-11-30
Project acronym 3DPROTEINPUZZLES
Project Shape-directed protein assembly design
Researcher (PI) Lars Ingemar ANDRÉ
Host Institution (HI) LUNDS UNIVERSITET
Call Details Consolidator Grant (CoG), LS9, ERC-2017-COG
Summary Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Summary
Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Max ERC Funding
2 325 292 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
