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Project acronym 1stProposal
Project An alternative development of analytic number theory and applications
Researcher (PI) ANDREW Granville
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Summary The traditional (Riemann) approach to analytic number theory uses the zeros of zeta functions. This requires the associated multiplicative function, say f(n), to have special enough properties that the associated Dirichlet series may be analytically continued. In this proposal we continue to develop an approach which requires less of the multiplicative function, linking the original question with the mean value of f. Such techniques have been around for a long time but have generally been regarded as "ad hoc". In this project we aim to show that one can develop a coherent approach to the whole subject, not only reproving all of the old results, but also many new ones that appear inaccessible to traditional methods. Our first goal is to complete a monograph yielding a reworking of all the classical theory using these new methods and then to push forward in new directions. The most important is to extend these techniques to GL(n) L-functions, which we hope will now be feasible having found the correct framework in which to proceed. Since we rarely know how to analytically continue such L-functions this could be of great benefit to the subject. We are developing the large sieve so that it can be used for individual moduli, and will determine a strong form of that. Also a new method to give asymptotics for mean values, when they are not too small. We wish to incorporate techniques of analytic number theory into our theory, for example recent advances on mean values of Dirichlet polynomials. Also the recent breakthroughs on the sieve suggest strong links that need further exploration. Additive combinatorics yields important results in many areas. There are strong analogies between its results, and those for multiplicative functions, especially in large value spectrum theory, and its applications. We hope to develop these further. Much of this is joint work with K Soundararajan of Stanford University.
The traditional (Riemann) approach to analytic number theory uses the zeros of zeta functions. This requires the associated multiplicative function, say f(n), to have special enough properties that the associated Dirichlet series may be analytically continued. In this proposal we continue to develop an approach which requires less of the multiplicative function, linking the original question with the mean value of f. Such techniques have been around for a long time but have generally been regarded as "ad hoc". In this project we aim to show that one can develop a coherent approach to the whole subject, not only reproving all of the old results, but also many new ones that appear inaccessible to traditional methods. Our first goal is to complete a monograph yielding a reworking of all the classical theory using these new methods and then to push forward in new directions. The most important is to extend these techniques to GL(n) L-functions, which we hope will now be feasible having found the correct framework in which to proceed. Since we rarely know how to analytically continue such L-functions this could be of great benefit to the subject. We are developing the large sieve so that it can be used for individual moduli, and will determine a strong form of that. Also a new method to give asymptotics for mean values, when they are not too small. We wish to incorporate techniques of analytic number theory into our theory, for example recent advances on mean values of Dirichlet polynomials. Also the recent breakthroughs on the sieve suggest strong links that need further exploration. Additive combinatorics yields important results in many areas. There are strong analogies between its results, and those for multiplicative functions, especially in large value spectrum theory, and its applications. We hope to develop these further. Much of this is joint work with K Soundararajan of Stanford University.
Project acronym 1toStopVax
Project RNA virus attenuation by altering mutational robustness
Researcher (PI) Marco VIGNUZZI
Host Institution (HI) INSTITUT PASTEUR
Summary RNA viruses have extreme mutation frequencies. When a RNA virus replicates, nucleotide mutations are generated resulting in a population of variants. This genetic diversity creates a cloud of mutations that are potentially beneficial to viral survival, but the majority of mutations are detrimental to the virus. By increasing the mutation rate of a RNA virus, viral fitness is reduced because it generates more errors, and attenuates the virus during in vivo infection. Another feature that affects RNA virus fitness is mutational robustness. Mutational robustness is the ability to buffer the negative effects of mutation. The attenuation of RNA viruses for vaccine production faces problems of genetic instability and reversion to a pathogenic phenotype. The conventional method for attenuation is mostly empirical and specific to the particular RNA virus species.
Hence, it cannot be universally applied to a variety of virus types. We've developed a non-empirical, rational means of attenuating RNA viruses, targeting mutational robustness as modifiable trait.
We demonstrate that mutational robustness of RNA viruses can be modified without changing a virus' physical and biological properties for vaccine production; yet the virus is attenuated as it becomes victim of its naturally high mutation rate. Specifically, the genome of RNA viruses are modified so that a larger proportion of mutations become lethal Stop mutations. Our technology places the virus one step away from these Stop mutations (1-to-Stop). We succeeded in attenuating two RNA viruses from very different viral families, confirming the broad applicability of this approach. These viruses were attenuated in vivo, generated high levels of neutralizing antibody and protected mice from lethal challenge infection. The proposal now seeks to complete proof of concept studies and develop commercialization strategies to scale up this new technology to preclinical testing with industrial partners.
RNA viruses have extreme mutation frequencies. When a RNA virus replicates, nucleotide mutations are generated resulting in a population of variants. This genetic diversity creates a cloud of mutations that are potentially beneficial to viral survival, but the majority of mutations are detrimental to the virus. By increasing the mutation rate of a RNA virus, viral fitness is reduced because it generates more errors, and attenuates the virus during in vivo infection. Another feature that affects RNA virus fitness is mutational robustness. Mutational robustness is the ability to buffer the negative effects of mutation. The attenuation of RNA viruses for vaccine production faces problems of genetic instability and reversion to a pathogenic phenotype. The conventional method for attenuation is mostly empirical and specific to the particular RNA virus species.
Hence, it cannot be universally applied to a variety of virus types. We've developed a non-empirical, rational means of attenuating RNA viruses, targeting mutational robustness as modifiable trait.
We demonstrate that mutational robustness of RNA viruses can be modified without changing a virus' physical and biological properties for vaccine production; yet the virus is attenuated as it becomes victim of its naturally high mutation rate. Specifically, the genome of RNA viruses are modified so that a larger proportion of mutations become lethal Stop mutations. Our technology places the virus one step away from these Stop mutations (1-to-Stop). We succeeded in attenuating two RNA viruses from very different viral families, confirming the broad applicability of this approach. These viruses were attenuated in vivo, generated high levels of neutralizing antibody and protected mice from lethal challenge infection. The proposal now seeks to complete proof of concept studies and develop commercialization strategies to scale up this new technology to preclinical testing with industrial partners.
Project acronym 2-NanoSi
Project Ratiometric FRET Based Nanosensors for Trypsin Related Human Recessive Diseases
Researcher (PI) Emilio Jose Palomares Gil
Host Institution (HI) FUNDACIO PRIVADA INSTITUT CATALA D'INVESTIGACIO QUIMICA
Summary The project aims to create a demo system for cost effective, non-invasive device for rapid detection of cystic fibrosis in humans. The detection of human recessive diseases has been dominated by the use of fluorescent biomarkers, based on organic dyes, helping researchers to study and analyse gene expression, cell cycle, and enzymatic activity. Among several proteolytic enzymes, trypsin has attracted much attention, as it is a target in the study of various important human recessive diseases including, for example, cystic fibrosis (CF). We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of cystic in humans. Current detection technologies for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a fast (minutes), a single-step and with two times higher sensitivity than the state-of-the-art biomarkers based sensors for cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range (25-350 μg/L). Moreover, our approach can be used from the 4th day of life when the trypsin concentration is already the same as in adults. Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human phenotypes, i.e. normal (160-340 μg/L), CF homozygotic (0-90 μg/L), and CF heterozygotic (91-349 μg/L), respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescence biomarker for recessive genetic diseases alike human cystic fibrosis.
The project aims to create a demo system for cost effective, non-invasive device for rapid detection of cystic fibrosis in humans. The detection of human recessive diseases has been dominated by the use of fluorescent biomarkers, based on organic dyes, helping researchers to study and analyse gene expression, cell cycle, and enzymatic activity. Among several proteolytic enzymes, trypsin has attracted much attention, as it is a target in the study of various important human recessive diseases including, for example, cystic fibrosis (CF). We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of cystic in humans. Current detection technologies for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a fast (minutes), a single-step and with two times higher sensitivity than the state-of-the-art biomarkers based sensors for cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range (25-350 μg/L). Moreover, our approach can be used from the 4th day of life when the trypsin concentration is already the same as in adults. Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human phenotypes, i.e. normal (160-340 μg/L), CF homozygotic (0-90 μg/L), and CF heterozygotic (91-349 μg/L), respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescence biomarker for recessive genetic diseases alike human cystic fibrosis.
Project acronym 20SComplexity
Project An integrative approach to uncover the multilevel regulation of 20S proteasome degradation
Researcher (PI) Michal Sharon
Summary For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route. To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation: Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome. Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function. Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach. Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route. To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation: Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome. Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function. Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach. Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Project acronym 2D-Ink
Project Ink-Jet printed supercapacitors based on 2D nanomaterials.
Researcher (PI) Valeria Nicolosi
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Summary This proposal will determine the technical-economic viability of scaling-up ultra-thin, ink-jet printed films based on liquid-phase exfoliated single atomic layers of a range of nanomaterials. The PI has developed methods to produce in liquid nanosheets of a range of layered materials such as graphene, transition metal oxides, etc. These 2D-materials have immediate and far-reaching potential in several high-impact technological applications such as microelectronics, composites and energy harvesting and storage. 2DNanoCaps (ERC ref: 278516) has demonstrated that lab-scale ultra-thin graphene-based supercapacitor electrodes result in unusually high-power and extremely long device life-time (100% capacitance retention for 5000 charge-discharge cycles at the high power scan rate of 10,000 mV/s). This performance is an order of magnitude better than similar systems produced with conventional methods which cause materials restacking and aggregation. A following ERC PoC grant (2D-USD, Project-Number 620189) is currently focussed on up-scaling the production of thin-films deposition methods based on ultrasonic spray for the production of large-area electrodes for supercapacitors applications. In this proposal we want to explore the new concept of manufacturing conductive, robust, thin, easily assembled electrode and solid electrolytes to realize highly-flexible and all-solid-state supercapacitors by ink-jet printing. This opportunity is particularly relevant to the electronics and portable-device industry and offers the possibility to solve flammability issues, maintaining light weight, flexibility, transparency and portability. In order to do so it will be imperative to develop ink-jet printing methods and techniques. We believe our combination of unique materials and cost-effective, robust and production-scalable process of ultra- thin ink-jet printing will enable us to compete for significant global market opportunities in the energy-storage space.
This proposal will determine the technical-economic viability of scaling-up ultra-thin, ink-jet printed films based on liquid-phase exfoliated single atomic layers of a range of nanomaterials. The PI has developed methods to produce in liquid nanosheets of a range of layered materials such as graphene, transition metal oxides, etc. These 2D-materials have immediate and far-reaching potential in several high-impact technological applications such as microelectronics, composites and energy harvesting and storage. 2DNanoCaps (ERC ref: 278516) has demonstrated that lab-scale ultra-thin graphene-based supercapacitor electrodes result in unusually high-power and extremely long device life-time (100% capacitance retention for 5000 charge-discharge cycles at the high power scan rate of 10,000 mV/s). This performance is an order of magnitude better than similar systems produced with conventional methods which cause materials restacking and aggregation. A following ERC PoC grant (2D-USD, Project-Number 620189) is currently focussed on up-scaling the production of thin-films deposition methods based on ultrasonic spray for the production of large-area electrodes for supercapacitors applications. In this proposal we want to explore the new concept of manufacturing conductive, robust, thin, easily assembled electrode and solid electrolytes to realize highly-flexible and all-solid-state supercapacitors by ink-jet printing. This opportunity is particularly relevant to the electronics and portable-device industry and offers the possibility to solve flammability issues, maintaining light weight, flexibility, transparency and portability. In order to do so it will be imperative to develop ink-jet printing methods and techniques. We believe our combination of unique materials and cost-effective, robust and production-scalable process of ultra- thin ink-jet printing will enable us to compete for significant global market opportunities in the energy-storage space.
Project acronym 2DNANOPTICA
Project Nano-optics on flatland: from quantum nanotechnology to nano-bio-photonics
Researcher (PI) Pablo Alonso-González
Host Institution (HI) UNIVERSIDAD DE OVIEDO
Summary Ubiquitous in nature, light-matter interactions are of fundamental importance in science and all optical technologies. Understanding and controlling them has been a long-pursued objective in modern physics. However, so far, related experiments have relied on traditional optical schemes where, owing to the classical diffraction limit, control of optical fields to length scales below the wavelength of light is prevented. Importantly, this limitation impedes to exploit the extraordinary fundamental and scaling potentials of nanoscience and nanotechnology. A solution to concentrate optical fields into sub-diffracting volumes is the excitation of surface polaritons –coupled excitations of photons and mobile/bound charges in metals/polar materials (plasmons/phonons)-. However, their initial promises have been hindered by either strong optical losses or lack of electrical control in metals, and difficulties to fabricate high optical quality nanostructures in polar materials. With the advent of two-dimensional (2D) materials and their extraordinary optical properties, during the last 2-3 years the visualization of both low-loss and electrically tunable (active) plasmons in graphene and high optical quality phonons in monolayer and multilayer h-BN nanostructures have been demonstrated in the mid-infrared spectral range, thus introducing a very encouraging arena for scientifically ground-breaking discoveries in nano-optics. Inspired by these extraordinary prospects, this ERC project aims to make use of our knowledge and unique expertise in 2D nanoplasmonics, and the recent advances in nanophononics, to establish a technological platform that, including coherent sources, waveguides, routers, and efficient detectors, permits an unprecedented active control and manipulation (at room temperature) of light and light-matter interactions on the nanoscale, thus laying experimentally the foundations of a 2D nano-optics field.
Ubiquitous in nature, light-matter interactions are of fundamental importance in science and all optical technologies. Understanding and controlling them has been a long-pursued objective in modern physics. However, so far, related experiments have relied on traditional optical schemes where, owing to the classical diffraction limit, control of optical fields to length scales below the wavelength of light is prevented. Importantly, this limitation impedes to exploit the extraordinary fundamental and scaling potentials of nanoscience and nanotechnology. A solution to concentrate optical fields into sub-diffracting volumes is the excitation of surface polaritons –coupled excitations of photons and mobile/bound charges in metals/polar materials (plasmons/phonons)-. However, their initial promises have been hindered by either strong optical losses or lack of electrical control in metals, and difficulties to fabricate high optical quality nanostructures in polar materials. With the advent of two-dimensional (2D) materials and their extraordinary optical properties, during the last 2-3 years the visualization of both low-loss and electrically tunable (active) plasmons in graphene and high optical quality phonons in monolayer and multilayer h-BN nanostructures have been demonstrated in the mid-infrared spectral range, thus introducing a very encouraging arena for scientifically ground-breaking discoveries in nano-optics. Inspired by these extraordinary prospects, this ERC project aims to make use of our knowledge and unique expertise in 2D nanoplasmonics, and the recent advances in nanophononics, to establish a technological platform that, including coherent sources, waveguides, routers, and efficient detectors, permits an unprecedented active control and manipulation (at room temperature) of light and light-matter interactions on the nanoscale, thus laying experimentally the foundations of a 2D nano-optics field.
Project acronym 2DNanoSpec
Project Nanoscale Vibrational Spectroscopy of Sensitive 2D Molecular Materials
Researcher (PI) Renato ZENOBI
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Summary I propose to investigate the nanometer scale organization of delicate 2-dimensional molecular materials using nanoscale vibrational spectroscopy. 2D structures are of great scientific and technological importance, for example as novel materials (graphene, MoS2, WS2, etc.), and in the form of biological membranes and synthetic 2D-polymers. Powerful methods for their analysis and imaging with molecular selectivity and sufficient spatial resolution, however, are lacking. Tip-enhanced Raman spectroscopy (TERS) allows label-free spectroscopic identification of molecular species, with ≈10 nm spatial resolution, and with single molecule sensitivity for strong Raman scatterers. So far, however, TERS is not being carried out in liquids, which is the natural environment for membranes, and its application to poor Raman scatterers such as components of 2D polymers, lipids, or other membrane compounds (proteins, sugars) is difficult. TERS has the potential to overcome the restrictions of other optical/spectroscopic methods to study 2D materials, namely (i) insufficient spatial resolution of diffraction-limited optical methods; (ii) the need for labelling for all methods relying on fluorescence; and (iii) the inability of some methods to work in liquids. I propose to address a number of scientific questions associated with the spatial organization, and the occurrence of defects in sensitive 2D molecular materials. The success of these studies will also rely critically on technical innovations of TERS that notably address the problem of energy dissipation. This will for the first time allow its application to study of complex, delicate 2D molecular systems without photochemical damage.
I propose to investigate the nanometer scale organization of delicate 2-dimensional molecular materials using nanoscale vibrational spectroscopy. 2D structures are of great scientific and technological importance, for example as novel materials (graphene, MoS2, WS2, etc.), and in the form of biological membranes and synthetic 2D-polymers. Powerful methods for their analysis and imaging with molecular selectivity and sufficient spatial resolution, however, are lacking. Tip-enhanced Raman spectroscopy (TERS) allows label-free spectroscopic identification of molecular species, with ≈10 nm spatial resolution, and with single molecule sensitivity for strong Raman scatterers. So far, however, TERS is not being carried out in liquids, which is the natural environment for membranes, and its application to poor Raman scatterers such as components of 2D polymers, lipids, or other membrane compounds (proteins, sugars) is difficult. TERS has the potential to overcome the restrictions of other optical/spectroscopic methods to study 2D materials, namely (i) insufficient spatial resolution of diffraction-limited optical methods; (ii) the need for labelling for all methods relying on fluorescence; and (iii) the inability of some methods to work in liquids. I propose to address a number of scientific questions associated with the spatial organization, and the occurrence of defects in sensitive 2D molecular materials. The success of these studies will also rely critically on technical innovations of TERS that notably address the problem of energy dissipation. This will for the first time allow its application to study of complex, delicate 2D molecular systems without photochemical damage.
Project acronym 2DQP
Project Two-dimensional quantum photonics
Researcher (PI) Brian David GERARDOT
Host Institution (HI) HERIOT-WATT UNIVERSITY
Summary Quantum optics, the study of how discrete packets of light (photons) and matter interact, has led to the development of remarkable new technologies which exploit the bizarre properties of quantum mechanics. These quantum technologies are primed to revolutionize the fields of communication, information processing, and metrology in the coming years. Similar to contemporary technologies, the future quantum machinery will likely consist of a semiconductor platform to create and process the quantum information. However, to date the demanding requirements on a quantum photonic platform have yet to be satisfied with conventional bulk (three-dimensional) semiconductors. To surmount these well-known obstacles, a new paradigm in quantum photonics is required. Initiated by the recent discovery of single photon emitters in atomically flat (two-dimensional) semiconducting materials, 2DQP aims to be at the nucleus of a new approach by realizing quantum optics with ultra-stable (coherent) quantum states integrated into devices with electronic and photonic functionality. We will characterize, identify, engineer, and coherently manipulate localized quantum states in this two-dimensional quantum photonic platform. A vital component of 2DQP's vision is to go beyond the fundamental science and achieve the ideal solid-state single photon device yielding perfect extraction - 100% efficiency - of on-demand indistinguishable single photons. Finally, we will exploit this ideal device to implement the critical building block for a photonic quantum computer.
Quantum optics, the study of how discrete packets of light (photons) and matter interact, has led to the development of remarkable new technologies which exploit the bizarre properties of quantum mechanics. These quantum technologies are primed to revolutionize the fields of communication, information processing, and metrology in the coming years. Similar to contemporary technologies, the future quantum machinery will likely consist of a semiconductor platform to create and process the quantum information. However, to date the demanding requirements on a quantum photonic platform have yet to be satisfied with conventional bulk (three-dimensional) semiconductors. To surmount these well-known obstacles, a new paradigm in quantum photonics is required. Initiated by the recent discovery of single photon emitters in atomically flat (two-dimensional) semiconducting materials, 2DQP aims to be at the nucleus of a new approach by realizing quantum optics with ultra-stable (coherent) quantum states integrated into devices with electronic and photonic functionality. We will characterize, identify, engineer, and coherently manipulate localized quantum states in this two-dimensional quantum photonic platform. A vital component of 2DQP's vision is to go beyond the fundamental science and achieve the ideal solid-state single photon device yielding perfect extraction - 100% efficiency - of on-demand indistinguishable single photons. Finally, we will exploit this ideal device to implement the critical building block for a photonic quantum computer.
Project acronym 2O2ACTIVATION
Project Development of Direct Dehydrogenative Couplings mediated by Dioxygen
Researcher (PI) Frederic William Patureau
Summary The field of C-H bond activation has evolved at an exponential pace in the last 15 years. What appeals most in those novel synthetic techniques is clear: they bypass the pre-activation steps usually required in traditional cross-coupling chemistry by directly metalating C-H bonds. Many C-H bond functionalizations today however, rely on poorly atom and step efficient oxidants, leading to significant and costly chemical waste, thereby seriously undermining the overall sustainability of those methods. As restrictions in sustainability regulations will further increase, and the cost of certain chemical commodities will rise, atom efficiency in organic synthesis remains a top priority for research. The aim of 2O2ACTIVATION is to develop novel technologies utilizing O2 as sole terminal oxidant in order to allow useful, extremely sustainable, thermodynamically challenging, dehydrogenative C-N and C-O bond forming coupling reactions. However, the moderate reactivity of O2 towards many catalysts constitutes a major challenge. 2O2ACTIVATION will pioneer the design of new catalysts based on the ultra-simple propene motive, capable of direct activation of O2 for C-H activation based cross-couplings. The project is divided into 3 major lines: O2 activation using propene and its analogues (propenoids), 1) without metal or halide, 2) with hypervalent halide catalysis, 3) with metal catalyzed C-H activation. The philosophy of 2O2ACTIVATION is to focus C-H functionalization method development on the oxidative event. Consequently, 2O2ACTIVATION breakthroughs will dramatically shortcut synthetic routes through the use of inactivated, unprotected, and readily available building blocks; and thus should be easily scalable. This will lead to a strong decrease in the costs related to the production of many essential chemicals, while preserving the environment (water as terminal by-product). The resulting novels coupling methods will thus have a lasting impact on the chemical industry.
The field of C-H bond activation has evolved at an exponential pace in the last 15 years. What appeals most in those novel synthetic techniques is clear: they bypass the pre-activation steps usually required in traditional cross-coupling chemistry by directly metalating C-H bonds. Many C-H bond functionalizations today however, rely on poorly atom and step efficient oxidants, leading to significant and costly chemical waste, thereby seriously undermining the overall sustainability of those methods. As restrictions in sustainability regulations will further increase, and the cost of certain chemical commodities will rise, atom efficiency in organic synthesis remains a top priority for research. The aim of 2O2ACTIVATION is to develop novel technologies utilizing O2 as sole terminal oxidant in order to allow useful, extremely sustainable, thermodynamically challenging, dehydrogenative C-N and C-O bond forming coupling reactions. However, the moderate reactivity of O2 towards many catalysts constitutes a major challenge. 2O2ACTIVATION will pioneer the design of new catalysts based on the ultra-simple propene motive, capable of direct activation of O2 for C-H activation based cross-couplings. The project is divided into 3 major lines: O2 activation using propene and its analogues (propenoids), 1) without metal or halide, 2) with hypervalent halide catalysis, 3) with metal catalyzed C-H activation. The philosophy of 2O2ACTIVATION is to focus C-H functionalization method development on the oxidative event. Consequently, 2O2ACTIVATION breakthroughs will dramatically shortcut synthetic routes through the use of inactivated, unprotected, and readily available building blocks; and thus should be easily scalable. This will lead to a strong decrease in the costs related to the production of many essential chemicals, while preserving the environment (water as terminal by-product). The resulting novels coupling methods will thus have a lasting impact on the chemical industry.
Project acronym 321
Project from Cubic To Linear complexity in computational electromagnetics
Researcher (PI) Francesco Paolo ANDRIULLI
Host Institution (HI) POLITECNICO DI TORINO
Summary Computational Electromagnetics (CEM) is the scientific field at the origin of all new modeling and simulation tools required by the constantly arising design challenges of emerging and future technologies in applied electromagnetics. As in many other technological fields, however, the trend in all emerging technologies in electromagnetic engineering is going towards miniaturized, higher density and multi-scale scenarios. Computationally speaking this translates in the steep increase of the number of degrees of freedom. Given that the design cost (the cost of a multi-right-hand side problem dominated by matrix inversion) can scale as badly as cubically with these degrees of freedom, this fact, as pointed out by many, will sensibly compromise the practical impact of CEM on future and emerging technologies. For this reason, the CEM scientific community has been looking for years for a FFT-like paradigm shift: a dynamic fast direct solver providing a design cost that would scale only linearly with the degrees of freedom. Such a fast solver is considered today a Holy Grail of the discipline. The Grand Challenge of 321 will be to tackle this Holy Grail in Computational Electromagnetics by investigating a dynamic Fast Direct Solver for Maxwell Problems that would run in a linear-instead-of-cubic complexity for an arbitrary number and configuration of degrees of freedom. The failure of all previous attempts will be overcome by a game-changing transformation of the CEM classical problem that will leverage on a recent breakthrough of the PI. Starting from this, the project will investigate an entire new paradigm for impacting algorithms to achieve this grand challenge. The impact of the FFT's quadratic-to-linear paradigm shift shows how computational complexity reductions can be groundbreaking on applications. The cubic-to-linear paradigm shift, which the 321 project will aim for, will have such a rupturing impact on electromagnetic science and technology.
Computational Electromagnetics (CEM) is the scientific field at the origin of all new modeling and simulation tools required by the constantly arising design challenges of emerging and future technologies in applied electromagnetics. As in many other technological fields, however, the trend in all emerging technologies in electromagnetic engineering is going towards miniaturized, higher density and multi-scale scenarios. Computationally speaking this translates in the steep increase of the number of degrees of freedom. Given that the design cost (the cost of a multi-right-hand side problem dominated by matrix inversion) can scale as badly as cubically with these degrees of freedom, this fact, as pointed out by many, will sensibly compromise the practical impact of CEM on future and emerging technologies. For this reason, the CEM scientific community has been looking for years for a FFT-like paradigm shift: a dynamic fast direct solver providing a design cost that would scale only linearly with the degrees of freedom. Such a fast solver is considered today a Holy Grail of the discipline. The Grand Challenge of 321 will be to tackle this Holy Grail in Computational Electromagnetics by investigating a dynamic Fast Direct Solver for Maxwell Problems that would run in a linear-instead-of-cubic complexity for an arbitrary number and configuration of degrees of freedom. The failure of all previous attempts will be overcome by a game-changing transformation of the CEM classical problem that will leverage on a recent breakthrough of the PI. Starting from this, the project will investigate an entire new paradigm for impacting algorithms to achieve this grand challenge. The impact of the FFT's quadratic-to-linear paradigm shift shows how computational complexity reductions can be groundbreaking on applications. The cubic-to-linear paradigm shift, which the 321 project will aim for, will have such a rupturing impact on electromagnetic science and technology.
Project acronym 3D Reloaded
Project 3D Reloaded: Novel Algorithms for 3D Shape Inference and Analysis
Researcher (PI) Daniel Cremers
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Summary Despite their amazing success, we believe that computer vision algorithms have only scratched the surface of what can be done in terms of modeling and understanding our world from images. We believe that novel image analysis techniques will be a major enabler and driving force behind next-generation technologies, enhancing everyday life and opening up radically new possibilities. And we believe that the key to achieving this is to develop algorithms for reconstructing and analyzing the 3D structure of our world. In this project, we will focus on three lines of research: A) We will develop algorithms for 3D reconstruction from standard color cameras and from RGB-D cameras. In particular, we will promote real-time-capable direct and dense methods. In contrast to the classical two-stage approach of sparse feature-point based motion estimation and subsequent dense reconstruction, these methods optimally exploit all color information to jointly estimate dense geometry and camera motion. B) We will develop algorithms for 3D shape analysis, including rigid and non-rigid matching, decomposition and interpretation of 3D shapes. We will focus on algorithms which are optimal or near-optimal. One of the major computational challenges lies in generalizing existing 2D shape analysis techniques to shapes in 3D and 4D (temporal evolutions of 3D shape). C) We will develop shape priors for 3D reconstruction. These can be learned from sample shapes or acquired during the reconstruction process. For example, when reconstructing a larger office algorithms may exploit the geometric self-similarity of the scene, storing a model of a chair and its multiple instances only once rather than multiple times. Advancing the state of the art in geometric reconstruction and geometric analysis will have a profound impact well beyond computer vision. We strongly believe that we have the necessary competence to pursue this project. Preliminary results have been well received by the community.
Despite their amazing success, we believe that computer vision algorithms have only scratched the surface of what can be done in terms of modeling and understanding our world from images. We believe that novel image analysis techniques will be a major enabler and driving force behind next-generation technologies, enhancing everyday life and opening up radically new possibilities. And we believe that the key to achieving this is to develop algorithms for reconstructing and analyzing the 3D structure of our world. In this project, we will focus on three lines of research: A) We will develop algorithms for 3D reconstruction from standard color cameras and from RGB-D cameras. In particular, we will promote real-time-capable direct and dense methods. In contrast to the classical two-stage approach of sparse feature-point based motion estimation and subsequent dense reconstruction, these methods optimally exploit all color information to jointly estimate dense geometry and camera motion. B) We will develop algorithms for 3D shape analysis, including rigid and non-rigid matching, decomposition and interpretation of 3D shapes. We will focus on algorithms which are optimal or near-optimal. One of the major computational challenges lies in generalizing existing 2D shape analysis techniques to shapes in 3D and 4D (temporal evolutions of 3D shape). C) We will develop shape priors for 3D reconstruction. These can be learned from sample shapes or acquired during the reconstruction process. For example, when reconstructing a larger office algorithms may exploit the geometric self-similarity of the scene, storing a model of a chair and its multiple instances only once rather than multiple times. Advancing the state of the art in geometric reconstruction and geometric analysis will have a profound impact well beyond computer vision. We strongly believe that we have the necessary competence to pursue this project. Preliminary results have been well received by the community.
Project acronym 3D-BioMat
Project Deciphering biomineralization mechanisms through 3D explorations of mesoscale crystalline structure in calcareous biomaterials
Researcher (PI) VIRGINIE CHAMARD
Summary The fundamental 3D-BioMat project aims at providing a biomineralization model to explain the formation of microscopic calcareous single-crystals produced by living organisms. Although these crystals present a wide variety of shapes, associated to various organic materials, the observation of a nanoscale granular structure common to almost all calcareous crystallizing organisms, associated to an extended crystalline coherence, underlies a generic biomineralization and assembly process. A key to building realistic scenarios of biomineralization is to reveal the crystalline architecture, at the mesoscale, (i. e., over a few granules), which none of the existing nano-characterization tools is able to provide. 3D-BioMat is based on the recognized PI's expertise in the field of synchrotron coherent x-ray diffraction microscopy. It will extend the PI's disruptive pioneering microscopy formalism, towards an innovative high-throughput approach able at giving access to the 3D mesoscale image of the crystalline properties (crystal-line coherence, crystal plane tilts and strains) with the required flexibility, nanoscale resolution, and non-invasiveness. This achievement will be used to timely reveal the generics of the mesoscale crystalline structure through the pioneering explorations of a vast variety of crystalline biominerals produced by the famous Pinctada mar-garitifera oyster shell, and thereby build a realistic biomineralization scenario. The inferred biomineralization pathways, including both physico-chemical pathways and biological controls, will ultimately be validated by comparing the mesoscale structures produced by biomimetic samples with the biogenic ones. Beyond deciphering one of the most intriguing questions of material nanosciences, 3D-BioMat may contribute to new climate models, pave the way for new routes in material synthesis and supply answers to the pearl-culture calcification problems.
The fundamental 3D-BioMat project aims at providing a biomineralization model to explain the formation of microscopic calcareous single-crystals produced by living organisms. Although these crystals present a wide variety of shapes, associated to various organic materials, the observation of a nanoscale granular structure common to almost all calcareous crystallizing organisms, associated to an extended crystalline coherence, underlies a generic biomineralization and assembly process. A key to building realistic scenarios of biomineralization is to reveal the crystalline architecture, at the mesoscale, (i. e., over a few granules), which none of the existing nano-characterization tools is able to provide. 3D-BioMat is based on the recognized PI's expertise in the field of synchrotron coherent x-ray diffraction microscopy. It will extend the PI's disruptive pioneering microscopy formalism, towards an innovative high-throughput approach able at giving access to the 3D mesoscale image of the crystalline properties (crystal-line coherence, crystal plane tilts and strains) with the required flexibility, nanoscale resolution, and non-invasiveness. This achievement will be used to timely reveal the generics of the mesoscale crystalline structure through the pioneering explorations of a vast variety of crystalline biominerals produced by the famous Pinctada mar-garitifera oyster shell, and thereby build a realistic biomineralization scenario. The inferred biomineralization pathways, including both physico-chemical pathways and biological controls, will ultimately be validated by comparing the mesoscale structures produced by biomimetic samples with the biogenic ones. Beyond deciphering one of the most intriguing questions of material nanosciences, 3D-BioMat may contribute to new climate models, pave the way for new routes in material synthesis and supply answers to the pearl-culture calcification problems.
Project acronym 3D_Tryps
Project The role of three-dimensional genome architecture in antigenic variation
Researcher (PI) Tim Nicolai SIEGEL
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Summary Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism. The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression. I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen. The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.
Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism. The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression. I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen. The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.
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
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.
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.
Project acronym 3DSPIN
Project 3-Dimensional Maps of the Spinning Nucleon
Researcher (PI) Alessandro Bacchetta
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PAVIA
Summary How does the inside of the proton look like? What generates its spin?
3DSPIN will deliver essential information to answer these questions at the frontier of subnuclear physics. At present, we have detailed maps of the distribution of quarks and gluons in the nucleon in 1D (as a function of their momentum in a single direction). We also know that quark spins account for only about 1/3 of the spin of the nucleon. 3DSPIN will lead the way into a new stage of nucleon mapping, explore the distribution of quarks in full 3D momentum space and obtain unprecedented information on orbital angular momentum. Goals 1. extract from experimental data the 3D distribution of quarks (in momentum space), as described by Transverse-Momentum Distributions (TMDs); 2. obtain from TMDs information on quark Orbital Angular Momentum (OAM). Methodology 3DSPIN will implement state-of-the-art fitting procedures to analyze relevant experimental data and extract quark TMDs, similarly to global fits of standard parton distribution functions. Information about quark angular momentum will be obtained through assumptions based on theoretical considerations. The next five years represent an ideal time window to accomplish our goals, thanks to the wealth of expected data from deep-inelastic scattering experiments (COMPASS, Jefferson Lab), hadronic colliders (Fermilab, BNL, LHC), and electron-positron colliders (BELLE, BABAR). The PI has a strong reputation in this field. The group will operate in partnership with the Italian National Institute of Nuclear Physics and in close interaction with leading experts and experimental collaborations worldwide. Impact Mapping the 3D structure of chemical compounds has revolutionized chemistry. Similarly, mapping the 3D structure of the nucleon will have a deep impact on our understanding of the fundamental constituents of matter. We will open new perspectives on the dynamics of quarks and gluons and sharpen our view of high-energy processes involving nucleons.
How does the inside of the proton look like? What generates its spin?
3DSPIN will deliver essential information to answer these questions at the frontier of subnuclear physics. At present, we have detailed maps of the distribution of quarks and gluons in the nucleon in 1D (as a function of their momentum in a single direction). We also know that quark spins account for only about 1/3 of the spin of the nucleon. 3DSPIN will lead the way into a new stage of nucleon mapping, explore the distribution of quarks in full 3D momentum space and obtain unprecedented information on orbital angular momentum. Goals 1. extract from experimental data the 3D distribution of quarks (in momentum space), as described by Transverse-Momentum Distributions (TMDs); 2. obtain from TMDs information on quark Orbital Angular Momentum (OAM). Methodology 3DSPIN will implement state-of-the-art fitting procedures to analyze relevant experimental data and extract quark TMDs, similarly to global fits of standard parton distribution functions. Information about quark angular momentum will be obtained through assumptions based on theoretical considerations. The next five years represent an ideal time window to accomplish our goals, thanks to the wealth of expected data from deep-inelastic scattering experiments (COMPASS, Jefferson Lab), hadronic colliders (Fermilab, BNL, LHC), and electron-positron colliders (BELLE, BABAR). The PI has a strong reputation in this field. The group will operate in partnership with the Italian National Institute of Nuclear Physics and in close interaction with leading experts and experimental collaborations worldwide. Impact Mapping the 3D structure of chemical compounds has revolutionized chemistry. Similarly, mapping the 3D structure of the nucleon will have a deep impact on our understanding of the fundamental constituents of matter. We will open new perspectives on the dynamics of quarks and gluons and sharpen our view of high-energy processes involving nucleons.
Project acronym 3MC
Project 3D Model Catalysts to explore new routes to sustainable fuels
Researcher (PI) Petra Elisabeth De jongh
Host Institution (HI) UNIVERSITEIT UTRECHT
Summary Currently fuels, plastics, and drugs are predominantly manufactured from oil. A transition towards renewable resources critically depends on new catalysts, for instance to convert small molecules (such as solar or biomass derived hydrogen, carbon monoxide, water and carbon dioxide) into more complex ones (such as oxygenates, containing oxygen atoms in their structure). Catalyst development now often depends on trial and error rather than rational design, as the heterogeneity of these composite systems hampers detailed understanding of the role of each of the components. I propose 3D model catalysts as a novel enabling tool to overcome this problem. Their well-defined nature allows unprecedented precision in the variation of structural parameters (morphology, spatial distribution) of the individual components, while at the same time they mimic real catalysts closely enough to allow testing under industrially relevant conditions. Using this approach I will address fundamental questions, such as: * What are the mechanisms (structural, electronic, chemical) by which non-metal promoters influence the functionality of copper-based catalysts? * Which nanoalloys can be formed, how does their composition influence the surface active sites and catalytic functionality under reaction conditions? * Which size and interface effects occur, and how can we use them to tune the actitivity and selectivity towards desired products? Our 3D model catalysts will be assembled from ordered mesoporous silica and carbon support materials and Cu-based promoted and bimetallic nanoparticles. The combination with high resolution characterization and testing under realistic conditions allows detailed insight into the role of the different components; critical for the rational design of novel catalysts for a future more sustainable production of chemicals and fuels from renewable resources.
Currently fuels, plastics, and drugs are predominantly manufactured from oil. A transition towards renewable resources critically depends on new catalysts, for instance to convert small molecules (such as solar or biomass derived hydrogen, carbon monoxide, water and carbon dioxide) into more complex ones (such as oxygenates, containing oxygen atoms in their structure). Catalyst development now often depends on trial and error rather than rational design, as the heterogeneity of these composite systems hampers detailed understanding of the role of each of the components. I propose 3D model catalysts as a novel enabling tool to overcome this problem. Their well-defined nature allows unprecedented precision in the variation of structural parameters (morphology, spatial distribution) of the individual components, while at the same time they mimic real catalysts closely enough to allow testing under industrially relevant conditions. Using this approach I will address fundamental questions, such as: * What are the mechanisms (structural, electronic, chemical) by which non-metal promoters influence the functionality of copper-based catalysts? * Which nanoalloys can be formed, how does their composition influence the surface active sites and catalytic functionality under reaction conditions? * Which size and interface effects occur, and how can we use them to tune the actitivity and selectivity towards desired products? Our 3D model catalysts will be assembled from ordered mesoporous silica and carbon support materials and Cu-based promoted and bimetallic nanoparticles. The combination with high resolution characterization and testing under realistic conditions allows detailed insight into the role of the different components; critical for the rational design of novel catalysts for a future more sustainable production of chemicals and fuels from renewable resources.
Project acronym 4-TOPS
Project Four experiments in Topological Superconductivity.
Researcher (PI) Laurens Molenkamp
Host Institution (HI) JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Summary Topological materials have developed rapidly in recent years, with my previous ERC-AG project 3-TOP playing a major role in this development. While so far no bulk topological superconductor has been unambiguously demonstrated, their properties can be studied in a very flexible manner by inducing superconductivity through the proximity effect into the surface or edge states of a topological insulator. In 4-TOPS we will explore the possibilities of this approach in full, and conduct a thorough study of induced superconductivity in both two and three dimensional HgTe based topological insulators. The 4 avenues we will follow are: -SQUID based devices to investigate full phase dependent spectroscopy of the gapless Andreev bound state by studying their Josephson radiation and current-phase relationships. -Experiments aimed at providing unambiguous proof of localized Majorana states in TI junctions by studying tunnelling transport into such states. -Attempts to induce superconductivity in Quantum Hall states with the aim of creating a chiral topological superconductor. These chiral superconductors host Majorana fermions at their edges, which, at least in the case of a single QH edge mode, follow non-Abelian statistics and are therefore promising for explorations in topological quantum computing. -Studies of induced superconductivity in Weyl semimetals, a completely unexplored state of matter. Taken together, these four sets of experiments will greatly enhance our understanding of topological superconductivity, which is not only a subject of great academic interest as it constitutes the study of new phases of matter, but also has potential application in the field of quantum information processing.
Topological materials have developed rapidly in recent years, with my previous ERC-AG project 3-TOP playing a major role in this development. While so far no bulk topological superconductor has been unambiguously demonstrated, their properties can be studied in a very flexible manner by inducing superconductivity through the proximity effect into the surface or edge states of a topological insulator. In 4-TOPS we will explore the possibilities of this approach in full, and conduct a thorough study of induced superconductivity in both two and three dimensional HgTe based topological insulators. The 4 avenues we will follow are: -SQUID based devices to investigate full phase dependent spectroscopy of the gapless Andreev bound state by studying their Josephson radiation and current-phase relationships. -Experiments aimed at providing unambiguous proof of localized Majorana states in TI junctions by studying tunnelling transport into such states. -Attempts to induce superconductivity in Quantum Hall states with the aim of creating a chiral topological superconductor. These chiral superconductors host Majorana fermions at their edges, which, at least in the case of a single QH edge mode, follow non-Abelian statistics and are therefore promising for explorations in topological quantum computing. -Studies of induced superconductivity in Weyl semimetals, a completely unexplored state of matter. Taken together, these four sets of experiments will greatly enhance our understanding of topological superconductivity, which is not only a subject of great academic interest as it constitutes the study of new phases of matter, but also has potential application in the field of quantum information processing.
Project acronym 5HTCircuits
Project Modulation of cortical circuits and predictive neural coding by serotonin
Researcher (PI) Zachary Mainen
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Summary Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.
Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.
Project acronym 9 SALT
Project Reassessing Ninth Century Philosophy. A Synchronic Approach to the Logical Traditions
Researcher (PI) Christophe Florian Erismann
Host Institution (HI) UNIVERSITAT WIEN
Summary This project aims at a better understanding of the philosophical richness of ninth century thought using the unprecedented and highly innovative method of the synchronic approach. The hypothesis directing this synchronic approach is that studying together in parallel the four main philosophical traditions of the century – i.e. Latin, Greek, Syriac and Arabic – will bring results that the traditional enquiry limited to one tradition alone can never reach. This implies pioneering a new methodology to overcome the compartmentalization of research which prevails nowadays. Using this method is only possible because the four conditions of applicability – comparable intellectual environment, common text corpus, similar methodological perspective, commensurable problems – are fulfilled. The ninth century, a time of cultural renewal in the Carolingian, Byzantine and Abbasid empires, possesses the remarkable characteristic – which ensures commensurability – that the same texts, namely the writings of Aristotelian logic (mainly Porphyry's Isagoge and Aristotle's Categories) were read and commented upon in Latin, Greek, Syriac and Arabic alike. Logic is fundamental to philosophical enquiry. The contested question is the human capacity to rationalise, analyse and describe the sensible reality, to understand the ontological structure of the world, and to define the types of entities which exist. The use of this unprecedented synchronic approach will allow us a deeper understanding of the positions, a clear identification of the a priori postulates of the philosophical debates, and a critical evaluation of the arguments used. It provides a unique opportunity to compare the different traditions and highlight the heritage which is common, to stress the specificities of each tradition when tackling philosophical issues and to discover the doctrinal results triggered by their mutual interactions, be they constructive (scholarly exchanges) or polemic (religious controversies).
This project aims at a better understanding of the philosophical richness of ninth century thought using the unprecedented and highly innovative method of the synchronic approach. The hypothesis directing this synchronic approach is that studying together in parallel the four main philosophical traditions of the century – i.e. Latin, Greek, Syriac and Arabic – will bring results that the traditional enquiry limited to one tradition alone can never reach. This implies pioneering a new methodology to overcome the compartmentalization of research which prevails nowadays. Using this method is only possible because the four conditions of applicability – comparable intellectual environment, common text corpus, similar methodological perspective, commensurable problems – are fulfilled. The ninth century, a time of cultural renewal in the Carolingian, Byzantine and Abbasid empires, possesses the remarkable characteristic – which ensures commensurability – that the same texts, namely the writings of Aristotelian logic (mainly Porphyry's Isagoge and Aristotle's Categories) were read and commented upon in Latin, Greek, Syriac and Arabic alike. Logic is fundamental to philosophical enquiry. The contested question is the human capacity to rationalise, analyse and describe the sensible reality, to understand the ontological structure of the world, and to define the types of entities which exist. The use of this unprecedented synchronic approach will allow us a deeper understanding of the positions, a clear identification of the a priori postulates of the philosophical debates, and a critical evaluation of the arguments used. It provides a unique opportunity to compare the different traditions and highlight the heritage which is common, to stress the specificities of each tradition when tackling philosophical issues and to discover the doctrinal results triggered by their mutual interactions, be they constructive (scholarly exchanges) or polemic (religious controversies).
Project acronym A CACTUS
Project Antibody-free method for Counting All Circulating TUmour cellS while maintaining them alive and intact
Researcher (PI) Giacinto Scoles
Host Institution (HI) UNIVERSITA DEGLI STUDI DI UDINE
Summary The problem: Cancer metastases are responsible for 90% of cancer-associated deaths. Circulating tumour cells (CTCs) that enter the blood stream on their way to potential metastatic sites are of obvious interest to evaluate correctly patient treatment and therefore influence outcome. CTCs have been identified in bladder, gastric, prostate, lung, breast and colon cancer. The only FDA approved CTCs detection system is Veridex' CellSearch, which detects only epithelial cancer cells using antibody labelling. Recent evidence showed that non-epithelial cancer cells, which are not detected by CellSearch, are of critical importance in cancer progression. The idea: Our CTC detection method is based, instead of on antibody labelling, on metabolic features of cancer cells, thus providing potential for detecting both epithelial and mesenchymal cancer cells. Cancer cells induce environmental changes; e.g. in aerobic conditions most cancer cells display a high rate of glycolysis with lactate production in the cytosol, known as the Warburg effect. By separating cells into micro-droplets of pico-liter volume using micro-fluidic water-in-oil emulsions and by characterising the microenvironment surrounding them, CTCs are detected by probing for environmental changes using pH sensitive dyes or enzymatic lactate assays. Our inexpensive diagnostic method provides a way to count and isolate CTCs without any labelling while maintaining cells alive and intact for further studies. The project: "A CACTUS" is meant to assess the feasibility of commercialising the developed method for counting and sorting CTCs and develop a proper commercialisation strategy. The final goal of this project is to develop a proposition package consisting of technical proof of concept, the business proposition and strategy and an IP portfolio and strategy. This information will be presented in an attractive business plan that will be proposed to potential investors.
The problem: Cancer metastases are responsible for 90% of cancer-associated deaths. Circulating tumour cells (CTCs) that enter the blood stream on their way to potential metastatic sites are of obvious interest to evaluate correctly patient treatment and therefore influence outcome. CTCs have been identified in bladder, gastric, prostate, lung, breast and colon cancer. The only FDA approved CTCs detection system is Veridex' CellSearch, which detects only epithelial cancer cells using antibody labelling. Recent evidence showed that non-epithelial cancer cells, which are not detected by CellSearch, are of critical importance in cancer progression. The idea: Our CTC detection method is based, instead of on antibody labelling, on metabolic features of cancer cells, thus providing potential for detecting both epithelial and mesenchymal cancer cells. Cancer cells induce environmental changes; e.g. in aerobic conditions most cancer cells display a high rate of glycolysis with lactate production in the cytosol, known as the Warburg effect. By separating cells into micro-droplets of pico-liter volume using micro-fluidic water-in-oil emulsions and by characterising the microenvironment surrounding them, CTCs are detected by probing for environmental changes using pH sensitive dyes or enzymatic lactate assays. Our inexpensive diagnostic method provides a way to count and isolate CTCs without any labelling while maintaining cells alive and intact for further studies. The project: "A CACTUS" is meant to assess the feasibility of commercialising the developed method for counting and sorting CTCs and develop a proper commercialisation strategy. The final goal of this project is to develop a proposition package consisting of technical proof of concept, the business proposition and strategy and an IP portfolio and strategy. This information will be presented in an attractive business plan that will be proposed to potential investors.
Project acronym A-LIFE
Project Absorbing aerosol layers in a changing climate: aging, lifetime and dynamics
Researcher (PI) Bernadett Barbara Weinzierl
Summary Aerosols (i.e. tiny particles suspended in the air) are regularly transported in huge amounts over long distances impacting air quality, health, weather and climate thousands of kilometers downwind of the source. Aerosols affect the atmospheric radiation budget through scattering and absorption of solar radiation and through their role as cloud/ice nuclei. In particular, light absorption by aerosol particles such as mineral dust and black carbon (BC; thought to be the second strongest contribution to current global warming after CO2) is of fundamental importance from a climate perspective because the presence of absorbing particles (1) contributes to solar radiative forcing, (2) heats absorbing aerosol layers, (3) can evaporate clouds and (4) change atmospheric dynamics. Considering this prominent role of aerosols, vertically-resolved in-situ data on absorbing aerosols are surprisingly scarce and aerosol-dynamic interactions are poorly understood in general. This is, as recognized in the last IPCC report, a serious barrier for taking the accuracy of climate models and predictions to the next level. To overcome this barrier, I propose to investigate aging, lifetime and dynamics of absorbing aerosol layers with a holistic end-to-end approach including laboratory studies, airborne field experiments and numerical model simulations. Building on the internationally recognized results of my aerosol research group and my long-term experience with airborne aerosol measurements, the time seems ripe to systematically bridge the gap between in-situ measurements of aerosol microphysical and optical properties and the assessment of dynamical interactions of absorbing particles with aerosol layer lifetime through model simulations. The outcomes of this project will provide fundamental new understanding of absorbing aerosol layers in the climate system and important information for addressing the benefits of BC emission controls for mitigating climate change.
Aerosols (i.e. tiny particles suspended in the air) are regularly transported in huge amounts over long distances impacting air quality, health, weather and climate thousands of kilometers downwind of the source. Aerosols affect the atmospheric radiation budget through scattering and absorption of solar radiation and through their role as cloud/ice nuclei. In particular, light absorption by aerosol particles such as mineral dust and black carbon (BC; thought to be the second strongest contribution to current global warming after CO2) is of fundamental importance from a climate perspective because the presence of absorbing particles (1) contributes to solar radiative forcing, (2) heats absorbing aerosol layers, (3) can evaporate clouds and (4) change atmospheric dynamics. Considering this prominent role of aerosols, vertically-resolved in-situ data on absorbing aerosols are surprisingly scarce and aerosol-dynamic interactions are poorly understood in general. This is, as recognized in the last IPCC report, a serious barrier for taking the accuracy of climate models and predictions to the next level. To overcome this barrier, I propose to investigate aging, lifetime and dynamics of absorbing aerosol layers with a holistic end-to-end approach including laboratory studies, airborne field experiments and numerical model simulations. Building on the internationally recognized results of my aerosol research group and my long-term experience with airborne aerosol measurements, the time seems ripe to systematically bridge the gap between in-situ measurements of aerosol microphysical and optical properties and the assessment of dynamical interactions of absorbing particles with aerosol layer lifetime through model simulations. The outcomes of this project will provide fundamental new understanding of absorbing aerosol layers in the climate system and important information for addressing the benefits of BC emission controls for mitigating climate change.
Project acronym AArteMIS
Project Aneurysmal Arterial Mechanics: Into the Structure
Researcher (PI) Pierre Joseph Badel
Host Institution (HI) ASSOCIATION POUR LA RECHERCHE ET LE DEVELOPPEMENT DES METHODES ET PROCESSUS INDUSTRIELS
Summary The rupture of an Aortic Aneurysm (AA), which is often lethal, is a mechanical phenomenon that occurs when the wall stress state exceeds the local strength of the tissue. Our current understanding of arterial rupture mechanisms is poor, and the physics taking place at the microscopic scale in these collagenous structures remains an open area of research. Understanding, modelling, and quantifying the micro-mechanisms which drive the mechanical response of such tissue and locally trigger rupture represents the most challenging and promising pathway towards predictive diagnosis and personalized care of AA. The PI's group was recently able to detect, in advance, at the macro-scale, rupture-prone areas in bulging arterial tissues. The next step is to get into the details of the arterial microstructure to elucidate the underlying mechanisms. Through the achievements of AArteMIS, the local mechanical state of the fibrous microstructure of the tissue, especially close to its rupture state, will be quantitatively analyzed from multi-photon confocal microscopy and numerically reconstructed to establish quantitative micro-scale rupture criteria. AArteMIS will also address developing micro-macro models which are based on the collected quantitative data. The entire project will be completed through collaboration with medical doctors and engineers, experts in all required fields for the success of AArteMIS. AArteMIS is expected to open longed-for pathways for research in soft tissue mechanobiology which focuses on cell environment and to enable essential clinical applications for the quantitative assessment of AA rupture risk. It will significantly contribute to understanding fatal vascular events and improving cardiovascular treatments. It will provide a tremendous source of data and inspiration for subsequent applications and research by answering the most fundamental questions on AA rupture behaviour enabling ground-breaking clinical changes to take place.
The rupture of an Aortic Aneurysm (AA), which is often lethal, is a mechanical phenomenon that occurs when the wall stress state exceeds the local strength of the tissue. Our current understanding of arterial rupture mechanisms is poor, and the physics taking place at the microscopic scale in these collagenous structures remains an open area of research. Understanding, modelling, and quantifying the micro-mechanisms which drive the mechanical response of such tissue and locally trigger rupture represents the most challenging and promising pathway towards predictive diagnosis and personalized care of AA. The PI's group was recently able to detect, in advance, at the macro-scale, rupture-prone areas in bulging arterial tissues. The next step is to get into the details of the arterial microstructure to elucidate the underlying mechanisms. Through the achievements of AArteMIS, the local mechanical state of the fibrous microstructure of the tissue, especially close to its rupture state, will be quantitatively analyzed from multi-photon confocal microscopy and numerically reconstructed to establish quantitative micro-scale rupture criteria. AArteMIS will also address developing micro-macro models which are based on the collected quantitative data. The entire project will be completed through collaboration with medical doctors and engineers, experts in all required fields for the success of AArteMIS. AArteMIS is expected to open longed-for pathways for research in soft tissue mechanobiology which focuses on cell environment and to enable essential clinical applications for the quantitative assessment of AA rupture risk. It will significantly contribute to understanding fatal vascular events and improving cardiovascular treatments. It will provide a tremendous source of data and inspiration for subsequent applications and research by answering the most fundamental questions on AA rupture behaviour enabling ground-breaking clinical changes to take place.
Project acronym AB-SWITCH
Project Evaluation of commercial potential of a low-cost kit based on DNA-nanoswitches for the single-step measurement of diagnostic antibodies
Researcher (PI) Francesco RICCI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA TOR VERGATA
Summary "Antibodies are among the most widely monitored class of diagnostic biomarkers. Immunoassays market now covers about 1/3 of the global market of in-vitro diagnostics (about $50 billion). However, current methods for the detection of diagnostic antibodies are either qualitative or require cumbersome, resource-intensive laboratory procedures that need hours to provide clinicians with diagnostic information. A new method for fast and low-cost detection of antibodies will have a strong economic impact in the market of in-vitro diagnostics and Immunoassays. During our ERC Starting Grant project ""Nature Nanodevices"" we have developed a novel diagnostic technology for the detection of clinically relevant antibodies in serum and other body fluids. The platform (here named Ab-switch) supports the fluorescent detection of diagnostic antibodies (for example, HIV diagnostic antibodies) in a rapid (<3 minutes), single-step and low-cost fashion. The goal of this Proof of Concept project is to bring our promising platform to the proof of diagnostic market and exploit its innovative features for commercial purposes. We will focus our initial efforts in the development of rapid kits for the detection of antibodies diagnostic of HIV. We will 1) Fully characterize the Ab-switch product in terms of analytical performances (i.e. sensitivity, specificity, stability etc.) with direct comparison with other commercial kits; 2) Prepare a Manufacturing Plan for producing/testing the Ab-switch; 3) Establish an IP strategy for patent filing and maintenance; 4) Determine a business and commercialization planning."
"Antibodies are among the most widely monitored class of diagnostic biomarkers. Immunoassays market now covers about 1/3 of the global market of in-vitro diagnostics (about $50 billion). However, current methods for the detection of diagnostic antibodies are either qualitative or require cumbersome, resource-intensive laboratory procedures that need hours to provide clinicians with diagnostic information. A new method for fast and low-cost detection of antibodies will have a strong economic impact in the market of in-vitro diagnostics and Immunoassays. During our ERC Starting Grant project ""Nature Nanodevices"" we have developed a novel diagnostic technology for the detection of clinically relevant antibodies in serum and other body fluids. The platform (here named Ab-switch) supports the fluorescent detection of diagnostic antibodies (for example, HIV diagnostic antibodies) in a rapid (<3 minutes), single-step and low-cost fashion. The goal of this Proof of Concept project is to bring our promising platform to the proof of diagnostic market and exploit its innovative features for commercial purposes. We will focus our initial efforts in the development of rapid kits for the detection of antibodies diagnostic of HIV. We will 1) Fully characterize the Ab-switch product in terms of analytical performances (i.e. sensitivity, specificity, stability etc.) with direct comparison with other commercial kits; 2) Prepare a Manufacturing Plan for producing/testing the Ab-switch; 3) Establish an IP strategy for patent filing and maintenance; 4) Determine a business and commercialization planning."
Project acronym ABCvolume
Project The ABC of Cell Volume Regulation
Researcher (PI) Berend Poolman
Summary Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions. My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell. I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other. The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.
Cell volume regulation is crucial for any living cell because changes in volume determine the metabolic activity through e.g. changes in ionic strength, pH, macromolecular crowding and membrane tension. These physical chemical parameters influence interaction rates and affinities of biomolecules, folding rates, and fold stabilities in vivo. Understanding of the underlying volume regulatory mechanisms has immediate application in biotechnology and health, yet these factors are generally ignored in systems analyses of cellular functions. My team has uncovered a number of mechanisms and insights of cell volume regulation. The next step forward is to elucidate how the components of a cell volume regulatory circuit work together and control the physicochemical conditions of the cell. I propose construction of a synthetic cell in which an osmoregulatory transporter and mechanosensitive channel form a minimal volume regulatory network. My group has developed the technology to reconstitute membrane proteins into lipid vesicles (synthetic cells). One of the challenges is to incorporate into the vesicles an efficient pathway for ATP production and maintain energy homeostasis while the load on the system varies. We aim to control the transmembrane flux of osmolytes, which requires elucidation of the molecular mechanism of gating of the osmoregulatory transporter. We will focus on the glycine betaine ABC importer, which is one of the most complex transporters known to date with ten distinct protein domains, transiently interacting with each other. The proposed synthetic metabolic circuit constitutes a fascinating out-of-equilibrium system, allowing us to understand cell volume regulatory mechanisms in a context and at a level of complexity minimally needed for life. Analysis of this circuit will address many outstanding questions and eventually allow us to design more sophisticated vesicular systems with applications, for example as compartmentalized reaction networks.
Project acronym ABLASE
Project Advanced Bioderived and Biocompatible Lasers
Researcher (PI) Malte Christian Gather
Summary Naturally occurring optical phenomena attract great attention and transform our ability to study biological processes, with "the discovery and development of the green fluorescent protein (GFP)" (Nobel Prize in Chemistry 2008) being a particularly successful example. Although found only in very few species in nature, most organisms can be genetically programmed to produce the brightly fluorescent GFP molecules. Combined with modern fluorescence detection schemes, this has led to entirely new ways of monitoring biological processes. The applicant now demonstrated a biological laser – a completely novel, living source of coherent light based on a single biological cell bioengineered to produce GFP. Such a laser is intrinsically biocompatible, thus offering unique properties not shared by any existing laser. However, the physical processes involved in lasing from GFP remain poorly understood and so far biological lasers rely on bulky, impractical external resonators for optical feedback. Within this project, the applicant and his team will develop for the first time an understanding of stimulated emission in GFP and related proteins and create an unprecedented stand-alone single-cell biolaser based on intracellular optical feedback. These lasers will be deployed as microscopic and biocompatible imaging probes, thus opening in vivo microscopy to dense wavelength-multiplexing and enabling unmatched sensing of biomolecules and mechanical pressure. The evolutionarily evolved nano-structure of GFP will also enable novel ways of studying strong light-matter coupling and will bio-inspire advances of synthetic emitters. The proposed project is inter-disciplinary by its very nature, bridging photonics, genetic engineering and material science. The applicant's previous pioneering work and synergies with work on other lasers developed at the applicant's host institution provide an exclusive competitive edge. ERC support would transform this into a truly novel field of research.
Naturally occurring optical phenomena attract great attention and transform our ability to study biological processes, with "the discovery and development of the green fluorescent protein (GFP)" (Nobel Prize in Chemistry 2008) being a particularly successful example. Although found only in very few species in nature, most organisms can be genetically programmed to produce the brightly fluorescent GFP molecules. Combined with modern fluorescence detection schemes, this has led to entirely new ways of monitoring biological processes. The applicant now demonstrated a biological laser – a completely novel, living source of coherent light based on a single biological cell bioengineered to produce GFP. Such a laser is intrinsically biocompatible, thus offering unique properties not shared by any existing laser. However, the physical processes involved in lasing from GFP remain poorly understood and so far biological lasers rely on bulky, impractical external resonators for optical feedback. Within this project, the applicant and his team will develop for the first time an understanding of stimulated emission in GFP and related proteins and create an unprecedented stand-alone single-cell biolaser based on intracellular optical feedback. These lasers will be deployed as microscopic and biocompatible imaging probes, thus opening in vivo microscopy to dense wavelength-multiplexing and enabling unmatched sensing of biomolecules and mechanical pressure. The evolutionarily evolved nano-structure of GFP will also enable novel ways of studying strong light-matter coupling and will bio-inspire advances of synthetic emitters. The proposed project is inter-disciplinary by its very nature, bridging photonics, genetic engineering and material science. The applicant's previous pioneering work and synergies with work on other lasers developed at the applicant's host institution provide an exclusive competitive edge. ERC support would transform this into a truly novel field of research.
Project acronym ACCENT
Project Unravelling the architecture and the cartography of the human centriole
Researcher (PI) Paul, Philippe, Desiré GUICHARD
Host Institution (HI) UNIVERSITE DE GENEVE
Summary The centriole is the largest evolutionary conserved macromolecular structure responsible for building centrosomes and cilia or flagella in many eukaryotes. Centrioles are critical for the proper execution of important biological processes ranging from cell division to cell signaling. Moreover, centriolar defects have been associated to several human pathologies including ciliopathies and cancer. This state of facts emphasizes the importance of understanding centriole biogenesis. The study of centriole formation is a deep-rooted question, however our current knowledge on its molecular organization at high resolution remains fragmented and limited. In particular, exquisite details of the overall molecular architecture of the human centriole and in particular of its central core region are lacking to understand the basis of centriole organization and function. Resolving this important question represents a challenge that needs to be undertaken and will undoubtedly lead to groundbreaking advances. Another important question to tackle next is to develop innovative methods to enable the nanometric molecular mapping of centriolar proteins within distinct architectural elements of the centriole. This missing information will be key to unravel the molecular mechanisms behind centriolar organization. This research proposal aims at building a cartography of the human centriole by elucidating its molecular composition and architecture. To this end, we will combine the use of innovative and multidisciplinary techniques encompassing spatial proteomics, cryo-electron tomography, state-of-the-art microscopy and in vitro assays and to achieve a comprehensive molecular and structural view of the human centriole. All together, we expect that these advances will help understand basic principles underlying centriole and cilia formation as well as might have further relevance for human health.
The centriole is the largest evolutionary conserved macromolecular structure responsible for building centrosomes and cilia or flagella in many eukaryotes. Centrioles are critical for the proper execution of important biological processes ranging from cell division to cell signaling. Moreover, centriolar defects have been associated to several human pathologies including ciliopathies and cancer. This state of facts emphasizes the importance of understanding centriole biogenesis. The study of centriole formation is a deep-rooted question, however our current knowledge on its molecular organization at high resolution remains fragmented and limited. In particular, exquisite details of the overall molecular architecture of the human centriole and in particular of its central core region are lacking to understand the basis of centriole organization and function. Resolving this important question represents a challenge that needs to be undertaken and will undoubtedly lead to groundbreaking advances. Another important question to tackle next is to develop innovative methods to enable the nanometric molecular mapping of centriolar proteins within distinct architectural elements of the centriole. This missing information will be key to unravel the molecular mechanisms behind centriolar organization. This research proposal aims at building a cartography of the human centriole by elucidating its molecular composition and architecture. To this end, we will combine the use of innovative and multidisciplinary techniques encompassing spatial proteomics, cryo-electron tomography, state-of-the-art microscopy and in vitro assays and to achieve a comprehensive molecular and structural view of the human centriole. All together, we expect that these advances will help understand basic principles underlying centriole and cilia formation as well as might have further relevance for human health.
Project acronym ACETOGENS
Project Acetogenic bacteria: from basic physiology via gene regulation to application in industrial biotechnology
Researcher (PI) Volker MÜLLER
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Summary Demand for biofuels and other biologically derived commodities is growing worldwide as efforts increase to reduce reliance on fossil fuels and to limit climate change. Most commercial approaches rely on fermentations of organic matter with its inherent problems in producing CO2 and being in conflict with the food supply of humans. These problems are avoided if CO2 can be used as feedstock. Autotrophic organisms can fix CO2 by producing chemicals that are used as building blocks for the synthesis of cellular components (Biomass). Acetate-forming bacteria (acetogens) do neither require light nor oxygen for this and they can be used in bioreactors to reduce CO2 with hydrogen gas, carbon monoxide or an organic substrate. Gas fermentation using these bacteria has already been realized on an industrial level in two pre-commercial 100,000 gal/yr demonstration facilities to produce fuel ethanol from abundant waste gas resources (by LanzaTech). Acetogens can metabolise a wide variety of substrates that could be used for the production of biocommodities. However, their broad use to produce biofuels and platform chemicals from substrates other than gases or together with gases is hampered by our very limited knowledge about their metabolism and ability to use different substrates simultaneously. Nearly nothing is known about regulatory processes involved in substrate utilization or product formation but this is an absolute requirement for metabolic engineering approaches. The aim of this project is to provide this basic knowledge about metabolic routes in the acetogenic model strain Acetobacterium woodii and their regulation. We will unravel the function of "organelles" found in this bacterium and explore their potential as bio-nanoreactors for the production of biocommodities and pave the road for the industrial use of A. woodii in energy (hydrogen) storage. Thus, this project creates cutting-edge opportunities for the development of biosustainable technologies in Europe.
Demand for biofuels and other biologically derived commodities is growing worldwide as efforts increase to reduce reliance on fossil fuels and to limit climate change. Most commercial approaches rely on fermentations of organic matter with its inherent problems in producing CO2 and being in conflict with the food supply of humans. These problems are avoided if CO2 can be used as feedstock. Autotrophic organisms can fix CO2 by producing chemicals that are used as building blocks for the synthesis of cellular components (Biomass). Acetate-forming bacteria (acetogens) do neither require light nor oxygen for this and they can be used in bioreactors to reduce CO2 with hydrogen gas, carbon monoxide or an organic substrate. Gas fermentation using these bacteria has already been realized on an industrial level in two pre-commercial 100,000 gal/yr demonstration facilities to produce fuel ethanol from abundant waste gas resources (by LanzaTech). Acetogens can metabolise a wide variety of substrates that could be used for the production of biocommodities. However, their broad use to produce biofuels and platform chemicals from substrates other than gases or together with gases is hampered by our very limited knowledge about their metabolism and ability to use different substrates simultaneously. Nearly nothing is known about regulatory processes involved in substrate utilization or product formation but this is an absolute requirement for metabolic engineering approaches. The aim of this project is to provide this basic knowledge about metabolic routes in the acetogenic model strain Acetobacterium woodii and their regulation. We will unravel the function of "organelles" found in this bacterium and explore their potential as bio-nanoreactors for the production of biocommodities and pave the road for the industrial use of A. woodii in energy (hydrogen) storage. Thus, this project creates cutting-edge opportunities for the development of biosustainable technologies in Europe.
Project acronym ACHILLES-HEEL
Project Crop resistance improvement by mining natural and induced variation in host accessibility factors
Researcher (PI) Sebastian Schornack
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Summary Increasing crop yield to feed the world is a grand challenge of the 21st century but it is hampered by diseases caused by filamentous plant pathogens. The arms race between pathogen and plant demands constant adjustment of crop germplasm to tackle emerging pathogen races with new virulence features. To date, most crop disease resistance has relied on specific resistance genes that are effective only against a subset of races. We cannot solely rely on classical resistance genes to keep ahead of the pathogens. There is an urgent need to develop approaches based on knowledge of the pathogen's Achilles heel: core plant processes that are required for pathogen colonization. Our hypothesis is that disease resistance based on manipulation of host accessibility processes has a higher probability for durability, and is best identified using a broad host-range pathogen. I will employ the filamentous pathogen Phytophthora palmivora to mine plant alleles and unravel host processes providing microbial access in roots and leaves of monocot and dicot plants. In Aim 1 I will utilize plant symbiosis mutants and allelic variation to elucidate general mechanisms of colonization by filamentous microbes. Importantly, allelic variation will be studied in economically relevant barley and wheat to allow immediate translation into breeding programs. In Aim 2 I will perform a comparative study of microbial colonization in monocot and dicot roots and leaves. Transcriptional profiling of pathogen and plant will highlight common and contrasting principles and illustrate the impact of differential plant anatomies. We will challenge our findings by testing beneficial fungi to assess commonalities and differences between mutualist and pathogen colonization. We will use genetics, cell biology and genomics to find suitable resistance alleles highly relevant to crop production and global food security. At the completion of the project, I expect to have a set of genes for resistance breeding.
Increasing crop yield to feed the world is a grand challenge of the 21st century but it is hampered by diseases caused by filamentous plant pathogens. The arms race between pathogen and plant demands constant adjustment of crop germplasm to tackle emerging pathogen races with new virulence features. To date, most crop disease resistance has relied on specific resistance genes that are effective only against a subset of races. We cannot solely rely on classical resistance genes to keep ahead of the pathogens. There is an urgent need to develop approaches based on knowledge of the pathogen's Achilles heel: core plant processes that are required for pathogen colonization. Our hypothesis is that disease resistance based on manipulation of host accessibility processes has a higher probability for durability, and is best identified using a broad host-range pathogen. I will employ the filamentous pathogen Phytophthora palmivora to mine plant alleles and unravel host processes providing microbial access in roots and leaves of monocot and dicot plants. In Aim 1 I will utilize plant symbiosis mutants and allelic variation to elucidate general mechanisms of colonization by filamentous microbes. Importantly, allelic variation will be studied in economically relevant barley and wheat to allow immediate translation into breeding programs. In Aim 2 I will perform a comparative study of microbial colonization in monocot and dicot roots and leaves. Transcriptional profiling of pathogen and plant will highlight common and contrasting principles and illustrate the impact of differential plant anatomies. We will challenge our findings by testing beneficial fungi to assess commonalities and differences between mutualist and pathogen colonization. We will use genetics, cell biology and genomics to find suitable resistance alleles highly relevant to crop production and global food security. At the completion of the project, I expect to have a set of genes for resistance breeding.
Project acronym ACOFORS
Project Launching Acoustic Force Spectroscopy - unlocking the potential of biomolecular bungee jumping
Researcher (PI) Gijs Jan Lodewijk Wuite
Host Institution (HI) STICHTING VU
Summary ACOFORS has been designed with the ultimate goal of preparing commercialisation of Acoustic Force Spectroscopy (AFS). AFS is a completely new and powerful technique for determining biomolecular mechanics and structure of single molecules such as DNA and proteins. These studies are performed on a large scale by biologists and within pharmaceutical companies for e.g. drug discovery and development. Current technologies for force spectroscopy (FS) represent a $50+ million market, but are expensive, require high levels of specialism and are laborious. AFS, invented in the laboratory of Prof. Wuite, is much simpler to use, can be operated in high-throughput mode and can become available at relative low cost. As such, AFS vastly expands the possibilities of FS and makes it available to a much wider community. This makes AFS a very attractive technology for science and business, both from the perspective of the user and of the seller. In ACOFORS, a team of scientists and business developers will transform the current prototype in a marketable product, strengthen the intellectual property position, build a solid business case based on an extensive market analysis and take steps towards licensing the technology to industry.
ACOFORS has been designed with the ultimate goal of preparing commercialisation of Acoustic Force Spectroscopy (AFS). AFS is a completely new and powerful technique for determining biomolecular mechanics and structure of single molecules such as DNA and proteins. These studies are performed on a large scale by biologists and within pharmaceutical companies for e.g. drug discovery and development. Current technologies for force spectroscopy (FS) represent a $50+ million market, but are expensive, require high levels of specialism and are laborious. AFS, invented in the laboratory of Prof. Wuite, is much simpler to use, can be operated in high-throughput mode and can become available at relative low cost. As such, AFS vastly expands the possibilities of FS and makes it available to a much wider community. This makes AFS a very attractive technology for science and business, both from the perspective of the user and of the seller. In ACOFORS, a team of scientists and business developers will transform the current prototype in a marketable product, strengthen the intellectual property position, build a solid business case based on an extensive market analysis and take steps towards licensing the technology to industry.
Project acronym ACOUSEQ
Project Acoustics for Next Generation Sequencing
Researcher (PI) Jonathan Mark Cooper
Summary Since completion of the first human genome sequence, the demand for cheaper and faster sequencing methods has increased enormously. This need has driven the development of second-generation sequencing methods, or next-generation sequencing (also known as NGS or high throughput sequencing). The creation of these platforms has made sequencing accessible to more laboratories, rapidly increasing the volume of research, including clinical diagnostics and its use in directing treatment (precision medicine). The applications of NGS are also allowing rapid advances in clinically related fields such as public health and epidemiology. Such developments illustrate why sequencing is now the fastest-growing area in genomics (+23% p.a.). The activity is said to be worth $2.5B this year, and poised to reach ~$9B by 2020. In any workflow, prior to the sequencing reactions, a number of pre-sequencing steps are required, including the fragmentation of the DNA into smaller sizes for processing, size selection, library preparation and target enrichment. This proposal is specifically concerned with this latter area, namely DNA fragmentation – now widely acknowledged across the industry as being the most important technological bottleneck in the pre-sequencing workflow. Our new method for DNA fragmentation – involving using surface acoustic waves will enable sample preparation from lower sample volumes using lower powers. It also has the potential to allow the seamless integration of fragmentation into sequencing instrumentation, opening up the possibility of "sample to answer" diagnostics. In the near term this will enable the implementation of sample preparation pre-sequencing steps within the NGS instruments. In the longer term, our techniques will also enable us to develop methods for field-based DNA sequencing – as may be required for determining "microbial resistance" and informing the treatment of infectious disease in the face of the emergence of drug resistance.
Since completion of the first human genome sequence, the demand for cheaper and faster sequencing methods has increased enormously. This need has driven the development of second-generation sequencing methods, or next-generation sequencing (also known as NGS or high throughput sequencing). The creation of these platforms has made sequencing accessible to more laboratories, rapidly increasing the volume of research, including clinical diagnostics and its use in directing treatment (precision medicine). The applications of NGS are also allowing rapid advances in clinically related fields such as public health and epidemiology. Such developments illustrate why sequencing is now the fastest-growing area in genomics (+23% p.a.). The activity is said to be worth $2.5B this year, and poised to reach ~$9B by 2020. In any workflow, prior to the sequencing reactions, a number of pre-sequencing steps are required, including the fragmentation of the DNA into smaller sizes for processing, size selection, library preparation and target enrichment. This proposal is specifically concerned with this latter area, namely DNA fragmentation – now widely acknowledged across the industry as being the most important technological bottleneck in the pre-sequencing workflow. Our new method for DNA fragmentation – involving using surface acoustic waves will enable sample preparation from lower sample volumes using lower powers. It also has the potential to allow the seamless integration of fragmentation into sequencing instrumentation, opening up the possibility of "sample to answer" diagnostics. In the near term this will enable the implementation of sample preparation pre-sequencing steps within the NGS instruments. In the longer term, our techniques will also enable us to develop methods for field-based DNA sequencing – as may be required for determining "microbial resistance" and informing the treatment of infectious disease in the face of the emergence of drug resistance.
Project acronym aCROBAT
Project Circadian Regulation Of Brown Adipose Thermogenesis
Researcher (PI) Zachary Philip Gerhart-Hines
Host Institution (HI) KOBENHAVNS UNIVERSITET
Summary Obesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energy-dissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blood-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, small-scale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes.
Obesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energy-dissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blood-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, small-scale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes.
Project acronym ACrossWire
Project A Cross-Correlated Approach to Engineering Nitride Nanowires
Researcher (PI) Hannah Jane JOYCE
Summary Nanowires based on group III–nitride semiconductors exhibit outstanding potential for emerging applications in energy-efficient lighting, optoelectronics and solar energy harvesting. Nitride nanowires, tailored at the nanoscale, should overcome many of the challenges facing conventional planar nitride materials, and also add extraordinary new functionality to these materials. However, progress towards III–nitride nanowire devices has been hampered by the challenges in quantifying nanowire electrical properties using conventional contact-based measurements. Without reliable electrical transport data, it is extremely difficult to optimise nanowire growth and device design. This project aims to overcome this problem through an unconventional approach: advanced contact-free electrical measurements. Contact-free measurements, growth studies, and device studies will be cross-correlated to provide unprecedented insight into the growth mechanisms that govern nanowire electronic properties and ultimately dictate device performance. A key contact-free technique at the heart of this proposal is ultrafast terahertz conductivity spectroscopy: an advanced technique ideal for probing nanowire electrical properties. We will develop new methods to enable the full suite of contact-free (including terahertz, photoluminescence and cathodoluminescence measurements) and contact-based measurements to be performed with high spatial resolution on the same nanowires. This will provide accurate, comprehensive and cross-correlated feedback to guide growth studies and expedite the targeted development of nanowires with specified functionality. We will apply this powerful approach to tailor nanowires as photoelectrodes for solar photoelectrochemical water splitting. This is an application for which nitride nanowires have outstanding, yet unfulfilled, potential. This project will thus harness the true potential of nitride nanowires and bring them to the forefront of 21st century technology.
Nanowires based on group III–nitride semiconductors exhibit outstanding potential for emerging applications in energy-efficient lighting, optoelectronics and solar energy harvesting. Nitride nanowires, tailored at the nanoscale, should overcome many of the challenges facing conventional planar nitride materials, and also add extraordinary new functionality to these materials. However, progress towards III–nitride nanowire devices has been hampered by the challenges in quantifying nanowire electrical properties using conventional contact-based measurements. Without reliable electrical transport data, it is extremely difficult to optimise nanowire growth and device design. This project aims to overcome this problem through an unconventional approach: advanced contact-free electrical measurements. Contact-free measurements, growth studies, and device studies will be cross-correlated to provide unprecedented insight into the growth mechanisms that govern nanowire electronic properties and ultimately dictate device performance. A key contact-free technique at the heart of this proposal is ultrafast terahertz conductivity spectroscopy: an advanced technique ideal for probing nanowire electrical properties. We will develop new methods to enable the full suite of contact-free (including terahertz, photoluminescence and cathodoluminescence measurements) and contact-based measurements to be performed with high spatial resolution on the same nanowires. This will provide accurate, comprehensive and cross-correlated feedback to guide growth studies and expedite the targeted development of nanowires with specified functionality. We will apply this powerful approach to tailor nanowires as photoelectrodes for solar photoelectrochemical water splitting. This is an application for which nitride nanowires have outstanding, yet unfulfilled, potential. This project will thus harness the true potential of nitride nanowires and bring them to the forefront of 21st century technology.
Project acronym ACTICELL
Project Precision confiner for mechanical cell activation
Researcher (PI) Matthieu PIEL
Host Institution (HI) INSTITUT CURIE
Summary In tissues, cells have their physical space constrained by neighbouring cells and extracellular matrix. In the PROMICO ERC project, our team proposed to specifically address the effect of physical confinement on normal and cancer cells that are dividing and migrating, using new pathophysiologically relevant in vitro approaches based on innovative micro-fabrication techniques. One of the devices we developed was meant to quantitatively control two key parameters of the cell environment: its geometry and its surface chemical properties. The main technical breakthrough was achieved using micro-fabricated elastomeric structures bound to a hard substrate (Le Berre Integrative Biology, 2012). The method led to important fundamental discoveries in cell biology (Lancaster Dev Cell 2013, Le Berre PRL 2013, Liu Cell 2015, Raab Science 2016). In part based on our findings, the notion that confinement is a crucial parameter for cell physiology has spread through the cell biology. Based on this, our idea is that cell confinement could be used as a powerfull cell conditioning technology, to change the cell state and offer new opportunities for fundamental research in cell biology, but also in cell therapies and drug screening. However, our current method to confine cells is not adapted to large scale cell conditioning applications, because the throughput and reliability of the device is still too low and because the recovery of cells after confinement remain poorly controlled. It is thus now timely to develop a robust and versatile cell confiner adapted to use in any cell biology lab, in academy and in industry, with no prior experience in micro-fabrication. Achieving this goal involves a complete change of technology compared to the 'homemade' PDMS device we have been using so far. We will also perform proofs of concept of its use for its application in cell based therapies, such as cancer immunotherapy, by testing the possibility to mechanically activate dendritic cells.
In tissues, cells have their physical space constrained by neighbouring cells and extracellular matrix. In the PROMICO ERC project, our team proposed to specifically address the effect of physical confinement on normal and cancer cells that are dividing and migrating, using new pathophysiologically relevant in vitro approaches based on innovative micro-fabrication techniques. One of the devices we developed was meant to quantitatively control two key parameters of the cell environment: its geometry and its surface chemical properties. The main technical breakthrough was achieved using micro-fabricated elastomeric structures bound to a hard substrate (Le Berre Integrative Biology, 2012). The method led to important fundamental discoveries in cell biology (Lancaster Dev Cell 2013, Le Berre PRL 2013, Liu Cell 2015, Raab Science 2016). In part based on our findings, the notion that confinement is a crucial parameter for cell physiology has spread through the cell biology. Based on this, our idea is that cell confinement could be used as a powerfull cell conditioning technology, to change the cell state and offer new opportunities for fundamental research in cell biology, but also in cell therapies and drug screening. However, our current method to confine cells is not adapted to large scale cell conditioning applications, because the throughput and reliability of the device is still too low and because the recovery of cells after confinement remain poorly controlled. It is thus now timely to develop a robust and versatile cell confiner adapted to use in any cell biology lab, in academy and in industry, with no prior experience in micro-fabrication. Achieving this goal involves a complete change of technology compared to the 'homemade' PDMS device we have been using so far. We will also perform proofs of concept of its use for its application in cell based therapies, such as cancer immunotherapy, by testing the possibility to mechanically activate dendritic cells.
Project acronym ACTINIT
Project Brain-behavior forecasting: The causal determinants of spontaneous self-initiated action in the study of volition and the development of asynchronous brain-computer interfaces.
Researcher (PI) Aaron Schurger
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Summary "How are actions initiated by the human brain when there is no external sensory cue or other immediate imperative? How do subtle ongoing interactions within the brain and between the brain, body, and sensory context influence the spontaneous initiation of action? How should we approach the problem of trying to identify the neural events that cause spontaneous voluntary action? Much is understood about how the brain decides between competing alternatives, leading to different behavioral responses. But far less is known about how the brain decides "when" to perform an action, or "whether" to perform an action in the first place, especially in a context where there is no sensory cue to act such as during foraging. This project seeks to open a new chapter in the study of spontaneous voluntary action building on a novel hypothesis recently introduced by the applicant (Schurger et al, PNAS 2012) concerning the role of ongoing neural activity in action initiation. We introduce brain-behavior forecasting, the converse of movement-locked averaging, as an approach to identifying the neurodynamic states that commit the motor system to performing an action "now", and will apply it in the context of information foraging. Spontaneous action remains a profound mystery in the brain basis of behavior, in humans and other animals, and is also central to the problem of asynchronous intention-detection in brain-computer interfaces (BCIs). A BCI must not only interpret what the user intends, but also must detect "when" the user intends to act, and not respond otherwise. This remains the biggest challenge in the development of high-performance BCIs, whether invasive or non-invasive. This project will take a systematic and collaborative approach to the study of spontaneous self-initiated action, incorporating computational modeling, neuroimaging, and machine learning techniques towards a deeper understanding of voluntary behavior and the robust asynchronous detection of decisions-to-act."
"How are actions initiated by the human brain when there is no external sensory cue or other immediate imperative? How do subtle ongoing interactions within the brain and between the brain, body, and sensory context influence the spontaneous initiation of action? How should we approach the problem of trying to identify the neural events that cause spontaneous voluntary action? Much is understood about how the brain decides between competing alternatives, leading to different behavioral responses. But far less is known about how the brain decides "when" to perform an action, or "whether" to perform an action in the first place, especially in a context where there is no sensory cue to act such as during foraging. This project seeks to open a new chapter in the study of spontaneous voluntary action building on a novel hypothesis recently introduced by the applicant (Schurger et al, PNAS 2012) concerning the role of ongoing neural activity in action initiation. We introduce brain-behavior forecasting, the converse of movement-locked averaging, as an approach to identifying the neurodynamic states that commit the motor system to performing an action "now", and will apply it in the context of information foraging. Spontaneous action remains a profound mystery in the brain basis of behavior, in humans and other animals, and is also central to the problem of asynchronous intention-detection in brain-computer interfaces (BCIs). A BCI must not only interpret what the user intends, but also must detect "when" the user intends to act, and not respond otherwise. This remains the biggest challenge in the development of high-performance BCIs, whether invasive or non-invasive. This project will take a systematic and collaborative approach to the study of spontaneous self-initiated action, incorporating computational modeling, neuroimaging, and machine learning techniques towards a deeper understanding of voluntary behavior and the robust asynchronous detection of decisions-to-act."
Project acronym ActiveBioFluids
Project Origins of Collective Motion in Active Biofluids
Researcher (PI) Daniel TAM
Summary The emergence of coherent behaviour is ubiquitous in the natural world and has long captivated biologists and physicists alike. One area of growing interest is the collective motion and synchronization arising within and between simple motile organisms. My goal is to develop and use a novel experimental approach to unravel the origins of spontaneous coherent motion in three model systems of biofluids: (1) the synchronization of the two flagella of green algae Chlamydomonas Rheinhardtii, (2) the metachronal wave in the cilia of protist Paramecium and (3) the collective motion of swimming microorganisms in active suspensions. Understanding the mechanisms leading to collective motion is of tremendous importance because it is crucial to many biological processes such as mechanical signal transduction, embryonic development and biofilm formation. Up till now, most of the work has been theoretical and has led to the dominant view that hydrodynamic interactions are the main driving force for synchronization and collective motion. Recent experiments have challenged this view and highlighted the importance of direct mechanical contact. New experimental studies are now crucially needed. The state-of-the-art of experimental approaches consists of observations of unperturbed cells. The key innovation in our approach is to dynamically interact with microorganisms in real-time, at the relevant time and length scales. I will investigate the origins of coherent motion by reproducing synthetically the mechanical signatures of physiological flows and direct mechanical interactions and track precisely the response of the organism to the perturbations. Our new approach will incorporate optical tweezers to interact with motile cells, and a unique μ-Tomographic PIV setup to track their 3D micron-scale motion. This proposal tackles a timely question in biophysics and will yield new insight into the fundamental principles underlying collective motion in active biological matter.
The emergence of coherent behaviour is ubiquitous in the natural world and has long captivated biologists and physicists alike. One area of growing interest is the collective motion and synchronization arising within and between simple motile organisms. My goal is to develop and use a novel experimental approach to unravel the origins of spontaneous coherent motion in three model systems of biofluids: (1) the synchronization of the two flagella of green algae Chlamydomonas Rheinhardtii, (2) the metachronal wave in the cilia of protist Paramecium and (3) the collective motion of swimming microorganisms in active suspensions. Understanding the mechanisms leading to collective motion is of tremendous importance because it is crucial to many biological processes such as mechanical signal transduction, embryonic development and biofilm formation. Up till now, most of the work has been theoretical and has led to the dominant view that hydrodynamic interactions are the main driving force for synchronization and collective motion. Recent experiments have challenged this view and highlighted the importance of direct mechanical contact. New experimental studies are now crucially needed. The state-of-the-art of experimental approaches consists of observations of unperturbed cells. The key innovation in our approach is to dynamically interact with microorganisms in real-time, at the relevant time and length scales. I will investigate the origins of coherent motion by reproducing synthetically the mechanical signatures of physiological flows and direct mechanical interactions and track precisely the response of the organism to the perturbations. Our new approach will incorporate optical tweezers to interact with motile cells, and a unique μ-Tomographic PIV setup to track their 3D micron-scale motion. This proposal tackles a timely question in biophysics and will yield new insight into the fundamental principles underlying collective motion in active biological matter.
Project acronym ActiveCortex
Project Active dendrites and cortical associations
Researcher (PI) Matthew Larkum
Host Institution (HI) HUMBOLDT-UNIVERSITAET ZU BERLIN
Summary Converging studies from psychophysics in humans to single-cell recordings in monkeys and rodents indicate that most important cognitive processes depend on both feed-forward and feedback information interacting in the brain. Intriguingly, feedback to early cortical processing stages appears to play a causal role in these processes. Despite the central nature of this fact to understanding brain cognition, there is still no mechanistic explanation as to how this information could be so pivotal and what events take place that might be decisive. In this research program, we will test the hypothesis that the extraordinary performance of the cortex derives from an associative mechanism built into the basic neuronal unit: the pyramidal cell. The hypothesis is based on two important facts: (1) feedback information is conveyed predominantly to layer 1 and (2) the apical tuft dendrites that are the major recipient of this feedback information are highly electrogenic. The research program is divided in to several workpackages to systematically investigate the hypothesis at every level. As a whole, we will investigate the causal link between intrinsic cellular activity and behaviour. To do this we will use eletrophysiological and optical techniques to record and influence cell the intrinsic properties of cells (in particular dendritic activity) in vivo and in vitro in rodents. In vivo experiments will have a specific focus on context driven behaviour and in vitro experiments on the impact of long-range (feedback-carrying) fibers on cell activity. The study will also focus on synaptic plasticity at the interface of feedback information and dendritic electrogenesis, namely synapses on to the tuft dendrite of pyramidal neurons. The proposed program will not only address a long-standing and important hypothesis but also provide a transformational contribution towards understanding the operation of the cerebral cortex.
Converging studies from psychophysics in humans to single-cell recordings in monkeys and rodents indicate that most important cognitive processes depend on both feed-forward and feedback information interacting in the brain. Intriguingly, feedback to early cortical processing stages appears to play a causal role in these processes. Despite the central nature of this fact to understanding brain cognition, there is still no mechanistic explanation as to how this information could be so pivotal and what events take place that might be decisive. In this research program, we will test the hypothesis that the extraordinary performance of the cortex derives from an associative mechanism built into the basic neuronal unit: the pyramidal cell. The hypothesis is based on two important facts: (1) feedback information is conveyed predominantly to layer 1 and (2) the apical tuft dendrites that are the major recipient of this feedback information are highly electrogenic. The research program is divided in to several workpackages to systematically investigate the hypothesis at every level. As a whole, we will investigate the causal link between intrinsic cellular activity and behaviour. To do this we will use eletrophysiological and optical techniques to record and influence cell the intrinsic properties of cells (in particular dendritic activity) in vivo and in vitro in rodents. In vivo experiments will have a specific focus on context driven behaviour and in vitro experiments on the impact of long-range (feedback-carrying) fibers on cell activity. The study will also focus on synaptic plasticity at the interface of feedback information and dendritic electrogenesis, namely synapses on to the tuft dendrite of pyramidal neurons. The proposed program will not only address a long-standing and important hypothesis but also provide a transformational contribution towards understanding the operation of the cerebral cortex.
Project acronym ACTIVEPHANTOM
Project Active Organ Phantoms for Medical Robotics
Researcher (PI) Peer FISCHER
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Summary Robot-assisted and minimally invasive medical procedures are impacting medical care by increasing accuracy, reducing cost, and minimizing patient discomfort and recovery times after interventions. Developers of commercial robotic surgical systems and medical device manufacturers look for realistic phantoms that can be used in place of animal experiments or cadavers to test procedures and to train medical personnel. Existing phantoms are either made from hard materials, or they lack anatomical detail, and they are mainly passive and thus unrealistic. Here, we use recently developed fabrication know-how and expertise within our ERC-funded research to develop the first active artificial urinary tract model that includes a kidney, a bladder, and a prostate. Rapid prototyping is combined with a fabrication step that we have developed to permit the incorporation of active elements, such as a peristaltic system and fluidic valves in the phantom. We have developed smart material composites that reproduce the mechanical and haptic properties, and that give ultrasound contrast indistinguishable from real organs, while permitting anatomical details to be reproduced with a mean error of as little as 500 microns. Feedback from a major medical device company indicates that ours is a unique phantom with unprecedented accuracy for which there is a market. Within this POC grant we want to develop a complete prototype, and to demonstrate a series of medical interventions on the phantom, including endoscopic diagnostic procedures (cystoscopy and ureterorenoscopy) and endoscopic treatment procedures (laser lithotripsy). The grant will allow us to protect our know-how, identify further markets, and develop a commercialization strategy. Overall, this project will generate the first active phantom system that permits the testing of surgical instruments and procedures, with a sizeable market potential.
Robot-assisted and minimally invasive medical procedures are impacting medical care by increasing accuracy, reducing cost, and minimizing patient discomfort and recovery times after interventions. Developers of commercial robotic surgical systems and medical device manufacturers look for realistic phantoms that can be used in place of animal experiments or cadavers to test procedures and to train medical personnel. Existing phantoms are either made from hard materials, or they lack anatomical detail, and they are mainly passive and thus unrealistic. Here, we use recently developed fabrication know-how and expertise within our ERC-funded research to develop the first active artificial urinary tract model that includes a kidney, a bladder, and a prostate. Rapid prototyping is combined with a fabrication step that we have developed to permit the incorporation of active elements, such as a peristaltic system and fluidic valves in the phantom. We have developed smart material composites that reproduce the mechanical and haptic properties, and that give ultrasound contrast indistinguishable from real organs, while permitting anatomical details to be reproduced with a mean error of as little as 500 microns. Feedback from a major medical device company indicates that ours is a unique phantom with unprecedented accuracy for which there is a market. Within this POC grant we want to develop a complete prototype, and to demonstrate a series of medical interventions on the phantom, including endoscopic diagnostic procedures (cystoscopy and ureterorenoscopy) and endoscopic treatment procedures (laser lithotripsy). The grant will allow us to protect our know-how, identify further markets, and develop a commercialization strategy. Overall, this project will generate the first active phantom system that permits the testing of surgical instruments and procedures, with a sizeable market potential.
Project acronym ADAPTIVE
Project Industrial implementation of adaptive computational methods for turbulent flow and fluid-structure interaction
Researcher (PI) Johan Kjell Robert Hoffman
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Summary The ERC StG project UNICON (Project ID 202984) was completed in July 2013. The goal of UNICON was to develop new adaptive finite element methods for computer simulation of fluid-structure interaction, in particular for problems involving turbulent flow. Simulation of turbulent flow is an outstanding computational challenge, where the UNICON project made significant progress beyond the state of the art. The scientific results of the UNICON project include a new theoretical and methodological framework, and a computer implementation of the methods as open source software, published as part of the FEniCS project, co-founded by the PI (Hoffman) in 2003. FEniCS is today a world leading open source software for computer simulation based on differential equations, with an estimated 50 000 downloads per year, and the PI today leads the PRACE Tier-0 project FEniCS-HPC, in which algorithms and software are developed for the most powerful supercomputers in Europe. Compared to competing simulation software, free as well as commercial, UNICON computational technology has proven to exhibit unique features with respect to accuracy and efficiency. The idea of this ERC PoC project is to commercialize the UNICON simulation technology. In particular, ADAPTIVE targets civil (non-military) industry, with a focus on subsonic fluid dynamics. The strategy is to deliver services and products tailored to each customer, from deliverance of a simulation result, to education and support for integration of the simulation tools in the workflow of a customer.
The ERC StG project UNICON (Project ID 202984) was completed in July 2013. The goal of UNICON was to develop new adaptive finite element methods for computer simulation of fluid-structure interaction, in particular for problems involving turbulent flow. Simulation of turbulent flow is an outstanding computational challenge, where the UNICON project made significant progress beyond the state of the art. The scientific results of the UNICON project include a new theoretical and methodological framework, and a computer implementation of the methods as open source software, published as part of the FEniCS project, co-founded by the PI (Hoffman) in 2003. FEniCS is today a world leading open source software for computer simulation based on differential equations, with an estimated 50 000 downloads per year, and the PI today leads the PRACE Tier-0 project FEniCS-HPC, in which algorithms and software are developed for the most powerful supercomputers in Europe. Compared to competing simulation software, free as well as commercial, UNICON computational technology has proven to exhibit unique features with respect to accuracy and efficiency. The idea of this ERC PoC project is to commercialize the UNICON simulation technology. In particular, ADAPTIVE targets civil (non-military) industry, with a focus on subsonic fluid dynamics. The strategy is to deliver services and products tailored to each customer, from deliverance of a simulation result, to education and support for integration of the simulation tools in the workflow of a customer.
Project Analysing Diversity with a Phenomic approach: Trends in Vertebrate Evolution
Researcher (PI) Anjali Goswami
Host Institution (HI) NATURAL HISTORY MUSEUM
Summary What processes shape vertebrate diversity through deep time? Approaches to this question can focus on many different factors, from life history and ecology to large-scale environmental change and extinction. To date, the majority of studies on the evolution of vertebrate diversity have focused on relatively simple metrics, specifically taxon counts or univariate measures, such as body size. However, multivariate morphological data provides a more complete picture of evolutionary and palaeoecological change. Morphological data can also bridge deep-time palaeobiological analyses with studies of the genetic and developmental factors that shape variation and must also influence large-scale patterns of evolutionary change. Thus, accurately reconstructing the patterns and processes underlying evolution requires an approach that can fully represent an organism's phenome, the sum total of their observable traits. Recent advances in imaging and data analysis allow large-scale study of phenomic evolution. In this project, I propose to quantitatively analyse the deep-time evolutionary diversity of tetrapods (amphibians, reptiles, birds, and mammals). Specifically, I will apply and extend new imaging, morphometric, and analytical tools to construct a multivariate phenomic dataset for living and extinct tetrapods from 3-D scans. I will use these data to rigorously compare extinction selectivity, timing, pace, and shape of adaptive radiations, and ecomorphological response to large-scale climatic shifts across all tetrapod clades. To do so, I will quantify morphological diversity (disparity) and rates of evolution spanning over 300 million years of tetrapod history. I will further analyse the evolution of phenotypic integration by quantifying not just the traits themselves, but changes in the relationships among traits, which reflect the genetic, developmental, and functional interactions that shape variation, the raw material for natural selection.
What processes shape vertebrate diversity through deep time? Approaches to this question can focus on many different factors, from life history and ecology to large-scale environmental change and extinction. To date, the majority of studies on the evolution of vertebrate diversity have focused on relatively simple metrics, specifically taxon counts or univariate measures, such as body size. However, multivariate morphological data provides a more complete picture of evolutionary and palaeoecological change. Morphological data can also bridge deep-time palaeobiological analyses with studies of the genetic and developmental factors that shape variation and must also influence large-scale patterns of evolutionary change. Thus, accurately reconstructing the patterns and processes underlying evolution requires an approach that can fully represent an organism's phenome, the sum total of their observable traits. Recent advances in imaging and data analysis allow large-scale study of phenomic evolution. In this project, I propose to quantitatively analyse the deep-time evolutionary diversity of tetrapods (amphibians, reptiles, birds, and mammals). Specifically, I will apply and extend new imaging, morphometric, and analytical tools to construct a multivariate phenomic dataset for living and extinct tetrapods from 3-D scans. I will use these data to rigorously compare extinction selectivity, timing, pace, and shape of adaptive radiations, and ecomorphological response to large-scale climatic shifts across all tetrapod clades. To do so, I will quantify morphological diversity (disparity) and rates of evolution spanning over 300 million years of tetrapod history. I will further analyse the evolution of phenotypic integration by quantifying not just the traits themselves, but changes in the relationships among traits, which reflect the genetic, developmental, and functional interactions that shape variation, the raw material for natural selection.
Project acronym AdaptoSCOPE
Project Using cis-regulatory mutations to highlight polygenic adaptation in natural plant systems
Researcher (PI) Juliette de Meaux
Host Institution (HI) UNIVERSITAET ZU KOELN
Summary The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
Project acronym AdaSmartRes
Project Adapter for a commercial grade camera or a smart phone to perform depth resolved imaging
Researcher (PI) Adrian PODOLEANU
Host Institution (HI) UNIVERSITY OF KENT
Summary The proposal refers to a patented adapter that can transform a commercial grade digital camera or the camera in a smart phone into a depth resolved imaging instrument. Several adapters will be assembled, making use of optical coherence tomography (OCT) technology protected by some other of PI's patents. The activity takes advantage of recent progress in commercial grade cameras in terms of their modes of operation as well as in terms of parameters of their devices, such as sensitivity and speed of their photodetector arrays. Three versions of low cost functional OCT systems will be assembled as proof of concepts responding to needs of three possible markets that can be addressed by such an adapter: 1. En-face depth resolved, high transversal resolution microscope; 2. Fast cross sectioning imager. 3. Swept source volumetric analyser. Industrial input comes from a company involved in professional eye imaging systems, a company already selling adapters for smart phones to perform medical imaging, a company specialised in digital photographic equipment and a company efficient in prototyping photonics equipment and handling medical images. Clinical input is provided by two specialists in the two highest potential medical imaging markets of the adapter serving ophthalmology and ear, nose and throat speciality.
The proposal refers to a patented adapter that can transform a commercial grade digital camera or the camera in a smart phone into a depth resolved imaging instrument. Several adapters will be assembled, making use of optical coherence tomography (OCT) technology protected by some other of PI's patents. The activity takes advantage of recent progress in commercial grade cameras in terms of their modes of operation as well as in terms of parameters of their devices, such as sensitivity and speed of their photodetector arrays. Three versions of low cost functional OCT systems will be assembled as proof of concepts responding to needs of three possible markets that can be addressed by such an adapter: 1. En-face depth resolved, high transversal resolution microscope; 2. Fast cross sectioning imager. 3. Swept source volumetric analyser. Industrial input comes from a company involved in professional eye imaging systems, a company already selling adapters for smart phones to perform medical imaging, a company specialised in digital photographic equipment and a company efficient in prototyping photonics equipment and handling medical images. Clinical input is provided by two specialists in the two highest potential medical imaging markets of the adapter serving ophthalmology and ear, nose and throat speciality.
Project acronym ADIPOR
Project Molecular and structural pharmacology of adiponectin receptor: towards innovative treatments of obesity-related diseases.
Researcher (PI) Sebastien Jean Antoine Granier
Summary The human kind is witnessing an escalation of obesity-related health problems such as cardiovascular diseases and type 2 diabetes. A recent groundbreaking study revealed adiponectin receptors (ADIPOR) as key targets for treating such obesity-related diseases. Indeed, the modulation of this integral membrane protein by small molecules agonists ameliorates diabetes and prolongs lifespan of genetically obese rodent model. Despite these exciting results and the importance of ADIPOR in human physiology, there is a complete lack of knowledge of ADIPOR mechanisms of action and pharmacology. This is mainly due to the challenges associated with the characterization of membrane protein structure and function. To fill this gap of knowledge and based on my extensive experience in membrane protein biology, I propose here to characterize the the proximal signaling pathways associated with ADIPOR activation as well as the molecular and structural mechanisms of ADIPOR activation. We will develop an innovative integrated strategy combining state-of-the-art molecular and structural pharmacology approaches including 1) molecular analyses of ADIPOR network of interaction using resonance energy transfer measurement in living cells and a proteomic analysis and 2) structural analyses of ADIPOR and signaling complexes using biophysics and X-ray crystallography. Our data will have a major impact on drug discovery for treating obesity-related diseases as it will enable the application of structure-based drug design and in silico screening for the molecular control of ADIPOR activity. The proposed high-risk endeavor of obtaining structural data on these atypical membrane signaling complexes is a new direction both for my career and for the field of adiponectin biology; the exceptionally high gain from these studies fully justifies the risks; the feasibility of this project is supported by my recent success in membrane protein pharmacology, biochemistry, biophysics and crystallography.
The human kind is witnessing an escalation of obesity-related health problems such as cardiovascular diseases and type 2 diabetes. A recent groundbreaking study revealed adiponectin receptors (ADIPOR) as key targets for treating such obesity-related diseases. Indeed, the modulation of this integral membrane protein by small molecules agonists ameliorates diabetes and prolongs lifespan of genetically obese rodent model. Despite these exciting results and the importance of ADIPOR in human physiology, there is a complete lack of knowledge of ADIPOR mechanisms of action and pharmacology. This is mainly due to the challenges associated with the characterization of membrane protein structure and function. To fill this gap of knowledge and based on my extensive experience in membrane protein biology, I propose here to characterize the the proximal signaling pathways associated with ADIPOR activation as well as the molecular and structural mechanisms of ADIPOR activation. We will develop an innovative integrated strategy combining state-of-the-art molecular and structural pharmacology approaches including 1) molecular analyses of ADIPOR network of interaction using resonance energy transfer measurement in living cells and a proteomic analysis and 2) structural analyses of ADIPOR and signaling complexes using biophysics and X-ray crystallography. Our data will have a major impact on drug discovery for treating obesity-related diseases as it will enable the application of structure-based drug design and in silico screening for the molecular control of ADIPOR activity. The proposed high-risk endeavor of obtaining structural data on these atypical membrane signaling complexes is a new direction both for my career and for the field of adiponectin biology; the exceptionally high gain from these studies fully justifies the risks; the feasibility of this project is supported by my recent success in membrane protein pharmacology, biochemistry, biophysics and crystallography.
Project acronym ADJUV-ANT VACCINES
Project Elucidating the Molecular Mechanisms of Synthetic Saponin Adjuvants and Development of Novel Self-Adjuvanting Vaccines
Researcher (PI) Alberto FERNANDEZ TEJADA
Host Institution (HI) ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS
Summary The clinical success of anticancer and antiviral vaccines often requires the use of an adjuvant, a substance that helps stimulate the body's immune response to the vaccine, making it work better. However, few adjuvants are sufficiently potent and non-toxic for clinical use; moreover, it is not really known how they work. Current vaccine approaches based on weak carbohydrate and glycopeptide antigens are not being particularly effective to induce the human immune system to mount an effective fight against cancer. Despite intensive research and several clinical trials, no such carbohydrate-based antitumor vaccine has yet been approved for public use. In this context, the proposed project has a double, ultimate goal based on applying chemistry to address the above clear gaps in the adjuvant-vaccine field. First, I will develop new improved adjuvants and novel chemical strategies towards more effective, self-adjuvanting synthetic vaccines. Second, I will probe deeply into the molecular mechanisms of the synthetic constructs by combining extensive immunological evaluations with molecular target identification and detailed conformational studies. Thus, the singularity of this multidisciplinary proposal stems from the integration of its main objectives and approaches connecting chemical synthesis and chemical/structural biology with cellular and molecular immunology. This ground-breaking project at the chemistry-biology frontier will allow me to establish my own independent research group and explore key unresolved mechanistic questions in the adjuvant/vaccine arena with extraordinary chemical precision. Therefore, with this transformative and timely research program I aim to (a) develop novel synthetic antitumor and antiviral vaccines with improved properties and efficacy for their prospective translation into the clinic and (b) gain new critical insights into the molecular basis and three-dimensional structure underlying the biological activity of these constructs.
The clinical success of anticancer and antiviral vaccines often requires the use of an adjuvant, a substance that helps stimulate the body's immune response to the vaccine, making it work better. However, few adjuvants are sufficiently potent and non-toxic for clinical use; moreover, it is not really known how they work. Current vaccine approaches based on weak carbohydrate and glycopeptide antigens are not being particularly effective to induce the human immune system to mount an effective fight against cancer. Despite intensive research and several clinical trials, no such carbohydrate-based antitumor vaccine has yet been approved for public use. In this context, the proposed project has a double, ultimate goal based on applying chemistry to address the above clear gaps in the adjuvant-vaccine field. First, I will develop new improved adjuvants and novel chemical strategies towards more effective, self-adjuvanting synthetic vaccines. Second, I will probe deeply into the molecular mechanisms of the synthetic constructs by combining extensive immunological evaluations with molecular target identification and detailed conformational studies. Thus, the singularity of this multidisciplinary proposal stems from the integration of its main objectives and approaches connecting chemical synthesis and chemical/structural biology with cellular and molecular immunology. This ground-breaking project at the chemistry-biology frontier will allow me to establish my own independent research group and explore key unresolved mechanistic questions in the adjuvant/vaccine arena with extraordinary chemical precision. Therefore, with this transformative and timely research program I aim to (a) develop novel synthetic antitumor and antiviral vaccines with improved properties and efficacy for their prospective translation into the clinic and (b) gain new critical insights into the molecular basis and three-dimensional structure underlying the biological activity of these constructs.