Project acronym ADSNeSP
Project Active and Driven Systems: Nonequilibrium Statistical Physics
Researcher (PI) Michael Elmhirst CATES
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), PE3, ERC-2016-ADG
Summary Active Matter systems, such as self-propelled colloids, violate time-reversal symmetry by producing entropy locally, typically converting fuel into mechanical motion at the particle scale. Other driven systems instead produce entropy because of global forcing by external fields, or boundary conditions that impose macroscopic fluxes (such as the momentum flux across a fluid sheared between moving parallel walls).
Nonequilibrium statistical physics (NeSP) is the basic toolbox for both classes of system. In recent years, much progress in NeSP has stemmed from bottom-up work on driven systems. This has provided a number of exactly solved benchmark models, and extended approximation techniques to address driven non-ergodic systems, such as sheared glasses. Meanwhile, work on fluctuation theorems and stochastic thermodynamics have created profound, model-independent insights into dynamics far from equilibrium.
More recently, the field of Active Matter has moved forward rapidly, leaving in its wake a series of generic and profound NeSP questions that now need answers: When is time-reversal symmetry, broken at the microscale, restored by coarse-graining? If it is restored, is an effective thermodynamic description is possible? How different is an active system's behaviour from a globally forced one?
ADSNeSP aims to distil from recent Active Matter research such fundamental questions; answer them first in the context of specific models and second in more general terms; and then, using the tools and insights gained, shed new light on longstanding problems in the wider class of driven systems.
I believe these new tools and insights will be substantial, because local activity takes systems far from equilibrium in a conceptually distinct direction from most types of global driving. By focusing on general principles and on simple models of activity, I seek to create a new vantage point that can inform, and potentially transform, wider areas of statistical physics.
Summary
Active Matter systems, such as self-propelled colloids, violate time-reversal symmetry by producing entropy locally, typically converting fuel into mechanical motion at the particle scale. Other driven systems instead produce entropy because of global forcing by external fields, or boundary conditions that impose macroscopic fluxes (such as the momentum flux across a fluid sheared between moving parallel walls).
Nonequilibrium statistical physics (NeSP) is the basic toolbox for both classes of system. In recent years, much progress in NeSP has stemmed from bottom-up work on driven systems. This has provided a number of exactly solved benchmark models, and extended approximation techniques to address driven non-ergodic systems, such as sheared glasses. Meanwhile, work on fluctuation theorems and stochastic thermodynamics have created profound, model-independent insights into dynamics far from equilibrium.
More recently, the field of Active Matter has moved forward rapidly, leaving in its wake a series of generic and profound NeSP questions that now need answers: When is time-reversal symmetry, broken at the microscale, restored by coarse-graining? If it is restored, is an effective thermodynamic description is possible? How different is an active system's behaviour from a globally forced one?
ADSNeSP aims to distil from recent Active Matter research such fundamental questions; answer them first in the context of specific models and second in more general terms; and then, using the tools and insights gained, shed new light on longstanding problems in the wider class of driven systems.
I believe these new tools and insights will be substantial, because local activity takes systems far from equilibrium in a conceptually distinct direction from most types of global driving. By focusing on general principles and on simple models of activity, I seek to create a new vantage point that can inform, and potentially transform, wider areas of statistical physics.
Max ERC Funding
2 043 630 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym ALEXANDRIA
Project Large-Scale Formal Proof for the Working Mathematician
Researcher (PI) Lawrence PAULSON
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), PE6, ERC-2016-ADG
Summary Mathematical proofs have always been prone to error. Today, proofs can be hundreds of pages long and combine results from many specialisms, making them almost impossible to check. One solution is to deploy modern verification technology. Interactive theorem provers have demonstrated their potential as vehicles for formalising mathematics through achievements such as the verification of the Kepler Conjecture. Proofs done using such tools reach a high standard of correctness.
However, existing theorem provers are unsuitable for mathematics. Their formal proofs are unreadable. They struggle to do simple tasks, such as evaluating limits. They lack much basic mathematics, and the material they do have is difficult to locate and apply.
ALEXANDRIA will create a proof development environment attractive to working mathematicians, utilising the best technology available across computer science. Its focus will be the management and use of large-scale mathematical knowledge, both theorems and algorithms. The project will employ mathematicians to investigate the formalisation of mathematics in practice. Our already substantial formalised libraries will serve as the starting point. They will be extended and annotated to support sophisticated searches. Techniques will be borrowed from machine learning, information retrieval and natural language processing. Algorithms will be treated similarly: ALEXANDRIA will help users find and invoke the proof methods and algorithms appropriate for the task.
ALEXANDRIA will provide (1) comprehensive formal mathematical libraries; (2) search within libraries, and the mining of libraries for proof patterns; (3) automated support for the construction of large formal proofs; (4) sound and practical computer algebra tools.
ALEXANDRIA will be based on legible structured proofs. Formal proofs should be not mere code, but a machine-checkable form of communication between mathematicians.
Summary
Mathematical proofs have always been prone to error. Today, proofs can be hundreds of pages long and combine results from many specialisms, making them almost impossible to check. One solution is to deploy modern verification technology. Interactive theorem provers have demonstrated their potential as vehicles for formalising mathematics through achievements such as the verification of the Kepler Conjecture. Proofs done using such tools reach a high standard of correctness.
However, existing theorem provers are unsuitable for mathematics. Their formal proofs are unreadable. They struggle to do simple tasks, such as evaluating limits. They lack much basic mathematics, and the material they do have is difficult to locate and apply.
ALEXANDRIA will create a proof development environment attractive to working mathematicians, utilising the best technology available across computer science. Its focus will be the management and use of large-scale mathematical knowledge, both theorems and algorithms. The project will employ mathematicians to investigate the formalisation of mathematics in practice. Our already substantial formalised libraries will serve as the starting point. They will be extended and annotated to support sophisticated searches. Techniques will be borrowed from machine learning, information retrieval and natural language processing. Algorithms will be treated similarly: ALEXANDRIA will help users find and invoke the proof methods and algorithms appropriate for the task.
ALEXANDRIA will provide (1) comprehensive formal mathematical libraries; (2) search within libraries, and the mining of libraries for proof patterns; (3) automated support for the construction of large formal proofs; (4) sound and practical computer algebra tools.
ALEXANDRIA will be based on legible structured proofs. Formal proofs should be not mere code, but a machine-checkable form of communication between mathematicians.
Max ERC Funding
2 430 140 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BIO-H-BORROW
Project Biocatalytic Amine Synthesis via Hydrogen Borrowing
Researcher (PI) Nicholas TURNER
Host Institution (HI) THE UNIVERSITY OF MANCHESTER
Call Details Advanced Grant (AdG), PE5, ERC-2016-ADG
Summary Amine containing compounds are ubiquitous in everyday life and find applications ranging from polymers to pharmaceuticals. The vast majority of amines are synthetic and manufactured on large scale which creates waste as well as requiring high temperatures and pressures. The increasing availability of biocatalysts, together with an understanding of how they can be used in organic synthesis (biocatalytic retrosynthesis), has stimulated chemists to consider new ways of making target molecules. In this context, the iterative construction of C-N bonds via biocatalytic hydrogen borrowing represents a powerful and unexplored way to synthesise a wide range of target amine molecules in an efficient manner. Hydrogen borrowing involves telescoping redox neutral reactions together using only catalytic amounts of hydrogen.
In this project we will engineer the three key target biocatalysts (reductive aminase, amine dehydrogenase, alcohol dehydrogenase) required for biocatalytic hydrogen borrowing such that they possess the required regio-, chemo- and stereo-selectivity for practical application. Recently discovered reductive aminases (RedAms) and amine dehydrogenases (AmDHs) will be engineered for enantioselective coupling of alcohols (1o, 2o) with ammonia/amines (1o, 2o, 3o) under redox neutral conditions. Alcohol dehydrogenases will be engineered for low enantioselectivity. Hydrogen borrowing requires mutually compatible cofactors shared by two enzymes and in some cases will require redesign of cofactor specificity. Thereafter we shall develop conditions for the combined use of these biocatalysts under hydrogen borrowing conditions (catalytic NADH, NADPH), to enable the conversion of simple and sustainable feedstocks (alcohols) into amines using ammonia as the nitrogen source.
The main deliverables of BIO-H-BORROW will be a set of novel engineered biocatalysts together with redox neutral cascades for the synthesis of amine products from inexpensive and renewable precursors.
Summary
Amine containing compounds are ubiquitous in everyday life and find applications ranging from polymers to pharmaceuticals. The vast majority of amines are synthetic and manufactured on large scale which creates waste as well as requiring high temperatures and pressures. The increasing availability of biocatalysts, together with an understanding of how they can be used in organic synthesis (biocatalytic retrosynthesis), has stimulated chemists to consider new ways of making target molecules. In this context, the iterative construction of C-N bonds via biocatalytic hydrogen borrowing represents a powerful and unexplored way to synthesise a wide range of target amine molecules in an efficient manner. Hydrogen borrowing involves telescoping redox neutral reactions together using only catalytic amounts of hydrogen.
In this project we will engineer the three key target biocatalysts (reductive aminase, amine dehydrogenase, alcohol dehydrogenase) required for biocatalytic hydrogen borrowing such that they possess the required regio-, chemo- and stereo-selectivity for practical application. Recently discovered reductive aminases (RedAms) and amine dehydrogenases (AmDHs) will be engineered for enantioselective coupling of alcohols (1o, 2o) with ammonia/amines (1o, 2o, 3o) under redox neutral conditions. Alcohol dehydrogenases will be engineered for low enantioselectivity. Hydrogen borrowing requires mutually compatible cofactors shared by two enzymes and in some cases will require redesign of cofactor specificity. Thereafter we shall develop conditions for the combined use of these biocatalysts under hydrogen borrowing conditions (catalytic NADH, NADPH), to enable the conversion of simple and sustainable feedstocks (alcohols) into amines using ammonia as the nitrogen source.
The main deliverables of BIO-H-BORROW will be a set of novel engineered biocatalysts together with redox neutral cascades for the synthesis of amine products from inexpensive and renewable precursors.
Max ERC Funding
2 337 548 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym BLASTOFF
Project Retooling plant immunity for resistance to blast fungi
Researcher (PI) Sophien KAMOUN
Host Institution (HI) THE SAINSBURY LABORATORY
Call Details Advanced Grant (AdG), LS9, ERC-2016-ADG
Summary Plant NLR-type immune receptors tend to have a narrow spectrum of pathogen recognition, which is currently limiting their value in agriculture. NLRs can recognize pathogen effectors through unconventional domains that have evolved by duplication of an effector target followed by fusion into the NLR. One NLR with an integrated domain is the rice resistance protein Pik-1, which binds an effector of the blast fungus Magnaporthe oryzae via its Heavy-Metal Associated (HMA) domain. We solved the crystal structure of the HMA domain of Pik-1 in complex with a blast fungus effector and gained an unprecedented level of detail of the molecular interactions that define pathogen recognition. This led to the overall aim of this proposal to generate a complete picture of the biophysical interactions between blast fungus effectors and HMA-containing cereal proteins to guide the retooling of the plant immune system towards resistance to blast diseases. M. oryzae is a general cereal killer that infects wheat, barley and rice, which are staple food for a majority of the world population. The central hypothesis of the proposed research is that mutations in cereal HMA-containing proteins will result in broad-spectrum resistance to blast fungi.
To achieve our goal, we will pursue the following objectives:
1. BIOPHYSICS. Define the biophysical properties that underpin binding of M. oryzae effectors to HMA-containing proteins of cereal crops.
2. RECEPTOR ENGINEERING. Develop Pik-1 receptors that respond to a wide-spectrum of M. oryzae effectors.
3. GENOME EDITING. Mutate HMA domain-containing genes in cereal genomes to confer broad-spectrum blast resistance.
At the completion of this project, we will generate a thorough understanding of the biophysical properties of pathogen effector binding to cereal HMA proteins, and deliver traits and non-transgenic cultivars for breeding blast disease resistance in cereal crops.
Summary
Plant NLR-type immune receptors tend to have a narrow spectrum of pathogen recognition, which is currently limiting their value in agriculture. NLRs can recognize pathogen effectors through unconventional domains that have evolved by duplication of an effector target followed by fusion into the NLR. One NLR with an integrated domain is the rice resistance protein Pik-1, which binds an effector of the blast fungus Magnaporthe oryzae via its Heavy-Metal Associated (HMA) domain. We solved the crystal structure of the HMA domain of Pik-1 in complex with a blast fungus effector and gained an unprecedented level of detail of the molecular interactions that define pathogen recognition. This led to the overall aim of this proposal to generate a complete picture of the biophysical interactions between blast fungus effectors and HMA-containing cereal proteins to guide the retooling of the plant immune system towards resistance to blast diseases. M. oryzae is a general cereal killer that infects wheat, barley and rice, which are staple food for a majority of the world population. The central hypothesis of the proposed research is that mutations in cereal HMA-containing proteins will result in broad-spectrum resistance to blast fungi.
To achieve our goal, we will pursue the following objectives:
1. BIOPHYSICS. Define the biophysical properties that underpin binding of M. oryzae effectors to HMA-containing proteins of cereal crops.
2. RECEPTOR ENGINEERING. Develop Pik-1 receptors that respond to a wide-spectrum of M. oryzae effectors.
3. GENOME EDITING. Mutate HMA domain-containing genes in cereal genomes to confer broad-spectrum blast resistance.
At the completion of this project, we will generate a thorough understanding of the biophysical properties of pathogen effector binding to cereal HMA proteins, and deliver traits and non-transgenic cultivars for breeding blast disease resistance in cereal crops.
Max ERC Funding
2 491 893 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BrainEnergy
Project Control of cerebral blood flow by capillary pericytes in health and disease
Researcher (PI) David ATTWELL
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS5, ERC-2016-ADG
Summary Pericytes, located at intervals along capillaries, have recently been revealed as major controllers of brain blood flow. Normally, they dilate capillaries in response to neuronal activity, increasing local blood flow and energy supply. But in pathology they have a more sinister role. After artery block causes a stroke, the brain suffers from the so-called “no-reflow” phenomenon - a failure to fully reperfuse capillaries, even after the upstream occluded artery has been reperfused successfully. The resulting long-lasting decrease of energy supply damages neurons. I have shown that a major cause of no-reflow lies in pericytes: during ischaemia they constrict and then die in rigor. This reduces capillary diameter and blood flow, and probably degrades blood-brain barrier function. However, despite their crucial role in regulating blood flow physiologically and in pathology, little is known about the mechanisms by which pericytes function.
By using blood vessel imaging, patch-clamping, two-photon imaging, optogenetics, immunohistochemistry, mathematical modelling, and live human tissue obtained from neurosurgery, this programme of research will:
(i) define the signalling mechanisms controlling capillary constriction and dilation in health and disease;
(ii) identify the relative contributions of neurons, astrocytes and microglia to regulating pericyte tone;
(iii) develop approaches to preventing brain pericyte constriction and death during ischaemia;
(iv) define how pericyte constriction of capillaries and pericyte death contribute to Alzheimer’s disease;
(v) extend these results from rodent brain to human brain pericytes as a prelude to developing therapies.
The diseases to which pericytes contribute include stroke, spinal cord injury, diabetes and Alzheimer’s disease. These all have an enormous economic impact, as well as causing great suffering for patients and their carers. This work will provide novel therapeutic approaches for treating these diseases.
Summary
Pericytes, located at intervals along capillaries, have recently been revealed as major controllers of brain blood flow. Normally, they dilate capillaries in response to neuronal activity, increasing local blood flow and energy supply. But in pathology they have a more sinister role. After artery block causes a stroke, the brain suffers from the so-called “no-reflow” phenomenon - a failure to fully reperfuse capillaries, even after the upstream occluded artery has been reperfused successfully. The resulting long-lasting decrease of energy supply damages neurons. I have shown that a major cause of no-reflow lies in pericytes: during ischaemia they constrict and then die in rigor. This reduces capillary diameter and blood flow, and probably degrades blood-brain barrier function. However, despite their crucial role in regulating blood flow physiologically and in pathology, little is known about the mechanisms by which pericytes function.
By using blood vessel imaging, patch-clamping, two-photon imaging, optogenetics, immunohistochemistry, mathematical modelling, and live human tissue obtained from neurosurgery, this programme of research will:
(i) define the signalling mechanisms controlling capillary constriction and dilation in health and disease;
(ii) identify the relative contributions of neurons, astrocytes and microglia to regulating pericyte tone;
(iii) develop approaches to preventing brain pericyte constriction and death during ischaemia;
(iv) define how pericyte constriction of capillaries and pericyte death contribute to Alzheimer’s disease;
(v) extend these results from rodent brain to human brain pericytes as a prelude to developing therapies.
The diseases to which pericytes contribute include stroke, spinal cord injury, diabetes and Alzheimer’s disease. These all have an enormous economic impact, as well as causing great suffering for patients and their carers. This work will provide novel therapeutic approaches for treating these diseases.
Max ERC Funding
2 499 954 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym BRCA-ERC
Project Understanding cancer development in BRCA 1/2 mutation carriers for improved Early detection and Risk Control
Researcher (PI) Martin WIDSCHWENDTER
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Recent evidence demonstrates that cancer is overtaking cardiovascular disease as the number one cause of mortality in Europe. This is largely due to the lack of preventative measures for common (e.g. breast) or highly fatal (e.g. ovarian) human cancers. Most cancers are multifactorial in origin. The core hypothesis of this research programme is that the extremely high risk of BRCA1/2 germline mutation carriers to develop breast and ovarian cancer is a net consequence of cell-autonomous (direct effect of BRCA mutation in cells at risk) and cell non-autonomous (produced in distant organs and affecting organs at risk) factors which both trigger epigenetic, cancer-initiating effects.
The project’s aims are centered around the principles of systems medicine and built on a large cohort of BRCA mutation carriers and controls who will be offered newly established cancer screening programmes. We will uncover how ‘cell non-autonomous’ factors work, provide detail on the epigenetic changes in at-risk tissues and investigate whether these changes are mechanistically linked to cancer, study whether we can neutralise this process and measure success in the organs at risk, and ideally in easy to access samples such as blood, buccal and cervical cells.
In my Department for Women’s Cancer we have assembled a powerful interdisciplinary team including computational biologists, functionalists, immunologists and clinician scientists linked to leading patient advocacy groups which is extremely well placed to lead this pioneering project to develop the fundamental understanding of cancer development in women with BRCA mutations. To reset the epigenome, re-establishing normal cell identity and consequently reducing cancer risk without the need for surgery and being able to monitor the efficacy using multicellular epigenetic outcome predictors will be a major scientific and medical breakthrough and possibly applicable to other chronic diseases.
Summary
Recent evidence demonstrates that cancer is overtaking cardiovascular disease as the number one cause of mortality in Europe. This is largely due to the lack of preventative measures for common (e.g. breast) or highly fatal (e.g. ovarian) human cancers. Most cancers are multifactorial in origin. The core hypothesis of this research programme is that the extremely high risk of BRCA1/2 germline mutation carriers to develop breast and ovarian cancer is a net consequence of cell-autonomous (direct effect of BRCA mutation in cells at risk) and cell non-autonomous (produced in distant organs and affecting organs at risk) factors which both trigger epigenetic, cancer-initiating effects.
The project’s aims are centered around the principles of systems medicine and built on a large cohort of BRCA mutation carriers and controls who will be offered newly established cancer screening programmes. We will uncover how ‘cell non-autonomous’ factors work, provide detail on the epigenetic changes in at-risk tissues and investigate whether these changes are mechanistically linked to cancer, study whether we can neutralise this process and measure success in the organs at risk, and ideally in easy to access samples such as blood, buccal and cervical cells.
In my Department for Women’s Cancer we have assembled a powerful interdisciplinary team including computational biologists, functionalists, immunologists and clinician scientists linked to leading patient advocacy groups which is extremely well placed to lead this pioneering project to develop the fundamental understanding of cancer development in women with BRCA mutations. To reset the epigenome, re-establishing normal cell identity and consequently reducing cancer risk without the need for surgery and being able to monitor the efficacy using multicellular epigenetic outcome predictors will be a major scientific and medical breakthrough and possibly applicable to other chronic diseases.
Max ERC Funding
2 497 841 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym CAPaCITy
Project Designing Conjugated Polymers for Photocatalysis and Ion Transport
Researcher (PI) Jenny NELSON
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Advanced Grant (AdG), PE8, ERC-2016-ADG
Summary Solar energy conversion will play an essential role in the future supply of clean energy. Secure access to energy sources will require energy conversion technologies that are low impact, distributed and accessible both technically and financially. Molecular electronic materials embody these possibilities, offering facile synthesis, low energy production and the versatility to allow performance to be maximized for specific applications. Moreover, they bring appealing similarities with nature’s intrinsically low impact energy conversion materials. Whilst molecular semiconductors have been studied in detail for solar-to-electric energy conversion they have seldom been studied for solar-to-chemical conversion or for charge storage. However, they bring exciting potential advantages in terms of their light harvesting properties, the range of microstructures possible and the ability to tune their electrical properties. Polymer materials applied to solar chemical generation could open up an innovative route to artificial fuels, with the option to control light harvesting and charge separation through structural control. Polymer materials applied to mixed (electronic / ionic) conduction provide a route to lower cost electrochemical storage, as well as to biocompatible devices and sensors. Stimulated by recent experimental breakthroughs in the application of polymers as photocatalysts and ion transport media I will exploit my expertise in multi-scale modelling and functional characterization of molecular electronic materials and devices to develop a design framework for energy conversion and storage in conjugated polymer materials. This proposal aims to disentangle the parameters that govern the performance of conjugated polymer based photocatalysts and ion transport media to discover the underlying functional mechanisms. The tools generated will serve to enable the design and development of high performance materials for energy conversion devices.
Summary
Solar energy conversion will play an essential role in the future supply of clean energy. Secure access to energy sources will require energy conversion technologies that are low impact, distributed and accessible both technically and financially. Molecular electronic materials embody these possibilities, offering facile synthesis, low energy production and the versatility to allow performance to be maximized for specific applications. Moreover, they bring appealing similarities with nature’s intrinsically low impact energy conversion materials. Whilst molecular semiconductors have been studied in detail for solar-to-electric energy conversion they have seldom been studied for solar-to-chemical conversion or for charge storage. However, they bring exciting potential advantages in terms of their light harvesting properties, the range of microstructures possible and the ability to tune their electrical properties. Polymer materials applied to solar chemical generation could open up an innovative route to artificial fuels, with the option to control light harvesting and charge separation through structural control. Polymer materials applied to mixed (electronic / ionic) conduction provide a route to lower cost electrochemical storage, as well as to biocompatible devices and sensors. Stimulated by recent experimental breakthroughs in the application of polymers as photocatalysts and ion transport media I will exploit my expertise in multi-scale modelling and functional characterization of molecular electronic materials and devices to develop a design framework for energy conversion and storage in conjugated polymer materials. This proposal aims to disentangle the parameters that govern the performance of conjugated polymer based photocatalysts and ion transport media to discover the underlying functional mechanisms. The tools generated will serve to enable the design and development of high performance materials for energy conversion devices.
Max ERC Funding
2 351 550 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym ChAMPioN
Project Game-changing Precision Medicine for Curing All Myeloproliferative Neoplasms
Researcher (PI) Tessa Holyoake
Host Institution (HI) UNIVERSITY OF GLASGOW
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Despite decades of research, developing ways to overcome drug resistance in cancer is the most challenging bottleneck for curative therapies. This is because, in some forms of cancer, the cancer stem cells from which the diseases arise are constantly evolving, particularly under the selective pressures of drug therapies, in order to survive. The events leading to drug resistance can occur within one or more individual cancer stem cell(s) – and the features of each of these cells need to be studied in detail in order to develop drugs or drug combinations that can eradicate all of them. The BCR-ABL+ and BCR-ABL- myeloproliferative neoplasms (MPN) are a group of proliferative blood diseases that can be considered both exemplars of precision medicine and of the drug resistance bottleneck. While significant advances in the management of MPN have been made using life-long and expensive tyrosine kinase inhibitors (TKI), patients are rarely cured of their disease. This is because TKI fail to eradicate the leukaemia stem cells (LSC) from which MPN arise and which persist in patients on treatment, often leading to pervasive drug resistance, loss of response to therapy and progression to fatal forms of acute leukaemia. My goal is to change the way we study the LSC that persist in MPN patients as a means of delivering more effective precision medicine in MPN that is a “game-changer” leading to therapy-free remission (TFR) and cure. Here, I will apply an innovative strategy, ChAMPioN, to study the response of the MPN LSC to TKI in innovative pre-clinical laboratory models and directly in patients with MPN - up to the resolution of individual LSC. This work will reveal, for the first time, the molecular and clonal evolution of LSC during TKI therapies, thus enabling the development of more accurate predictions of TKI efficacy and resistance and rational approaches for curative drug therapies.
Summary
Despite decades of research, developing ways to overcome drug resistance in cancer is the most challenging bottleneck for curative therapies. This is because, in some forms of cancer, the cancer stem cells from which the diseases arise are constantly evolving, particularly under the selective pressures of drug therapies, in order to survive. The events leading to drug resistance can occur within one or more individual cancer stem cell(s) – and the features of each of these cells need to be studied in detail in order to develop drugs or drug combinations that can eradicate all of them. The BCR-ABL+ and BCR-ABL- myeloproliferative neoplasms (MPN) are a group of proliferative blood diseases that can be considered both exemplars of precision medicine and of the drug resistance bottleneck. While significant advances in the management of MPN have been made using life-long and expensive tyrosine kinase inhibitors (TKI), patients are rarely cured of their disease. This is because TKI fail to eradicate the leukaemia stem cells (LSC) from which MPN arise and which persist in patients on treatment, often leading to pervasive drug resistance, loss of response to therapy and progression to fatal forms of acute leukaemia. My goal is to change the way we study the LSC that persist in MPN patients as a means of delivering more effective precision medicine in MPN that is a “game-changer” leading to therapy-free remission (TFR) and cure. Here, I will apply an innovative strategy, ChAMPioN, to study the response of the MPN LSC to TKI in innovative pre-clinical laboratory models and directly in patients with MPN - up to the resolution of individual LSC. This work will reveal, for the first time, the molecular and clonal evolution of LSC during TKI therapies, thus enabling the development of more accurate predictions of TKI efficacy and resistance and rational approaches for curative drug therapies.
Max ERC Funding
3 005 818 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym CLCLCL
Project Civil Law, Common Law, Customary Law: Consonance, Divergence and Transformation in Western Europe from the late eleventh to the thirteenth centuries
Researcher (PI) John HUDSON
Host Institution (HI) THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
Call Details Advanced Grant (AdG), SH6, ERC-2016-ADG
Summary A highly significant division in present-day Europe is between two types of legal system: the Continental with foundations in Civil Law (law with an ultimately Roman law basis), and English Common Law. Both trace their continuous history back to the twelfth century. The present project re-evaluates this vital period in legal history, by comparing not just English Common Law and Continental Civil Law (or “Ius commune”), but also the customary laws crucially important in Continental Europe even beyond the twelfth century. Such laws shared many features with English law, and the comparison thus disrupts the simplistic English:Continental distinction. The project first analyses the form, functioning and development of local, national, and supra-national laws. Similarities, differences, and influences will then be examined from perspectives of longer-term European legal development. Proper historical re-examination of the subject is very timely because of current invocation of supposed legal histories, be it Eurosceptic celebration of English Common Law or rhetorical use of Ius commune as precedent for a common European Law.
F. W. Maitland wrote that ‘there is not much “comparative jurisprudence” for those who do not know thoroughly well the things to be compared’. A comparative project requires collaboration – PI, senior researcher, post-doctoral and doctoral researchers, and Advisory Board. It also needs an integrated approach, through carefully selected areas, themes, and sources. The purpose is not just to provide geographical and thematic coverage but to assemble scholars who overcome divisions of approach in legal historiography: between lawyers and historians, between national traditions, between Common Law and Civil Law. The project is thus very significant in developing methods for writing comparative legal history - and legal history and comparative law more widely - in terms of uncovering patterns, constructing narratives, and testing theories of causation.
Summary
A highly significant division in present-day Europe is between two types of legal system: the Continental with foundations in Civil Law (law with an ultimately Roman law basis), and English Common Law. Both trace their continuous history back to the twelfth century. The present project re-evaluates this vital period in legal history, by comparing not just English Common Law and Continental Civil Law (or “Ius commune”), but also the customary laws crucially important in Continental Europe even beyond the twelfth century. Such laws shared many features with English law, and the comparison thus disrupts the simplistic English:Continental distinction. The project first analyses the form, functioning and development of local, national, and supra-national laws. Similarities, differences, and influences will then be examined from perspectives of longer-term European legal development. Proper historical re-examination of the subject is very timely because of current invocation of supposed legal histories, be it Eurosceptic celebration of English Common Law or rhetorical use of Ius commune as precedent for a common European Law.
F. W. Maitland wrote that ‘there is not much “comparative jurisprudence” for those who do not know thoroughly well the things to be compared’. A comparative project requires collaboration – PI, senior researcher, post-doctoral and doctoral researchers, and Advisory Board. It also needs an integrated approach, through carefully selected areas, themes, and sources. The purpose is not just to provide geographical and thematic coverage but to assemble scholars who overcome divisions of approach in legal historiography: between lawyers and historians, between national traditions, between Common Law and Civil Law. The project is thus very significant in developing methods for writing comparative legal history - and legal history and comparative law more widely - in terms of uncovering patterns, constructing narratives, and testing theories of causation.
Max ERC Funding
2 161 502 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym COMPASS
Project COMPASS: Climate-relevant Ocean Measurements and Processes on the Antarctic continental Shelf and Slope
Researcher (PI) Karen HEYWOOD
Host Institution (HI) UNIVERSITY OF EAST ANGLIA
Call Details Advanced Grant (AdG), PE10, ERC-2016-ADG
Summary Processes on the Antarctic continental shelf and slope are crucially important for determining the rate of future sea level rise, setting the properties and volume of dense bottom water exported globally, and regulating the carbon cycle. Yet our ability to model and predict these processes over future decades remains rudimentary. This deficiency in understanding originates in a lack of observations in this inaccessible region. The COMPASS project seeks to rectify that by exploiting new technology - autonomous marine vehicles called gliders - to observe, quantify and elucidate processes on the continental shelf and slope of Antarctica that are important for climate.
The COMPASS objective is to make a step-change in our quantitative understanding of:
(i) the ocean front that marks the boundary between the Antarctic continental shelf and the open ocean, and its associated current system;
(ii) the interaction between ocean, atmosphere and sea-ice on the Antarctic continental shelf; and
(iii) the exchange of heat, salt and freshwater with the cavities beneath ice shelves.
These goals will be met by a series of targeted ocean glider campaigns around Antarctica, spanning different flow regimes, including areas where warm water is able to access the continental shelf and influence ice shelves, areas where the continental shelf is cold and fresh, and areas where the continental shelf hosts cold, salty, dense water that eventually spills into the abyss. A unique circumpolar assessment of ocean properties and dynamics, including instabilities and mixing, will be undertaken. COMPASS will develop new technology to deploy a profiling glider into inaccessible environments such as Antarctic polynyas (regions of open water surrounded by sea-ice). As well as scientific breakthroughs that will feed into future climate assessments, improving projections of future sea level rise and global temperatures, COMPASS will deliver enhanced design for future ocean observing systems.
Summary
Processes on the Antarctic continental shelf and slope are crucially important for determining the rate of future sea level rise, setting the properties and volume of dense bottom water exported globally, and regulating the carbon cycle. Yet our ability to model and predict these processes over future decades remains rudimentary. This deficiency in understanding originates in a lack of observations in this inaccessible region. The COMPASS project seeks to rectify that by exploiting new technology - autonomous marine vehicles called gliders - to observe, quantify and elucidate processes on the continental shelf and slope of Antarctica that are important for climate.
The COMPASS objective is to make a step-change in our quantitative understanding of:
(i) the ocean front that marks the boundary between the Antarctic continental shelf and the open ocean, and its associated current system;
(ii) the interaction between ocean, atmosphere and sea-ice on the Antarctic continental shelf; and
(iii) the exchange of heat, salt and freshwater with the cavities beneath ice shelves.
These goals will be met by a series of targeted ocean glider campaigns around Antarctica, spanning different flow regimes, including areas where warm water is able to access the continental shelf and influence ice shelves, areas where the continental shelf is cold and fresh, and areas where the continental shelf hosts cold, salty, dense water that eventually spills into the abyss. A unique circumpolar assessment of ocean properties and dynamics, including instabilities and mixing, will be undertaken. COMPASS will develop new technology to deploy a profiling glider into inaccessible environments such as Antarctic polynyas (regions of open water surrounded by sea-ice). As well as scientific breakthroughs that will feed into future climate assessments, improving projections of future sea level rise and global temperatures, COMPASS will deliver enhanced design for future ocean observing systems.
Max ERC Funding
3 499 270 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
