NIHRDataInsights/HRCSData huggingface dataset:
Title: Miniaturised 3D-printed biomedical imaging system using optical MEMS
Funder: Royal Academy of Engineering

Abstract: How does electricity flow through a single molecule? To answer this question, I’mbuilding extremely small electrodes – 10,000 times smaller than the diameter of ahuman hair – that are just wide enough to capture individual DNA molecules. Bymeasuring the electrical current through these molecules, I try to read the chemicalticker tapes that encode the genetic instructions of all living organisms, includinghumans, in what is known as DNA sequencing. The development of fast, inexpensive,and reliable DNA sequencing techniques will pave the way towards personalizedhealthcare that is perfectly tailored to each individual patient.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Microstructural Imaging Data Centre (MIDaC)
Funder: Science and Technology Facilities Council

Abstract: Characterising microstructure in vivo is key to understanding tissue properties and processes in health and disease. Central to this mission, the UK's National Facility for In Vivo MR Imaging of Human Tissue Microstructure (NMIF) houses one of the world's three 'Connectom' MRI scanners, fitted with unique hardware and optimised for imaging tissue microstructure in unprecedented detail. The potential to enable new breakthroughs in neuroscience/medicine with such equipment is huge. While extremely valuable, however, such resources are also expensive and scarce. Making their data open and widely available to the community in a well-documented, scientifically usable form would maximise their impact. With few exceptions, such practice is rarely adopted by medical imaging researchers. Our multi-disciplinary team, drawing on data sharing principles developed by the Cardiff Astronomy Instrumentation Group (AIG), will define and pioneer a unique scientific and technological platform for sharing NMIF data with the worldwide brain research community, extending the value and scientific applications of the resource. Ancillary information and novel processing workflows will also be published. The Microstructural Imaging Data Centre (MIDaC) will 'blaze a trail' that promotes open data in brain imaging research, and offer a unique resource of state-of-the-art data from one of the most powerful medical imaging instruments currently available.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Bioinformatics and computational biology
Funder: The Francis Crick Institute

Abstract: Cellular life must recognise and respond appropriately to diverse internal and external stimuli. By ensuring the correct expression of specific genes at the appropriate times, the transcriptional regulatory system plays a central role in controlling many biological processes: these range from cell cycle progression and maintenance of intracellular metabolic and physiological balance, to cellular differentiation and developmental time-courses. Numerous diseases arise from a breakdown in the regulatory system and a third of human developmental disorders have been attributed to dysfunctional transcription factors. Furthermore, changes in the activity and regulatory specificity of these factors provide a major source for species diversity and evolutionary adaptation. Indeed, increased sophistication of the regulatory system appears to have been a principal requirement for the emergence of metazoan life. Much of our basic knowledge of transcriptional control has traditionally derived from molecular biological and genetic investigation. This knowledge has continued to be complemented by the availability of genome-scale techniques that measure the activity and output of different components of the regulatory system from a whole-organism perspective. Improvements also mean that experimental methods are precise enough to provide quantitative information. However, these advances mean that many observations are unexpected and appear to complicate the traditional view of gene expression control. Our research is dedicated to understanding: (i) how transcription is regulated and (ii) how this regulatory system controls biologically interesting phenomena. Our work is computationally driven and applies a combination of statistical, bioinformatic and genomic approaches to answer these questions. Much of the research examines publicly available data or bespoke datasets generated in close collaboration with experimental laboratories.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Dynamics and evolution of metabolic networks
Funder: The Francis Crick Institute

Abstract: For a long time, metabolism has been viewed as a static series of biochemical reactions. Recent research however reveals that cellular metabolism is indeed highly dynamic, and is implicated in many biologically important phenomena, such as ageing, cellular robustness, and adaptation to ever changing environments. These properties bring metabolism center-stage both for developing therapies against cancer and neurodegenerative disorders and for understanding the ageing process. We investigate regulatory functions of the metabolic network and how its dynamics are maintained. We study how metabolism evolved, how it interacts with the genome, and address a model situation where the metabolome has regulatory function is the adaptation to stress conditions. When cells are exposed to oxidants, when cells age or when a cancer cell starts proliferation, their metabolism changes. We found that under those conditions the metabolic network can reconfigure very quickly, and that metabolism can temporarily adjust without requiring regulation at the transcriptome and proteome layer. There is also evidence that these quick metabolic adjustments can be involved in the induction of transcriptional stress responses. We address these questions often in the yeast Saccharomyces cerevisiae. Working with this single-cellular eukaryote removes some complexity from our investigations, as a plethora of genetic and biochemical techniques are available, reducing bias from altered metabolic activity that is found in cell culture systems, allowing us to work with thousands of mutants in parallel. To study the metabolic network, we use quantitative mass spectrometry coupled to high-pressure and/or nano-flow liquid chromatography for targeted analysis of proteins and small molecules.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: The molecular basis of mesoderm formation
Funder: The Francis Crick Institute

Abstract: The different cell types of the body are formed in the right place and at the right time in response to signals that are produced by special organiser regions of the embryo. These so-called morphogens act in a concentration-dependent manner to induce the formation of different cell types at different positions within developing tissues. One of the earliest interactions of this kind is mesoderm induction, which results in the formation of organs and cell types such as heart, muscle, kidney and bone. We use frog, zebrafish and mouse embryos to study mesoderm-inducing factors and to ask how cells respond to them. One aim is to understand how the signals exert long-range effects in the embryo, and how cells distinguish between different morphogen concentrations to activate different genes. We go on to explore how these different genes then participate in the genetic regulatory networks that result in the formation of specific cell types. This work involves extensive use of high-throughput sequencing technologies to reveal the transcriptomes of cells from the early embryo, to look at transcription factor binding sites, and to understand chromatin architecture. Through this work we have discovered that events in the very early embryo are required to allow cells to respond to inducing signals. These early stages of development also involve dramatic changes in the cell cycle, and we are exploring the regulation of cell division at these early stages of embryogenesis. The principles we define in the early embryo inform additional work on events in later development, including the heart and vasculature, and on the differentiation of embryonic stem cells, where we hope that our work will help direct ES cells down particular developmental pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Synthetic and systems biochemistry of the microtubule cytoskeleton
Funder: The Francis Crick Institute

Abstract: The microtubule cytoskeleton is essential for the life of eukaryotic cells. It is critical for establishing the internal organisation of cells and for performing various mechano-chemical tasks. One important function is spindle assembly and chromosome segregation during cell division. A hallmark of the cytoskeleton is its dynamic nature and plasticity. Our aim is to understand the molecular mechanisms underlying microtubule cytoskeleton dynamics and function. We develop in vitro biochemical reconstitution approaches combined with fluorescence and electron microscopy in order to produce biomimetic minimal cytoskeletal subsystems and to observe their dynamic behaviour. Quantitative analysis is then used to extract the physico-chemical design principles underlying local and global cytoskeleton behaviour. We focus on essential cytoskeletal functions, mostly on processes important for cell division. Most proteins that we study are implicated in disease, mostly in cancer and neurodevelopmental disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Control of tissue growth and architecture
Funder: The Francis Crick Institute

Abstract: How does each cell in a developing animal “know” to stop growing and dividing when the correct body size and shape has been reached? The control of tissue size during development underpins the evolution of animal size and shape and is of fundamental importance to our understanding of diseases such as cancer. Furthermore, understanding and manipulating tissue growth is essential for regenerative medicine. In order to achieve consistent organ and body size in individuals of the same species, cell growth and cell number must be tightly controlled, not only during development, but also to prevent tumour formation during adult homeostasis. Our work is aimed at understanding how tissue and animal size is defined during development and maintained in adult life. Genetic screens in Drosophila have identified the Hippo (Hpo) pathway as a determinant of tissue size control. The Hpo pathway restricts tissue and organ size by both inhibiting cell proliferation and promoting apoptosis. Subsequent studies in mammals have shown that this growth control function is conserved and that Hpo signalling is dysregulated in many types of cancer. The core of the Hpo pathway is a kinase cascade comprising the Ste20-related kinase Hpo and the Dbf2-related kinase Warts (Wts). Upon Hpo activation, the downstream kinase Wts phosphorylates and inhibits the pro-growth transcriptional co-activator Yorkie (Yki). Rather than a pathway defined by a single ligand family, Hpo signalling appears to sit at the interface between diverse inputs such as cell-cell contacts, polarity, mechanical forces and metabolism. We mostly study three research areas. 1) how do mechanical forces and tissue architecture influence developmental growth and the timing of growth arrest? 2) how Hpo signalling receives and integrates inputs from metabolism, hormonal and nutrient signals. 3) how phosphatase complexes control tissue architecture and growth through the Hpo pathway. We are particularly interested in how and when the Hippo pathway interfaces with its upstream signal during development. We aim to use this knowledge in order to identify therapeutic avenues that can be exploited for cancer and regenerative medicine. To achieve our research goals, we use a large array of methods, from Drosophila and mouse genetics, live imaging, through to proteomics, functional genomics and mathematical modelling. We collaborate broadly with scientists from diverse disciplines such as physics, computer science, systems biology and structural biology.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Systems microscopy studies of cell division and cell fate determination
Funder: The Francis Crick Institute

Abstract: My research aims to elucidate the molecular mechanisms that underlie chromosome segregation and asymmetric cell division. It has focused in particular on understanding regulation of the kinetochore, the essential protein complex that anchors chromosomes to the mitotic spindle and directs their accurate segregation. The kinetochore lies at the heart of cell division and inheritance, yet its complex regulation remains largely uncharacterised. My lab has developed powerful proteomic and microscopy techniques that have allowed us to identify kinetochore regulators and reveal key mechanisms that control chromosome segregation and cellular asymmetry. Our previous work has generated a roster of candidate proteins involved in kinetochore regulation. Within this, we were surprised to find a number of phosphoregulators, some of which have not previously been linked to kinetochore control. This supports our contention that phosphorylation has a central and largely overlooked role in kinetochore control. To test this idea further, we aim to characterise the kinases, phosphatases and other candidate regulators and better define their mechanisms of action. Our methods allow us to pinpoint where a regulator acts within the kinetochore, and what processes are affected when it does. We have a more ambitious goal for this work: to use our ability to create forced protein associations to build synthetic pathways that direct cell behaviour. Using synthetic physical interactions, we already showed that we could drive synthetic mitotic checkpoint activation and separate the steps of checkpoint activation and kinetochore association. As we uncover details of kinetochore regulation, we expect that there will be many opportunities to drive synthetic regulatory circuits that control mitosis. This will initially be used to test hypotheses about the function of specific proteins – but it raises the exciting possibility of carrying out broader cell engineering by forcing targeted interactions that constitute entirely artificial regulatory pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Patterning and homeostatis in developing epithelia
Funder: The Francis Crick Institute

Abstract: My lab investigates cell signalling in the context of developing epithelia. We are particularly interested in the signals that control patterning, growth and apoptosis, which include Wnts, TGF-B, Hedgehog, EGFR, and JNK. Our activities fall into three specific categories. (1) We study the cell biological mechanisms that control the secretion, release of Wnts as well as the subsequent events that modulate signalling activity. Currently we are devoting significant energy to understand how Wnts, which are appended with palmitoloeate are handed over from secreting to receiving cells. Our studies of Wnts have also led us to characterise Notum, a deacylase that inactivate Wnts. We are now devising small molecule inhibitors of Notum as well as assessing the value of Notum as a possible target for the treatment of Alzheimer’s disease. (2),We investigate the mechanism that ensure the elimination of defective or mispecified cells from developing epithelia. We have found that loss of epithelial integrity leads to activation of JNK signalling, which in turn controls the cell death machinery. We continue to investigate this signal transduction flow at the molecular level. In parallel, we uncovered the mechanism that triggers apoptosis in response to developmental mistakes. We recently found that normal patterning sustains sufficient activation of EGFR signalling and this is needed for cells of the embryo to survive. (3) We study how tissue growth if modulated during development, using the Drosophila wing as a model system. As a first step, we will uncover how patterning signals (Wingless, a Wnt and Dpp, a TGF-B) link molecularly with the cellular growth control machinery. To this end, we are developing optogenetic and thermo-sensitive means of controlling signal transduction so that we can identify the immediate early targets that promote growth. In addition, we will investigate whether the activity of patterning signals might be affected by the growth rate, as this could account for scaling. Tissue growth is also regulated by dedicated - local and systemic - signals that convey information about tissue architecture and nutritional status. We are therefore also investigating how the pro-growth effects of the patterning signals are coordinated with those from mechanical constraints and metabolism. These experiments will uncover, in molecular detail, how various signals are integrated to ensure that tissues grow in a timely and proportionate manner.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Theoretical physics of biology
Funder: The Francis Crick Institute

Abstract: We are a theoretical physics group, studying how physical principles play a role in biology, in order to attain a quantitative description of biological processes at the cellular and tissue scale. To reach that goal, we use methods from soft matter physics and non-linear dynamics and develop new theoretical and computational tools. Since biological systems function out-of-equilibrium, we also aim at understanding better the physical properties of active matter. We are especially interested in mechanics and shape generation at the level of cells and tissues. At the cell level, the cytoskeleton is driving cellular deformations and the motion of cell organelles, allowing for instance for cell division and migration. To understand these cellular processes, we need to ask how cytoskeletal filaments and motors work together and interact with other cellular components. At the tissue level, properly orchestrated morphogenetic movements in epithelia and tissues allow animals to develop and establish their shape. Morphogenetic events rely on force generation in the cell, which has to be regulated biologically. We then ask from a physical point of view how genetic regulation and forces act together to shape the embryo. We work in close collaboration with experimentalists to address these questions. We have been working recently in particular on the physics of cell migration, on the mechanics of early zebrafish gastrulation, on the flow of cells occurring in morphogenesis of tissues, on the 3D shape of epithelia and formation of folds in Drosophila embryo.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: Control principles in cell decision making: lessons from quantitative biology
Funder: The Francis Crick Institute

Abstract: Control principles in cell decision making: lessons from quantitative biology During cell decision-making, gene and protein networks dynamically change in response to cues in order to trigger different cellular states. How information is decoded and transmitted in order to commit to specific cell fates has been a fundamental question in cell and developmental biology. One way to understand this is to quantitatively monitor input-output relationships in single cells during decision-making. In this context, I have been focused on investigating spatio-temporal control and remodelling of intracellular networks in two cellular decisions: cell division and cellular differentiation. The decision to divide is a fundamental decision and the conserved networks that trigger cell division adapt and remodel in a variety of biological contexts including developmental transitions and malignancy. I have been exploring spatio-temporal control of cell division in mammalian cells (Santos et al Cell 2012, Araujo et al Mol Cell 2016 and Araujo et al in revision) and remodelling of cell cycle networks during developmental transitions, using human embryonic stem (hES) cells as a model system. Embryonic stem cells have the propensity to differentiate into the three germ layers. The switch between pluripotency and differentiation in these cells has been our paradigm of choice to understand how protein and gene networks decode cellular signals and thereby encode irreversible commitment to different cell fates (Gunne-Braden et al submitted and Gharibi et al submitted). Both lines of investigation are likely to have profound impact in the understanding of normal human development and the transition from healthy to disease states. My research has been shaped by multidisciplinary approaches, which combine single cell studies with “omics” approaches (RNA sequencing and proteomics) and mathematical modelling. Quantitative approaches have revolutionized the way we ask biological questions and will continue to play an important part in doing innovative, world-class research.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Comparative biology of mitotic division
Funder: The Francis Crick Institute

Abstract: We compare related yeast species to study how cells grow and divide. Cells come in different shapes and forms but all multiply by splitting in two. A copy of the genetic information held in an original cell is passed into each new, daughter cell when it divides. Scientists call this inheritance process mitosis. If a mistake is made during mitosis then inaccurate genetic information in the new cells can lead to developmental defects or disease. Our lab aims to understand mitosis and the different approaches organisms use to complete it. During mitosis, some cells break open the protective envelope that surrounds the nucleus, the part of the cell where genetic information is held. Other cells keep this envelope closed all the time. The envelope must restructure during mitosis to let new nuclei form. Both nuclei should contain exactly the same genetic information if mitosis has worked well. We compare nuclear envelope remodelling and cellular division site positioning in two species of yeast called Schizosaccharomyces pombe and Schizosaccharomyces japonicus. These two types of yeast have evolved strikingly different strategies to complete mitosis and divide, but both are successful. We use this ‘experiment of Nature’ to answer questions about the nuclear envelope and the process of mitosis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE