ISSF Junior Interdisciplinary Fellowships - previous awardees
ISSF Junior Interdisciplinary Fellowships - previous awardees
Round 1
Dr Andrea Jiménez Dalmaroni
Project: Physical models to investigate the role of cytoskeletal dynamics and cytoplasmic streaming in the regulation of cell polarity during Drosophila oogenesis.
Supervisors:
Dr Pietro Cicuta (Physics, School of the Physical Sciences)
Dr Isabel Palacios (Zoology, School of the Biological Sciences)
Abstract:
My research aims to unravel the underlying mechanisms by which animal cells regulate cell polarity. My approach is to explore the reorganisation of the cytoskeleton in response to geometrical cues. Individual cells integrate physical and biochemical extracellular signals to establish a directional axis of internal organization (cell polarity). Cell polarisation has to be communicated to the neighbouring cells, preserved, and transmitted through cell division. On the other hand, motile cells rely on dynamical changes of their polarity to achieve a directed migration. A disruption of cell polarity can induce a tissue cell to become motile and metastatic, and thus it represents a hallmark of cancer. Despite the biological relevance of cell polarity, little is known about how cells organise their internal polar structure in the presence of various extracellular cues. Recent experiments have shown that the reorganisation of the cytoskeleton (the internal cellular scaffolding) in response to controlled changes in cell shape imposed externally by substrate adhesion or mechanical forces can cause dramatic changes in cell polarity. Although these experiments provide a detailed description of the role of the individual cellular components and a characterisation of the global cellular behaviour during regulation of polarity, they cannot determine how the global behaviour arises from the molecular interactions. Quantitative modelling, which provides a means to predict the dynamics of interacting systems based on physical principles, can help to achieve a full understanding of these biological processes. My research proposes to bridge the gap between the molecular level and global cellular phenomena by developing a physical description to study the cytoskeletal responses to defined geometrical cues, and explore the role of these responses in the regulation of cell polarity in simple cases in vitro; hence, attaining a quantitative understanding with predictive power in more complex cases in vivo. I combine my theoretical work with close experimental collaborations with the groups of Isabel Palacios (Zoology Department) and Pietro Cicuta (Cavendish Laboratory), where novel microfluidics and optical devices have been developed to control cell geometry.
Dr Dorothea Pinotsi
Project: Super-resolution microscopy and multi-parametric, quantitative fluorescence spectroscopy of protein aggregation
Supervisors:
Professor Clemens Kaminski (Chemical Engineering and Biotechnology, School of Technology)
Professor St George-Hyslop (Cambridge Institute of Medical Research, School of Clinical Medicine)
Abstract:
This project aims at developing and applying optical techniques for the quantitative and multi-parametric study of the formation of protein aggregates and fibrillar structures associated with neurodegenerative and protein misfolding diseases. Fluorescence lifetime and super-resolution imaging are employed in novel kinetic assays which enable one to follow the amyloid fibril formation in real-time, in vitro and in vivo, and to reveal details on the molecular level of the underlying mechanisms. The morphology, location and pathological role of the aggregate species is measured directly within their biological environment with all-optical techniques. The ultimate goal is to explore the properties of the amyloid-like structures and the implications of the individual steps throughout the process of aggregation, for neurotoxicity.
Round 2
Dr Sarra Achouri
Project: Mechanics in embryo development
Supervisors:
Dr Kevin Chalut (Physics, School of the Physical Sciences)
Dr Kristian Franze (Physiology, Development and Neuroscience, School of the Biological Sciences)
Abstract:
During past decades, biology has mainly focused on molecular aspects of life. However, cells live in a physical world and obey physical laws. Cells migrate over large distances and tissue layers self-segregate, which necessarily involves the application of forces. Hence, mechanics should be crucially involved in these processes. However, mechanical aspects of vertebrate development are currently poorly understood. To fill this gap, novel, quantitative techniques from physics need to be introduced to biological research. Forces exerted by cells need to be quantified, mechanical properties of the cellular environment measured. In the proposed research, I will investigate how mechanics contributes to self-segregation of tissue layers during early embryonic development. The biological process I will focus on in this project is that of the segregation of the inner cell mass of the mouse embryo into two layers with distinct functions. The first layer is the primitive endoderm (PrE), which is an extraembryonic layer that provides structural support. The second is the epiblast (EPI), which has a property called pluripotency, i.e. it is the founder tissue for the entire organism from which the germ cells arise.
Dr Frederic Brochu
Project: Application of Monte Carlo computational techniques from particle physics to model the clinical risk of toxicity and second cancers in patients suitable for high precision, curative radiotherapy
Supervisors:
Prof Neil Burnet (Oncology, School of Clinical Medicine)
Prof Andy Parker (Physics, School of the Physical Sciences)
Abstract:
The overall aim of this project is to translate advanced Monte Carlo computational techniques developed in the particle physics environment to the problem of radiation toxicity in patients receiving radiotherapy. We will apply two powerful software applications from the field of particle physics, namely FLUKA and GEANT4, to the problems of radiation toxicity and second cancer risk. We will adapt these applications to model energy deposition in tissue. A better understanding of this issue will contribute to reducing side-effects in patients, and should allow for higher curative doses to be delivered without an increase in toxicity. A particular issue in the UK is concern about second cancer risk as a result of X-ray doses used for image guidance for advanced radiotherapy. This has led to under-use of image guidance in some centres, with likely detriment to patients. A better understanding of the effect of this will inform the approach to risk management, and aid the optimisation and rational roll out of image guidance. The project will consider state-of-the-art X-ray radiotherapy, using high precision, image-guided, intensity-modulated radiotherapy (IG-IMRT) techniques.
Dr Cynthia Fisher
Project: Study of chromatin dynamics under strain in embryonic stem cells
Supervisors:
Dr Kevin Chalut (Physics, School of the Physical Sciences & the Wellcome Trust /MRC Stem Cell Institute, School of the Biological Sciences)
Dr Alexandre Kabla (Engineering, School of Technology)
Abstract:
The Chalut laboratory is currently using microfluidics to translocate embryonic stem (ES) cells, to probe their mechanical properties, and to investigate the response of the nucleus to confinement and compression. They have observed that there is a significant volume increase in the nucleus as the cells are confined in narrow channels, exemplified by a large axial strain and small transverse strain (as opposed to the cell which exhibits volume conservation). We ask: how does this significant volume change and dramatic strain affect chromatin dynamics? We will apply granularity models developed by the Kabla laboratory to interpret the data we acquire, which will illuminate how chromatin changes in various regions of the nucleus. Following on from exploring the question of how substantial nuclear shape modifications and strain modulate chromatin dynamics, we will investigate whether these strains correlate with changes in gene expression. In the context of an established interplay between chromatin dynamics and gene expression, we will use our model system to elucidate connections between ES cell function, chromatin structure, and nuclear shape changes. This should provide insight towards understanding cell shape changes that are known to naturally occur in stem cell and developmental systems including early embryogenesis and organogenesis.
Round 3
Dr Tanya Hutter
Project: Development of Optical Point-of-Care Devices for Blood Diagnostics
Supervisors:
Prof Stephen Elliott (Chemistry, School of the Physical Sciences)
Prof Willem Ouwehand (Haematology, School of Clinical Medicine)
Abstract:
More than 400 million haemoglobin lab tests -to detect common blood disorders like anaemia - are performed in the U.S. each year, making it the most common clinically-ordered type of blood test. However, such tests require central lab facilities and have a slow turnaround. There is an urgent need to develop a low-cost, rapid test to determine, on the spot whether a person is anaemic. For instance, in an acute care setting, to determine whether a patient is anaemic so that they can receive immediate appropriate treatment, or as part of their routine work-up at each blood donation session to assess whether each donor has adequate capacity to donate on that occasion. Currently the routine test performed during the work-up to a standard blood donation is for a simple 'Copper sulphate test' to be performed. Here, a drop of blood from a fingerprick will sink if the prospective donor's red cells have enough iron to give a specific gravity greater than the copper sulphate solution. This simple test can give falsely positive results in donors who are borderline anaemic and should be advised to defer in order to recover. By providing a quick test to determine the RBC blood count, RBC size distribution and haemoglobin content, one would have much more information than is provided by the current test, thus reducing the health risks associated with chronic anaemia in donors. Department of Haematology and Department of Chemistry are working together to develop an optical point-of-care (PoC) diagnostic test that will provide healthcare professionals with the required blood-test result quickly and cheaply. We aim to develop a microfluidic chip and the optical setup, which is able to provide an RBC count, size distribution and morphological information, as well as haemoglobin content.
Dr Thomas Mitchell
Project: Selective tumour cell binding by antibody coated nanoparticles to enhance ultrasound diagnostics and novel cancer therapeutics
Supervisors:
Prof Lisa Hall (Chemical Engineering and Biotechnology, School of Technology)
Prof Richard Prager (Engineering, School of Technology)
Abstract:
In the accurate diagnosis of cancer the sensitivity of biopsy to detect significant disease is often dependent upon the accurate radiological localisation of the tumour. The diagnosis of prostate cancer has historically been made from random samples of the tissue, guided by ultrasound to ensure that representative samples have been taken. We propose a method that may increase the sensitivity and specificity of this diagnostic process. Hollow silica nanoparticles have been developed at the University of Cambridge to tight size specification and may be coated with appropriate antibodies to tumour cells. Initially, we plan to optimise the particle and coating characteristics for both tissue binding and non-invasive ultrasound detection using immuno-histochemistry on prostate cancer tissue micro-arrays. These results will guide conditions for the next stage which will be to determine whether nanoparticle binding is specific and detectable non-invasively in our well characterised in vivo murine models of prostate cancer. If this pilot study is successful, this could provide a very useful developmental platform for other applications. The hollow nano-particles are very adaptable such that other image modalities may be utilised – for instance enclosing fluorescent particles to aid fluorescent imaging of tumour margins during robot-assisted prostatectomy. They also could be used to encapsulate cytotoxicb agents, activated either during enzyme controlled degradation or ultrasound bursting.
Dr Alexander Paraskevov
Project: Phase response curves and spike timing-dependent plasticity in entorhinal cortex neurons
Supervisors:
Prof Ole Paulsen (Physiology, Development and Neuroscience, School of the Biological Sciences)
Dr Mate Lengyel (Department of Engineering, School of Technology)
Abstract:
The hippocampus and neocortex play important and complementary roles in the formation, maintenance, and retrieval of long-term memories. The entorhinal cortex (EC) forms a gateway between these two brain areas, but its role in mediating hippocampal-neocortical interactions during memory processing is largely unknown. We will study, using a combined experimentaltheoretical approach, how the dynamical interactions of EC neurons contribute to memory processing. In particular, using the dynamical clamp method, we will measure phase response curves (PRCs) in EC neurons. PRCs characterise the phase-shift response of a system exhibiting self-sustained periodical oscillations to small input perturbation, such as a presynaptic spike. Experimentally measured PRCs will be compared to those derived from a theory of auto-associative memory that predicts a matching between the form of spike-timing dependent plasticity (STDP) of synapses and the shape of PRCs in a neural population. The STDP rule will be extracted from published experimental data, and the comparison with measured PRCs will specify the functional roles of EC neurons. This project builds on previous collaboration of the two Principal Investigators using similar experimental and theoretical methods for the study of hippocampal PRCs (Lengyel et al, Nat Neurosci 2005).
Round 4
Dr Anshul Sirur
Project: Identifying electro-physiological markers of visuo-spatial memory performance in adults and children: looking at applications to research on developmental dyscalculia
Supervisors:
Dr Denes Szucz (Department of Psychology, School of the Biological Sciences)
Professor William J Fitzgerald (Department of Engineering, School of Technology)
Abstract:
One of the largest studies on mathematical learning difficulties in children (Szucs et al. 2013) found that visual working memory is crucial to mathematical development. However, research on visual working memory (WM) is still neglected and not much is known about its development. We aim to study one of the most important questions for current research: what determines individual variability in visual WM performance? Studying human individual differences in a robust manner is a challenge for current neuroscience methods and is particularly important in the study of developmental disabilities where neuroscience based interventions must function at the individual level. We will use a modern experimental protocol and combine electro-physiology with state of the art data analysis methods enabled by high performance computing algorithms produced by the candidate. At the end of the project we will have improved theoretical insights into the determinants of visual WM variability; assess individual differences in visual WM variability in adults and children in robust data; have a software package for the efficient analysis of large volumes of individual data; be able to apply new knowledge and analysis software for the study of mathematical learning difficulties and for other types of neuroscience date.
Dr Marco Aita
Project: Dancing in the Dark: the physical biology of circumnutation
Supervisors:
Dr Siobhan Braybrook (The Sainsbury Laboratory, School of the Biological Sciences)
Professor Ray Goldstein (DAMTP, School of Physical Sciences)
Abstract:
Circumnutation is the phenomenon by which the growing tip a plant moves on a plane orthogonal to the axis of growth proscribing a "circular" pattern, hence the name. Although historically studied by many authors a satisfactory explanation of this complex phenomenon is still missing. To this end, we will perform a robust quantification of the movement and growth during circumnutation, and formulate a physical model to describe the pattern generation see therein. Our specific aims of this project are: 1) Build on past measurements of circumnutation to characterize the 3D motion of circumnutation and underlying growth patterns. Our organs of study will be the sunflower (Helianthus annuus) hypocotyl and the rice (Oryza sativa) coleoptile, under various conditions: illumination, temperature, chemical and mechanical stress. Observations will be made using 3D capture, motion tracking and quantitative imaging. 2) Develop 3D physical and biological models of circumnutation, with the ultimate goal of integrating the micromechanical characteristics of plant cells (cell wall structure, turgor) and the biochemistry of growth (hormone trafficking and regulation, response to stimuli) into a unitary description of the mechanism of circumnutation. 3) Use biological perturbations to refine, test, and validate models. Altering various environmental and physical parameters can affect circumnutation. These will be used to experimentally explore our model parameter space.
Round 5
Dr José Teles
Project:Exploring the interplay between molecular and mechanical signals during plant stem cell fate decisions using microfluidic technologies
Supervisors:
Dr Henrik Jönsson (The Sainsbury Laboratory, School of the Biological Sciences)
Dr Kevin Chalut (Department of Physics, School of Physical Sciences)
Abstract:
The main objective of this project is the application of microfluidic technologies in the context of plant stem cells in order to provide a comprehensive single-cell level characterization of the regulatory cross-talk underlying stem cell fate decisions. In plants, stem cells responsible for the generation of all above ground organs such as leafs and flowers are located in the shoot apex, more specifically in the shoot apical meristem (SAM). The normal establishment of the complex plant developmental patterns observed in nature requires a strict regulation of stem cell function. The spatiotemporal coordination of these stem cell pools is primarily regulated by a core gene regulatory network that assures a dynamic balance in the number and spatial localization of stem and differentiating cells. Plant hormones, such as auxin and cytokinin, act as long range signals that cross-talk with this core regulatory circuit. Mechanical forces are a ubiquitous component of plant tissue growth and constitute a third layer of regulatory signals. Microfluidic platforms allow the capture of single cells and the fine-grained and systematic manipulation of their microenvironment. Using the Arabidopsis thaliana model system, we will couple these platforms with live imaging of single cells in order to generate high-resolution temporal data on the dynamics of the stem cell core regulatory network, the impact of hormones in the expression of master regulators and the effects of mechanical signals on nuclear dynamics and chromatin organization. This data will be integrated with detailed computational models of SAM development as well as in vivo live imaging data of meristem growth, providing a quantitative understanding of the dynamic interplay between complex regulatory signals and how their integration impacts cell fate decisions in a stem cell niche.
Dr. Xiaohao Cai
Project:Development of Image Analysis Algorithms for Monitoring Forest Health from Aircraft
Supervisors:
Dr. David Coomes (Department of Plant Sciences, School of the Biological Sciences)
Dr. Carola-Bibiane Schönlieb (DAMTP, School of Physical Sciences)
Abstract:
Forests are well recognised as being important for human health but are themselves threatened by deforestation, disease and degradation. The Coomes' group is at the forefront of developing new technologies for remote sensing of forests from aircraft, with the aim of providing assessments of forest health in a rapidly changing world. We use low-flying aircraft equipped with a hyperspectral sensor, 3-D laser scanner and camera to provide high-resolution information on tree physiological processes and structural attributes. This project's objective is to develop an algorithm that is capable of identifying, and tracking, the health of individual trees, applying techniques already used routinely in medical imaging to identify specific cells in tissue samples. Current tree-recognition algorithms use the point clouds produced by the aircraft's 3-D laser scanner, but are not very effective. We envisage developing a new segmentation method that makes use of additional information provided by hyperspectral sensors and aerial photographs, in order to enhance the accuracy and reliability of the conclusions drawn. The challenges of such an approach are the faultless matching of the different data types, the correct use of the matched data in a hybrid segmentation method and its computational realisation for big amounts of data collected from the aircraft.
Round 6
Dr Priscilla Cañizares-Martinez
Project: Development of a Compressive Fluorescence Microscopy Imaging (CFMI) system for studying the emergence of neuronal activity
Supervisors:
Dr Matthias Landgraf (Department of Zoology, School of the Biological Sciences)
Dr Anders Hansen (Department of Applied Mathematics and Theoretical Physics [DAMTP], School of the Physical Sciences)
Dr Kevin O Holleran (Cambridge Advanced Imaging Centre [CAIC], School of the Biological Sciences)
Abstract:
Live fluorescence imaging over prolonged periods and at high resolution has led to remarkable dis-coveries about the behaviour of cells and the development of organs. Yet, current fluorescence mi-croscopy techniques are dogged by limiting tradeoffs such as photo bleaching, photo-toxicity, sub-optimal resolution and restrictions on specimen preparation. Many of these compromises result from the traditional sampling stratagem of exhaustive point-by-point sampling of specimens thought necessary for attaining accurate image information. This proposal aims to break with this tradition by applying novel compressed sensing techniques to fluorescence microscopy. Because images are highly structured one can exploit this fact and apply structured sparse sampling (of as little as 5%) and extract accurate image information. Algorithms can be scaled to gain resolution outperforming traditional fluorescence imaging. Compressive imaging promises a paradigm shift in fluorescence microscopy, permitting gentle, low bleaching imaging at high resolution and speed at vastly reduced data volumes. Specifically, I will develop a Compressive Fluorescence Microscopy Imaging system. I will apply this to image the emergence of neuronal function during neural net-work development, which requires prolonged high resolution, yet low bleaching imaging.
Dr Armando Maestro
Project: Endocytosis across scales: from molecular structures to a functional process
Supervisors:
Dr Pietro Cicuta (Department of Physics, School of the Physical Sciences)
Professor David Owen (Department of Clinical Biochemistry, Cambridge Institute for Medical Research [CIMR], School of Clinical Medicine)
Abstract:
Clathrin-mediated endocytosis is the main mechanism by which proteins are controllably removed from the plasma membrane, and is thus vital to cellular life. It is a beautiful example of controlled molecular choreography, involving length-scales from the molecular (10's Å) to the vesicle (100s nm), and also very long-range processes of membrane-mediated interaction. Such complexity has prevented a full understanding of this key cellular process, despite very precise knowledge on specific molecular detail. On the structural biology side, most of the main proteins are fully characterised, and at the cell biology level there are many clear results showing the order of assembly, and the consequences on vesicle size as a result of under or over expression of various proteins. In-vitro experiments have been very insightful, but this has not been enough, and big questions such as the role of various adapter proteins, and the effect of cargo in controlling vesicle architecture, remain controversial. On the physics side, there are decades of knowledge on the mechanics of phospholipid membranes, including recent developments on membrane curvature-mediated protein recruitment, but few attempts at seriously matching biological conditions. This project will shed new light, starting from physical characterisation of mechanics and rheology of precisely formulated in-vitro conditions, with state of the art tools.
Dr Julia Tischler
Project: Quantitative Single-Cell Dynamics of the Early Mouse Embryonic Cell Cycle and its Interplay with Cell Fate Specification
Supervisors:
Professor Ben Simons (Department of Physics, School of the Physical Sciences)
Professor Azim Surani (Physiology, Development and Neuroscience Department, School of the Biological Sciences)
Abstract:
Specification of cell fates is a highly orchestrated process, which is mediated at the level of individual cells. I propose to study the process at single-cell-resolution, using a well-defined in vitro model that drives naïve mouse embryonic stem cells (ESCs) through epiblast-like cell fates (EpiLCs), as they acquire competence for germ cell fate. I aim to combine direct quantitative observations of the transcriptional and cell cycle states, to elucidate the dynamic behaviour of individual cells, with mathematical modelling. In particular, this will reveal the interplay between the unusual early embryonic cell cycle and cell fate specification. To begin with, I will employ quantitative single-cell time-lapse imaging of fluorescent fate markers in a 'Fucci' cell cycle reporter to follow individual cells during the ESC-to- EpiLC transition in vitro. I will then use these direct measurements to develop quantitative models of regulatory relationships between cell cycle dynamics and cell fate specification. Together, these analyses will offer novel insight into the molecular mechanisms underlying cell fate specification and a framework for experimentally testable predictions for the mechanistic basis for cell fate decisions.
Round 7
Mr Peyman Gifani
Project: Developing a novel design-analysis-construction framework for synthetic biology and bio-inspired robotics
Supervisors:
Dr Gos Micklem (Department of Genetics)
Dr Fumiya Iida (Department of Engineering)
Abstract:
Rational reengineering of biological systems for biomedical or biotechnological purposes has been the central goal of the emerging field of synthetic biology. Despite many achievements in the last decade, the current design approaches do not take advantage of key links between experimental and theoretical knowledge, and instead rely on inefficient trial and error experimental redesigns. The proposed project will be a highly multidisciplinary collaboration between the Micklem Lab and the Cambridge Robotics Lab, capitalising on the unique intersection between theoretical and experimental developments in nonlinear dynamics, genetics, synthetic biology, and bio-inspired robotics. The aim of the proposed project is to develop a novel design-analysis-construction tool that is applicable to any field tackling nonlinear dynamical systems, with immediate application in both synthetic biology and bio-inspired robotics. The proposed project consists of three elements: I- Developing a design tool which enables biologists to interactively design circuits via a novel graphical method. II- Developing an analysis tool to ensure that the designed circuits are both biologically feasible and meaningful. III- Developing a methodology to translate mathematical models of target circuit structures to relevant biologically meaningful components for implementation. The flexibility afforded by this approach simplifies the design process and subsequently expands the application horizon of synthetic biology and bio-inspired robotics.
Dr Matthew Patrick
Project: Making scientific software easier to understand, test and communicate through modern advances in software engineering
Supervisors:
Professor Chris Gilligan (Department of Plant Sciences)
Dr Andrew Rice (Computer Laboratory)
Abstract:
Mathematical models are used to describe the stochastic behaviour of biological systems over a range of spatiotemporal scales, as well as to perform Bayesian and other forms of statistical inferences. These models frequently involve complex interactions between species, with highly nonlinear dynamics. Whilst the mathematical and statistical behaviours of these models are well understood by researchers, there is often a disconnect between the sophistication and transparency of the models and the computational methods used to implement them. Scientific software typically includes undocumented assumptions; it is unclear why these assumptions were made or how they impact the results. This increases the risk of undetected errors that could compromise the inferences made from the models. The lack of transparency makes it difficult to reproduce results and constrains the use of models by other researchers.
We propose to alleviate these problems by creating a scientific development environment, which enables the user to separate the model and hypotheses from the program code, as well as representing the reasoning behind each implementation assumption. The success of the project is supported by the candidate’s training in Software Engineering, complemented by his experience and exposure to a range of models within the areas of epidemiology and ecology.
Dr Tristan Whitmarsh
Project: High-resolution imaging in anti-sclerostin antibody treatment for osteoporotic vertebrae
Supervisors:
Dr Graham M. Treece (Department of Engineering)
Dr Kenneth E.S. Poole (Department of Medicine)
Abstract:
Osteoporosis is a disease characterized by a deterioration of bone micro-structure, increasing the risk of fragility fractures. Several drugs have been introduced for the prevention of osteoporotic fractures, but anti-sclerostin monoclonal antibody therapy with the Wnt signalling derepressor romosozumab, represents a truly new paradign in bone biology. Hitherto considered impossible, blocking sclerostin seems to stimulate the quiescent bone lining cells of the endocortex back into active service as osteoblasts, causing bone formation without prior resorption. Our recent studies have shown that romosozumab massively increases vertebral cortical bone. However, whether these increases relate to the long sought-after activation of modelling within the cortical and endocortical compartments remains unknown due to the limited resolution of CT. With this project I will develop a technique to generate 3D volumes from large sets of histological slices. This is a surprisingly difficult problem due to tissue distortion and inconsistent staining between slices, and has yet to be successfully addressed in this field. The resulting 3D structural measurements will allow us to relate the effects seen with romosozumab using clinical CT to those structures seen on a microscopic scale. This will provide more insight into the mechanism of action of anti-sclerostin antibodies on the vertebral endocortex.
Round 8
Dr Ulrich Dobramysl
Project: Experimentally driven modelling of filopodia
Supervisors:
Dr Jennifer Gallop (Gurdon Institute & Department of Biochemistry)
Professor Benjamin Simons (Cavendish Laboratory & Gurdon Institute)
Abstract:Filopodia are dynamic fingerlike protrusions from the cell membranes, consisting of bundles of actin microfilaments. They play a crucial role in many cellular functions, especially cell movement and they are connected with a variety of diseases such as cancer. A thorough clarification of the molecular and cellular properties of filopodia, their mechanics and dynamics is thus central to an understanding of disease and health. Recent modelling efforts proposed a wealth of mechanisms for the growth of filopodia and actin bundles, however progress has been impeded by the lack of detailed experimental data. Dr Gallop’s laboratory measures quantitative data on the properties of filopodia and actin bundles, which are essential for a mechanistic explanation of their dynamics. We propose to combine my expertise in the mathematical modelling of spatial stochastic processes with the experimental efforts at Dr Gallop’s lab to match experimental filopodial growth statistics to microscopic simulation models. Moreover, we propose to measure the distribution of the actin filament crosslinking protein fascin inside filopodial actin bundles and, via modelling of the mechanics, understand the resulting bundle morphology. Finally, we propose to use modelling to explain an exciting counterintuitive finding that actin growth is enhanced by the dilution of protein source.
Dr Thomas Meany
Project: Microfluidic circuits for multiplexed cell communication networks
Supervisors:
Dr Jim Haseloff (Department of Plant Sciences)
Professor Lisa Hall (Department of Chemical Engineering and Biotechnology)
Abstract:
The cell is a powerful processor, yet even more extraordinary is the actions of cells in unison which operate in parallel to form complex organisms. Synthetic biology holds the promise of off the shelf organic computers which could be harnessed for applications such as fighting disease, producing pharmaceuticals and repairing defective genes. In achieving this goal it is crucial that we begin by developing understanding of intra- and inter- cellular interaction rigorously and quantitatively. This project will develop microfluidic circuits for the controlled interaction of cells using reconfigurable communication channels. Individual cells will be isolated in in microfluidic chambers with neighbouring cells accessible through engineered channels, forming diffusion networks which can be monitored using fluorescence microscopy. This approach will allow us to study how basic cell networks operate. This is the bedrock for truly quantitative studies of small scale developmental biology. This project will leverage the Haseloff group’s expertise in synthetic biological circuits and exploit my expertise in developing lab-on-chip devices which exploit microfluidic networks. It will also incorporate a novel collaborative relationship with the analytical biotechnology group of Prof. Hall who will act as supporter of both bio-sensor networks and micro-fabricated devices.
Dr Christoph Messner
Project: Metal ion-metabolite complexes in hydrothermal conditions: Chemistry important for the origins of life that can improve the synthesis of carbon nanoparticles
Supervisors:
Dr. Markus Ralser (Department of Biochemistry)
Dr Michael de Volder (Institute for Manufacturing, Department of Engineering)
Abstract:
Metabolism of all living cells is based on a conserved network of chemical reactions, the metabolic network, whose origins in evolution represent a yet unsolved problem in Biology. We have recently provided evidence that several carbohydrate metabolic reactions that contribute to the core part of the metabolic network can be replicated non-enzymatically in chemical environments similar to those prevailing on the early Earth, and found that diverse catalytic properties of metal ions could have been essential to give rise to metabolism. The chemical and quantum mechanical details that underlie these reactions are so far however barely understood. Interestingly, the conditions found in hydrothermal vents, fissure in a planet's surface from which geothermally heated water issues, are key to early earth physico/chemical pathways, but also replicate chemical reaction conditions exploited in the synthesis of carbon nanoparticles. In this cross-disciplinary proposal we would like to exploit non-enzymatic metabolism like reactions occurring in artificial hydrothermal reactors a) to understand at the mechanistic level the molecular processes that facilitate iron catalysis in the origin of the metabolic network, b) exploit this chemistry in nano engineering for extending macromolecular assemblies of carbon nanodots, and c) elaborate the potential of hydrothermal chemistry on carbon fixation leading to biological molecules. This project will thus shed light on chemical reactions important for the origin of metabolism, and reveal strategies how to exploit these reactions for the design of novel nanomaterials.
Round 9
Name: Dr Joanna Brunker
Project: Understanding the role of hypoxia in cancer progression
Supervisors:
Dr Sarah Bohndiek (Physics/CRUK Cambridge Institute)
Prof Margaret Ashcroft (Medicine)
Abstract:
The absence of oxygen (hypoxia) in solid tumours has been linked with resistance to chemo- and radio-therapy and poor patient outcomes. Non-invasive imaging of tumour hypoxia could therefore improve disease staging and therapeutic monitoring.
Photoacoustic imaging is an emerging modality that combines high optical contrast with the high resolution of ultrasound detection to provide real-time images at 150μm resolution with up to 3cm depth in tissue. This unprecedented spatiotemporal resolution, coupled with the differential absorption of light by oxy- and deoxy-hemoglobin, enables unique insight into oxygen supply during tumour development. As a result, this technology has entered early phase trials in breast cancer at Addenbrooke’s.
We have previously shown that advanced mathematical modelling (Brochu, Brunker et al 2016 IEEE TMI) could help to extract quantitative images of blood oxygenation and concentration within tissues. While promising, these measurements report on the oxygenation of the blood, rather than of the tissue, and hence do not directly probe tissue hypoxia.
Here, we propose to develop genetically engineered hypoxia responsive ‘chromoproteins’. These operate similarly to fluorescent reporters such as GFP, but have a low fluorescent quantum yield thus providing an enhanced photoacoustic signal. Using these chromoproteins we will ask how acute (perfusion-limited) and chronic (diffusion-limited) hypoxia in solid tumours impact disease progression in breast cancer. The expected outcome of the fellowship will be advanced knowledge of the interplay between oxygen supply and demand in breast cancer, including a model system that can inform further studies on the role of hypoxia in chemo- and radio-resistance.
Name: Dr Anna Huefner
Project: Development of spectral data analysis and calibration algorithms for a diagnostic device for patients suffering from traumatic brain injury
Supervisors:
Professor Peter Hutchinson (Clinical Neurosciences)
Professor Stephen Elliott (Chemistry)
Abstract:
Traumatic brain injury is one of the major causes of death in people aged less than 40 years in the developed world. As a result of brain injury, the brain’s metabolism is altered, resulting in complex and dynamic changes of the brain chemistry. Monitoring these changes is the necessary basis for clinicians to decide on the best treatment to improve patient outcome. However, molecular concentrations of metabolites in the brain fluid can at present only be assessed hourly due to small sample volumes and the detection methods used. This has vast implications on the timescale of therapeutic intervention and ultimately on the patient outcome.
This project will tackle this shortcoming by assisting in the development of a diagnostic sensor to assess molecular concentrations in the brain fluid on a continuous basis. It aims to drive the implementation of sensor technology developed within the Chemistry Department to clinical testing on patient samples in the Department of Clinical Neurosciences. The project focusses on the development of sensor data processing, calibration and algorithm building to make information generated by the sensor accessible and comprehensible to clinical staff. Bridging this gap is a crucial step in order to facilitate important feedback between technical development and clinical application and hence allows for optimisation of this new technology, which will open up its great potential to improve patient management and therapy.
Name: Dr Emma Talbot
Project: Artificial cells for tissue mimics: bio-sensing in multiscale networks
Supervisors:
Professor Jim Haseloff (Plant Sciences)
Professor Pietro Cicuta (Physics)
Abstract:
Compartmentalised lipid assemblies are ideal structures for artificial cells, enabling synthetic biological processes to take place within an enclosing membrane. The assembly of these artificial cells into a network which is responsive to external stimuli would provide an artificial tissue mimic, and offers exciting opportunities for compartmentalised reactions across an array with well-defined structure. However, forming ordered networks requires regulation of the assembly of well-defined building blocks, for which control over membrane curvature and patterning poses a significant challenge. A synergy between synthetic biology and microfluidics-based physics methods for bilayer-assembly will be used to overcome this problem and form artificial cell building blocks of pre-defined geometrical shape and membrane patterning, with encapsulated reaction species. This approach will enable complex chain reactions to be explored for bio-sensing applications in cell mimics with large numbers of compartments. The controlled patterning will be used to connect building blocks in an ordered array, mimicking a tissue, with an extended pattern over long length-scales that can be linked to membrane-controlled processes.