All projects commence in October 2021 and provide a full scholarship for our four year 1+3 MRes in Chemical Biology and Bio-Entrepreneurship PhD training programme.

Available studentships

A full list of current available studentships is in the list below. We hope to release a further 9 studentships in late March/early April.

2021 projects

Communication within the membrane during complement activation

Title

Communication within the membrane during complement activation

Programme

4 years’ fully-funded [1+3] MRes + PhD in Chemical Biology and Bio-Entrepreneurship, commencing October 2021

Supervisors

  • Dr Doryen Bubeck
  • Dr Nick Brooks

Abstract

The membrane attack complex (MAC) is one of the immune system’s first responders. Complement proteins assemble on target microbial or self-cell membranes to form pores that lyse pathogens and affect tissue homeostasis. While MAC assembly is known to cause changes in some key membrane mechanical properties, there remain significant questions about the protein - membrane interplay and interactions that bring about these changes and the impact that membrane – protein co-structuring has on a wealth of other physiologically critical biophysical membrane parameters. Understanding these biophysical mechanisms is critical to developing new strategies to intervene in complement immune deficiencies that have devastating consequences for human health. Here, we will use newly developed approaches to investigate the effect of MAC assembly on key biophysical parameters of biological and biomimetic membranes, and the feedback of these changes on the subsequent MAC assembly steps and eventual membrane rupture.

This project is co-funded by the European Research Council and the EPSRC Centre for Doctoral Training in Chemical Biology: Innovation for the Life Sciences.

Biomimetic control of ovarian follicle development: combining multi-scale soft biomaterials with biochemical interactions

Title

Biomimetic control of ovarian follicle development: combining multi-scale soft biomaterials with biochemical interactions

Supervisors

  • Dr Iain Dunlop
  • Professor Kate Hardy
  • Professor Stephen Franks

Abstract

Ovarian bioengineering is emerging as a new interdisciplinary field. Recent advances show that eggs, and their encapsulating follicle structures, are directed in their development by their physical and biomechanical microenvironments, in addition to traditional ideas of hormonal control. New work by our labs reveals a complex multiscale biomechanical environment inside the ovary (https://www.biorxiv.org/content/10.1101/2021.01.03.425098v1.)

The student will apply these insights to create new in vitro culture systems, structured over micro- to nano-lengthscales, that mimic the ovary interior. These will combine soft biomaterials chemistry with microfluidic fabrication and biochemical approaches to cell-stimulation. This technology platform will be used to investigate the systems biology of the ovary, aiming for an integrated physical/biochemical understanding. This has implications for fertility, since dysregulation of follicle development is a major driver of female infertility, e.g. polycystic ovary syndrome (PCOS); premature ovarian insufficiency (POI). The project will fit a student with a Chemistry, Materials, Bioengineering, Chemical Engineering or Physics background and a strong interest in interdisciplinary research.

 

Filled studentships

Characterising novel insecticide transport to maximise efficiency and minimize environmental impact

This project is co-sponsored by the Institute of Chemical Biology, Imperial College London, and BASF SE. 

Title

Characterising novel insecticide transport to maximise efficiency and minimize environmental impact

Supervisors

Abstract

One of the greatest global priorities is finding strategies that will support the supply of high quality, nutritious food for the worlds fast-growing population. One vital strand that will support this is the development of novel efficient, safe agrochemicals with low environmental impact.

The development of insecticides has been highly successful at targeting specific active protein sites, however, while there has been progress in both modelling and machine learning approaches to predicting the transport and efficacy of insecticides, these approaches are also severely hampered by lack of input characterization data relating to membrane transport.

In this project we aim to develop an integrated measurement platform that will allow rapid characterisation of the transport of insecticides across model membranes and physical barriers. This data will allow direct rapid screening and prediction of efficiency of agrochemical formulations, and we will couple this to machine learning approaches that will allow us to predict membrane transport based on specific molecular features.

By significantly expanding the developmental parameter space beyond target site identification and interactions, we anticipate that, in the future this will lead to development of insecticide formulations with lower applied concentrations, increased specificity and improved environmental performance. 

Structural and pathological consequences of aSyn/lipid membrane interactions

Title

Structural and pathological consequences of aSyn/lipid membrane interactions

Supervisors

  • Dr Francesco Aprile
  • Dr Marina Kuimova
  • Professor Joshua Edel
  • Dr Aleksander Ivanov

Abstract

Lipid membranes play a key role in biological and pathological processes of our body. The formation of aggregates of several neurodegenerative proteins in the brain is modulated by the interaction of these proteins with lipids [Nat. Chem. 2018, 10, 673]. In particular, alpha-synuclein (aSyn) aggregates are linked to Parkinson’s disease (PD) and dementia and form as a direct consequence of the monomer interaction with neuronal membranes. Currently, we still lack information regarding the mechanism of this process. The goal of our project is to determine the mechanisms by which various lipids affect the formation, structure and toxicity of aSyn aggregates and, in turn, how aggregates affect neuronal membranes. We will do so by combining antibody discovery, fluorescent environmental probes, and single-molecule detection. This project will not only unveil key pathological mechanism in PD and other forms of dementia but will also provide foundational physical knowledge on protein-lipid interactions and lead to new ultrasensitive detection methods for biomolecules.

Development of novel photochemical probes to investigate quadruplex DNA interactome in livings cells

Title

Development of novel photochemical probes to investigate quadruplex DNA interactome in livings cells

Supervisors

  • Professor Ramon Vilar Compte
  • Professor Ed Tate
  • Dr Marco Di Antonio

Abstract

Genomic DNA is mainly folded into a double-stranded structure. However, guanine-rich regions can fold into alternative DNA structures called G-quadruplexes (G4), which have been recently visualized in human cells. G4s have been associated with genomic instability, regulation of gene expression and replication, and they are potential drug targets in a range of diseases. While the past decade has seen significant advances in the characterisation of G4 DNA structures, there remains a significant lack of understanding of the proteins responsible for G4-recongition in cells, which is key to further elucidate G4s’ biological significance. This project aims to bridge this gap by developing photoactivatable probes that can label proteins bound to G4s in living cells. We recently demonstrated that Pt(II) complexes known to bind to G4s can also efficiently generate short-lived reactive oxygen species (ROS) under light irradiation. We propose to use the generated ROS to efficiently label proteins bound to G4s, which will be subsequently analysed by quantitative proteomics methods.

Developing a DNA based synthetic cytoskeleton

Title

Developing a DNA based synthetic cytoskeleton

Supervisors

Dr Nick Brooks
Dr Lorenzo Di Michele
Professor Jake Baum

Abstract

The cell’s plasma membrane mechanical properties are thought to play a key role in a wide range of diseases, including malaria, atherosclerosis and cancer. The mechanical behaviour of cellular membranes is not only determined by the composition of the lipid bilayer, but also by a myriad of other membrane-anchored cellular elements, including membrane proteins and the cytoskeleton. However, mimicking biology’s exquisite membrane mechanical control via cytoskeleton assembly remains elusive in synthetic assemblies. This shortcoming in bottomup synthetic biology limits our ability to probe the molecular interactions that underpin membrane behaviour and responses under stress, such as osmotic pressure or shear flow, and constricts the application of bottom-up synthetic biology approaches in harsh environments such as environmental remediation and industrial processing. In this project, we will develop methods to build model lipid membranes with synthetic DNA nanostructures, which can be polymerized to form a supporting scaffold. Using these custom designed DNA architectures, whose size, interactions, and stiffness can be finely controlled, we will be able to tune membrane rigidity and viscosity, as well as enabling response to environmental cues (e.g. temperature, pH, enzymatic activity). We will characterize the effect of the DNA scaffolds on the membrane’s mechanical properties by unique in-house synthesized viscosity-sensitive fluorescent probes (molecular rotors) together with other techniques such as the Fourier analysis of membrane’s thermal fluctuations and micropipette aspiration. This highly multidisciplinary project will provide experimental training in soft matter science. membrane biophysics, DNA nanotechnology, fluorescence spectroscopy and microscopy, and rapid prototyping approaches, automation and machine learning will form key pillars of the project.

Targeting G-quadruplex DNA to overcome resistance to PARP inhibitors

Title

Targeting G-quadruplex DNA to overcome resistance to PARP inhibitors

Supervisors

  • Dr Marco Di Antonio
  • Professor Hector Keun
  • Professor Ramon Vilar Compte

Abstract

PARP inhibitors such as Olaparib have revolutionised treatment of ovarian and breast cancers, which are typically BRCA2 deficient. However, resistance to PARP inhibitors has been already observed in the clinic, rising the need of alternative BRCA2-selective therapies. G-quadruplex ligands have recently emerged as potential therapeutic tools that displayed increased toxicity in BRCA2 deficient genetic backgrounds, retaining their activity also in Olaparib resistant cancers. However, there is a lack of understanding of the fundamental biology linking PARP activity, NAD+ metabolism and G-quadruplex formation, which hampers to investigate further this therapeutic avenue. In this project, we propose to combine synthesis, metabolomics and genomics to unravel the crosstalk between PARP activity and G-quadruplex formation. This study, will shed light on the fundamental mechanisms linking Gquadruplex formation and NAD+ metabolism, providing a platform for the rational design of the next generation of drugs to treat PARP-resistant cancer patients.

Novel senolytic drugs as anticancer therapies

Note that this project is jointly funded by the CRUK Imperial Centre and Institute of Chemical Biology EPSRC Centre for Doctoral Training for a 4 year PhD

Title

Novel senolytic drugs as anticancer therapies

Supervisors

  • Professor Jesús Gil
  • Professor Ed Tate

Abstract

Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells. In addition to becoming cell cycle arrested, senescent cells undergo a number of changes, the most notorious being the secretion of a complex mixture of mostly pro-inflammatory factors collectively referred as the senescence-associated secretory phenotype (SASP). The chronic accumulation of senescent cells contributes to aging, disease and cancer, whilst eliminating senescent cells genetically or using so called ‘senolytic’ drugs increases health span and lifespan. Targeting senescent cells is rapidly gaining traction as an anticancer therapy and has been highlighted as a Grand Challenge by CRUK. Existing cancer treatments (including chemo-, radio- and targeted therapies) induce senescence of cancer cells which can be eliminated with senolytics in a so-called “one-two punch” approach. 

In this PhD you will be at the centre of a multidisciplinary collaboration to discover and understand the mode of action of senolytic compounds targeting PTM pathways, with broad applications in many cancers and diseases of aging. You will apply chemical proteomic tools and novel drugs currently in preclinical development in the Tate and Gil labs to drive validation of drug targets in these pathways. Your research will be based in the lead supervisors’ labs at the state-of-the-art Molecular Sciences Research Hub and the MRC London Institute of Medical Science, on the adjacent Imperial White City and Hammersmith Hospital campuses. You will also collaborate with scientists in industry and at the Francis Crick Institute. You will receive training in all relevant aspects of chemical biology, proteomics, cancer cell biology and in vivo models, and you will benefit from membership of the Imperial Cancer Research UK Centre and the Institute of Chemical Biology.

This project would ideally suit candidates with a Masters level qualification in chemistry or a closely related subject, with research experience in chemical biology or medicinal chemistry, and a strong interest in drug target validation and novel approaches to target cancer.

The effect of membrane asymmetry on electron transfer in complex membrane proteins

Title

The effect of membrane asymmetry on electron transfer in complex membrane proteins

Supervisors

  • Dr Maxie Roessler
  • Professor Oscar Ces
  • Professor Bill Rutherford

Abstract

The asymmetric nature of biological membranes is emerging as an important factor in membrane protein function with the molecular basis and role of asymmetry remaining one of the most poorly understood phenomena in biology. We will investigate the impact of membrane asymmetry on the function and mechanisms of membranebound oxidoreductase enzymes at the heart of bioenergetics building on physical sciences innovation consisting of new microfluidic technology for reconstituting them into artificial membrane vesicles, with tunable lipidcomposition, curvature and asymmetry. The development of novel pulse EPR approaches will allow the detection of low concentrations of spins from key radical intermediates. The technological innovations are expected to be broadly applicable to membrane proteins including redox- and metalloenzymes. The advances in understanding structural and mechanistic aspects of respiration and photosynthesis will pave the way to applications in medicine and energy technology.