Title

Engineering synthetic cells using next-generation robotics and machine learning

Supervisors

• Dr James Hindley (Department of Chemistry, Imperial)
• Professor Oscar Ces (Department of Chemistry, Imperial)
• Dr Antonio Del Rio Chanona (Department of Chemical Engineering, Imperial)

Abstract

Bottom-up synthetic biology has ushered in a new era of synthetic cell science where biomimetic entities including microrobots are constructed from non-living and living components to create tailorable structural elements and complex life-like behaviours. Synthetic cells can model systems to unravel biological processes including signal transduction and have the potential to act as microrobots for therapeutics, agrochemical delivery, diagnostics and regenerative medicine. Although significant progress has been made in developing synthetic cells with individual behaviours such as motility, biosynthesis and communication, a crucial lack of high-throughput production and screening technologies hinders the design of next generation systems.

Here, we propose to unlock this potential by developing robotic synthetic cell production methods and coupling these with machine learning-powered feedback. Such methods will be used to design and develop a suite of new synthetic cells that are capable of sensing, computation and biosynthesis using a variety of molecular parts from membrane proteins to DNA circuitry. Integration of machine learning methods will facilitate rapid data analysis and inform future experimental design, unlocking new high-throughput production workflows. Such processes will be critical in translating fundamental synthetic cell technologies to tackle societal challenges in medicine and industry, acting as new delivery systems, microreactors and diagnostics.

Application deadline: 12 April 2024 

Posted: 6 March 2024

Title

Developing novel transition metal complexes to enhance crop yields

Supervisors

• Dr Laura Barter (Department of Chemistry, Imperial)
• Dr Rudiger Woscholski (Department of Chemistry, Imperial)
• Professor Nicholas Long (Department of Chemistry, Imperial)

Abstract

This studentship will explore novel synthetic chemistry and chemical biological routes to tackle the global challenge of food security, by developing molecular tools, with the potential to transform crop security across the globe. It will enable plants to exceed performance levels that are limited by in-built pathway inefficiencies, currently only being addressed via expensive & often perceived as controversial genetic engineering approaches. This novel form of crop enhancement will enable plants to function at levels beyond that set by their natural performance and will target the inefficient process of photosynthesis and in particular the wasteful photorespiration reactions, where O2 competes with CO2, lowering photosynthetic efficiency by ~50%. It will mitigate this by increasing local CO2 concentrations, minimising photorespiration & thereby increase photosynthetic efficiencies and crop yields. This studentship will design, synthesise (transition metal complexes of multidentate ligands), test & optimise (in an iterative manner) a suite of these novel, molecular CO2 delivery vehicles, to investigate their mode of action. This will support the rational optimisation of efficacy, solubility and bioavailability and demonstrate their potential as a viable, scalable & cost-effective tool able to supercharge photosynthesis, resulting in increased crop yield.

Applications will be reviewed on an on-going basis and the studentship awarded when a suitable candidate is found.

Posted: 6 March 2024

Title

Transforming our understanding of electron transfer in membrane proteins through automation, additive manufacturing and spectroelectrochemistry

Supervisors

• Dr Maxie Roessler (Department of Chemistry, Imperial)
• Professor Oscar Ces (Department of Chemistry, Imperial)
• Dr James Hindley (Department of Chemistry, Imperial)

Abstract

Electron transfer processes in membrane proteins underpin fundamentally important biological processes, such as respiration and photosynthesis. Capturing paramagnetic reaction intermediates is key to understanding how these proteins function. However, capturing truly catalytic intermediates (rather than resting or off-cycle states), while harnessing information on both reactivity and structure, has remained a holy grail. We will enable the generation and interrogation of such catalytic intermediates in two exemplary and important membrane-bound oxidoreductase enzymes through the development of film-electrochemical EPR (FE-EPR) for membrane proteins. The challenging physical sciences innovation required to unlock the ability to study the time-dependent nature of these molecular interactions is timely and made possible by developing automated platforms for placing membrane proteins into artificial vesicles which incorporate in situ measurement of protein activity and computer-guided optimization processes, as well as additive manufacturing of tailored electrodes. Another crucial element is our recent proof-of concept demonstration that small-molecular catalysts can be interrogated with real-time FE-EPR (Nature Chemistry 2024). The advances in understanding the molecular interactions that underpin respiration and photosynthesis will pave the way to healthy ageing and sustainable agriculture, whilst the methodologies developed will be widely applicable in chemical biology and beyond. 

Deadline for applications: 7th April 2024

Posted: 6 March 2024

Title

Unravelling the role of G-quadruplex structures in brain ageing and neurodegeneration.

Supervisors

• Dr Marco Di Antonio (Department of Chemistry, Imperial)
• Dr Raffaella Nativio (Department of Brain Sciences, Imperial)
• Dr Silvia Galli (Department of Chemistry, Imperial)

Abstract

The increasing incidence of neurodegenerative disorders is posing a significant threat to the NHS and public health services world-wide. Epigenetic regulation has emerged as a critical player in ageing of model organisms and because of its role in integrating environmental stimuli into the genome, represents a therapeutically tractable player in brain ageing and neurodegeneration. Studies from Nativio et al. (Nat. Neuro 2018, Nat. Genet. 2020) have revealed that different epigenetic modifications are differently associated with healthy ageing and Alzheimer’s, driving distinct functional pathways. The Di Antonio group has recently demonstrated that the formation of DNA secondary structures known as G-quadruplex (G4) is linked to neurodegeneration (Nat. Commun. 2023) and that the mutation of key proteins that resolve G4s leads to accelerated ageing (J. Am. Chem. Soc. 2021). In this project, we propose to leverage this knowledge to systematically investigate the role of G4-formation in ageing neuron models that are established in the Nativio’s group. To achieve this, we plan to combine genome-wide mapping strategies to assess the changes in G4-distribution in ageing neurons with the development of chemical-biology probes to disrupt G4-structures and assess their potential as anti-ageing targets. We anticipate that this project will lead to the identification of G4s that could be targeted to prevent epigenetic dysregulation associated with neurodegeneration.

Application deadline: 12th April 2024

Posted: 6 March 2024

Title

Target-directed Synthesis of Protein-Protein Interaction Inhibitors

This project is funded via the Institute of Chemical Biology and The NIHR Imperial Biomedical Research Centre (BRC)

Supervisors

• Dr Anna Barnard (Department of Chemistry, Imperial)
• Professor Alan Armstrong (Department of Chemistry, Imperial)
• Dr David Mann (Department of Life Sciences, Imperial)

Abstract

Protein-protein interactions (PPIs) play critical roles in many biological pathways, the mis-regulation of which can result in disease. Therefore, PPIs have long been considered attractive drug targets, but the number of successful inhibitors generated remains limited. Current screening methods using established compound libraries often lack the structural properties necessary to identify inhibitors of the characteristically large and flat interfaces of most PPIs. We will combine the advantages of robotically enabled screening and a novel assay developed in the Armstrong and Mann groups to establish a high-throughput technology for the identification of PPI inhibitors with the target protein present in the screening conditions to enable it to select for its preferred ligands. This will enable the rapid identification of either peptide or small molecule ligands for any target PPI.

Application deadline: 7 April 2024. However, applicants may be considered after this date until a suitable candidate is found.

Posted: 6 March 2024

Title

Visualising the effects of pollution nanoparticles on respiratory epithelial cells at air-liquid interface

This project is funded via the Institute of Chemical Biology and The NIHR Imperial Biomedical Research Centre (BRC)

Supervisors

• Professor Marina Kuimova (Department of Chemistry, Imperial)
• Professor Alexandra Porter (Department of Materials, Imperial)
• Professor Fan Chung (National Heart & Lung Institute, Imperial)
• Professor Ian Adcock (National Heart & Lung Institute, Imperial)

Abstract

Pollution nanoparticles, termed particulate matter (PM), carry enormous population health burden, through direct and indirect effects that are thought to involve oxidation and inflammation. However, currently there is no single imaging or biochemical technique available to unequivocally assign the exact timing and the (bio)-chemical effects of PM components, thus preventing the implementation of solid strategies for the mitigation of their deleterious effects. This proposal will establish the exact site, sequence and timings of PM interaction with human airway epithelial cell and organelles. By establishing the relationship between these events this work will pinpoint the crucial subcellular processes that lead to oxidative stress and inflammation both at a single cell level and in whole cell populations. We will develop protocols to assess localisation via analytical cryo-electron microscope (cryo-EM) and direct oxidation pathways via fluorescence lifetime imaging microscopy (FLIM) in primary human bronchial epithelial cells (HBECs) grown in submerged culture and at air-liquid interface (ALI), which is the only model that accurately reflects airway pathophysiology, for the first time. 

Applications will be reviewed on an on-going basis and the studentship awarded when a suitable candidate is found.

Posted: 6 March 2024

Title

3D printed synthetic tissues for patterned interactions with cellular populations

This project is funded via the Institute of Chemical Biology and The NIHR Imperial Biomedical Research Centre (BRC)

Supervisors

• Dr Ravinash Krishna Kumar (Department of Infectious Disease, Imperial)
• Dr Yuval Elani (Department of Chemical Engineering, Imperial)
• Professor Karen Polizzi (Department of Chemical Engineering, Imperial)

Abstract

Cellular communities, consisting of cells (microbial and/or eukaryotic) living and interacting in various environments, are starting to be used in applications ranging from environmental remediation, agriculture, food science, bioproduction, and biomedicine. Moreover, it is increasingly being realized that communities of interacting cells underpin many aspects of human health (i.e. microbiomes). A global research priority therefore is to understand and engineer these communities for our own goals. Patterned population gene expression in cellular communities is critical for the establishment and development of both microbial communities and eukaryotic tissues. However, external control over target-cell populations is hugely limited due to the lack of smart-patterned release systems that can integrate and deliver effector molecules to cells when required. Here we propose to solve this, by using a custom-built 3D printer to build a smart-patterned release system for controlling population gene expression in cells with high spatial and temporal resolution. These printed systems will comprise of 100s of pL-sized aqueous droplets networked by interfaced lipid bilayers, of which we call synthetic tissues. Critically, we will develop these synthetic tissues to function in aqueous environments where encapsulated effector molecules will be released through membrane proteins present in the connected bilayers. Further, we will develop these 3D printed patterned release systems to be robust and adaptive to their external environment, and validate our system by interrogating patterned gene expression in both defined bacterial and mammalian cell populations. 

Application deadline: 7 May 2024. However, applications will be reviewed on an on-going basis and the studentship awarded when a suitable candidate is found.

Posted: 6 March 2024

Title

Highly multiplexed detection of cancer biomarkers from clinical samples using nanopore sequencing

This project is funded via the Institute of Chemical Biology and is co-sponsored by Oxford Nanopore Technologies

Supervisors

• Professor Joshua Edel (Department of Chemistry, Imperial)
• Dr Aleksandar Ivanov (Department of Chemistry, Imperial)
• Caroline Koch (Department of Chemistry, Imperial)
• Dr Nadia Guerra (Department of Life Sciences, Imperial)
• Dr Richard Gutierrez (Oxford Nanopore Technologies)
• Dr Mark Bruce (Oxford Nanopore Technologies)
• Dr Lakmal Jayasinghe (Oxford Nanopore Technologies)

Abstract

The unmet need in cancer diagnostics lies in the discovery and detection of novel biomarkers with both prognostic and predictive value. This is essential for enhancing early detection, optimizing treatment strategies and improving patient outcomes through personalized care. Currently, the majority of blood tests are conducted within a clinical environment and only examine a limited number of indicators. The potential for clinical diagnostics to progress beyond the customary single biomarker model lies in developing an inexpensive, rapid, and highly multiplexed platforms. To this end, we propose the creation of a novel technology that leverages nanopore sequencing and barcoded molecular probes building on work from our groups as shown in Koch et al. Nature Nanotechnology, 18, 1483 (2023). This innovative approach will facilitate the simultaneous multiplexed detection of analytes implicated in liver cancer within a single sample. The platform will allow for precise de-multiplexing of single molecule detection, enabling the simultaneous quantitative detection of hundreds of miRNAs and proteins and the generation of large single molecule data sets to build Modified Hidden Markov ML models. This adaptable method can also be expanded to detect a vast array of molecules, depending on the specific application required. To ensure the success of this project, we have assembled a team composed of Imperial physical and life scientists as well as an industrial partner, Oxford Nanopore Technologies (ONT), who we will collaborate with to deliver proof of concept and preclinical studies.

Applications will be reviewed on an on-going basis and the studentship awarded when a suitable candidate is found.

Posted: 6 March 2024

Title

Understanding and optimising RNA therapeutic delivery, efficacy, and toxicity with chemical biology

This project is funded via the Institute of Chemical Biology and co-sponsored by AstraZeneca

Supervisors

• Professor Ed Tate (Department of Chemistry, Imperial)
• Dr Santiago Vernia (MRC Laboratory of Medical Sciences)
• Laurent Knerr (AstraZeneca)

Abstract

Chemically modified RNAs have recently emerged as a unique and powerful therapeutic approach since they can be designed to address almost any disease state by directly and specifically modulating gene expression. These molecules operate through a diverse range of mechanisms, and include antisense oligonucleotides (ASOs), small interfering RNA (siRNA), micro-RNA (miRNA), messenger RNA (mRNA) and RNA vaccines, and splice-switching oligonucleotides (SSOs). However, these advanced therapeutics are currently limited by lack of understanding of mechanisms of uptake and delivery to target disease, whilst avoiding toxicity and non-specific delivery to off-target tissues.

In this project you will develop and apply a platform of chemical biology technologies to explore the interactome of any oligonucleotide therapeutic in living cells, combining synthetic oligonucleotide probes with quantitative proximity labelling proteomics. Your platform will be used to discover and explore the interacting partners of diverse oligonucleotide modalities, establishing mediators of delivery, uptake, and mechanisms of action in cells and in plasma. You will then proceed to explore the impact of chemical modifications commonly used to modulate delivery, providing a framework for knowledge-led optimisation of next generation oligonucleotide therapies.

You will benefit from a unique supervision team and access to state-of-the-art facilities, including expertise in chemical biology and proteomics (Tate, Imperial/Crick), RNA biology and therapeutics (Vernia, MRC Laboratory of Medical Sciences), and RNA therapeutic discovery (Knerr, AstraZeneca Sweden).

This project would ideally suit a medicinal chemist or chemical biologist with a passion for developing the next generation of advanced targeted therapeutics. Whilst training in all relevant techniques will be provided, some experience in biochemistry, molecular biology, or related areas would be an advantage.

Deadline for applications: 25th March 2024

Posted: 6 March 2024

Title

Phosphine Oxides as Rising Stars in Drug Discovery

This project is funded via the Institute of Chemical Biology and co-sponsored by UCB

Supervisors

• Dr James Bull (Department of Chemistry, Imperial)
• Dr Jeffrey Bruffaerts (UCB)

Abstract

Phosphine oxides represent a noticeably underrepresented chemotype in drug discovery. However, the clinical validation of Brigatinib, containing dimethyl phosphine oxide, and the disclosure of other therapeutic preclinical compounds featuring these polar and hydrophilic functional groups have sparked a revived interest across the pharmaceutical sector. The surge in relevant publications have further highlighted an untapped potential in drug-like chemical space, as these analogues were shown to present beneficial physicochemical and ADMET properties. Phosphine oxides notably exhibit a highly polarized P=O bond, translating in enhanced hydrophilicity, and thus aqueous solubility and enhanced metabolic stability. 

Acknowledging the current synthetic knowledge gap, enabling new synthetic methodologies to access this vastly uncharted chemical space is thus critical to capture the potential of phosphine oxides more extensively in drug design. This project will combine synthetic chemistry and ADME studies. Phosphine oxides motifs in new chemical space will be designed and prepared aiming to maximise the understanding of how this highly polar functional group can be best exploited in medicinal chemistry.

Applications will be reviewed on an on-going basis and the studentship awarded when a suitable candidate is found.

Posted: 6 March 2024