Title

Modelling hair lubrication in the presence of additives

This project is co-sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Procter & Gamble

Supervisors

• Professor Daniele Dini
• Dr James Ewen
• Dr Stefano Angioletti-Uberti
• Dr Nick Brooks

Abstract

This project will study the molecular-level interactions and fundamental mechanisms responsible for wet friction in hair-to-hair contacts in the presence of new additives used in silicone-free conditioners and sulfate-free shampoos. Particular emphasis will be placed upon natural products with lower environmental impact. Molecular Dynamics (MD) and Non-Equilibrium Molecular Dynamics (NEMD) simulations will be used to study changes on the hair surface chemistry in presence of surfactants, polymers, and natural products and their impact on hair-hair lubrication. We will also explore the use of continuum-based models and hybrid molecular-continuum simulations to capture the impact of the surface changes induced by the improved formulations on macroscale friction.

The project will utilise coarse-grained molecular models that we have recently developed for the surface of human hair [1] that reproduce its friction properties [2,3].

[1] Weiand et al., Soft Matter, 2022, 18, 1779 (https://doi.org/10.1039/D1SM01720A)

[2] Weiand et al., Nanoscale, 2023, 15, 7086 (https://doi.org/10.1039/D2NR05545G)

[3] Handa, Chemistry World, 2023 (https://www.chemistryworld.com/news/study-untangles-friction-and-surface-chemistry-in-chemically-damaged-hair/4017403.article)

This project was released on 27 March 2023.

Title

Dynamic protein biosynthesis via an integrated cell-on-a-chip platform device

Supervisors

• Dr Nazila Kamaly (Department of Chemistry, ICL)
• Professor Oscar Ces (Department of Chemistry, ICL)
• Dr Yuval Elani (Department of Chemical Engineering, ICL)

Abstract

Producing a target protein in living microorganisms using biotechnological approaches can be laborious, and limitations associated with ‘living’ biochemical factories are proving to be bottlenecks in many bio-manufacturing processes. In this project we aim to develop the underlying technologies to remedy this, by developing a microfluidic analogue of a living cell: a cell-on-chip. Our proposition is that cell-free lab-on-a-chip devices have the potential to act as robust microreactors where synthetic microcompartments can be designed and tuned to work in an integrated manner, in order to perform specific biological outputs including gene expression, protein synthesis, post-translational modifications and energy generation. These features are all integrated biological outputs that can eventually enable cell-cell signalling leading to cell differentiation and higher-order biological entities.

In this project, we aim to utilise a multidisciplinary approach to realise such cell-on-a-chip devices with compartmentalised organelle-like environments that are connected via microfluidic valves. The final goal of this project is to create a microscale synthetic cell-on-chip for dynamic and precision protein synthesis and bioprocess engineering. The miniaturisation of expression systems can enhance production capacity and also offer a novel manufacturing process that can lead to substantial space-time yields and short development times. It will have game-changing implications for the biopharmaceutical market and beyond, and will also serve as platform to explore the rules underpinning cell biology.

Title

A new platform to understand and control protein liquid-liquid phase separation

Supervisors

• Dr Francesco Aprile (Department of Chemistry, ICL)
• Professor Ramon Vilar (Department of Chemistry, ICL)
• Professor Marina Kuimova (Department of Chemistry, ICL)

Abstract

Proteins can undergo liquid-liquid phase separation (LLPS) and form liquid droplets. This self-assembly mechanism plays a central role in biology and disease (e.g. Alzheimer’s and Parkinson’s disease). Nevertheless, it is still largely uncharacterised due to the lack of analytical tools to monitor it in biologically relevant complex systems, such as cells. Environmentally responsive probes offer unparalleled opportunities to probe biomolecular self-assembly events in cells and provide a read-out for their location, timing, and downstream consequences.

In this project, we will deliver a platform to quantitatively monitor LLPS in live cells, for the first time. We will investigate ɑ-synuclein, a crucial protein of the nervous system, whose LLPS has been hypothesised to be important for the protein’s normal function and for inducing amyloid aggregation linked to Parkinson’s disease. This multidisciplinary project will involve a combination of biophysical protein characterisation, optical probe development and live cell microscopy.

Title

Development of optical probes based on encoded aptamers for RNA visualization in live cells

Supervisors

• Professor Ramon Vilar (Department of Chemistry, ICL)
• Professor Marina Kuimova (Department of Chemistry, ICL)
• Professor David Rueda (Department of Infectious Disease, ICL)

Abstract

RNA is the carrier of genetic information from DNA to proteins. In addition, non-coding RNAs have been found to assist in many essential regulatory functions, which are still being discovered and studied. To fully understand RNAs’ varied functions, there is increasing interest in developing methods to visualize them in live cells. In this project we propose to develop a series of small-molecule probes which in combination with an encoded aptamer will be used to visualize RNA dynamics in live cells. To achieve this, we will build on recent optical probes developed in our group which have unique photophysical properties; in combination with the proposed aptamers, it will yield the first encoded RNA visualization tool that employs fluorescence lifetime to study RNA dynamics in single cells. We will also aim to develop this further to utilize super-resolution microscopy. This multidisciplinary project will involve the development of new small-molecule optical probes, nucleic acid chemical biology, and live cell microscopy. 

Title

Systematic discovery of functional allostery for next generation chemical modulators

Supervisors

• Dr Matthew Child (Department of Life Sciences, ICL)
• Professor Sophia Yaliraki (Department of Chemistry, ICL)
• Professor Ed Tate (Department of Chemistry, ICL & Francis Crick Institute)
• Dr Louise Walport (Department of Chemistry, ICL & Francis Crick Institute)

Abstract

Allosteric sites provide a fundamentally important mechanism for regulation of protein function, whereby molecular interactions at a remote allosteric site trigger changes in activity at the primary site of protein function - for example an enzyme active site or protein interaction interface. They are highly sought after as sites for selective and unique drug discovery as they are generally less highly conserved across families than the primary site and offer a powerful mechanism to influence otherwise undruggable active sites. A general approach for de novo identification and validation of druggable allosteric molecular pathways would offer game-changing potential for drug discovery against currently intractable targets across all areas of disease. 

In this project you will integrate a suite of emerging computational and experimental technologies from our labs to establish the first high-throughput platform for universal discovery, validation, and targeting of functional allosteric sites across the proteome. You will demonstrate proof of concept for your multidisciplinary approach through generation of the first allosteric modulators of human protein translation, deepening our understanding of the rules of life governing functional allostery, as well as underpinning new approaches to anticancer and antiviral therapeutics. 

Working across our labs, you will learn and apply new skills and technologies including covalent ligand screening and medicinal chemistry optimisation, in silico modelling and machine learning, CRISPR-Cas gene editing, and molecular cell biology. This project would therefore ideally suit a student with research experience in medicinal chemistry or chemical biology and the ambition to integrate expertise across these areas to create a new drug discovery paradigm.

Title

Unlocking deubiquitinase (DUB) probe discovery by high-throughput in-cell chemical proteomics

This project is sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and Ubiquigent

Supervisors

• Professor Ed Tate (Department of Chemistry, ICL & Francis Crick Institute)
• Dr Sheelagh Frame (Ubiquigent Ltd)
• Dr Joao Oliveira (Ubiquigent Ltd)
• Dr Jack Houghton (Department of Chemistry, ICL)

Abstract

The ubiquitin proteasome system (UPS) regulates myriad intracellular processes including protein turnover, through attachment of ubiquitin (Ub), a protein post-translational modification which tags proteins for degradation at the proteasome. More than 100 deubiquitinase (DUB) proteases catalyse Ub hydrolysis, thereby counteracting Ub ligase activity and regulating protein turnover. Altered DUB activity has been linked to a number of diseases and several DUBs are considered promising drug targets, with DUB inhibitors at various stages of preclinical or clinical development. However, target validation for DUB inhibitors has proven challenging, and there remains a pressing need for novel small molecule activity-based probes (ABPs) which can overcome the limitations of current generations of probes based on Ub which cannot be applied directly in intact cells or organisms. 

Building on recent advances in small molecule ABPs at Imperial (e.g. JACS 2020, 12020; J Med Chem 2020, 3756; ACS Chem Biol 2016, 3268; JACS 2021, 8911; JACS 2022, 22493) and the industry-leading discovery and screening platforms at Ubiquigent (https://www.ubiquigent.com/platform) you will develop a new high-throughput chemical proteomic technology platform to comprehensively explore and interrogate DUB activity in intact cells. Working across a range of cancer cell line models, you will deliver the first in-cell screens of large compound libraries to identify new and selective DUB probes and inhibitors, revealing starting points for new classes of medicines. You will acquire a deep and wide range of expertise in this essential area for future drug discovery, including chemical probe design, chemical proteomics, machine learning and proteomics automation.

This project would suit a candidate interested in new approaches for drug discovery which apply chemistry to understand complex biological systems and cell biology. Prior experience in a multidisciplinary research environment, for example in chemical biology, would be an advantage. You will be mentored at Imperial by Prof Ed Tate and Dr Jack Houghton (http://www.imperial.ac.uk/tate-group/), and at Ubiquigent by Dr Sheelagh Frame (CSO) and Dr Joao Oliveira (Principal Scientist), in state-of-the-art chemical biology labs in the new £170M Molecular Sciences Research Hub at Imperial White City campus.

Title

Developing new technologies to monitor translocation of chemicals in plant leaf

This project is sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and BASF

Supervisors

• Professor Marina Kuimova (Department of Chemistry, ICL)
• Dr Markus Rueckel (BASF)
• Dr Nick Brooks (Department of Chemistry, ICL)

Abstract

The effectiveness of pesticides (including herbicides, fungicides and insecticides) for crop protection crucially depends on the permeability of the formulation’s active ingredient across various leaf layers and membranes. Chemical adjuvants are often used to soften the top wax layer of the leaf and enable herbicide transport across this protective barrier. In practice the link between active ingredient uptake, wax softness and/or permeability and the effectiveness of a herbicide is very challenging to measure. Engineering effective adjuvants and understanding the gains and losses in efficacy are, therefore, significant agrotech challenges.

This project is a collaboration between BASF and the Institute of Chemical Biology EPSTC Centre for Doctoral Training, and will develop a suite of novel methods to measure wax softening and permeability in two complementary ways:

1. direct imaging of permeability of highly controllable wax barrier in droplet interface bilayer tool; and,
2. via directly imaging of wax viscosity using environmentally sensitive molecular rotors and advanced optical microscopy.

Update 5 April 2023: We are no longer accepting applications for this position

Title

A microfluidic toolkit for drug delivery particle discovery

This project is co-sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and AstraZeneca 

Supervisors

• Dr Yuval Elani (Department of Chemical Engineering, ICL) 
• Dr Nick Brooks (Department of Chemistry, ICL)
• Professor Molly Stevens (Department of Materials, ICL)
• Dr Morag Rose Hunter (AstraZeneca)

Abstract

Automation and high throughput screens are used in the pharma industry to manufacture and test massive numbers of compounds in the therapeutic development process. Drugs are chosen to cover large areas of chemical diversity to broadly probe biological function without earlier assumptions. Although this has proven hugely successful in the discovery of active pharmaceutical ingredients (APIs), such concepts are currently not used to develop soft matter drug delivery vehicles (liposomes, LNPs etc) themselves. There is huge scope for innovation in terms of the architectures of the delivery particle themselves, driven by the lack of technologies to manufacture libraries of such structures.

In this project we will develop microfluidic platforms to create massive libraries of different lipid NP formulations, morphology, charge, sizes, amphiphile composition, and encapsulated genetic material type. Building on this, we will develop integrated lab-on-chip platforms to test their ability to deliver genetic material to cells via in vitro assays. In doing so, we aim to establish the infrastructure for a new frontier in high-throughput manufacture and screening of soft nanoparticle libraries. We use this as a basis for a high-throughput screening platform, where we will screen the nanoparticle itself (as opposed to the active ingredient). This offers a conceptual shift from existing approaches that rely on one-by-one rational design and manufacture of particle types. Together with our industrial collaborators (AstraZeneca) we will apply our technology to scientific priorities of the pharmaceutical sector. Once established, our platforms can be applied to *any* application where soft matter particle discovery is needed, including in drug/vaccine therapeutic delivery applications and in biosensing.

This project was released on 21 February 2023. Recruitment will continue until the post is filled.

Title

An integrated chemical biology platform for discovery of next generation antibody-drug conjugate (ADC) linkers

This project is sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and AstraZeneca

Supervisors

• Professor Ed Tate (Department of Chemistry, ICL & Francis Crick Institute)
• Dr Max Lee (AstraZeneca)
• Dr Neki Patel (AstraZeneca)

Abstract

Antibody-drug conjugates (ADCs) have decisively impacted cancer treatment, with 10 approvals and >80 progressing though clinical trials. ADCs typically deliver a toxin ‘payload’ linked to a monoclonal antibody against a protein expressed predominantly on the surface of cancer cells, thereby achieving enhanced on-target activity in tumours. However, despite the great promise of this drug modality, dosing-limiting toxicities often arise from payload release in normal tissue, in some cases leading to product withdrawal.

Here you will directly address this unmet need for enhanced specificity of payload release in a collaborative project between the team of Prof Ed Tate at Imperial College and ADC discovery scientists at AstraZeneca. Leveraging a unique discovery platform recently developed in our labs, you will demonstrate proof of concept for an innovative new approach to overcome the challenge of non-specific payload release in ADCs.

Title

Developing novel label-free technologies for studying drug molecules and their ability to induce protein complex formation in cells

This project is co-sponsored by the Institute of Chemical Biology EPSRC Centre for Doctoral Training and AstraZeneca.

Supervisors

• Professor Oscar Ces (Department of Chemistry, ICL)
• Dr Jorge Bernardino de la Serna (National Heart & Lung Institute, ICL)
• Dr Liming Ying (National Heart & Lung Institute, ICL)
• Dr Nazila Kamaly (Department of Chemistry, ICL)
• Dr Philip Hopcroft (AstraZeneca)
• Dr Andy Thomas (AstraZeneca)

Abstract

Real time imaging of drug efficacy in model in-vitro systems and living cells is vital to the development of novel drug molecules in the pharmaceutical industry.  Traditionally drugs are chemically modified to facilitate their observation and mode of action under a microscope using e.g. fluorescence but this is problematic as these modifications result in changes in drug efficacy. The development of novel imaging techniques that allows for label-free imaging of drugs with no phototoxicity is therefore vital to unlocking drug discovery pipelines. Applications of such label free imaging would include studying the ability of drug molecules to trigger protein complex formation.  

This studentship will directly address this bottleneck through the development of novel label free imaging techniques (holotomography) that exploit changes in refractive indices. This exciting technology will be coupled with model membranes and synthetic biological cells into which protein complexes of interest have been embedded. By exposing these biological membranes to drug candidates it will then be possible to dynamically monitor the formation of protein complexes.  These synthetic cells will be arrayed so as to generate high-throughput screens, with subsequent studies looking at complex formation in 3-D printed cells and organ on a chip platforms. All results will be validated with fluorescence imaging and spectroscopy, including single molecule approaches such as fluorescence correlation spectroscopy (FCS).

This exciting project will enable the successful student applicant to gain extensive experience of microfluidics, label-free imaging, 3D-bioprinting, cell culture, synthetic cell construction and drug discovery science.

Title

A Molecular Magnifying Glass to Dissect the Interaction Between Cancer and Host

This 4 year PhD is sponsored by Cancer Research UK and is only open to applicants with 'Home' fee status. This studentship open to applicants from Life or Biomedical Sciences backgrounds (2:1 or higher).

Supervisors

• Dr Ben Schumann, Department of Chemistry, Imperial College London and The Francis Crick Institute
• Ilaria Malanchi, The Francis Crick Institute
• Paul Huang, The Institute of Cancer Research

Abstract

Every cell in our body displays on the surface sugars, so-called glycans, that are linked to other biomolecules such as proteins. When a cell turns into a cancer cell, it displays different types of glycoproteins that help the cancer survive. Some of the current biomarkers used by the NHS to detect cancer are proteins that contain very high amounts of glycans. While cancer glycoproteins have outstanding clinical potential for both diagnosis and therapy, it is very challenging to distinguish them from native glycoproteins from the host by methods of biology alone. Through ground-breaking new developments in our groups (Nat. Commun. 2022; J. Proteom. 2021; Nature 2019;) the tools are finally within reach to accurately profile cancer-derived glycoproteins and understand how they change during tumorigenesis, for instance when surrounded by host-derived cells or in metastasis.

In this studentship, you will apply innovative tools in ex vivo cell biology (Cancer Lett. 2022; Nat. Protoc. 2020),  chemical biology (Nat. Commun. 2022; Curr. Opin. Chem. Biol. 2021) and mass spectrometry (glyco-)proteomics (J. Proteom. 2018; Dis. Model and Mech. 2020; J. Amer. Soc. Mass Spectrom. 2021) to study the glycoproteins specifically produced by breast cancer cells, and their role in disease formation. In close collaboration with members of all three groups, you will use these tools to understand how the presence of host cells "shapes" the signature of these glycoproteins. The project builds on prior work of all three labs and will focus on ex vivo tissue co-culture as well as mass spectrometry glycoproteome analysis.

This project will be based at the Francis Crick Institute, a flagship of biomedical science with outstanding strong support in all aspects of research including a state-of-the-art Proteomics Science Technology Platform (STP). At the Crick, you will be jointly supervised by Dr. Ben Schumann and Dr. Ilaria Malanchi, with close relationships with the lab of Dr. Paul Huang at the top-tier Institute of Cancer Research. You will work with lab members of all three groups as well as the STPs. We are looking for candidates with an excellent background in biology, biochemistry, chemical biology or related fields. Experience in mammalian cell culture and/or mass spectrometry proteomics is desirable, with training opportunities in a highly supportive environment. We put heavy emphasis on strong communication skills, collegiality, scientific integrity and mindfulness of all aspects of health and safety. You will be integrated in the Institute of Chemical Biology PhD programme at the Imperial College Chemistry Department of Chemistry, featuring outstanding support, regular progress reports and assessments. This project requires no experience or background in synthetic chemistry. Please note that this project might require working with cells or tissues derived from laboratory animals. Direct animal work is not required.

 References:

• Calle et al., J. Amer. Soc. Mass Spectrom. 32, 2021.
• Cioce et al., Nat. Commun. 13, 2022.
• Cioce et al., Curr. Opin. Chem. Biol. 60, 2021.
• Krasny et al., J. Proteom. 189, 2018.
• Krasny et al., Dis. Model and Mech. 13, 2020.
• Milighetti et al.,  J. Proteom. 241, 2021.
• Ombrato et al., Nature 572, 2019.
• Ombrato et al., Nat. Protoc. 16, 2020.
• Rosell et al., Cancer Lett. 544, 2022.