EPSRC Centre for Doctoral Training in Chemical Biology: Innovation in Life Sciences

The ICB CDT is training a new generation of PhD graduates in the art of multidisciplinary Chemical Biology research, giving them the exciting opportunity to develop the next generation of molecular tools and technologies for making, measuring, modelling and manipulating molecular interactions in biological systems.

EPSRC Centre for Doctoral Training in Chemical Biology: Innovation in Life Sciences Studentships 2019

Currently Available Studentships at the ICB CDT

Artificial Cells for Tracking Cancer

Funded by the CDT in Chemical Biology: Innovation in Life Sciences – 1+3 year PhD studentships - APPLY HERE

Supervisors: Professor Oscar CesProfessor Charlotte BevanDr Yuval ElaniProfessor Rob Law

This project will look at the development of artificial cells capable of identifying and targeting cancer cells. The project will build on recently developed new approaches in our groups whereby we have demonstrated it is possible for artificial cells to communicate with cancer cells thereby enabling them to make assessments of their local environment. In turn, when in close proximity to cancer cells these artificial cells release an onboard cargo that is designed to kill these cells. This approach differs substantially from previous philosophies that rely on disassembly of cargo carrier and instead offer a controlled delivery mechanism. This exciting project will cover a variety of areas ranging from microfluidics and microscopy through to membrane biophysics and cancer engineering.

Chemical approaches to improving photosynthesis

Funded by the CDT in Chemical Biology: Innovation in Life Sciences – 1+3 year PhD studentships - APPLY HERE

Supervisors: Dr Laura Barter | Professor Nick Long | Dr Rudiger Woscholski 

This project is focused upon the synthesis, application and analysis of suite of compounds able to produce CO2 within plants. These compounds have the potential to revolutionise the agri-science sector by increasing crop yields, overcoming the inefficiency of the carbon fixating step of photosynthesis. Rubisco is an enzyme involved in this step, catalysing the incorporation of CO2. Unfortunately a competing reaction with Oxygen can also take place, which causes a loss to the plant! To overcome this limitation, this project will focus upon new chemical catalysts that can generate higher CO2 levels within the plant, thus increasing Rubisco efficiency and ultimately plant yields. We are looking for chemists who are interested in combining their synthesis skills with biological applications to address the important global challenge of providing enough food for our growing global population. Students will gain expertise in synthetic chemistry, as well as biological techniques including protein purification, enzyme assays, as well as imaging methodologies. If you would like to know more about this exciting project, please feel free to contact us.

Combining Machine Learning, Molecular Dynamics and Membrane Biophysics to identify new therapeutics for the treatment of Tuberculosis

Funded by the CDT in Chemical Biology: Innovation in Life Sciences – 1+3 year PhD studentships - APPLY HERE

Supervisors: Professor Ian GouldDr Nick BrooksProfessor Bernadette Byrne

Tuberculosis (TB) is currently one of the world’s leading causes of mortality with 10 million new cases reported in 2017 alone and 1.3 million deaths (Global Tuberculosis Report 2018 WHO), a further complicating factor is the evolution of multi-drug and totally drug resistant strains. There is an urgent need to develop effective new therapeutic agents to target TB and critical in this process is the identification of a suitable protein to target. MmpL3 is a transmembrane protein which is essential for the replication and viability of bacterial cells and therefore represents a suitable target. The recent determination of the structure of MmpL3 from M. smegmatis (Cell 2019; 176: 636-648) provides the starting point for developing new therapeutic strategies. Molecular Dynamics (MD) simulations will be utilised to construct a model of MmpL3 for M. tuberculosis (Mtb) facilitating investigation of drug-protein interactions, known inhibitors will be modelled at physiological conditions with the protein embedded in a realistic representation of the cell membrane. Validation of the computational model will be achieved through the investigation of the structure and mechanics of model membranes, in which Mtb MmpL3 is embedded, via X-ray diffraction and light microscopy. Identification of the binding modes of know inhibitors to Mtb MmpL3 and known drug resistant mutants will be used as input into Machine Learning (ML) to generate rules to search large compound libraries, in particular the Zinc database, to identify suitable compounds to screen. This project will provide the student with a broad range of skills, computational modelling, machine learning, protein expression and purification and experimental membrane biophysics. 

Combining multiple bullets against a sweet target - Fragment-based drug discovery to tackle cancer glycosylation

Funded by the CDT in Chemical Biology: Innovation in Life Sciences – 1+3 year PhD studentships - APPLY HERE

This studentship in the ICB CDT is co-funded with GSK

Supervisors: Dr Benjamin Schumann | Dr David House | Professor Ed Tate

Glycosylation is a ubiquitous posttranslational protein modification, and highly glycosylated proteins are overexpressed as a hallmark of metastatic cancer. The addiction of cancer cells to structural alterations of glycans makes the process of glycosylation an important yet underexplored target for therapeutic intervention. This project, co-funded by GlaxoSmithKline, will focus on fragment-based drug discovery to generate glycosylation enzyme inhibitors. We will combine newly-available chemical space and modelling approaches to generate lead compounds with suitable interaction profiles. Biological evaluation will be performed to develop a drug that hits glycosylation, the sweet tooth of cancer.

This multidisciplinary project will be performed at the Francis Crick Institute (London), one of the world's leading biomedical research institutes. Embedded in this exceptional environment that includes access to the Crick Science Technology Platforms, the student will be a part of the Chemical Glycobiology Group and establish close ties with the GSK LinkLabs at the Crick. The student will be trained in methods of protein expression and crystallography, modelling, enzyme assays and lead development as well as in-depth biological evaluation. A research placement at GSK’s R&D site in Stevenage will expose the student to cutting-edge drug discovery infrastructure. We are looking for an outstanding student with a chemistry, chemical biology or related background and exposure to biological research, ideally in the context of drug discovery. Theoretical knowledge in any facet of drug discovery and glycobiology is highly desirable.

Development of a bedside diagnostic tool to determine low levels of free haemoglobin in whole blood

Funded by the CDT in Chemical Biology: Innovation in Life Sciences – 1+3 year PhD studentships - APPLY HERE

This studentship in the ICB CDT is co-funded with Roche.

Supervisors: Professor Alan Spivey | Professor Tony CassDr Greg Quinlan 

Haemoglobin (Hb) is predominantly localised within the cellular compartment of red blood cells. However, traumatic injuries, surgery and some disease states (e.g. sickle cell, thalassemia and malaria) cause red cell rupture/haemolysis which releases free Hb into the circulation. Endogenous protection is afforded by the Hb binding and removal protein haptoglobin (Ha), but this reserve is rapidly overwhelmed. Free Hb has recently been implicated in kidney failures, infection, sepsis, acute respiratory distress syndrome (ARDS), hypertension and pulmonary arterial hypertension. Thus there is an emerging need to develop a sensitive and rapid, bedside, free Hb quantitation method to help inform diagnosis and clinical management of patients. In this project, we will explore two potential solutions to this challenge one based on electrochemical detection and the other spectrophotometry.

Gut on a Chip 4.0: next generation models to study gut-microbiome-metabolism interactions

Funded by the CDT in Chemical Biology: Innovation in Life Sciences – 1+3 year PhD studentshipsAPPLY HERE

Supervisors: Prof Gary FrostProf Joshua EdelDr Aylin HanyalogluProf Ed Tate

There is currently no readily accessible and realistic model for human gut signaling. Such a model would need to combine computational modelling with functional readouts in a physiologically relevant setting, in the presence of diverse metabolites and receptors in a dynamic microbiota environment, and under the influence of nutrition. This unsolved technological challenge holds back progress in understanding the roles of metabolite signaling for the treatment of obesity and metabolic disease. The aim of the PhD will be to deliver a new human colon microfluidic technology platform that will enable analysis of gut signaling in a near physiological setting, through a computational and physical model. To achieve this we will deliver a human in vitro colonic microfluidic model, complete with mechanically active bacterial microenvironment and neuronal system. This ambitious aim, which has never been achieved before, requires a highly inter-disciplinary PhD necessitating specialists in 4 main areas in order for the project to progress and succeed: device design and fabrication, GPCR biology, chemical probes, and organoid transfer to the device. Our industrial partner Emulate will play an active role in the PhD.  We are seeking students to have a keen interest in advanced cell models and hands on experimental biology. 

By the end of the PhD the we envisage that the student will have delivered a near human colonic model which can be used to understand the complexed relationship between nutrition, microbiota and multidimensional GPCR signaling pathways.

Next generation Disease Screening using Nanosensors

Funded by the CDT in Chemical Biology: Innovation in Life Sciences – 1+3 year PhD studentships - APPLY HERE

This studentship in the ICB CDT is co-funded with Oxford Nanopore Technologies.

Supervisors: Professor Joshua EdelDr Alex IvanovAndy Heron | Richard Gutierrez | Professor Tony Cass

There is an enormous need for analytical methods that can achieve simultaneous detection of multiple  proteins and miRNA in complex biological fluids. A technology that can achieve this holds the promise of far-reaching impact in multiple healthcare grand challenges ranging from neurodegenerative disease to several major cancers. In a collaboration between Imperial College London and Oxford Nanopore Technologies, this project aims to develop a multiplexed label-free detection strategy for the detection of soluble proteins and miRNA in biofluids.

We have demonstrated proof of principle of using molecular carriers which we showed enables improved selectivity and sensitivity in complex biological solutions. (Nature Communications 2017, Nature Communications 2019).

Within this multidisciplinary project the technology will be further expanded to a panel of key proteins and microRNA sequence linked to major neurodegenerative diseases and cancers which are either up or down regulated in patients. The proposed strategy is universal and if successful this pilot work will build the basis for a general approach for the detection of proteins and small molecules such as miRNA and neurotransmitters in complex unmodified samples. 

 

Surgery on a Single Cell

Funded by the CDT in Chemical Biology: Innovation in Life Sciences – 1+3 year PhD studentships - APPLY HERE

Supervisors: Dr Alex Ivanov | Dr Nick Jones | Professor Joshua B Edel | Professor Patrick Chinnery | Dr Michael Devine

We currently have no basic understanding of how mutations spread within single cells. For example, the spread of specific mitochondrial mutations likely has a central role in neurodegenerative diseases such as Parkinson’s and fundamental life processes such as ageing. 

This multidisciplinary project is based around novel single molecule - single-cell biophysical technology developed in our groups that combine spatial mapping, extraction and genomic profiling of individual mitochondria from living cells. (Nature Nanotechnology 2019 and news article Nature Medicine)

This is a highly multidisciplinary research project and is ideally suited for an MRes/PhD, building up competences step-by-step ensuring the foundations are in place. It is important to emphasize that based on our preliminary data that automated mitochondrial extraction and sequencing is readily within our reach. The student will receive training in techniques such as nanofabrication, cell culture, and imaging. Furthermore, the student will actively collaborate with colleagues that will perform mtDNA sequencing and modelling.

These activities will be complemented by established expertise in mitochondrial research, mitochondrial sequencing and sequence informatics and mathematical modelling across leading groups at University of Cambridge, UCL and Imperial College London.

Targeting ovarian cancer using fragment-based drug discovery

Funded by the CDT in Chemical Biology: Innovation in Life Sciences – 1+3 year PhD studentships - APPLY HERE

Supervisors: Professor Iain McNeishProfessor Alan ArmstrongDr David MannDr James Bull

High-grade serous carcinoma is the commonest type of ovarian cancer and accounts for approximately two-thirds of all cases and nearly 80% of deaths. Treatment relies on the use of platinum agents but resistance arises, this being associated with amplification of the CCNE1 gene.  The protein product of this gene (cyclin E1) is a cell cycle regulator that binds to and activates the kinase cdk2 to promote proliferation.  Thus, the cyclin E1/cdk2 protein/protein interaction (PPI) offers an opportunity for an urgently required targeted therapy. This project will define novel chemical entities to regulate this interaction, exploiting our covalent screening platform (qIT, Angew Chem Int Ed Engl. (2018) 57:5257-5261). The project will be a mix of biochemistry, biophysics, structural biology, synthetic and medicinal chemistry. The student will develop new technology to attach and display chemical fragments for screening, then identify, characterise and develop hit fragments to be regulators of cyclin E1 activity.  These compounds will then be tested in established ovarian cancer cell lines with and without acquired resistance to platinum agents.  

For more information on the eligibility criterea and how to apply for ICB CDT studentships please visit the ICB CDT website.