Funded by the Leverhulme Doctoral Scholarship Programme in Cellular Bionics – 3 year PhD studentships

Supervisors: Dr Guy-Bart Stan | Dr John Heap | Dr Connor Myant

Natural and engineered bacteria possess extraordinary biosynthetic capabilities. These can serve almost any application imaginable: from functionalised bacterial cellulose patches for antimicrobial wound dressing to bacterial self-healing concrete or the use of bacteria to produce nacre-inspired composite materials. The ability to harness such great manufacturing potential into customised designs with defined three-dimensional shape and composition remains, however, largely elusive.

Current 3D bacterial printing approaches rely on the use of scaffolds or conventional layer-by-layer additive manufacturing strategies to shape their designs, often resulting in unsophisticated structures with restricted geometries and monotonous physico-chemical and mechanical properties. In contrast, one-body yet heterogeneous composite materials with seamless transitions between disparate properties (functionally graded composite materials) have long been a holy grail for designers and engineers.

This project will employ a new 3D printing method, developed by the project supervisors, that is merging the fields of synthetic biology and 3D Printing. 3D Printing has enabled the creation of complex geometric structures previously unavailable to design engineers and scientists. However, this vast new pallet of object geometries has been limited to non-living materials. The ability to create bespoke biological structures directly from a 3D printing process has so far eluded us. The focus of this project is to challenge this limitation and open a new era of 3D bio-printing.

More specifically, this project will develop a novel 3D printing process that employs nature as the 3D printer, at a cellular level; whilst utilising engineering’s ability for highly accurate spatial control. It will build on ongoing efforts to bridge the gap between synthetic biology and 3D printing technology and will focus on further developing the necessary biological tools for the effective manufacturing of bio-materials in 3D. In the initial phases of the project, less-sophisticated, simple proof-of-concept structures will be generated. This will help identify and delimit expected and also unexpected challenges for the production of more complex composite materials. Next steps will include, but not be limited to, optimisation of biosynthetic pathways in the working chassis; finding appropriate external 3D control strategies to improve printing efficiency and accuracy; incorporation of biomolecular feedback control into genetic designs; development of efficient secretion systems and alternative “secretion” strategies (e.g. enzyme display for extracellular biosynthesis of one or more constituents of the composite material); bio-material engineering (e.g. through incorporation of bacterial amyloids) and functionalisation (e.g. silver nanoparticles); development and integration of mathematically-modelled gene expression systems into 3D printing software for true computer-guided bio-fabrication; etc. Finally, resultant next-generation 3D bio-materials will be analysed for their physico-chemical and mechanical behaviour and compared with existing bio-materials.

The successful development of this bio-printing technology could have significant impact in the medical field, biotechnology, and pharmaceutical industries. From the development of high throughput pharmaceutical screening equipment to 3D microfluidics and novel biomaterials. In addition the 3D printing technique offers a new paradigm in 3D manufacturing applications were the printing process is not limited to 2D planar layer stacks but rather a true 3D object.

The ideal candidate will have a background in some of these areas: bacterial synthetic biology (e.g. E. coli), genetic engineering, optogenetics, metabolic engineering, biomolecular feedback design and implementation, modelling in biology, computational modelling

The project will bring together a truly multidisciplinary team of synthetic biologists, bioengineers, and design engineers. The work will be support by a parallel project run by the supervisors; Dr Guy Bart Stan from the Department of Bioengineering, Dr John Heap from the Department of Life Sciences, and Dr Connor Myant from the Dyson School of Design Engineering. If you have any questions regarding the application please email Dr Guy-Bart Stan (g.stan@imperial.ac.uk).

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

Supervisors: Professor Oscar Ces | Professor Charlotte Bevan | Dr Yuval Elani | Professor 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.

Funded by the Leverhulme Doctoral Scholarship Programme in Cellular Bionics – 3 year PhD studentships

Supervisors: Dr Elani Yuval | Dr Nick Brooks | Dr Marina Kuimova

Can we engineer semi-synthetic cells that can alter their global mechanical properties on-demand, in response to external stimuli? Can we link these mechanical properties to downstream protocellular ‘behaviours’ that are relevant to therapeutic and biotechnological applications? This project aims to address these questions using a cellular bionics approach. By intermingling both biological and synthetic components, an actin cortex will be manufactured/disassembled within vesicle-based synthetic cells in response to light of defined wavelengths. This will allow the synthetic cell to dynamically switch between mechanically distinct states (i.e. different rigidities and viscosities). Coupling cell biomechanics to different behaviours, in this case the cell’s ability to squeeze through constrictions under flow, will be investigated using a microfluidic device. This project will first require an understanding of the effect of the actin cortex on cell mechanics to be developed using molecular rotors and flickering analysis. These insights will then allow us to controllably engineer the stimuli-responsive systems. 

Funded by the Leverhulme Doctoral Scholarship Programme in Cellular Bionics – 3 year PhD studentships

Supervisors: Dr Thomas Ouldridge | Dr Danny O'Hare | Dr Rodrigo Ledesma

The 20^th Century was characterized by the growth of a myriad of technologies based on digital electronics. Engineering of biological systems has the potential to be similarly revolutionary in the 21^st Century. Before this dream can be realized, however, precise, programmable control of complex biological systems needs to become simpler, and the interface with other engineered technologies needs to be made more robust. In this project, the student will develop a modular system for interfacing electronic signals with engineered cells. The proposed mechanism utilizes electrochemical oxidation and reduction of redox molecules at electrodes, and the subsequent activation of redox-sensitive transcription factors in the vicinity of those electrodes. The electrogenetic module will allow implementation of precise spatio-temporal control of biological systems from a smartphone or personal computer, with applications in bioproduction, biomaterials, biosensors, diagnostics and more.  

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

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 CO_2. 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.

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

Supervisors: Professor Ian Gould | Dr Nick Brooks | Professor 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. 

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

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.

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

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

Supervisors: Professor Alan Spivey | Professor Tony Cass | Dr 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.

Funded by the Leverhulme Doctoral Scholarship Programme in Cellular Bionics – 3 year PhD studentships

Supervisors: Dr Nick Brooks | Prof Oscar Ces | Prof Rob Law 

One of the key markers of life is its ability to adapt and evolve in response to its surroundings, helping organisms to survive in their ecological niches. Such adaptations can be structural, behavioural or physiological. In the case of extremophiles this trait extends to enabling life to thrive in forbidding environments that were once not thought to be able to sustain life: from extremes of pressure all the way through to extremes of temperature. This studentship aims for the first time to generate biological-synthetic hybrid systems that are capable of surviving extremes of pressure (equivalent to being at the bottom of the Mariana Trench, the deepest ocean point in the world; >1000atm)-synthetic extremophiles. By fusing living and non-living systems we will generate ensembles that are able to modify their composition and make-up in response to external changes in hydrostatic pressure. This has the potential to transform our understanding of how molecular components come together to introduce emergent behaviour. In addition, it will lead to the manufacture of biological components that are ideally suited to a wide range of industrial, biotechnical and consumer applications where performance under extreme conditions and the capability to respond to extreme operating conditions are fundamental prerequisites.

Funded by The Department of Chemistry 

Supervisors: Dr Yuval Elani | Prof John Seddon 

Cell mimicry – the ability to imitate the physical architecture, function and behaviour of cells – is proving to be an increasingly useful conceptual framework in (i) furthering our understanding of biological systems and (ii) constructing novel bio-inspired devices for clinical and industrial applications. The ability to generate membrane-based structures is proving to be especially powerful in both respects. However, the field has reached an impasse: although plasma membrane mimics are well established, mimics of alternative membrane structures are lacking. In this project, a suite of droplet-based technologies to assemble, manipulate, and functionalise synthetic analogues of a repertoire of membranous motifs — including fusogenic exosomes, synapses, and double membranes — will be developed, and their biophysical properties characterised. The use of these structures as functional components in vesicles microreactors and synthetic tissues will be explored.  This project will lead to a step change in our ability to generate Synthetic Biology systems from the bottom up, allowing us to reproduce features associated with intra-cellular compartmentalisation and inter-cellular communication. This project is multidisciplinary, incorporating elements of chemical biology, microfluidics, biophysics and biointerface science.

For further information please contact Yuval at y.elani@imperial.ac.uk

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

Supervisors: Prof Gary Frost | Prof Joshua Edel | Dr Aylin Hanyaloglu | Prof 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.

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

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

Supervisors: Professor Joshua Edel | Dr Alex Ivanov | Andy 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. 

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

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.