PhD position: Persistent biochemical computation for sense and respond applications. 

We invite applications for a UKRI-EPSRC Industrial CASE 4-year PhD studentship, "Persistent biochemical computation for sense and respond applications". This experimental project will be a collaboration between Dr Thomas Ouldridge’s "Principles of Molecular Systems" group [1] within the Department of Bioengineering at Imperial College London, and Dr Neal Hopkins at DSTL [2]. Students interested in interdisciplinary work at the interface of biology, chemistry, physics and engineering are encouraged to apply. Please note that applications are only open to UK nationals, due to the nature of the industrial collaborator.  

Biological systems sense and respond to their changing environment as an essential enabler of survival. Engineering Biology to undertake related operations in designed sensing applications is an attractive prospect; the student will seek to engineer a persistent biochemical “computational system” that can support sense and respond functions over time.  

DNA nanotechnology [3] provides a tangible foundation to build from, but the current state-of-the art focuses on single-shot systems, rather than continuously responsive devices. Key questions that arise in moving to more lifelike, continuously responsive systems include: How can such a system be fuelled and sustained? How can essential functions operate consistently (e.g. maintaining functional resilience throughout environmental variations in temperature or biochemical flux). How can an event log be composed from biochemical parts to form a memory of system operation? How can response functions that are triggered by multimodal stimuli be coordinated? How can other native biochemical computational/information networks (e.g. cascades of metabolic processes, phosphorylation or allosteric assemblies) interface with a central DNA computational hub?  

Under the supervision of Dr Ouldridge and Dr Hopkins, and in collaboration with other members of the relevant research groups, the student will leverage computational and modelling tools for rational design of sensing systems, then test the designs in wet lab experiments. This process will be iterated to take advantage of what is learnt at each stage. Candidates from a wide range of backgrounds, with a degree in engineering, physical or life sciences, will be considered. However, experience in a wet lab is highly desirable, as is a track record of implementing molecular reactions in vitro. Prior work with nucleic acids would be beneficial. 

To apply for this position, please email a single PDF file including: a (1 page max) cover letter describing your interests and research experience, a CV detailing academic performance (including grades/marks) and names and contact information of two referees, to Dr Thomas Ouldridge (t.ouldridge@imperial.ac.uk). Candidates will be considered continuously until the position is filled, with an initial shortlisting based on applications submitted by 5pm on 1/3/2024.  

Funding Notes: 

This project is funded by the UKRI through the EPSRC as an Industrial CASE studentship. DSTL will also contribute funds to the project as an industrial partner. Funding includes payment of college fees and a tax-free stipend of £25,150 for four years. 

References 

[1] http://www.imperial.ac.uk/principles-of-biomolecular-systems/ 

[2] Defence Science and Technology Laboratory - GOV.UK (www.gov.uk) 

[2] Dynamic DNA nanotechnology: toward functional nanoscale devices - Nanoscale Horizons (RSC Publishing)   

PhD position: Model-guided engineering of novel DNA-based circuits for nucleic acid signal detection [currently under offer]

We invite applications for a 4-year PhD studentship, "Model-guided engineering of novel DNA-based circuits for nucleic acid signal detection". This project is a collaboration between Dr Thomas Ouldridge’s "Principles of Molecular Systems" group [4] within the Department of Bioengineering at Imperial College London, and an industrial partner, Nanovery [6], and is part of the recently-funded Program Grant “Efficient Engineering and Control of Predictable and Reliable Biosystems” [5]. The project will have a large component of theoretical modelling and simulation, which will connect to DNA-based experiments performed by either the student themselves or collaborators. Students interested in interdisciplinary work at the interface of biology, chemistry, physics and engineering are encouraged to apply. We will consider applications from students of any nationality. 

Nanovery have developed a platform technology capable of quantifying a target nucleic acid sequence with excellent accuracy and precision down to the low pM range. The target nucleic acids are typically short (15-25 nt) single stranded species. This platform technology is isothermal, enzyme-free, suitable for complex biological environments and can be performed in a standard plate reader using either 96-well or 384-well plates. 

Detection and quantification are achieved via signal amplification which is government by rationally designed dynamic DNA reaction networks. The underlying mechanism that drives this process is toehold-mediated strand displacement (TMSD). 

Nanovery’s current R&D efforts are focused on improving the platforms sensitivity. This requires the coupling of multiple signal amplification circuits and introducing autocatalytic behaviour. The primary challenge faced is leakage (undesirable crosstalk between components). 

Nanovery are looking to develop dynamic DNA reaction networks which are exclusively comprised of double-stranded motifs. The deployment of double-stranded components drastically reduces leakage (crosstalk) between modules and can furnish more robust and predictable reaction networks. Networks containing single-stranded species suffer from secondary structures and non-specific binding. Unfortunately, the rate of TMSD is detrimentally reduced when using double-stranded components and 4-way branch migrations. 

The incorporation of mismatches within double-stranded TMSD rection networks could facilitate increased rates of TMSD while maintaining the benefits of double-stranded components. Exploring this idea would require in-silico simulations which would narrow the potential number of wet lab experiments and aid in the design of dynamic reaction networks. 

The Ouldridge Group has expertise with regards to the kinetics of TMSD [1], the use of mismatches to modulate the rate of TMSD [2], and possesses unique expertise with regards to in-silico analysis of dynamic DNA systems via the oxDNA molecular model [1,2,3]. This research project will focus on applying this expertise to the optimisation of double-stranded signal amplification circuits, with the ultimate goal of achieving autocatalytic signal amplification.   

The student will develop and apply computational models of DNA and DNA strand displacement. This theoretical work will be complemented by wet lab experiments performed by the student or collaborators. The student will be based in London, but will spend periods of the project at the Nanovery lab in Newcastle. Candidates from a wide range of backgrounds, with a degree in engineering, physical or life sciences, will be considered. Experience in a computational or theoretical modelling is highly desirable, and prior wet lab experience would be beneficial. 

To apply for this position, please email a single PDF file including: a (1 page max) cover letter describing your interests and research experience, a CV detailing academic performance (including grades/marks) and names and contact information of two referees, to Dr Thomas Ouldridge (t.ouldridge@imperial.ac.uk).  

Deadline: There is an opportunity to apply to convert this scholarship into an EPSRC CASE Conversion Studentship with enhanced funding/stipend. We will consider putting forward any candidates eligible for UK fee status that apply by 23:59 GMT on 23/1/2024 for that scholarship. If we do not manage to fill the position by that route, we will collate applications submitted by 23:59 GMT 1/3/2024. 

Funding notes: As a default, this project will be joint funded by Nanovery and the Department of Bioengineering at Imperial College London. Funding includes payment of college fees (including international fees, where relevant) and a tax-free stipend for four years. The value of this stipend is £20,622 in 23/24, and will be uprated inflation annually. In the event that a UK-based applicant secures the EPSRC CASE Conversion Studentship, this stipend will be further augmented. 

References: 

[1] Nucleic Acids Research, 2013, 41, 22, 10641–10658 

[2] Nature Communications, 2020, 11, 2562 

[3] Front. Mol. Biosci., 2021, 8, 69371 

[4] http://www.imperial.ac.uk/principles-of-biomolecular-systems/  

[5] EEBio: Efficient Engineering and Control of Predictable and Reliable Biosystems (ukri.org) 

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[6] Nanovery was founded 2018 with a mission is to support human health by providing powerful and accessible nanorobotic tools in the life sciences, drug development and diagnostics. 

Their platform harnesses DNA nanotechnology to give s simple assay process that overcomes limitations of qPCR. A user can access the technology via their design service that tailors reagents to specific target sequences and preferred workflow. 

This Industrial PhD will both push forward the field of TMSD and in collaboration with Nanovery, the systems developed will be deployed to create real-world solutions.  

Websitehttp://www.nanovery.co.ukTelephone: 0191 580 610, Location: The Biosphere, Newcastle upon Tyne, NE4 5BX  

Get in touch

We're always happy to hear from undergraduates, graduates and Postdocs that are excited by the research of the group. We will be offering several projects for MEng and MSc students, so please check them out. For excellent graduate students, it is possible to apply for funding through the Department or the College, so contact Tom if interested. Tom is also potentially able to support applications for independent Postdoctoral/fellowship positions.