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A low velocity molecular collider for computer-controlled biochemical reactions.
Closing date
Supervisors
Professor Geraint Thomas, g.thomas@ucl.ac.uk, Professor of Biochemistry, University College London
Project Details

There are diverse techniques for studying biomolecular interactions e.g. proteins-ligand, proteins-nucleic acid and protein-protein interactions. On-rates, off-rates and equilibrium constants are of wide interest in industrial and fundamental research. Drug development needs to quickly isolate, identify and characterise “strong binder” small molecules or biologics, especially in screening. Cryo-EM has energised the study of multi-component protein machines and the disciplines of mechanistic biochemistry are being revived. However, proteins are expensive to produce and purify but for biological realism must be used at high concentration but most analytical approaches create large dilutions. This creates demand for miniaturised reaction systems that concentrate samples, allow precise manipulation of reactions conditions and give molecular characterisation. Beyond determination of physical constants there is also the need to establish if one protein modifies another during interaction e.g. some components of complexes are enzymes and assembled (or partly assembled) complexes may be enzymes.

We will use radically new electrophoretic methods to create a platform for computer manipulation of biochemical interactions through the generation and manipulation of the motions of ultra-sharp molecular bands in a microfluidic channel. By developing a system for protein work in this project we aim to discover how to control protein concentrations, band composition, band width and direction of motion of bands inside a fluid channel. We will then “collide” bands with each other in the sense of crossing motion paths while characteristics of speed, concentration, encounter time/duration and temperature are controlled by software.

A device of this sort has potential to complement and then surpass well-established analytical approaches. It avoids steric hindrance from absorption of interaction partners to surfaces and negates mass transport limitations. Such a device would preserve the advantages of existing microscale approaches because dilute species would be concentrated on fluidic chip and the motions and interactions of proteins controlled simultaneously. Ultimately this creates the possibility for logical operations and loops to control the progression of biochemical processes. Having software controlled biological reactions can create possibilities of mimicking complex, sequential biochemical processes. Such a system could lend itself to quantitative (screening) and qualitative (analytical) investigations. Using purified proteins, the project will specifically investigate protein-protein interactions seen in cellular signal transduction but also create “value branch points” at which the research progress can be captured as design principles for new devices useful in other applications (drug screening).

The project is a collaboration between UCL-based researchers (Prof. Geraint Thomas, Cell & Developmental Biology, UCL and Dr John Timms, Women’s Cancer Research Department, UCL EGA Institute of Women’s Health) and Genetic MicroDevices Ltd (GMD, Dr Dimitrios Sideris). GMD have a strong track record of collaborative student placements and are conveniently located in London providing flexible and efficient partnership. GMD aim to demonstrate the potential impact of their innovations and seek academic partnerships to develop specific applications. Building upon demonstrated high-resolution separation and protein control systems, the partnership looks to expand these promising first principles into wider biochemical applications. This project will look to prototype using well established protein-protein interaction reporter systems (FRET and Enzyme Fragment Complementation) to reference for biochemical interaction studies with a high accuracy and minimal reagent use. Investigations of signalling protein-protein interactions kinetics using protein kinases and different binding partners will follow. This will provide the company with a focused commercial application in market on a competitive timescale in market capitalisation.

The student will be embedded to gain a fully-authentic experience of commercial SME-scale technology research and be close to the heart of the business and all of its operations. This will be an ideal complement to the LIDo DTP business-oriented training courses for CASE students and the rich entrepreneurial, innovation and enterprise environment around UCL. There will be 2 x 6-month flexible placements at GMD for different aspects of the research and the necessary background and training to run, optimise, troubleshoot, collect and analyse high-quality data on the prototype platform.

References

Meran L., Massie I., Weston A., Gaifulina R., Faull P., Orford M., Kucharska A., Baulies A., Hirst E., Konig J., Tedeschi A.M., Pellegata A.F., Eli S, Snijders A., Collinson L., Thaper N., Thomas GM, Eaton S., Bonfanti P., De Coppi P. and Li V. (2020). Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure. Nature Medicine (in the press) doi.org/10.1038/s41591-020-1024-z

Gaifulina, R., Caruana, D., Oukrif, D., Guppy, N., Culley, S., Brown, R., Bell, I., Rodriguez-Justo, M., Lau, K, and Thomas, G.M. (2020). Rapid and complete paraffin removal from human tissue sections delivers enhanced Raman spectroscopic and histopathological analysis. The Analyst, 145, pp1499 – 1510. doi:10.1039/c9an01030k

Stanley, R., & Thomas, G. M. (2016). Activation of G Proteins by Guanine Nucleotide Exchange Factors Relies on GTPase Activity. PLoS One 11 (3) e0151861.

Whitwell HJ, Worthington J, Blyuss O, Gentry-Maharaj A, Ryan A, Gunu R, Kalsi J, Menon U, Jacobs I, Zaikin A, Timms JF (2020). Improved early detection of ovarian cancer using longitudinal multimarker models. British Journal of Cancer. doi:10.1038/s41416-019-0718-9

Whitwell HJ, Blyuss O, Menon U, Timms JF and Zaikin A. Parenclitic networks for predicting ovarian cancer. Oncotarget (2018); 9(32): 22717-22726

Cuenco J, Wehnert N, Blyuss O, Kazarian A, Whitwell H, Menon U, Dawnay A, Manns MP, Pereira SP and Timms JF. Identification of a serum biomarker panel for the differential diagnosis of cholangiocarcinoma and primary sclerosing cholangitis. Oncotarget 2018; 9(25): 17430-17442.

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Alexandra Richardson

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