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Personal profile

Research interests

Our research interests span synthetic biology, molecular detection/recognition and chemical biology. We are currently exploring a number of research areas including; i) the development and application of genetically encoded biosensors, to detect molecules of bio-medical and biotechnological interest, ii) the application of  riboswitch-based gene expression tools in the context of developing of tuneable recombinant protein production systems, iii) cellular capacity matching for the optimisation of cellular protein production and secretion, iv) small molecule-RNA-protein interactions associated with allostery, molecular recognition and context engineering.

The driver of these applied research areas is the development of new chemical and synthetic biology tools to both i) help understand fundamental biological processes, ii) permit more efficient protein production process, and iii) optimise whole-cell bio-catalytic processes supporting the bio-based economy.

For further information: https://dixonlab.org/research/

 

Opportunities

Production of complex biologics: Host capacity analysis and capability engineering

This project will utilise next generation synthetic biology regulatory tools, to enhance the production and secretion of complex multimeric protein-based biologics from bacterial hosts. RNA-based regulatory tools (riboswitches) have been developed that control gene expression at the level of translation initiation [1-3]. Previously we have used these tools to match our biotechnological demand to host cell synthetic capacity, for example matching expression rates to secretion capacity and inner membrane protein biogenesis allowing enhanced periplasmic secretion and production of recombinant inner membrane protein [4]. This PhD project will seek to co-express and secrete commercially and clinically important multimeric protein-based biologics, such as F(abs), F(ab’)2, and T-cell receptors. This project will provide training in cutting-edge biotechnology, namely synthetic biology enabled host engineering, stress response engineering, and bio-processing engineering important for future careers in both academic and industrial R&D.

[1] Dixon et al 2010 Reengineering orthogonally selective riboswitches Proc Natl Acad Sci USA. p 2830 
[2] Dixon et al 2012 Orthogonal riboswitches for tuneable coexpression in bacteria. Angew Chem Int Ed Engl. p3620 
[3] Morra et al 2016 Dual transcriptional-translational cascade permits cellular level tuneable expression control. 
Nucleic Acids Res. e21 
[4] Morra et al 2017 Optimization of Membrane Protein Production Using Titratable Strains of E. coli. Methods Mol Biol. p83

Dynamic Ribo-regulator Tools for Expression Control in Mammalian Cells

The development of novel SynBio gene expression tools offers the potential to refine expression and co-expression of both native host and recombinant proteins [1]. Ribo-regulation offers an attractive alternative means of control gene expression by control translation, stability and/or processing of mRNA [2]. The ability to finely regulate expression in mammalian has many biotechnological application and huge potential biological and biomedical impact. These range from producing recombinant therapeutic proteins to engineering cellular safety switches for cell therapy applications [3]. However such tools to permit fine tuned regulation in mammalian cells are currently limited. The series of inducible systems used in mammalian cell systems are restricted to transcriptional control sites and are relatively coarse in their control parameters [4]. For example, as post-transcriptional events are known to restrict the expression and processing of commercially-valuable secreted biopharmaceuticals [5], the ability to develop fine tuned control of post-transcriptional events offers wide scope for more efficient production processes. Uniquely, a combination of transcriptional and Ribo-regulation offers the opportunity to develop combinatorial, multiplexed regulation of cellular events (e.g. mRNA production, specific mRNA ribosomal engagement, secretory vesicular transit, precursor availability – and multiples thereof) to maximise the effectiveness of the host cell platform as a “factory” for desired protein manufacture. 

 This PhD project will seek to enhance the production of protein-based biotherapeutics, to lower manufacturing costs of these important medicines and reduce the burden upon the NHS and other national healthcare providers. This will entail the use of ribo-regulators and synthetic biology methods (Dixon), and mammalian cell (Chinese Hamster Ovary, CHO, and HEK) culture and bioprocess optimisation (Dickson). The driver of this applied research is to provide enhanced production processes and training to support the knowledge-based bio economy (KBBE). This PhD project will provide training in state of the art synthetic/molecular biology techniques, advanced analytical methods, and bioprocess performance analysis.

[1] Neil Dixon, et al. Orthogonal Riboswitches for Tuneable Co-expression in Bacteria. Angewandte Chemie International Edition (2012)

 [2] Rosa Morra, Jayendra Shankar, Neil Dixon et alDual transcriptional-translational cascade permits cellular level tuneable expression control. Nucleic Acids Research (2016)

[3] Di Stasi A, et al. Inducible apoptosis as a safety switch for adoptive cell therapy N Engl J Med. (2011)

[4] Misaghi, S, et al (2014) It’s time to regulate: Coping with product-induced non-genetic clonal instability in CHO cell lines via regulated protein expression. Biotechnol. Prog. 30: 1432-1440.

[5] Hussain, H et al (2014) The endoplasmic reticulum and unfolded protein response in the control of mammalian recombinant protein expression Biotechnol. Lett. 36: 1581-1593. 

For further details please contact Neil Dixon or Alan Dickson

Biography

Neil Dixon received a 1st class Hons degree in Medicinal Chemistry from the University of Leeds (UK) in 2000 and then undertook in his PhD in Bioorganic Chemistry also at Leeds on “Probing the inhibition of the vacuolar (H⁺)-ATPase: targeting osteoporosis” (2004). After an extended period travel in Latin America he then pursued post-doctoral research in Chemical Biology at the University of Manchester (UK) on the topic re-engineering the molecular recognition properties of regulatory RNAs termed riboswitches, using rational design, high-throughput screening, directed evolution, along with structural and and biophysical characterization (2006-2010).

Neil Dixon previously held a BBSRC David Phillips Fellowship and a BBSRC Enterprise fellow based at the Manchester Institute of Biotechnology(MIB). His research group is focused on developing engineering tools and technologies to enhance the capacity and introduce new capability into biological hosts for biotech and biomed applications. His group currently comprising of 3 post doctoral scientists, 5 PhD students and 2 Research Techniciasn is supported from BBSRC, EPSRC, Innovate UK, Wellcome Trust, Brazilian and Indonesian Governments.

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being
  • SDG 7 - Affordable and Clean Energy
  • SDG 12 - Responsible Consumption and Production

Research Beacons, Institutes and Platforms

  • Biotechnology
  • Sustainable Futures
  • Manchester Institute of Biotechnology
  • Manchester Environmental Research Institute

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