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Building and commercialisation of a new mammalian cell factory platform


Department of Chemical Engineering & Analytical Science

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Prof A J Dickson No more applications being accepted Funded PhD Project (UK Students Only)

About the Project

Biopharmaceuticals (eg. antibodies, other protein- and nucleic acid-based medicines, viral vectors, vaccines) are used for treatment and cure of many diseases and have presented astounding therapeutic and commercial success. The manufacture of biopharmaceuticals utilises cells as factories using the cellular machinery to manufacture these complex products from building blocks under the direction of recombinant genes introduced into the cells. Many of the products for human therapy have structural features that are inserted via post-translational modification (PTM) and the product function, stability and safety are dependent on the correct PTM. The necessary PTMs require the use of mammalian cells and the Chinese hamster ovary (CHO) cell is the major workhorse used to obtained correctly manufactured products. The Dickson lab has made extensive progress in enhancing the efficiency of CHO cells developing understanding of the importance of apoptosis, how stress signalling engages with the efficiency of protein secretion and of the capacity to use ‘omics approaches to improve the growth and productivity of CHO cells.

 

The standard approach for manufacture of biopharmaceuticals is to introduce the gene encoding for the desired recombinant product into CHO cells and to use markers on vector cassettes to select for cells that can synthesis the desired product. The producing cells are then grown in scale-up cultures (up to 10,000L in fed-batch conditions) for product harvest, purification and commercialisation. There are two major expression platforms used with CHO cells, involving cells deficient for expression of either dihydrofolate reductase (DHFR) or glutamine synthase (GS). Vectors that carry DHFR or GS sequences (as appropriate) plus the desired recombinant product are introduced into CXHO cells and cells that have taken up the vector are selected and grown in specific media types. This format provides the basis (vector, cell, medium) of all batch (or fed-batch or other format) culture used today for generation of almost all commercial therapeutic products manufactured by CHO cells.

 

Although very well established, DHFR- and GS-platform technologies are protected and can be highly expensive to licence. For start-up companies attempting to develop proof-of-principle for manufacture and therapeutic use of recombinant proteins, the costs can be prohibitive. Consequently, there is strong market to develop and introduce new platforms that could compete with the existing ones. The metabolic background of work undertaken within the Dickson lab has identified potential novel selection systems that could fill the niche demand within the sector. This is the focus of the PhD, which has the intention of building and proving a new platform. The science that underpins this is incredibly interesting and provides training in the technologies that are essential for so many career directions. In addition, targeting commercialisation (and hence tangible outcome) provides experience in the translation of science findings to impact. Hence the complete package of the PhD offers a strong industrially-relevant training.  

 

This is the general background but what will you do in your PhD? You will become an expert in mammalian cell culture, vector design and construction, assessment of recombinant gene expression and the use of metabolomics to design bespoke culture media and feeds. You will become expert in the underpinning technologies and the associated data handling/interpretation and you should think of the overall goal of the research programme as defining approaches/targets to produce the highest possible yield of recombinant protein (of the correct functional status). Your work will identify engineering strategies (process and/or genetic) to maximise the output from the application of your platform to CHO cells and how these strategies could be applied in the processes of industrial scale-up.

 

In addition to the direct experimental skills you obtain from this project, you will benefit from working in both industrial and academic environments and you will develop skills in project and organisational management, data presentation and experimental design. As part of your PhD you will be registered on the training programme developed by IBioIC (https://www.ibioicctp.com) which will develop your generic skills set and expose you to industrial and commercialisation studies. Within the context of specific translational outcomes for your own project, you will work with Pathway Biopharma to determine the commercial impact of the platform through market research, interview of potential customers and analysis of market reports, assess commercialisation options and value (e.g. exclusive or non-exclusive licensing, spin out or trade sale to an existing tools and technology provider) and prepare a business plan and commercialisation strategy.  

 

The research collaboration: The Dickson lab is based in the Manchester Institute of Biotechnology (http://www.mib.ac.uk), an excellent academic environment for research in biopharmaceuticals with unique facilities and multidisciplinary research programmes. Pathway Biopharma is a micro-SME, based in Edinburgh, created to guide early stage companies to progress their idea to market.


Funding Notes

This PhD is fully-funded as part of BBSRC CTP programme administered by IBioIC and is a collaboration with financial and technical input from the industrial partner, Pathway Biopharma. This is a 4-year scholarship to start in October 2021 that will cover tuition fees and provide a tax-free stipend at the UKRI standard rate (£15,609 in the 2021/22 academic session) to cover living costs. A linked Research Training Support Grant will allow for reimbursement of research related expenses.

References

Dickson lab publications:
Mauro Torres, Mark Elvin, Zeynep Betts, Svetlana Place, Claire Gaffney, Alan J. Dickson (2020) “Metabolic profiling of CHO cell cultures at different working volumes and agitation speeds using spin tube reactors” (2020) Biotechnol Prog e3099,https://doi.org/10.1002/btpr.3099
Torres, M, Akhtar, S, McKenzie, EA & Dickson, AJ (2020) “Temperature down-shift modifies expression of UPR-/ERAD-related genes and enhances production of a chimeric fusion protein in CHO cells” Biotechnol. J. DOI: 10.1002/biot.202000081
Gaffney, CE, Dickson AJ & Elvin, M (2019) “Metabolite profiling of mammalian cells” in Cell Culture Engineering: Recombinant Protein Production”, Advanced Biotechnology Series (Lee, SY, Nielsen, J & Stephanopolous, eds.), Weinheim, https://doi.org/10.1002/9783527811410.ch10
Martella, A, Firth, M, Taylor, B, Goeppert, A, Cuomo, E, Roth, R, Dickson, A & Fisher, D (2019) "Systematic evaluation of CRISPRa and CRISPRi modalities enables development of a multiplexed, orthogonal gene activation and repression system" ACS Synthetic Biology 8: 1998-2006.
Carballo-Amador, MA, McKenzie, EA, Dickson, AJ & Warwicker, J (2019) “Surface patches on recombinant erythropoietin predict protein solubility: Engineering proteins to minimise aggregation” BMC Biotechnology 19: 26 doi.org/10.1186/s12896-019-0520-z
Torres, M, Berrios, J, Rigual, Y, Latorre, Y, Vergara, M, Dickson, AJ & Altamirano, C (2019) “Metabolic flux analysis during galactose and lactate co-consumption reveals enhanced energy metabolism in continuous CHO cell cultures” Chem. Eng. Sci. 205: 201-211.
Torres, M, Altamirano, C & Dickson, AJ (2018) “Process and metabolic engineering perspectives of lactate production in mammalian cell cultures” Curr Opinion Chem Eng 22: 184-190.
Hussain, H, Fisher, DI, Roth, RG, Abbott, WM, Carballo-Amador, MA, Warwicker, J & Dickson, AJ (2018) “A protein chimera strategy supports production of a model ‘difficult-to-express’ recombinant target” FEBS Lett. 592: 2499-2511
Maldonado-Agurto, R & Dickson, AJ (2017) “Multiplexed digital mRNA expression analysis profiles system-wide changes in mRNA abundance and responsiveness of UPR-specific gene expression changes during batch culture of recombinant Chinese Hamster Ovary cells” Biotechnol. J. 13: DOI: 10.1002/biot.201700429
Hussain. H, Fisher, DI, Abbott, WM, Roth, RG & Dickson, AJ (2017) “Use of a protein
engineering strategy to overcome limitations in the production of ‘Difficult to express’
recombinant proteins” Biotechnol. Bioeng. 114: 2348-2359.


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