Overview
My interests lie in the area of biotechnology with particular focus on the application of systems engineering principles to bioprocessing. The group's research involves the systematic integration of model-based tools, such as sensitivity analysis, design of experiments and optimisation, with experimentation on mammalian cell culture systems with a focus on metabolism and protein glycosylation.
In parallel, the group is working on optimal upstream operating strategies that minimise the burden on downstream purification. There is a rising concern of downstream performance being affected by composition of the process lines, which is primarily determined by the upstream activities. However, knowledge on dynamics between the upstream and downstream operations has not yet been explored. It is therefore an untapped research in the biopharmaceutical field to understand the integration and communication between these two operations, leading to the main research objective of this PhD - to develop a robust framework for analysing and simulating the cell culture process with respect to the build-up of host cell protein impurities, which enables us to analyse how upstream decisions impact downstream performance according to the concept of Quality by Design.
As a member of the Future Vaccine Manufacturing Hub, my group also works on vaccine manufacturing processes, their design, optimisation and techno-economic analysis.
Current research projects include:
cell-free glycoprotein synthesis
In collaboration with Professor Karen Polizzi and AstraZeneca
Researcher: Dr Elli Makrydaki
Recent developments have begun to unravel the link between an individual’s genetic makeup and disease status, paving the way for the development of personalised medicines. These will require a different manufacturing strategy than previous therapies. To this end, we have developed a novel cell-free protein synthesis platform to support the R&D and manufacture of stratified medicines. In this project, we will translate our proof-of-concept into industry.
CHo cell factory modelling
In collaboration with AstraZeneca
Researcher: Mr James Morrissey
The goal of this project is to generate a modular cell factory modelling platform that integrates kinetic models with flux balance analysis to quantitatively and accurately describe (i) how the stoichiometric relationships between extracellular and intracellular metabolites vary during cell culture processes, (ii) how these shifts in stoichiometry influence the dynamics of CHO cell growth, and (iii) how cellular metabolism, product biosynthesis, assembly and secretion, all combine to yield different productivity levels.
engineering glycoprotein therapeutics
In collaboration with Professor Stuart Haslam
Researcher: Mr Roberto Donini
Biopharmaceuticals, new medical drugs produced using industrial biotechnology processes, are one of the fastest growing sectors of the pharmaceutical industry. Many important biopharmaceuticals, such as therapeutic antibodies with commercial sales in the billions of pounds are glycoproteins. Glycosylation of the biopharmaceuticals can greatly affect their functional properties. This can significantly affect the potential therapeutic value of the products. This project involves glycoengineering of CHO cells to both control and homogenize glycosylation patterns.
cho cell engineering directed by genome-scale modelling
In collaboration with GSK, Stevenage
Researcher: Mr. Ben Strain
Genome-scale modelling is emerging as a methodology for identifying genetic engineering interventions that lead to desired phenotypes. Originally applied to metabolic networks to compute intracellular fluxes, it has been augmented to include gene expression regulation and the protein secretory pathway. in this project, we aim to develop a comprehensive GeM approach that is aligned with state-of-the-art data acquisition methods and can be used to inform cell line selection protocols and genetic engineering strategies.
towards process automation in biopharmaceuticals production
In collaboration with Dr Maria Papathanasiou and Dr Gary Finka, GSK
Researcher: Mr. Thomas Kavanagh
A key aspect that contributes to the high costs of biopharmaceutical process development and therapeutic protein manufacture is the complex nature of the molecules and the inherent variability of bioprocess inputs and outputs. Process optimisation results in pre-designed operational strategies applicable to the cell line/product in question. Often, the method of developing such optimised processes is empirical, and the associated capability lies within a few individuals in an organisation. With a model-based approach, we can map a wide range of process conditions and rapidly explore and assess different operational strategies. In this project we aim to develop and conduct the first closed-loop demonstration of process control in upstream bioprocessing.
optimisation of cell culture systems using genome-scale metabolic modelling
In collaboration with Dr Alexandros Kiparissides, UCL
PhD student: Mr. Athanasios Antonakoudis
The diametrically opposed objective functions of growth and antibody production can lead to low specific productivity of the recombinant product. In this project, we apply optimization techniques to a genome-scale metabolic network (GeM) of the CHO cell to design a strains with increased specific antibody productivity. This involved detecting the essential for growth genes and reactions using the gene-protein-reaction of the GeM and then applying bilevel optimization algorithms to couple the production of antibody and growth rate of the GeM model by upregulating, knocking out and downregulating the intracellular reaction fluxes, as long that are not essential.
The metabolic pathway of mammalian nucleotide sugar metabolism
Alumni
Dr. Pavlos Kotidis (2021)
PhD: Enhanced understanding of protein glycosylation in CHO cells through computational tools and experimentation
Dr. Rodrigo Barbosa (2021)
PhD: Development of hybrid platforms for antibody manufacturing optimisation
Dr. Calum McIntosh (2021)
PhD: Controlling Fab terminal sialylation in antibodies
Dr. Elli Makrydaki (2021)
PhD: Artificial Golgi reactions for targeted glycosylation
Dr. Chiara Heide (2020)
PhD: Development of a CHO cell-free protein synthesis platform for accelerated antibody screening
Dr. Sakhr Alhuthali (2020)
PhD: Towards advanced modelling of whole bioprocesses
Dr. Cher Goey (2018)
PhD: Cascading effects in bioprocessing: the impact of cell culture environment on CHO cell behaviour and host cell protein species
Dr. Kristian Mc Caul (2017)
PhD: A platform for the optimisation of metabolic pathways for glycosylation to achieve a narrow and targeted glycoform distribution
Dr. Susie Nga Sou (2016)
PhD: Understanding the impact of bioprocess conditions on monoclonal antibody glycosylation in mammalian cell cultures through experimental and computational analyses
Dr. Philip Jedrzejewski (2016)
PhD: A platform for the optimisation of metabolic pathways for glycosylation to achieve a narrow and targeted glycoform distribution
Dr. Ioanna Stefani (2015)
PhD: Unravelling the role of endoplasmic reticulum stress in familial Alzheimer's Disease
Dr. Sarantos Kyriakopoulos (2014)
PhD: Amino acid transport and metabolicm in CHO cells
Dr. Ali Behjousiar (2014)
PhD: In situ FRET biosensors for the in vivo measurement of metabolites during cell culture
Dr. Kate Royle (2014)
PhD: Improving the specific productivity of Pichia pastoris
Dr. Ning Chen (2013)
PhD: Modelling of protein-producing Chinese hamster ovary cells (in collaboration with Lonza Biologics)
Dr. Ioscani Jimenez del Val (2013)
PhD: Assessment of the interactions between bioprocess conditions and protein glycosylation in antibody-producing mammalian cell cultures
Ms. Ioanna Psygka (2014)
MSc: Designing an artificial Golgi reactor
Mr. Albert Garcia Madrid (2014)
MSc: The effects of mild hypothermia in GS-CHO fed-batch culture
Mr. Sambit Ghosh (2013)
MSc: Advanced modelling of whole bioprocesses
Mr. François-Xavier Blaudin de The (2012)
MSc: Computational analysis of the role of ER stress in Alzheimer’s disease
Mr. Andrew Nosakhare Amenaghawon (2010)
MSc: Evaluation of ethanol stripping from fermenters
Mr. Themis Kyprianou (2010)
MSc: Designing artificial signalling networks to detect and correct protein aggregation
Mr. John Bender (2009)
MSc: Optimization of Productivity of antibody-secreting mammalian cell cultures
Mr. Rahul Bagga (2009)
MSc: Model-Based analysis of nutrient membrane transport and cell metabolism
Research Staff
Constantinou,A
Fadda,S
Klymenko,O
Niu,H
Penumathsa,B