Unravelling signalling– and metabolic–dependent molecular switches underlying network rewiring in the onset of cancer and autoimmune disorders (Ref FHMS - FF - 31 BIO)

A PhD Studentship in Systems Biology is available under the supervision of Matteo Barberis and Gianne Derks at the University of Surrey, to construct, analyse and simulate mathematical models of the molecular networks controlling cellular proliferation. Models will be integrated with experimental data available in literature and, when feasible, tested through international collaboration. In recent years, efforts were made to investigate properties that emerge from interactions among molecules of cellular networks. It was discovered that alteration of the interaction landscape of a network (network rewiring) may be responsible for changes associated to healthy or disease states. In the cancer-related field: (i) a minimal network of the eukaryotic cell division cycle was shown to exhibit oscillations [3]; and (ii) poor cancer prognosis in tissue development was observed when cells acquire hybrid epithelial/mesenchymal cellular states, with the underlying network switching from bistability (two equilibrium states) to multi-stability [6]. In the immune diseases field: (i) acute and chronic inflammation states reflected bistability of the immune cell activation network [9]; and (ii) cytokines dosage was shown to trigger different immune cell differentiation states, exhibiting oscillatory (chronic inflammation) or switch-like (prevent chronic inflammation) behaviours [11]. In this scenario, the aim of the research project is to investigate the molecular alterations of a network’s interaction landscape that are responsible for the switch from a network state to another, i.e. from a healthy state to a disease state, and vice versa. As application cases, the cell cycle and immune networks will be investigated for their ability to exhibit switches from different states, and the connection to healthy and diseased states will be drawn. A systems biology approach that integrates mathematical modelling and experiments will be undertaken. The models generated will be analysed using the System Design Space methodology [3] as well as bifurcation and sensitivity analyses, to identify alterations in the interaction landscape that are responsible for network switches. Relevant model predictions will be tested against the available literature and, when feasible, by molecular biology and biochemistry experiments through international collaboration. The systems biology approach will lead to an understanding of the mechanisms responsible for healthy versus diseased states of a cellular network of interactions. This acquired knowledge may lead to the identification of interaction targets for drug design, potentially including metabolic targets that may modulate the imbalance among immune cells phenotypes (states) [16], resulting in a switch from an autoimmune disease state to a healthy state, or to a ‘less diseased’ state.

References 

1. Mondeel TDGA, Ivanov O, Westerhoff HV, Liebermeister W, Barberis, M*. Clb3-centered regulations are recurrent across distinct parameter regions in minimal autonomous cell cycle oscillator designs. NPJ Syst. Biol. Appl. 2020, 6: 8. 
2. Jia D, Jolly MK, Tripathi SC, Hollander PD, Huang B, Lu M, Celiktas M, Peña ER, Ben-Jacob E, Onuchic JN, et al. Distinguishing mechanisms underlying EMT tristability. Cancer Converg. 2017, 1(1):2.
3. 3. Abudukelimu A, Barberis M, Redegeld F, Sahin N, Westerhoff HV. Predictable irreversible switching between acute and chronic inflammation. Front Immunol. 2018, 9:1596.
4. Wertheim KY, Puniya BL, La Fleur A, Shah AR, Barberis M*, Helikar T*. A multi-approach and multi-scale platform to model CD4+ T cells responding to infections. PLoS Comput Biol. 2021, 17(8):e1009209. 
5. Barberis M*, Rojas Lopez A. T cell phenotype switching in autoimmune disorders: Clinical significance of targeting metabolism. Clin Transl Med. 2022, 12(7):e898.

Principle Supervisor - Dr Matteo Barberis

Dr Matteo Barberis' background integrates Computational Modelling with Biochemistry and Molecular Biology. Dr Barberis carries out Systems Biology research to decipher design principles underlying cellular organization of complex biological systems. He employs Ordinary Differential Equations (ODE)-based modelling, and applies advanced computational analyses (e.g. Systems Design Space methodology) to predict regulatory systems properties – among which dynamic behaviours of cell cycle and immunology networks and metabolic pathway regulations – which serve as platform for experimental testing. Dr Barberis’ research aims to unravel molecular mechanisms underlying switches responsible for spatio-temporal dynamics of biochemical networks, such as the cell division cycle in eukaryotes. Dr Barberis is Reader in Systems Biology and covers international roles, serving as Executive Director of the International Society for Systems Biology; Editor-in-Chief of Current Opinion in Systems Biology; and Editor-in-Chief of In Silico Biology – Journal of Biological Systems Modeling and Multi-Scale Simulation. 

[Email Address Removed]

Entry requirements

Open to UK and international students with the project starting in October 2023. Note that a maximum of 30% of the studentships will be offered to international students.

You will need to meet the minimum entry requirements for our PhD programme https://www.surrey.ac.uk/postgraduate/biosciences-and-medicine-phd#entry.

How to apply

Applicants are strongly encouraged to contact the relevant principal supervisor(s) to discuss the project(s) before submitting their application.

Applications should be submitted via the [https://www.surrey.ac.uk/postgraduate/biosciences-and-medicine-phd programme page (N.B. Please select the October 2023 start date when applying).

You may opt to apply for a single project or for 2 of these Faculty-funded studentship projects

When completing your application, in place of a research proposal, please provide a brief motivational document (1 page maximum) which specifies:

• the reference numbers(s) for the project or two projects you are applying for 
• the project title(s) and principal supervisor name(s) 
• if applying for two projects, please also indicate your order of preference for the projects
• an explanation of your motivations for wanting to study for a PhD 
• an explanation of your reasons for selecting the project(s) you have chosen

Additionally, to complete a full application, you MUST also email a copy of your CV and 1-page motivational document directly to the relevant project principal supervisor of each project you apply for. Due to short turnaround times for applicant shortlisting, failure to do this may mean that your application is not considered.

Please note that online interviews for shortlisted applicants are expected to take place during the week commencing 30th January.