The CDT in BioDesign Engineering is currently inviting applications for the below projects for the 2020 intake:

Design, engineering, and analysis of viability, growth and bioproduction impact of synthetic ribosomal RNAs in yeast

  • Lead supervisor: Prof P. Cai (University of Manchester)
  • Co-supervisor: Prof G-B. Stan (Imperial College London)

Ribosomal DNA (rDNA) is known to play key roles in many biological processes, such as maintaining genome integrity, aging, translation control during mammalian development, and adaptation to environmental stressors. This proposal aims to synthetically engineer and functionally dissect roles of ribosomal RNAs through synthetic genomics approaches, coupled with complementary quantitative mathematical modelling and data analysis. Overall, this project has the potential to develop optimised yeast strains with much reduced intrinsic cellular burden caused by rRNA transcription, which occupies up to 80% of the total transcriptional resources.  

Objective 1. Engineer functional synthetic rRNA sequences:
We will explore the intrinsic evolvability of and structural constraints on the rRNAs that form the ribosomal scaffold and chemical peptidyl transferase centre of eukaryotic ribosomes. As a second step, we will design a set of synthetic rRNA sequences which are sequence-divergent but can support the viability of a synthetic yeast strain which is completely lacking the wild-type rDNA loci. 

Objective 2. Assemble and characterise functional synthetic rRNA arrays:
Using the synthetic rRNA sequences from objective 1, we will integrate them stepwise into synthetic rRNA arrays containing different copy numbers of rRNAs. We will investigate transcription levels of the rRNA genes within the array and identify whether there is a link between the copy number of rDNA and the viability, growth rate, heterologous expression rates and lifespan of yeast cells.

Objective 3. Computational modelling and prediction of resource demand in wild-type and engineered strains:
In parallel with the characterisation objective 2, the student will develop a resources-based whole-cell model aimed at capturing availability of transcriptional and translational resources in wild-type and engineered yeast strains with synthetic rRNA arrays. In particular, the model will focus on resource demand for transcription and translation during native and synthetic gene expression. This model will be developed in collaboration with the Stan group, who have extensive experience in computational whole-cell modelling for burden characterisation, prediction and mitigation. The experimental data generated will be analysed and fit into the developed whole-cell model, allowing to better understand the tradeoffs dictated by rRNA abundance during native and heterologous gene expression.

This project will be based at the University of Manchester.

 

Designing next-generation therapeutics for atopic eczema by controlling skin microbiome

  • Lead supervisor: Dr R. Tanaka (Imperial College London)
  • Co-supervisor: Dr R. Ledesma-Amaro (Imperial College London)

This project will train a BioDesign engineer, who can develop novel therapeutics by applying repeated cycles of “learn-design-build-test” using mathematical modelling and synthesis of microbiomes. We will specifically bio-design a next-generation treatment for atopic dermatitis (AD, also known as eczema), a very common devastating chronic skin disease with high socioeconomic burdens. Controlling skin microbiome has been recently demonstrated as possible novel AD treatment. However, the mechanisms behind these potential interventions and the role of skin microbiome in the pathogenesis of AD remain to be elucidated, making systematic design of new treatment challenging.

The project will build directly on the engineering methodologies developed in the Tanaka group to design personalised AD treatment strategies using mechanistic modelling and machine learning, and the Ledesma-Amaro group’s cutting-edge techniques of engineering microbiomes using synthetic biology. The project will give the student the opportunity to make a direct impact on a clinically important problem. We will apply a rigorous BioDesign engineering approach to elucidate mechanisms by which controlling skin microbiome could improve AD symptoms and to design microbial population that provides protection against AD development.

Our BioDesign engineering approach will allow us to think beyond the current limits of AD treatment and develop therapeutics of future by combining mathematical modelling, genome engineering and synthetic microbial communities.

This project will be based at Imperial College London.