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Glen Gowers' papers on new screening approaches for yeast synthetic biology are now published in Nature Communications and ACS Synthetic Biology. Glen did this work during his PhD in our group, co-supervised by David Tew and Marcelo Kern from GSK. This work set out to design and test two new workflows for higher throughput screening of biosynthetic yeast cells.
We began by a frustration that many of the tools used in synthetic biology (such as combinatorial libraries and SCRaMbLE, for example) require high throughput screening, something that is not always available with most metabolites of industrial relevance.
We first addressed various bottlenecks in a standard LCMS workflow by using a combination of automation and an ultra-fast modified version of LCMS, resulting in a ~4-fold faster screening workflow. Through a collaboration with SynbiCITE and the London DNA Biofoundry this workflow was put through its paces by screening over 1,000 yeast colonies that had undergone genome diversification by SCRaMbLE. Using this workflow, we quickly identified a strain with 7-fold improved betulinic acid biosynthesis and were able to characterise the genome rearrangements using nanopore sequencing. Read more about this work here.
This was great, but it still required sample preparation which includes a culturing step that cannot be sped up. We contacted the Takats lab (Imperial) who developed an ambient mass spectrometry instrument that can screen biomass for metabolite fingerprinting by using a high-powered laser to vaporise a portion biomass, generating ions for mass spectrometry. In this fruitful collaboration we adapted this technology and were able to screen over 450 yeast colonies for increased betulinic acid production directly from the colony, at a rate of 6 per minute. Read more about this work here.
We are really proud of this work that resulted from two great collaborations. We hope that these tools will enable future researchers to develop and test new synthetic biology tools to improve the biosynthesis of a wide range of industrial metabolites.
Gowers, G-O. F., Chee, S. M., Bell, D., et al. Improved betulinic acid biosynthesis using synthetic yeast chromosome recombination and semi-automated rapid LC-MS screening. Nat. Commun. 11, 868 (2020).
Gowers. G-O.F.*, Cameron. J.S.*, Perdones-Montero. A., et al. Off-Colony Screening of Biosynthetic Libraries by Rapid Laser-Enabled Mass Spectrometry. ACS Synth. Biol. 8, 2566-2575 (2019). *Co-first authorship
Rapid host strain improvement by in vivo rearrangement of a synthetic yeast chromosome. BA Blount, et al. Nat. Comms.
In this paper we use the SCRaMbLE system in Sc2.0 synthetic genome chromosomes to rapidly improve performance of heterologous metabolic pathways.
Burden-driven feedback control of gene expression.
F Ceroni, et al. Nature Methods
In this paper we use RNAseq to understand burden and develop a dCas9-based autofeedback controller to optimise cells.
Engineering a model cell for rational tuning of GPCR signaling.
W Shaw, et al. Cell
In this paper, we engineer a GPCR signalling pathway in yeast to enable rationally tunable biosensors for molecules relevant to human health.
Engineering control of bacterial cellulose production using a genetic toolkit and a new cellulose-producing strain.
M Florea, et al. PNAS
In this paper we build a genetic toolkit for a new bacterial cellulose producing bacteria
Biosynthesis of the Antibiotic Nonribosomal Peptide Penicillin in Baker’s Yeast.
AR Awan, et al. Nat. Comms.
In this paper we engineer yeast to produce Penicillin G using state of the art methods
Quantifying cellular capacity identifies gene expression designs with reduced burden.
F Ceroni, et al. Nature Methods,
In this paper we characterise the effect of DNA circuit design on the imposed burden on a cell