Ellis:Research: Difference between revisions

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{{Ellis Top}}
'''Latest Update: April 2010'''
'''Latest Update: Dec 2014'''
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Research in the Ellis Lab focuses on advancing biotechnology through the use of synthetic biology. Projects fall into one of two categories or belong in both:<br>
Research in the Ellis Lab focuses on advancing our understanding of nature through genome engineering and accelerating biotechnology through the use of synthetic biology. Projects are either ''foundational'' work, ''applied'' work or a nice mix of both.


== Current Projects ==
'''Synthetic Yeast Chromosome XI'''<br>
Project Type: ''Foundational'' and ''Applied''<br>
Project Members: ''Ben Blount, Rob McKiernan, Maureen Driessen, Dejana Jovicevic''<br>
Collaborators: ''Jef Boeke (NYU), Yizhi Cai & Al Elfick (Edinburgh), Steve Oliver (Cam), Paul Freemont, Sc2.0 Consortium''<br>
Sc2.0 is a high-profile, international project to do the first full synthesis of a eukaryotic cell genome, the model yeast species ''Saccharomyces cerevisiae''. Led by Prof Jef Boeke at NYU, USA, an international consortium is now established to re-synthesis and make to design changes to all 16 yeast chromosomes. Our group is leading the UK effort in the consortium, aiming to design, synthesise and assemble the complete 666 kbp chromosome XI. During construction we will investigate genome design and topological effects such as nuclear structures and how these can be used to optimise gene expression in metabolic engineering.


* '''1. Foundational Synthetic Biology'''
'''Synthetic Biology with engineered modular regulation'''<br>
Developing the tools for rapid, predictable engineering of biological devices and systems. <br>
Project Type: ''Foundational'' and ''Applied''<br>
 
Project Members: ''Ben Blount, Tim Weenink, Robert Chen''<br>
''Examples: biopart design, assembly techniques and device synthesis, part and device characterisation, standardisation, chassis systems, mathematical models, design simulations''<br>
TAL effectors and CRISPRi are a relatively new forms of DNA-binding protein that have a programmable DNA-recognition code. This means that they can be re-engineered repeatedly to bind to custom DNA sequences. We have now shown that modular TAL-effectors can be customised to be orthogonal repressors (TALORS) for yeast promoters - effectively acting as independent wires in logic systems. This offers a route to scalable logic systems in yeast synthetic biology. We are now looking to improve on this technology to generate a range of custom-built transcription factors which we can apply to advanced logic networks such as oscillators and memory systems.
 
 
* '''2. Applied Synthetic Biology'''
Using the synthetic biology approach in biotechnology applications . <br>
 
''Examples: combinatorial synthesis of pathways, modular design of biosensors, cheap inducer systems for biosynthesis''
 
 
== Current Projects ==


'''New standards for BIOFAB projects'''<br>
Project Type: ''Foundational''<br>
Project Members: ''Ben Blount, Serge Vasylechko, Riham Satti''<br>
Collaborators: ''Richard Kitney, BIOFAB USA''<br>
Synthetic biology requires professional characterisation of standardised parts to enable predictable and scalable construction of complex and robust devices and systems. To characterise biological parts it is useful to have a reference standard part to which it can be compared. This has been demonstrated by Kelly ''et al.'' for housekeeping promoters in ''E.coli''. Working in a collaboration with BIOFAB USA and Imperial's own BIOFAB group, we are developing two new standards for part characterisation: (1) a standard reference promoter for yeast selected from systems biology screening, and (2) an ultra-efficient GFP coding region with various degradation tags for dynamical characterisation at low copy numbers.
'''Investigating device-chassis interactions'''<br>
'''Investigating device-chassis interactions'''<br>
Project Type: ''Foundational''<br>
Project Type: ''Foundational''<br>
Project Members: ''Rhys Algar, Hung Hsu''<br>
Project Members: ''Francesa Ceroni, Olivier Borkowski, Arinbjorn Kolbeinsson''<br>
Collaborators: ''Guy-Bart Stan''<br>
Collaborators: ''Guy-Bart Stan, Rhys Algar, Richard Murray (Caltech)''<br>
Most gene devices demonstrated in synthetic biology have been high-expression strength regulatory networks hosted on mid-to-high copy number plasmids in ''E.coli''. Despite being relatively simple and small, these devices are thought to be close to the maximum tolerated by the host cell - if they were any larger they would impinge on the host cell's own mechanisms. In this project, we are trying to quantify the threshold for gene device cloning into the ''E.coli'' chassis by examining a standard synthetic feed-forward loop motif expressed at a variety of different strengths in plasmid systems of varying copy number. The intention is to define a quantitative standard for inserting gene devices into chassis cells and build a predictive model to aid future design.
Most gene devices demonstrated in synthetic biology have been high-expression strength regulatory networks hosted on mid-to-high copy number plasmids in ''E.coli''. Despite being relatively simple and small, these devices are thought to be close to the maximum tolerated by the host cell - if they were any larger they would impinge on the host cell's own mechanisms. In this project, we are trying to quantify the threshold for gene device cloning into the ''E.coli'' chassis by examining a standard synthetic networks expressed at a variety of different strengths in plasmid systems of varying copy number. The intention is to define a quantitative standard for inserting gene devices into chassis cells and build a predictive model to aid future design of cells with predictable growth rates.
 
'''Combinatorial modular assembly of gene networks and pathways'''<br>
Project Type: ''Foundational'' and ''Applied''<br>
Project Members: ''Arturo Casini, Ali Raza Awan, Carlos Bricio, Simon Arsene''<br>
Collaborators: ''Geoff Baldwin, Sphere Fluidics''<br>
The availability of gene synthesis is increasing rapidly, yet there is no straightforward lab-bench method to arrange modular gene units into larger assemblies with pre-defined positions. In this project we will demonstrate a new method to rapidly assemble gene units in a pre-defined order and showcase the technique to combinatorially assemble diverse synthesis pathways and gene regulatory networks using standardized parts. As well as demonstrating a rapid new assembly technique, the project will yield synthetic cells with high production of high-value therapeutic molecules which can be screened with interesting new microfluidic technologies.


'''Combinatorial modular assembly of diverse Carotenoid production pathways in yeast'''<br>
'''Engineering thermophilic synthetic biology'''<br>
Project Type: ''Foundational'' and ''Applied''<br>
Project Type: ''Foundational'' and ''Applied''<br>
Project Members: ''Arturo Casini''<br>
Project Members: ''Elena Martinez-Klimova, Ben Reeve, Alex Esin''<br>
Collaborators: ''Geoff Baldwin''<br>
Collaborators: ''David Leak, Tobias Warnecke''<br>
The availability of gene synthesis is increasing rapidly, yet there is no straightforward lab-bench method to arrange modular gene units into larger assemblies with pre-defined positions. In this project we will demonstrate a new method to rapidly assemble gene units in a pre-defined order and showcase the technique to combinatorially assemble diverse synthesis pathways in yeast. The modular gene units from the carotenoid pathways are driven by regulated promoters from a pre-existing library, and combinatorial assembly with these will produce pathways with a variety of metabolic fluxes. As well as demonstrating a rapid new assembly technique, the project will yield synthetic yeasts with high production of high-value carotenoid molecules.
Engineering new function into well-characterised cells is one of the major goals of synthetic biology, but one phenotype almost impossible to add to cells like ''E.coli'' is thermostability. Instead, our lab is kick-starting synthetic biology in a Geobacillus species thermophile by developing standard measurement protocols with aerobic and anaerobic fluorescent proteins and charactersing libraries of standard, synthetic parts. We will use these to improve and diversify existing biofuel production pathways to generate high-yields and new products.
 
'''Engineering materials from bacteria'''<br>
Project Type: ''Applied''<br>
Project Members: ''Ben Reeve, Michael Florea, Charlie Gilbert, Olivier Borkowski''<br>
Collaborators: ''Textiles Futures Research Centre''<br>
The materials of the future will be manufactured by biology put programmed by synthetic biology to have diverse functions. We are working with bacteria that overproduce carbohydrate material polymers and functionalising this material as it is made in order to give it new properties. We are also working on programming the polymerisation of protein-based materials with enzymatic and sensing functions built in.


'''Bottom-up design of orthogonal ''E.coli'' promoters'''<br>
'''Pattern Formation'''<br>
Project Type: ''Foundational''<br>
Project Type: ''Foundational'' <br>
Project Members: ''Fabio Chizzolini''<br>
Project Members: ''Georgios Pothoulakis''<br>
Synthetic biology has made great advances in its first decade but the complexity of devices has not exploded exponentially as expected. One of the major reasons for this is the lack of different parts, and specifically a dearth of regulated promoters is holding synthetic biology back. In ''E.coli'' our understanding of these promoters is advancing fast enough to consider building them up from scratch, but where do we start? In this project we will evolve a new ''orthogonal'' promoter system that uses a mutated Sigma Factor and mutated core promoter DNA sequence, so that these designer promoters are only recognised by the designer sigma factor under our control. This will lay the foundation for building a whole set of 'synthetic biology ONLY' promoters and devices that can sit in cells and yet only have limited interaction with the host cell systems.  
Collaborators: ''The Leverhulme Trust''<br>
Differentiation of genetically-equivalent cells allows single-cell cultures to diversify into patterns or achieve division of labour for tasks. In lab yeast, we are adding genes from ancestral strains that grow in a filamentous form when stressed and placing these under control of tunable, inducible promoters so that we can switch yeast colony growth from standard to branched fractal patterns.


'''Part characterisation for thermophilic bacteria'''<br>
'''Therapeutic Synthetic Biology'''<br>
Project Type: ''Foundational''<br>
Project Type: ''Applied''<br>
Project Members: ''Elena Martinez-Klimova''<br>
Project Members: ''Will Shaw, Marios Koutsakos, Despoina Paschou''<br>
Collaborators: ''David Leak''<br>
Collaborators: ''Sophie Helaine, AstraZeneca''<br>
Synthetic Biology has had considerable success importing function from throughout nature into the industrial workhorse organisms of ''E.coli'' and yeast. However, one function desirable in industrial biotechnology - growth at high temperatures - would be almost impossible to introduce, as it would require radical rewriting of every gene to code for heat-resistance. The sensible alternative is to begin to describe synthetic biology for a thermophilic chassis. In this project we have identified an organism which we believe is the "''E.coli'' of thermophiles" and intend to characterise bioparts for this chassis using flow cytometry with an engineered thermophilic GFP.
shhh... these are secret projects ;)

Revision as of 01:13, 2 December 2014

Latest Update: Dec 2014

Research in the Ellis Lab focuses on advancing our understanding of nature through genome engineering and accelerating biotechnology through the use of synthetic biology. Projects are either foundational work, applied work or a nice mix of both.

Current Projects

Synthetic Yeast Chromosome XI
Project Type: Foundational and Applied
Project Members: Ben Blount, Rob McKiernan, Maureen Driessen, Dejana Jovicevic
Collaborators: Jef Boeke (NYU), Yizhi Cai & Al Elfick (Edinburgh), Steve Oliver (Cam), Paul Freemont, Sc2.0 Consortium
Sc2.0 is a high-profile, international project to do the first full synthesis of a eukaryotic cell genome, the model yeast species Saccharomyces cerevisiae. Led by Prof Jef Boeke at NYU, USA, an international consortium is now established to re-synthesis and make to design changes to all 16 yeast chromosomes. Our group is leading the UK effort in the consortium, aiming to design, synthesise and assemble the complete 666 kbp chromosome XI. During construction we will investigate genome design and topological effects such as nuclear structures and how these can be used to optimise gene expression in metabolic engineering.

Synthetic Biology with engineered modular regulation
Project Type: Foundational and Applied
Project Members: Ben Blount, Tim Weenink, Robert Chen
TAL effectors and CRISPRi are a relatively new forms of DNA-binding protein that have a programmable DNA-recognition code. This means that they can be re-engineered repeatedly to bind to custom DNA sequences. We have now shown that modular TAL-effectors can be customised to be orthogonal repressors (TALORS) for yeast promoters - effectively acting as independent wires in logic systems. This offers a route to scalable logic systems in yeast synthetic biology. We are now looking to improve on this technology to generate a range of custom-built transcription factors which we can apply to advanced logic networks such as oscillators and memory systems.

Investigating device-chassis interactions
Project Type: Foundational
Project Members: Francesa Ceroni, Olivier Borkowski, Arinbjorn Kolbeinsson
Collaborators: Guy-Bart Stan, Rhys Algar, Richard Murray (Caltech)
Most gene devices demonstrated in synthetic biology have been high-expression strength regulatory networks hosted on mid-to-high copy number plasmids in E.coli. Despite being relatively simple and small, these devices are thought to be close to the maximum tolerated by the host cell - if they were any larger they would impinge on the host cell's own mechanisms. In this project, we are trying to quantify the threshold for gene device cloning into the E.coli chassis by examining a standard synthetic networks expressed at a variety of different strengths in plasmid systems of varying copy number. The intention is to define a quantitative standard for inserting gene devices into chassis cells and build a predictive model to aid future design of cells with predictable growth rates.

Combinatorial modular assembly of gene networks and pathways
Project Type: Foundational and Applied
Project Members: Arturo Casini, Ali Raza Awan, Carlos Bricio, Simon Arsene
Collaborators: Geoff Baldwin, Sphere Fluidics
The availability of gene synthesis is increasing rapidly, yet there is no straightforward lab-bench method to arrange modular gene units into larger assemblies with pre-defined positions. In this project we will demonstrate a new method to rapidly assemble gene units in a pre-defined order and showcase the technique to combinatorially assemble diverse synthesis pathways and gene regulatory networks using standardized parts. As well as demonstrating a rapid new assembly technique, the project will yield synthetic cells with high production of high-value therapeutic molecules which can be screened with interesting new microfluidic technologies.

Engineering thermophilic synthetic biology
Project Type: Foundational and Applied
Project Members: Elena Martinez-Klimova, Ben Reeve, Alex Esin
Collaborators: David Leak, Tobias Warnecke
Engineering new function into well-characterised cells is one of the major goals of synthetic biology, but one phenotype almost impossible to add to cells like E.coli is thermostability. Instead, our lab is kick-starting synthetic biology in a Geobacillus species thermophile by developing standard measurement protocols with aerobic and anaerobic fluorescent proteins and charactersing libraries of standard, synthetic parts. We will use these to improve and diversify existing biofuel production pathways to generate high-yields and new products.

Engineering materials from bacteria
Project Type: Applied
Project Members: Ben Reeve, Michael Florea, Charlie Gilbert, Olivier Borkowski
Collaborators: Textiles Futures Research Centre
The materials of the future will be manufactured by biology put programmed by synthetic biology to have diverse functions. We are working with bacteria that overproduce carbohydrate material polymers and functionalising this material as it is made in order to give it new properties. We are also working on programming the polymerisation of protein-based materials with enzymatic and sensing functions built in.

Pattern Formation
Project Type: Foundational
Project Members: Georgios Pothoulakis
Collaborators: The Leverhulme Trust
Differentiation of genetically-equivalent cells allows single-cell cultures to diversify into patterns or achieve division of labour for tasks. In lab yeast, we are adding genes from ancestral strains that grow in a filamentous form when stressed and placing these under control of tunable, inducible promoters so that we can switch yeast colony growth from standard to branched fractal patterns.

Therapeutic Synthetic Biology
Project Type: Applied
Project Members: Will Shaw, Marios Koutsakos, Despoina Paschou
Collaborators: Sophie Helaine, AstraZeneca
shhh... these are secret projects ;)

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