Creating and evaluating a library of effector modules for synthetic morphology

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Integrative Physiology

Abstract

This project is concerned with extending the abilities of a new type of biological research, which is part of the general field called 'synthetic biology'. There are two broad types of synthetic biology; (1) the ethically-contentious type that seeks to create life from scratch and (2) the ethically more benign type that seeks to re-connect existing biological entities (genes, proteins etc) in new ways to give cells new and useful capabilities that random evolution has not created but that human design can create. This project is concerned only with the second type of synthetic biology. The progress that has been made so far in this type of synthetic biology has seen the development of genetic 'modules' that, when put into cells, perform functions such as chemical sensing, computing logic and memory. These modules can be obtained 'off the shelf' and can be connected together inside cells in a way analogous to the way engineers can connect off-the-shelf electronic components. So far, though, these modules have been used to create designed 'programs' that control the production of chemicals by the cells. In this project, we shall produce additional modules, of the same general type and compatible with the existing sensor and logic modules, that will result not in the production of chemicals but in particular types of cell behaviour; specifically, the types of cell behaviour that organize cells into tissues and create biological form. By combining the modules we will create with existing sensors and logic modules, we and other researchers (to whom the modules will be freely available) will be able to create cells programmed to produce structures that do not necessarily exist in evolved nature. There are two reasons that doing this is important, one to do with the progress of science and one with medical technology. The scientific reason is that we think we have a good idea about how biological form is created, but only by trying to create it by genetic circuits we have designed ourselves will we really be able to test this understanding. It is a bit like the difference between thinking you understand flight just by studying birds gliding, and making a paper aeroplane to prove that you do really understand it. The medical reason is that, as our ability to make artificial organ/limb substitutes gets more sophisticated, there will be an increasing need to develop living interfaces between body tissues and human technology. All of the techniques of regenerative medicine (stem cells etc) will only be good for making structures that already exist in a normal body. To make completely novel structures, as interfaces, we need to be able to program cells to do new things. This means synthetic biology, and this project is the first attempt to move the field in the direction of structures. As well as making these modules, this project seeks to demonstrate their use in a series of bioengineering tasks simple enough to do within the project but complex enough to prove the modules work and to attract attention to them.

Technical Summary

Synthetic biology can be defined as taking parts from living systems and reassembling them to construct designed devices that might or might not have analogues in evolved living systems. So far, synthetic biology has been used mainly to create sensors and logic systems that drive a reporter gene according to the environmental cues present, in both prokaryotic and eukaryotic systems. Importantly, most are based on independent genetic 'modules' that can be connected together to yield different functions. What is missing, though, are modules that drive a specific morphogenetic change in response to the sensory and logic modules that do exist. In a recent paper, I argued that such modules could form the basis of very advanced tissue engineering ('synthetic morphology') in which we are not limited by what cells can already do for themselves but can make them do other things, to test our basic understanding of morphogenesis and to perform a practical task such as interfacing with an artificial limb or making an extracorporeal organ substitute for critical care. The purpose of this project is to construct modules, compatible with existing logic and sensory modules, that will result in any mammalian cells performing a specific one of the 13 basic morphogenetic events that underlie mammalian morphogenesis. The modules will be constructed using the 'Gateway' system to maximise their flexibility. They will be made freely available through synthetic biology repositories. We will verify the action of each module in a variety of cell lines and will connect them to existing modules to perform feats of synthetic morphology for demonstration purposes. These range from programmed motility and adhesion through programmed sorting and formation of multilayers to an artificial 'life cycle' of a multicellular entity. We hope that such demonstrations will contribute significantly to kick-starting the extension of synthetic biology into the domain of tissue engineering.

Publications

10 25 50
 
Description We have developed a library of synthetic morphology effector molecules (paper published in Biological Engineering). We have developed a novel pattern-generating system and have obtained funding to develop it further; a paper from this has been published in Scientific Reports. We then combined these, to have a system that self-patterns and then undergoes patterned morphogenesis. This was published in Eng Biol.
Exploitation Route They are being used as a foundation for mammalian synthetic morphology; we have already succeeded in raising further funds for this. The modules are also being used for training (a further Postdoc) in mammalian synthetic biology. In a more general way, some of the ideas of self-organizing systems are being taken up by members of the architectural community (please see the narrative section). The post-doc now has an independent position, in which she is conducting her own work in mammalian synthetic biology (we collaborate on some things and work entirely independently on others)
Sectors Construction,Creative Economy,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL http://golgi.ana.ed.ac.uk/Davieslab/
 
Description The data have been published and including one book intended for the general public ("Synthetic Biology, A Very Short Introduction" OUP 2018). The DNA constructs have been requested by others (and given, of course), and the published papers have been cited. I have also been invited to give several conference talks on the work in the UK and abroad. (and have done so). We have used them to obtain one further grant (Leverhulme) and as part of a successful RCUK's Synthetic Biology Research Centre bid. The work has also been picked up by the architectural community: I have been invited to write (and have written and published) a review on biological architecture for a leading architecture journal and have been asked to be an external assessor for the Bartlett School of Architecture, London., for an MSc course: this is evidence of impact beyond science.
First Year Of Impact 2011
Sector Construction,Creative Economy,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Societal

 
Description FET
Amount € 5,000,000 (EUR)
Funding ID CyGenTiG 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 10/2018 
End 09/2023
 
Title Library of Synthetic Morphology Modules 
Description A library of synthetic biological modules for driving morphogenetic events in mammalian cells, made freely available via the Addgene repository. 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact We know 14 other laboratories have obtained the library but they have not yet published with it (correct Dec 2016). We have used it an published subsequent work with it. 
 
Title Optogenetic control of cell death 
Description Cells can be saved from drug-inducible cell death by an optogenetic construct 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact It has been one of the foundations of a 5 million Euro collaborative project (CyGenTiG), in which light will be used to control morphogenesis. 
 
Description Collaboration leading to Synthsys Mammalian 
Organisation University of Edinburgh
Department Centre for Systems Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Brought components and ideas to a collaborative proposal for a Synthetic Biology Research Centre (Synthsys Mammalian)
Collaborator Contribution Brought components and ideas to a collaborative proposal for a Synthetic Biology Research Centre (Synthsys Mammalian)
Impact Publications, public engagement activities, conferences.
Start Year 2015
 
Description Collaboration with Dr Elise Cachat 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Elise Cachat was the post-doc on this grant, but partly on the strength of what she achieved she now has an independent position and we now collaborate as equals.
Collaborator Contribution Experimental design and computer modelling.
Impact Publication: Cachat E, Liu W, Davies JA (2017) Synthetic self-patterning and morphogenesis in mammalian cells: a proof-of-concept step towards synthetic tissue development. Eng Biol 1: doi: 10.1049/enb.2017.0013
Start Year 2016
 
Description Broadcast on BBC World Service 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Participation in a 3-way discussion (+ Bridget Kendal as Chair) for a 50-minute BBC World Service "Forum" programme, on mechanisms of self-assembly and self-organization. This included discussion of the MRC-funded renal tissue engineering project, and the BBSRC-funded synthetic morphology project although I am afraid the specific sentence about funding this was lost on the edit.

No directly measurable ones (and none were expected - this was about show-casing an interesting field of science to a world-wide pubic audience).
Year(s) Of Engagement Activity 2014
URL http://www.bbc.co.uk/programmes/p027gcpk
 
Description Edinburgh Science Festival - Synthetic Biology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Edinburgh Science Festival talk on Synthetic Biology
Year(s) Of Engagement Activity 2019
 
Description Participation in Royal Society of Biology careers event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Workshops on careers for biology graduates, held at the University of Highlands and Islands, and attended mainly by professional careers advisors, with some undergraduate attendance too. It was intended for the careers advisors.
Year(s) Of Engagement Activity 2017
 
Description Pint of Science presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Pint of Science pub-based talk and demonstration.
Year(s) Of Engagement Activity 2016
 
Description Presentation of Young European Scientist's Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Talk and workshop at the Young European Scientist's Meeting at Porto (which, despite the name, is actually mainly medical students from around Europe)
Year(s) Of Engagement Activity 2016
 
Description Public talk at Aye Write (Glasgow literary festival) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact About 60 people attended a talk on human development, with some discussion afterwards, both about the talk and about career paths into science.

One school pupil came to shadow someone in the lab for a week.
Year(s) Of Engagement Activity 2014