Creating and evaluating a library of effector modules for synthetic morphology

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.

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.