Application of Synthetic Biology to Regenerative Medicine

Abstract

Synthetic biology uses interchangeable and standardized "bio-parts" to construct complex genetic networks that include sensing, information processing and effector modules: these allow robust and tunable transgene expression in response to a change in signal input. The rise of this field has coincided closely with the emergence of regenerative medicine as a distinct discipline. Unlike synthetic biology, regenerative medicine uses the natural abilities of cells to make trophic factors and to produce new tissues as they would in normal development and tissue maintenance. In this article, we argue that bringing these young fields together, so that synthetic biology techniques are applied to the problem of regeneration, has the potential significantly to enhance our ability to help those in clinical need. We first review the synthetic tool kit available for engineered mammalian networks, then examine the main areas in which synthetic biology techniques might be applied to promote regeneration: (i) biosynthesis and controlled release of therapeutic molecules, (ii) synthesis of scaffold material, (iii) regulation of stem cells, and (iv) programming cells to organize themselves into novel tissues. We finally consider the long-term potential of synthetic biology for regenerative medicine, and the risks and challenges ahead.

Providing sustained transgene induction through affinity‐based drug delivery

“…Delivering these small molecule drug activators through systemic delivery is complicated by the classic challenges in drug delivery and pharmacology such as first pass metabolism, systemic side effects and inappropriate biodistribution particularly at the site of interest. Another problem of systemic delivery for transgenic devices applications is the potential immune response toward the transgene machinery, which is exacerbated when applied to the whole body versus applied locally. For example, when the transgene machinery is localized to a particular tissue as opposed to being exposed to the whole body the immune response is severely diminished .…”

“…Genetically modifying cells and bacteria represents a promising clinical tool in the fields of regenerative medicine, tissue engineering and synthetic biology, besides also being a widespread tool in molecular biology. 1,2 The body of work utilizing transgene systems is a rapidly growing field, yet only a small number of laboratories have used drug delivery principles to enable sustained gene expression from such genetically modified cells. 3,4 While transgene activating drugs can be easily administered to such cells as needed in vitro, this become much more challenging when cells genetically modified with transgenes are used in vivo.…”

A library of mammalian effector modules for synthetic morphology

“…T-REx-293 cells were used in combination with Gateway® pT-REx™-DEST vectors, so that driver genes could be conveniently inserted downstream of a tetracycline-inducible promoter from our library of pENTR library vectors. This way, effector modules could be switched on and off using tetracycline (Tet), without the need for construction and testing of the elaborate upstream logic modules that will control effector modules in advanced synthetic morphology projects [ 7 , 8 , 18 ]. After stable transfection, followed by clonal selection, independent clones were tested.…”

“…However, the recent report by Carvalho et al [ 6 ], who generated morphogen diffusion gradients from engineered cysts, illustrates the power of synthetic tools towards spatial engineering in mammalian cells. In recent essays, we have proposed the construction of genetic modules for ‘synthetic morphology’: programming mammalian cells to display specific morphogenetic behaviours using synthetic biology principles, the eventual aim being the self-organization of these cells into designer ‘tissues’ [ 7 , 8 ].…”

Rising influence of synthetic biology in regenerative medicine

“…Traditional methods in regenerative medicine have relied on utilising the natural, evolved behaviour of human cells, thereby supporting and stimulating the body's own self‐healing capability. When combined with synthetic biology, the potential to improve our ability to help those in clinical need greatly increases [36] and novel solutions are presented to help combat several of the challenges currently faced within the field [37].…”