Engineering and safeguarding synthetic genomes

The overarching goal of this proposal is the development of an integrated technological platform for efficiently and safely engineering biology at the genome scale. I propose tackling this ambitious goal with three complementary work packages. Work packages are substantial and significant, but complementary to each other. The successful delivery of this vision will require the coordinated co-developments of all three work packages.

First, I will develop a next-generation computer- assisted designer, capable of incorporating high- level, semantics-based features within higher eukaryotic genome design. The CAD software will provide sequence screening functionality to identify potentially harmful sequences. This sequence screening development will be coordinated with an international consortium backed by the Nuclear Threat Initiative (NTI), United Nations (UN) and World Economic Forum (WEF).

To improve the efficacy of genome synthesis and assembly, I will apply state-of-the-art robotics for the automation of genome synthesis and use process engineering principles to monitor and schedule genome assembly pipelines. I will also develop a new concurrent genome assembly method to parallelise construction. Transplanting synthetic genomes from yeast to other organisms is a significant challenge. I will tackle this obstacle by developing a new standardised modular assembly kit to efficiently assemble large synthetic chromosomes. I will then exploring and optimising three distinct genome transfer methods to shuttle these synthetic chromosomes across kingdoms. To trace potentially dangerous synthetic genomes, we will develop genomic steganography to embed traceable watermarks, which are tamper-resistant and do not interfere with normal cellular physiology, across synthesised genomes.

Finally, to minimise the risk of bioterrorism and bio-error arising from synthetic genome technology, I will develop SafeGuard technologies incorparating genetic code alterations and transcriptional, recom- binational, and protein stability switches to contain synthetic strains. I will characterise their respective performances under permissible and restrictive conditions. In summary, I propose a highly innovative and integrated engineering platform for genome design, manufacture, transfer and safeguarding.