We are interested in developing novel technologies and tools for genetic engineering, broadly defined for controlling and manipulating the genetic codes of life. We belive controlling genetics is fundamentally important to understanding genetics/genomics, and is a foundation for rationally designing and engineering the genome and cells for diagnosis and therapeutics. We regard such an approach as discovery-based synthetic biology, and aim to harness naturally occurring molecules and genetic elements as tools. Towards this goal, we have engineered the nuclease-dead Cas9 (dCas9) from the CRISPR system as a platform for multiple purposes: transcription regulation (activation or repression) of the genome (CRISPRi/a), genome imaging in living cells, and genome-wide single or combinatorial screens. Meantime, we appreciate the vast unknown molecules that are evolved during billion years that need to be understood and engineered for the goods of the science and society. Three topics are particularly interesting to us:
- New molecules, tools, methods, and technologies for genetic engineering.
- Genetic engineering and rational design of cells for immunological engineering and regenerative medicine.
- Quantitative understanding and control of human genes and epigenetics.
The invention of CRISPR technologies made it orders of magnitude easier for engineering the genome in diverse organisms. Beyond gene editing, we were the first to invent the nuclease-dead Cas9 (dCas9) and demonstrate the use of dCas9 for gene activation and repression in the genome. For this purpose, we developed a toolkit for non-editing genome engineering. We repurposed the CRISPR as CRISPRi/a (i for inhibition and a for activation) systems for transcription control and epigenetic modification of the genome. We continue to improve our tools for multiplexed genome control, identify new regulatory mechanisms for controlling the genome, and develop new approaches towards the goal of controlling any genes in any cell. Examples include:
CRISPRi in prokaryotic cells (Cell 2013; Cell 2016) and CRISPRi/a in eukaryotic and mammalian cells (Cell 2013; Cell 2014; Nature Methods 2016)
CRISPRi/a-based genetic screening (Cell 2014; Nature Methods 2017)
CRISPR for genome imaging (Cell 2013)