Programming Cells

Synthetic biology aims to build increasingly complex biological systems and engineer organisms to perform novel functions. A long-envisioned goal of rationally engineering microorganisms has undergone dramatic changes throughout the past decade with the aid of genomics revolution and rise of systems biology and the burgeoning field of synthetic biology. We are broadly interested in developing synthetic biological devices with applications in biosensing, imaging, and potentially in diagnostics and therapeutics.

As a specific example, we have developed rationally designed RNA computing systems as genetically encodable sensors and controllers, which we call ‘ribocomputing systems’ (Green*, Kim* et al, Nature; Kim et al, Biochemistry). This work builds on a recent breakthrough in nucleic-acid-based gene expression regulator, ‘toehold switch’, that provides a library of programmable, orthogonal, and high-performance parts for synthetic biology (Green et al, Cell).

<Reprinted with permission from Ribocomputing: Cellular Logic Computation Using RNA Devices, Biochemistry, 2018, 57 (6), pp 883–885. Copyright © 2017 American Chemical Society>

• Press Release: Wyss Institute at Harvard University, Arizona State University, Motherboard, Digital Journal, Kurzweil Accelerating Intelligence, etc

• Mechanism of the Toehold Switch

Programming Molecules

We are interested in developing synthetic biomolecular systems with precisely prescribed dynamical behavior. By interfacing with biological molecular systems through sensing a biological signal (e.g., mRNA, protein, small molecules) and producing a readout observable by a human user or actuating a biological response, these synthetic molecular devices can provide powerful experimental tools and technological platforms.

As specific examples, we have developed de–novo-designed transcriptional switches and demonstrated several synthetic programmable transcriptional circuits in vitro including bistable memory circuits (Kim et al., Molecular Systems Biology; Subsoontorn*, Kim* et al., ACS Synthetic Biology), a fold-change detector (Kim et al., Nucleic Acids Research), oscillators (Kim and Winfree, Molecular Systems Biology) interconnected to DNA nanodevices (Franco, Friedrichs, Kim et al., Proceedings of the National Academy of Sciences) and encapsulated in cell-like volumes (Weitz, Kim et al., Nature Chemistry).

• Press Release: California Institute of Technology, Technical University of Munich, University of California at Riverside, etc

Applications

Microbial communities are ubiquitous in the entire planet and play a crucial role in agriculture, biotechnology, and human health. Engineering probiotics with programmable interactions with commensal and pathogenic bacteria can provide opportunities for microbiome engineering in situ. Synthetic biological circuits, such as combinatorial logic and memory circuits, can be layered upon the basic designs of biological circuits in bacteria to further improve specificity and controllability of desired cellular dynamics. Our ability to program complex synthetic controllers using ribocomputing devices will provide a powerful tool to develop smart probiotics and reshape microbial community.

Molecular diagnostic technologies provide tools to probe biological systems for accurate detection and quantitation of biomolecules, e.g. DNA sequences and gene expression signatures, as indicators of disease prognosis and drug sensitivity among others. For instance, the gene expression profiles of cancer tissues form the basis of prognostic test of liver cancer (Kim et al, Cancer Science; Kwon*, Kim* et al, Clinical Cancer Research). We aim to further expand these capabilities through our ability to engineer nucleic acids for developing accurate, rapid, and multiplexed sequence detection systems. The highly specific and sensitive, yet cost-effective methods to detect the sequence variants will drive the adoption of precision medicine in the future.