Crispr Used to Create Circuit-Like Genes

Basic half-adder circuit. (Inductiveload, Wikimedia Commons)

17 Apr. 2019. A biotechnology team uses genome-editing to create synthetic genes acting like electronic circuits that can be arrayed in cells like computer components. Researchers from the lab of bioengineering professor Martin Fussenegger at ETH Zurich located in Basel, Switzerland, describe their techniques in the 9 April issue of Proceedings of the National Academy of Sciences.

Fussenegger and colleagues aim to build on earlier attempts at biological programming with proteins to control gene expression in a way that emulates the control and reliability of integrated circuits. Using proteins, however, makes possible only the most simple of circuits, processing one a single input at a time. The ETH Zurich team seeks a more flexible, modular, and scalable process enabling more complex and sophisticated biological circuits.

That process turns out to be the genome editing technique Crispr — short for clustered, regularly interspaced short palindromic repeats. Crispr makes it possible to edit genomes of organisms by harnessing bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. The actual editing of genomes with Crispr in most cases today uses an enzyme known as Crispr-associated protein 9 or Cas9, guided with RNA molecules to specific genes needing repair or modification.

In this study, the researchers use Crispr-Cas9 to edit genes so they perform in predictable ways, in this case coding for and expressing a specific protein. This predictable property makes it possible to connect these edited genes into circuit-like assemblies that perform Boolean logic computations. To prove the concept, the team connected the genes into a circuit that acts like a half-adder electronic component. A half-adder performs computations adding 2 single-digit binary numbers into a 2-digit output. Putting 2 half-adder components together performs full addition operations.

To further prove the concept, the ETH Zurich researchers assembled these edited genes configured to run like a central processing unit with dual cores, or 2 independent processing components. Gene circuits in the Crispr-CPU, as they call it, were taken from 2 different bacteria and assembled inside cells, including adult bone marrow stem cells. Tests of the gene circuits and Crispr-CPU, say the researchers, show they work efficiently and can be readily assembled into more complex circuit designs.

The team believes these gene circuits can be configured into programmable components that detect specific biomarkers. When assembled into half-adders, for example, the circuits can be programmed to detect 2 different biomarkers, then output both a detection alert protein and a therapeutic protein. The circuits could also be programmed to operate for specific periods of time, with longer-term circuits tracking the presence of disease-producing proteins after treatments.

The researchers’ next step is to construct multi-core processors resembling modern processing chips from these gene circuits. Fussenegger believes these biological circuits can become more efficient than electronic components. “Imagine a microtissue with billions of cells,” says  Fussenegger in an ETH Zurich statement, “each equipped with its own dual-core processor. Such ‘computational organs’ could theoretically attain computing power that far outstrips that of a digital supercomputer, and using just a fraction of the energy.”

More from Science & Enterprise:

• Biotechs Join Forces for Off-the-Shelf Stem Cells
• Start-Up Creating Off-the-Shelf Stem Cell Therapies
• Crispr Diagnostics Company Launches with $35M Funding
• Anti-Inflammatory Human Protein Produced in Plants
• Gene Editing Deactivates Cause of T-Cell Side Effects

*     *     *