Using Computer-Like Protein Logic Gates for Gene Control

The same basic tools that drive computer function are now being used to control life at the molecular level. Published today in Science, these advances have implications for future medicines and synthetic biology.

For their study, University of Washington researchers created artificial proteins that function as molecular logic gates. These tools, like their electronic counterparts, can be used to program the behavior of more complex systems. The team also showed that these new designer proteins can regulate gene expression inside human T-cells, a development that may improve the safety and durability of future cell-based therapies.

“Bioengineers have made logic gates out of DNA, RNA, and modified natural proteins before, but these are far from ideal,” says senior author David Baker. “Our logic gates built from de novo designed proteins are more modular and versatile and can be used in a wide range of biomedical applications.”

Whether electronic or biological, logic gates sense and respond to signals in predetermined ways. One of the simplest is the “AND” gate, which produces output only when one input and a second input are present. For example, when typing on a keyboard, pressing the “Shift” key and the “A” key produces an uppercase letter “A.” Logic gates made from biological parts aim to bring this level of control into bioengineered systems.

With the right gates operating inside living cells, inputs such as the presence of two different molecules (or one and not the other) can cause a cell to produce a specific output, such as activating or suppressing a gene.

“The whole Apollo 11 Guidance Computer was built from electronic NOR gates,” says lead author Zibo Chen. “We succeeded in making protein-based NOR gates. They are not as complicated as NASA’s guidance computers but nevertheless are a key step toward programming complex biological circuits from scratch.”

The researchers hope that their findings can be used to prevent T cell exhaustion, which is a stumbling block for the CAR-T cell therapy approach to targeting solid tumors. According to the researchers, genetically altered T cells can fight for only so long before they stop working. But with protein logic gates that respond to exhaustion signals, the team hopes to be able to prolong the activity of CAR T cells.

Image: This is a conceptual illustration of living cells containing protein AND gates that have been designed to detect multiple signals to become bioluminescent. Image courtesy of MolGraphics/UW Medicine Institute for Protein Design.