Researchers develop new sensors to detect gene activity

A team headed by researchers from the University of Warwick has developed genetic sensors that are capable of detecting the activity of genes, instead of only the genes themselves.

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The researchers from the University of Warwick and Keele University have designed microscopic machines based on the CRISPR gene-editing system. The machines employ these sensors to identify when genes are turned “on” or “off” inside a cell, and respond to those variations dynamically—rendering them a promisingly ideal monitoring system.

Such genetic sensors have been described in the latest article published in The CRISPR Journal, where the team showed a genetic device based on the CRISPR gene editing system within a cell of the bacteria. The researchers’ study is the first step towards developing genetic devices that can modify the expression of genes after sensing the prevailing gene activity inside a cell.

Currently, we don’t know how to design novel genetic systems to see which genes are on or off inside a cell. In nature, there are proteins that do that, they can sense the status of the cell, and the best we can do is to take those from one organism and put them in another one. We wanted to approach a new way of doing this, from scratch, to ask how we can program a system to listen to whatever we want inside a cell.”

Alfonso Jaramillo, Study Lead Author and Professor, School of Life Sciences, University of Warwick

Professor Jaramillo continued, “Cells contain a number of genes that are expressed to perform numerous functions, from sensing their environment and processing food. By having a sensor that can detect when those genes are active, scientists could program a machine to react to a specific process, such as when the cell digests its food.”

The investigators based their genetic device on the CRISPR gene editing system, which is being widely used for various gene editing applications, such as gene therapies. Through CRISPR molecules, researchers can target and alter particular genomic sequences inside the cells. The benefit of the CRISPR gene editing system is its programmability, which enables it to be redirected to almost any genetic targets, including genetic modifications that lead to diseases.

To create these innovative genetic devices, the team used the programmable part of the CRISPR system as a scaffold; this part is also responsible for binding and sequence recognition, known as guide RNA sequence (gRNA).

The team successfully redesigned the gRNA sequence by introducing a sensor within it, so that the CRISPR complex attaches to the DNA target only after being stimulated by a trigger signal, like short fragments of viral RNA sequences. The novel sensor can be activated by any selected RNA sequence and, in this manner it stimulates a CRISPR gene editing system at any point of the life cycle of a virus or a cell.

The study’s authors also tested the novel genetic devices in living Escherichia coli bacteria by introducing a fluorescent gene that could be switched on or off only after the interaction between the triggering molecule and the sensing device. The researchers further verified their system to identify an RNA molecule deriving from the HIV virus, demonstrating its potential use in medicine.

According to the team, the new system will prove useful for several scientists who are looking for ways to program cells with more sophistication, for instance, to produce new synthetic circuits.

This is quite different from gene editing, where you simply modify the genome. This is about watching the behaviour of the genome. If you have a monitor of the cell’s behaviour then you can make the cell correct that behaviour if you don’t like it, you can suppress it, or you can exploit that to switch on other genes.”

Alfonso Jaramillo, Study Lead Author and Professor, School of Life Sciences, University of Warwick

Jaramillo added, “The drive is to have a genetic device able to monitor the behaviour of a cell. Monitoring the behaviour allows us to reprogram the cell to respond to specific signals, this is the first step towards so many other things.”

Coupling a genetic sensor with CRISPR tools offers an unprecedented opportunity for researchers to take genetic editing technologies to a completely new dimension. Eukaryotic cells could be programmed to detect deleterious mutations that may arise within its own genes, or to respond when invaded by pathogens like bacteria naturally do against phages.”

Dr Roberto Galizi, Study Co-lead Author, School of Life Sciences, Keele University

Dr. Galizi continued, “One interesting feature is that we can program these molecular tools to sense any predesigned RNA molecule in a sequence-specific manner and, at the same time, target any desirable gene or genetic sequence to stimulate various genetic actions, all within the same cell.”

“Even genetic technologies aimed to control vector-borne diseases could benefit from such innovation. For example, we could engineer mosquitoes to sense and counteract pathogen transmission, or even mutations that make vector or pest insects resistant to insecticides,” Dr. Galizi concluded.