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Researchers at MIT's Broad Institute, Harvard, and MIT's McGovern Brain Institute have developed a system that can detect specific RNA sequences in living cells and produce a protein
of interest in the reaction.
Using this technique, the team showed how they could identify specific cell types, detect and measure changes in individual gene expression, track transcription status, and control the production
of proteins encoded by synthetic mRNA.
The platform, known as programmable ADAR sensors, or RADARS, even allows teams to target and kill specific cell types
.
The team says RADARS could one day help researchers discover and selectively kill tumor cells, or edit the genome
of specific cells.
The study, published today in the journal Nature Biotechnology, was led
by co-first authors Kaiyi Jiang (MIT), Jeremy Koob (Broad), Rohan Krajeski (Broad), Xi Chen (Broad), and Yifan Zhang (Broad).
"One of the revolutions in genomics is the ability to sequence the transcriptome of cells," said Fei Chen, an assistant professor and a core member of the Harvard Broad Megin Investigator and co-corresponding author
of the study.
"It really gives us an idea of the type and state
of the cells.
" But usually, we can't manipulate these cells
specifically.
RADARS is a big step
in this direction.
”
"Currently, the tools we have to harness cell labeling are difficult to develop and design," added
Omar Abudayyeh, a McGovern Institute researcher and co-corresponding author of the study.
"We really wanted to create a programmable way to sense and respond to cellular states
.
"
Jonathan Gootenberg, a researcher and co-corresponding author at the McGovern Institute, said his team is eager to build a tool that harnesses all the data provided by single-cell RNA sequencing, which reveals a large number of cell types and cell states
in the human body.
"We wanted to know how to manipulate cellular identity
in a way as easy as editing a genome with CRISPR," he said.
We're excited to see how the field will take advantage of it
.
”
The RADARS platform utilizes naturally occurring RNA editing in cells to generate desired proteins
when specific RNA is detected.
The system consists of a two-component RNA: a guide zone, which binds to the target RNA sequence that scientists want to sense in the cell, and a payload zone, which encodes proteins of interest, such as fluorescent signals or cell-killing enzymes
.
When the guide RNA binds to the RNA of interest, a short double-stranded RNA sequence is created that contains a mismatch
between the two bases in the sequence, adenosine (A) and cytosine (C).
This mismatch attracts a naturally occurring family of RNA-editing proteins called adenosine deaminases (ADARs)
that act on RNA.
In RADARS, the A-C mismatch appears in the "stop signal" of the guiding RNA, which prevents the production
of the desired payload protein.
ADARs edit and disable the stop signal, allowing the translation
of proteins.
The sequence of these molecular events is key to the function of RADARS as a sensor; The protein
of interest is produced only after the guide RNA binds to the target RNA and ADARs disable the stop signal.
The team tested RADARS
in different cell types, different target sequences, and protein products.
They found that RADARS distinguishes between kidney, uterus and liver cells and can produce different fluorescent signals as well as caspase
, an enzyme that kills cells.
RADARS can also measure gene expression over a large dynamic range, proving their utility as sensors
.
Most systems successfully detected the target sequence using the cell's own ADAR protein, but the team found that supplementing the cell with additional ADAR proteins increased signal intensity
.
Abudayyeh says both scenarios can be useful; Harnessing the cells' native editing proteins can minimize the chance of off-target editing in therapeutic applications, but when RADARS are used as a laboratory research tool, supplementing them can help produce stronger effects
.
Because both the guide RNA and the payload RNA are modifiable, Abudayyeh, Chen and Gootenberg say, others can easily redesign RADARS to target different cell types, producing different signals or payloads
.
They also engineered more complex RADARS, in which a cell produces one protein if it senses two RNA sequences, and another protein
if it senses one RNA sequence.
The team adds that similar RADARS could help scientists detect multiple cell types simultaneously, as well as complex cell states
that cannot be determined by individual RNA transcription.
Ultimately, the researchers hope to develop a set of design rules so that others can more easily develop RADARS for their own experiments
.
They suggest that other scientists could use RADARS to manipulate immune cell states, track neuronal activity in response to stimuli, or deliver therapeutic messenger RNA
to specific tissues.
"We think this is a very interesting paradigm for controlling gene expression," Chen said
.
"We can't even predict what's the best app
.
It really comes from a combination
of people who have interesting biological knowledge and the tools you develop.
”
