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Tuesday, March 22, 2016
Engineer demonstrates technique for targeting RNA inside living cells
When he’s not surfing in Mexico or listening to electronic
music, Dave Nelles is busy tinkering – inside living cells!
Growing up, Nelles always knew he wanted to develop
technology, but was intrigued by the complexity and diversity of processes in biology.
“Biology is on the verge of becoming a predictive and
quantitative pursuit,” says Nelles. “Compared to fields like physics where we
have many good models of natural phenomena, biology in general is less mature.
One reason for this is a lack of tools to measure and alter specific components
of living cells.”
Motivated by this gap, Nelles focused his graduate work in
materials science and engineering on technologies to measure and alter a
fundamental biological molecule: RNA. Inside cells, DNA is transcribed into messenger
RNA (mRNA), which is subsequently translated into protein.
Proteins are the building blocks of life – many functions
that take place inside of a cell are made possible by proteins.
“In many diseases, the processing of mRNA is dysfunctional,
meaning that the protein that is encoded for by that RNA will not be made
correctly, or at all,” said Nelles.
In molecular biology, there’s a technique called CRISPR-Cas9
that is used to modify DNA and has the potential to cure a range of genetic
diseases. Nelles and his collaborators have been able to demonstrate that
CRISPR-Cas9 can not only bind to DNA, but also to RNA. This approach is described in a paper
published on March 17th in the journal Cell.
Nelles explains, “Just as CRISPR-Cas9 is making genetic
engineering accessible to any scientist with access to basic equipment,
RNA-targeted Cas9 may support countless other efforts for studying the role of
RNA processing in disease or for identifying drugs that reverse defects in RNA
In collaboration with Mitchell O’Connell in the lab of
Jennifer Doudna at the University of California, Berkeley, Nelles tagged Cas9
with a fluorescent protein and targeted various RNAs to track their movement
inside living cells.
“This work is the first example, to our knowledge, of
targeting RNA in living cells with CRISPR-Cas9,” said senior author Gene Yeo,
PhD, associate professor of Cellular and Molecular Medicine. “Our current work
focuses on tracking the movement of RNA inside the cell, but future
developments could enable researchers to measure other RNA features or advance
therapeutic approaches to correct disease-causing RNA behaviors.”
“For many experiments involving RNA tracking, the cells need
to be dead or the targeted RNA must be genetically modified in order for the
RNA to be detectable,” said Nelles. “Our experiments were done inside living
cells with unmodified RNAs, which has many advantages – for example, we were
able to observe RNA being transported to stress granules over time.“
Stress granules are accumulations of RNA and protein in a
cell and their formation has been linked to neurodegenerative diseases. Nelles
and his team hope that providing a way to track these RNAs will assist with new
After graduating this Spring, Nelles will be continuing his
work as a postdoc at UC San Diego.