It means that research productivity will leap again and results will
soon be coming in fast and furiously from the present state of quick
enough. Of course it is excellent news and coming close to turning
it all into a gold rush were even modestly trained technicians could
participate. There is even room for outright stupidity.
It also means that outright gene therapy will now come into its own
as a easy to tap tool in the medical industries kit.
This is all great news for human health in the next decade.
Cheap and easy
technique to snip DNA could revolutionize gene therapy
By Robert
Sanders, Media Relations | January 7, 2013
BERKELEY —
A simple, precise
and inexpensive method for cutting DNA to insert genes into human
cells could transform genetic medicine, making routine what now are
expensive, complicated and rare procedures for replacing defective
genes in order to fix genetic disease or even cure AIDS.
Discovered last year
by Jennifer Doudna and Martin Jinek of the Howard Hughes Medical
Institute and University of California, Berkeley, and Emmanuelle
Charpentier of the Laboratory for Molecular Infection
Medicine-Sweden, the technique was labeled a “tour de force” in a
2012 review in the journal Nature Biotechnology.
That review was based
solely on the team’s June 28, 2012, Science paper, in
which the researchers described a new method of precisely targeting
and cutting DNA in bacteria.
Two new papers
published last week in the journal Science Express demonstrate
that the technique also works in human cells. A paper by Doudna and
her team reporting similarly successful results in human cells has
been accepted for publication by the new open-access journal eLife.
“The ability to
modify specific elements of an organism’s genes has been essential
to advance our understanding of biology, including human health,”
said Doudna, a professor of molecular and cell biology and of
chemistry and a Howard Hughes Medical Institute Investigator at UC
Berkeley. “However, the techniques for making these modifications
in animals and humans have been a huge bottleneck in both research
and the development of human therapeutics.
“This is going to
remove a major bottleneck in the field, because it means that
essentially anybody can use this kind of genome editing or
reprogramming to introduce genetic changes into mammalian or,
quite likely, other eukaryotic systems.”
“I think this is
going to be a real hit,” said George Church, professor of genetics
at Harvard Medical School and principal author of one of the Science
Express papers. “There are going to be a lot of people
practicing this method because it is easier and about 100 times more
compact than other techniques.”
“Based on the
feedback we’ve received, it’s possible that this technique will
completely revolutionize genome engineering in animals and plants,”
said Doudna, who also holds an appointment at Lawrence Berkeley
National Laboratory. “It’s easy to program and could
potentially be as powerful as the Polymerase Chain Reaction (PCR).”
The latter
technique made it easy to generate millions of copies of small pieces
of DNA and permanently altered biological research and medical
genetics.
Cruise missiles
Two developments –
zinc-finger nucleases and TALEN (Transcription Activator-Like
Effector Nucleases) proteins – have gotten a lot of attention
recently, including being together named one of the top 10 scientific
breakthroughs of 2012 by Science magazine. The magazine
labeled them “cruise missiles” because both techniques allow
researchers to home in on a particular part of a genome and snip the
double-stranded DNA there and there only.
Researchers can use
these methods to make two precise cuts to remove a piece of DNA and,
if an alternative piece of DNA is supplied, the cell will plug it
into the cut instead. In this way, doctors can excise a defective or
mutated gene and replace it with a normal copy. Sangamo Biosciences,
a clinical stage biospharmaceutical company, has already shown that
replacing one specific gene in a person infected with HIV can make
him or her resistant to AIDS.
Both the zinc finger
and TALEN techniques require synthesizing a large new gene encoding a
specific protein for each new site in the DNA that is to be changed.
By contrast, the new technique uses a single protein that requires
only a short RNA molecule to program it for site-specific DNA
recognition, Doudna said.
In the new Science
Express paper, Church compared the new technique, which involves
an enzyme called Cas9, with the TALEN method for inserting a gene
into a mammalian cell and found it five times more efficient.
“It (the Cas9-RNA
complex) is easier to make than TALEN proteins, and it’s smaller,”
making it easier to slip into cells and even to program hundreds of
snips simultaneously, he said. The complex also has lower toxicity in
mammalian cells than other techniques, he added.
“It’s too early to
declare total victory” over TALENs and zinc-fingers, Church said,
“but it looks promising.”
Based on the immune
systems of bacteria
Doudna discovered the
Cas9 enzyme while working on the immune system of bacteria that have
evolved enzymes that cut DNA to defend themselves against viruses.
These bacteria cut up viral DNA and stick pieces of it into their own
DNA, from which they make RNA that binds and inactivates the viruses.
UC Berkeley professor
of earth and planetary science Jill Banfield brought this unusual
viral immune system to Doudna’s attention a few years ago, and
Doudna became intrigued. Her research focuses on how cells use RNA
(ribonucleic acids), which are essentially the working copies that
cells make of the DNA in their genes.
Doudna and her team
worked out the details of how the enzyme-RNA complex cuts DNA: the
Cas9 protein assembles with two short lengths of RNA, and together
the complex binds a very specific area of DNA determined by the RNA
sequence. The scientists then simplified the system to work with only
one piece of RNA and showed in the earlier Science paper
that they could target and snip specific areas of bacterial DNA.
“The beauty of this
compared to any of the other systems that have come along over the
past few decades for doing genome engineering is that it uses a
single enzyme,” Doudna said. “The enzyme doesn’t have to change
for every site that you want to target – you simply have to
reprogram it with a different RNA transcript, which is easy to design
and implement.”
The three new papers
show this bacterial system works beautifully in human cells as well
as in bacteria.
“Out of this
somewhat obscure bacterial immune system comes a technology that has
the potential to really transform the way that we work on and
manipulate mammalian cells and other types of animal and plant
cells,” Doudna said. “This is a poster child for the role of
basic science in making fundamental discoveries that affect human
health.”
Doudna’s coauthors
include Jinek and Alexandra East, Aaron Cheng and Enbo Ma of UC
Berkeley’s Department of Molecular and Cell Biology.
Doudna’s work was
sponsored by the Howard Hughes Medical Institute.
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