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Activated immune cells may contribute to high blood BIOLOGY
pressure and offer a target for treatment.
are present,” Genome editor gets more
more traditional risk factors
Drummond says. These factors, which can
include a high-salt diet, stress, and a natu- versatile and precise
rally overactive sympathetic branch of the
nervous system, spur an initial increase in Modifying enzyme used by CRISPR brings four times more
blood pressure that damages blood vessels.
Immune cells detect that damage, and their DNA within reach of its molecular scissors
response sparks “a vicious circle that leads to
the progressive elevation of blood pressure,”
Schiffrin says. By Jon Cohen human genome has the right sequence.
Among other effects, immune cells disrupt “That’s been a real limitation,” Liu says.
the function of the endothelial layer, the lin- ou wouldn’t know it from the excite- The new work, reported online in the 28
ing of the blood vessels, counteracting “all ment generated by the revolutionary February issue of Nature, modifies the Cas9
the good things that the endothelial cells genome editing method known as enzyme, creating at least four times as many
produce,” says physiologist Brett Mitchell of CRISPR, but as practiced now, it is potential docking sites. In theory, this could
Texas A&M College of Medicine in College far from perfect. Its standard com- allow researchers to, say, cripple or replace
Station. For example, those cells normally Y ponents can find and cut DNA in many parts of genes associated with human
emit nitric oxide, which relaxes blood vessels only a limited fraction of the genome, and disease that CRISPR currently cannot touch.
and reduces blood pressure—and immune its molecular scissors are wobbly, leading Liu’s lab began by engineering a large va-
cells inhibit nitric oxide production. The cells to “off-target” mutations. Many groups are riety of slightly altered spCas9s. The group
also wreak havoc in the kidneys, stimulating trying to do better, and now, a team led by then selected for ones that could use a Downloaded from
the organs to hold on to more sodium, which chemist David Liu at Harvard University broader range of the 64 possible, three-base
in turn spurs the body to retain more water. has engineered a version of CRISPR that landing pads—technically referred to as pro-
“The question of the decade,” Harrison potentially is both more dexterous and tospacer adjacent motifs, or PAMs. They’ve
says, has been what switches on the immune more precise. dubbed their new enzymes xCas9s, and the
cells. His team thinks it has isolated one sig- best one works with NGN, a sequence that
nal: oxidized lipids known as isoketals that occurs in one-fourth of the genome.
form inside blood cells. In 2014, he and his Liu expected that in return for gaining the
colleagues discovered that these molecules ability to latch onto more places, xCas9 would http://science.sciencemag.org/
are unusually abundant in certain immune pay a penalty: more of the potentially dan-
cells of mice with high blood pressure—and gerous off-target cuts that concern research-
that the same is true in patients with hyper- ers hoping to unleash CRISPR in medicine.
tension. Isoketals adhere to and damage pro- After all, conventional thinking holds that
teins, and Harrison’s group found that the Cas9, naturally part of a bacterial immune
resulting injured proteins stimulate immune strategy, evolved to be as promiscuous in its
cells known as dendritic cells, which in turn DNA binding as it could be without compro-
activate T cells. It’s “a pretty good case,” says mising specificity. “PAM binding is supposed on March 1, 2018
nephrologist Richard Johnson of the Univer- The genome editor CRISPR cuts DNA with help to be the gatekeeper, and if your gatekeeper
sity of Colorado Anschutz Medical Campus from a guide RNA (green and red) and a Cas9 is drunk and lets lots of Cas9 into the dance,
in Aurora. enzyme (outline) that latches onto a three-base that should screw up the targeting,” Liu ex-
Harrison’s potential blood pressure treat- sequence (yellow). plains. But the opposite happened. “If you
ment, 2-HOBA, thwarts isoketals by muz- ask me for a detailed mechanistic explana-
zling their reactive ends. That probably won’t “This is very impressive and impor- tion for why that is, my answer is, ‘I don’t
impair our defenses against pathogens. But tant work,” says CRISPR pioneer Erik know,’” he says.
researchers are divided over whether to test Sontheimer of the University of Massachu- Stanley Qi, a CRISPR researcher at Stan-
the more powerful immune-suppressing setts Medical School in Worcester. ford University in Palo Alto, California, says
drugs that patients take for illnesses such as CRISPR comes in many flavors, but they this win-win situation is “amazing,” and
psoriasis, Crohn disease, and rheumatoid ar- all depend on a guide molecule composed should excite many labs. “The real test here
IMAGE: KC ROEYER/UNIVERSITY OF CALIFORNIA, BERKELEY to produce fatal symptoms get blood pres- the genome. This complex, however, homes this out for our applications.” to
of RNA to carry a DNA-cutting enzyme—
thritis. Schiffrin argues that these drugs are
is if people rush to use this xCas9 while for-
original
about
the most commonly used one is known by
getting
the
version,”
Qi says.
too risky to use in hypertension, which peo-
the shorthand Cas9—to a specific stretch of
“At least in my lab, we are very eager to try
ple can live with for decades. “We don’t want
in
a patient …
in on DNA landing pads that have specific
Liu cautions that the standard Cas9 has
because we were playing around with their
immune system.”
molecular features. The enzyme in the stan-
proved itself over the years; his lab has only
on a few dozen sites
Drummond, however,
xCas9
says such drugs
the
tested
dard CRISPR toolkit, called spCas9 for its
new
in the
so
could serve
natural source, the bacterium Streptococcus
genome
as short-term treatments for
far, compared with the
people who don’t respond to other therapies.
thousands the
on
only land
original has been shown
pyogenes, can
seg-
genome
important that
“It is so
we
hit. “I’m not 100% sure xCas9 is going to be
ments that have at one end a specific three-
sure under control,” he
strong justification” for a clinical trial to test
bases, followed by two guanines (Gs). Only
I
want to know
everyone
to test it because
about one-sixteenth of the 3.2-billion-base
the answer.” j
some of these drugs. j
2 MARCH 2018 • VOL 359 ISSUE 6379 967
SCIENCE sciencemag.org says, that “there is base trio: N, where N is any of DNA’s four flat out better than spCas9,” Liu says. “I want
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