44 | New Scientist | 16 January 2021
not an exact match for, its target, and Cas9 is
then able to cut such sequences. As a result,
there is a risk that, while being used to treat
a genetic disease, CRISPR-Cas9 could cause
harmful changes elsewhere in a person’s
genome – so-called off-target edits.
Beyond medical uses, the
consequences of uncontrolled gene
editing are equally concerning. In an
application called a gene drive, CRISPR-Cas9
can be used to boost the prevalence of certain
genes in a population by editing them to
increase their chances of being passed on to
the next generation. A gene drive could be
used to great effect: to eradicate a vector-
borne disease such as malaria, for example,
by promoting a gene that makes male
mosquitoes infertile or one that prevents
females from biting. But there is a danger
that such genetically edited organisms
might run amok in the environment
with unintended consequences.Take back control
We clearly need a way to more closely control
CRISPR-Cas9. That is where anti-CRISPR
comes in. CRISPR has been found lurking in
the genomes of half of all sequenced bacteria.
However, some phages have evolved their
own system to fight back.
Their defence consists of small proteins
called anti-CRISPRs (Acrs) encoded in their
genome. When a phage infects a bacterium,
it injects its genetic material and then hijacks
the host’s genetic machinery to make copies
of its own genes. The Acr genes are among
the first to be expressed, which means that
anti-CRISPR can get straight to work to block
the bacteria’s CRISPR response. It uses a
variety of mechanisms, including attaching
directly to the Cas enzyme and preventing
CRISPR-Cas from binding to DNA.
Anti-CRISPR was discovered by accident
in 2012, just as the CRISPR gene-editing
revolution was taking off. Working in
Davidson’s lab, microbiologist Joseph Bondy-
Denomy was surprised to find that phages
infecting a pneumonia-causing bacteriumweren’t being destroyed by the microbe’s
CRISPR system. Looking more closely, he
discovered that the virus had genes capable
of inactivating the bacteria’s defence. At first,
Bondy-Denomy didn’t realise the magnitude
of his discovery. Back then, no one was
thinking about the problem of keeping
CRISPR-Cas9 under control, let alone ways to
do so. Nevertheless, he continued studying
Acrs, finding them in a range of other phages.
For a while, he and his colleagues had the
field to themselves.Evolutionary
arms race
The defence mechanism that bacteria
have evolved in response to the viruses
that infect them is ingenious. Known as
CRISPR, it consists of two elements: a
stretch of DNA that can target viruses the
bacteria has encountered and an enzyme
that then chops up the invaders. This
ability to target and destroy has brought
CRISPR to the attention of researchers
aiming to develop gene editing (see main
story). However, in the natural world,
CRISPR’s power seems to be waning.
Some bacteria-infecting viruses have
evolved a protein-based counter-attack
called anti-CRISPR – and it is almost
always successful.
It is a bit of an evolutionary puzzle why
natural selection keeps CRISPR going
in bacteria that meet resistance from
anti-CRISPR. One possible explanation
is that CRISPR has acquired other useful
functions. For example, it seems to help
some bacteria form biofilms – diverse
communities of microbes that have
many advantages for the survival of
their inhabitants. In addition, some
bacteria use CRISPR to help regulate the
expression of their genes. It may also
have other uses yet to be discovered.
Another reason bacteria maintain
CRISPR is that it is still effective against
viruses with anti-CRISPR in certain
circumstances. The most important
factor appears to be the relative size
of the virus and host populations. The
CRISPR system takes energy to run, but
its big advantage is that it can respond
rapidly. So, when bacteria are under
attack from just a few viruses, CRISPR
can eliminate them before they
proliferate and activate their anti-
CRISPR, saving the microbes from
having to expend too much energy.Never-ending battle
It probably took thousands of years for
bacteria to evolve CRISPR. “It requires
huge genetic innovation,” says Edze
Westra at the University of Exeter, UK,
who studies the evolutionary ecology of
bacterial immunity. Yet, its evolutionary
future is uncertain. All we can be sure
of is that, in the arms race for survival,
bacteria will continue to evolve
innovative defences against viruses and
viruses will evolve ways to fight back.OHSU/KRISTYNA^ WEN
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