16 January 2021 | New Scientist | 43Taming CRISPR
The powerful gene-editing technique will transform medicine –
if we can control it. Now we may have a way, finds Gege Li
T
HERE is a technology that could tackle
some of life’s most pressing problems,
from disease to malnutrition. It could
fix medical conditions such as cystic fibrosis
and sickle cell anaemia simply by changing a
bit of genetic code. It could eliminate malaria
by making male mosquitoes infertile, or wipe
out pests that destroy crops. And it could
modify other organisms to increase their
usefulness, helping to create foods that are
tastier and more nutritious.
This is the promise of CRISPR, a
biochemical tool at the forefront of a gene-
editing revolution. Produced naturally by
bacteria, CRISPR has gained rock-star status
among scientists in the decade since its
extraordinary potential was first recognised,
and it is already starting to live up to the
promise. But behind all the excitement
lurk some dark questions. What if the editing
goes wrong? What if it has undesired effects?
What if we can’t stop it? Without a means
to keep CRISPR on target and halt it in its
tracks when needed, gene editing could
have disastrous consequences – both for
human health and for the planet.
What we need is an off-switch, one that can
be used at will. Researchers around the world
have spent years trying to find one, largely by
investigating various biochemical solutions.
However, it turns out that the answer may
be right under our noses. In an evolutionary
face-off between CRISPR-producing bacteria
and the viruses that infect them, nature
has already designed anti-CRISPR. The
challenge now is to harness this evolved
off-switch to our own ends and usher in
the golden age that gene editing promises.
Viruses, such as the one that causes
covid-19, don’t just pose a threat to humans –
they attack all living organisms, including
bacteria. In the ancient bacteria-virus rivalry,
CRISPR is one of the weapons bacteria have
evolved to combat bacteriophages, the
name given to viruses that infect them
(see “Evolutionary arms race”, page 44).
CRISPR forms part of many bacterial
genomes. It is made up of repeating DNA
sequences interspersed with fragments of
genetic code left behind by phages from past
viral attacks. When a phage invades again, the
bacterium makes RNA copies of these CRISPR
regions. These bits of genetic material then
hook up with a particular protein, an enzyme
called Cas. They latch on to matching
sequences in the invading virus’s genome,
and the accompanying Cas protein snips
the viral DNA strand, destroying the phage.
In effect, CRISPR works as a sort of genetic
memory of past viral attacks that confers
immunity against future ones.Elegant editing
Given the system’s simplicity and elegance,
it is perhaps unsurprising that researchers
eventually spotted CRISPR’s potential as a
gene-editing tool. The discovery won a Nobel
prize in 2020 for biochemist Jennifer Doudna
at the University of California, Berkeley, and
Emmanuelle Charpentier, now director of the
Max Planck Unit for the Science of Pathogens
in Germany. In research published in 2012,
they presented a CRISPR system thatcontained genetic sequences of their
choice, rather than ones from phages,
along with a Cas enzyme called Cas9. With
this tool, biologists can home in on a specific
DNA sequence and make a cut at a precise
location. This allows them to disable a target
gene or excise a faulty one and replace it
with a working version.
CRISPR-Cas9 has since been used
successfully many times to genetically edit
cells in the lab. But for it to be an effective
medical therapy, it must be delivered directly
to cells in the human body either physically,
such as by injection, or with a vector, usually
an engineered virus that encodes the desired
genes. In 2020, a team in the US achieved this
for the first time, injecting CRISPR into the
eyes of someone with an inherited form
of blindness caused by a single mutation.
Precisely targeting other parts of the body
is harder, however. The issue is how to get
CRISPR only to the cells of interest, while
also ensuring that enough editing takes
place in them to see the changes you want.
With vectors “there is no ‘magic bullet’ – it’s
a bit of a shotgun approach”, says molecular
biologist Erik Sontheimer at the University
of Massachusetts Medical School. This is
where concern begins to creep in.
Many scientists worry about the
consequences if gene editing is left
unchecked. “Expression of Cas9 in the
wrong place, or for too long, is going to
be very dangerous,” says microbiologist
Alan Davidson at the University of Toronto,
Canada. The main problem is that CRISPR can
zero in on sequences that are similar to, but >