You’ve probably heard of the molecular
scalpel CRISPR-Cas9, which can edit or
delete whole genes. Now, scientists have
developed a more precise version of the
DNA-editing tool that can repair smaller
segments of a person’s genome.
In two studies published in October,
one in Nature and another in Science,
researchers from the Broad Institute of
MIT and Harvard describe a new way to
edit DNA and RNA, called base editing.
The approach could one day treat a range
of inherited diseases, some of which currently have no treatment options.
The human genome contains six billion DNA letters, or chemical bases known
as A, C, G, and T. These letters pair o;—A
with T, and C with G—to form DNA’s double helix. Base editing, which uses a modified version of CRISPR, is able to change
a single one of these letters at a time without making breaks to the DNA’s structure.
That’s useful because sometimes just
one base pair in a long strand of DNA
gets swapped, deleted, or inserted—a phenomenon called a point mutation. Point
mutations make up 32,000 of the 50,000
changes in the human genome known to
be associated with diseases.
In the Nature study, researchers led
by David Liu, a Harvard chemistry professor and member of the Broad Institute, were able to change an A into a G.
Such a change would address about half
the 32,000 known point mutations that
To do it, they modified CRISPR so that
it would target just a single base. The edit-
ing tool was able to rearrange the atoms
in an A so that it instead resembled a G,
tricking cells into fixing the other DNA
strand to complete the switch. As a result,
an A-T base pair became a G-C one. The
technique essentially rewrites errors in
the genetic code instead of cutting and
replacing whole chunks of DNA.
“Standard genome-editing methods,
including the use of CRISPR-Cas9, make
double-stranded breaks in DNA, which is
especially useful when the goal is to insert
or delete DNA bases,” Liu told journalists
in October. “But when the goal is to simply
fix a point mutation, base editing o;ers a
more e;cient and cleaner solution.”
Liu said base editing isn’t meant to
replace CRISPR, but it’s another option
for altering the genome in an attempt to
correct disease. If CRISPR is akin to a
pair of scissors, base editing is more like
a pencil, he said.
Previously, researchers had created
base editors capable of making the oppo-
site kind of swap—changing a G into an
A. Substitutions of a G for an A in certain
parts of the DNA represent about 15 per-
cent of disease-associated point muta-
tions. In September, Chinese researchers
reported that they used one of these edit-
ing tools in an embryo to remove the
genetic mutation that causes anemia.
Working in cells taken from patients,
Liu and his colleagues used their base-editing tool to correct a point mutation
that causes hereditary hemochromatosis,
a disorder that causes the body to absorb
too much iron from food. This excess iron
can build up over time and cause liver
cancer and other liver diseases, diabetes,
heart disease, or joint disease.
Liu and his team also used the base
editor in human cells to induce a mutation that suppresses sickle-cell anemia.
In both studies, they detected virtually no
o;-target e;ects, or unwanted DNA insertions or deletions, which are a concern
with the traditional way of using CRISPR
to edit entire genes.
In the Science study, Feng Zhang, of
the Broad Institute and MIT, used a similar base-editing method to target individual letters in RNA, DNA’s chemical
cousin. RNA naturally degrades in the
body, so editing RNA wouldn’t result in a
permanent change to a person’s genome.
Ross Wilson, of the Innovative
Genomics Institute at the University of
California, Berkeley, says base editing may
eventually be a better way to treat some
diseases. He says a single base pair is like
a word in a paragraph of text. With conventional CRISPR technology, you would
have to replace the whole paragraph.
“It’s a lot of DNA to move around,”
he says. With base editing, you could just
change the single word.
Liu says he’s hopeful that base editing
of DNA and RNA could be used as com-
plimentary approaches for a “broad set of
potential therapeutic applications.”
His lab is exploring base editing to fix
blood disorders, neurological disorders,
hereditary deafness, and hereditary blind-
ness. —Emily Mullin
CRISPR 2.0 Is Here, and It’s Way
It could one day be used to treat a range of inherited diseases.