26/10/2017 Gene editing takes another step forward

Biotechnology
Gene editing takes another step forward
It can now edit individual genetic letters

Science and technology Oct 25th 2017

SINCE its discovery in 2012 CRISPR-Cas9, a gene-editing technique, has gone from
strength to strength. This tool, developed from a bacterial defence system that cuts
up the DNA of invading viruses, permits genetic material to be edited easily and
precisely. It has transformed research in biology, and promises to have wide
applications in agriculture and medicine.

But it is not ideal. One of its flaws is that its ability to replace genes works best in
cells that are replicating, and thus have the correct molecular furniture in place to
incorporate the new DNA being delivered. A second is that it starts by breaking the
DNA strands so that new material can be inserted into the gap. That can have
undesirable effects. A third is that it is not particularly good at correcting point
mutations. These are errors which affect only one or two of the bases, known
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26/10/2017 Gene editing takes another step forward

informally as genetic “letters”, in a gene’s DNA sequence. This flaw is especially

problematic because tens of thousands of genetic diseases are results of such point
mutations.

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There may, though, be a way around these

Latest updates
problems, particularly the third one. This is
The first data from a repository of living human
brain cells to alter specific bases without cutting the
SCIENCE AND TECHNOLOGY
DNA strands they are in. A paper published
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namely programmable protein machines
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than Britain thinks called base editors that rearrange the atoms
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of one base so that it becomes another. And
See all updates another paper describes how to achieve a
similar ultimate outcome—a change in the
protein encoded by a gene—but in a way that does not involve DNA directly at all.

Base camp
Base editing was invented last year, by David Liu of Harvard University and his
colleagues. DNA is composed of four sorts of bases, each attached to one of two
molecular backbones that twist together to form the molecule’s famous double
helix. The bases are often referred to as A, C, G and T, the initials of their full
chemical names, adenine, cytosine, guanine and thymine. The shapes of these
molecules mean that a C on one strand of the double helix is always paired with a G
on the opposite strand, and an A with a T. Dr Liu’s base editor combined CRISPR-

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26/10/2017 Gene editing takes another step forward

Cas9 with an enzyme called cytidine deaminase. It also employed a deactivated

version of Cas9, meaning that enzyme binds to, but no longer cuts, DNA. The
resulting molecular construction was able to find specific G-C base pairs in a cell
and convert them to T-A.

One of this week’s papers, published in Nature, describes how to extend the
technique to convert A-T pairs into G-C ones, extending the range of genetic errors
that can be corrected. Creating this second base editor was harder than the first
because an equivalent to the cytidine deaminase used by Dr Liu, which would be
needed to pull it off, does not exist in nature. Instead, one member of the group,
Nicole Gaudelli of Harvard University, set about creating it.

The enzyme needed is an adenine deaminase that works on DNA. Versions of this
enzyme do exist, but they act on RNA, a similar but not identical molecule. Dr
Gaudelli, though, thought she could tweak an RNA-specific version for use on DNA.

To do so, she started with a bacterium called Escherichia coli, which is much beloved
by biologists. The E. coli she used had defective antibiotic-resistance genes.
Crucially, the mutations that had broken these genes could in principle be fixed
with an adenine deaminase that worked on DNA. She therefore created a vast range
of variants of the RNA version of the gene, hoping that some might instead work on
DNA—and manifest that fact by saving bacteria that would otherwise die when they
were exposed to antibiotics.

By picking the most promising variants, mutating them again, and repeating the
process, she eventually arrived at an enzyme that could be attached to CRISPR-Cas9
in order to accomplish the conversion of A-T base pairs into G-C. And it works. The
combined base-editing tools have the desired effect more than half the time. Using
CRISPR-Cas9 alone for such point-mutation work is only 4% effective. Moreover,
CRISPR-Cas9 often creates unwanted insertions or deletions of DNA. Base editing
creates almost none.

Bases for progress

The second paper, published in Science, involves RNA more directly. One of RNA’s
most important jobs in a cell is carrying information from genes in the nucleus to
the protein-making machinery in the cytoplasm, to tell that machinery what to
make. In the paper Feng Zhang, of the Broad Institute, in Cambridge,
Massachusetts, who was one of the pioneers of the CRISPR-Cas9 technique,
describes a base editor made from Cas13, an enzyme that cuts RNA in the way that
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26/10/2017 Gene editing takes another step forward

Cas9 cuts DNA, and a second enzyme that can reverse the effect of G-to-A
mutations.

Though Dr Zhang’s editor works on RNA rather than DNA its effect, at least
temporarily, is the same. By substituting one base for another it changes the
composition—and therefore the activity—of a protein.

Though the papers are different, together they demonstrate a wider point, which is
that the toolkit of genetic engineering is expanding quickly. In particular, variants
of Cas9 are being tested to see if the CRISPR-Cas9 approach can be improved. And
another enzyme, Cpf1, is growing rapidly in popularity as a substitute for Cas9 in
conjunction with CRISPR.

The researchers who have developed base editing even dream of reaching into the
epigenome. This is the system by which some genes are switched off altogether by
a chemical process called methylation. It is part of the mechanism that determines
what type of cell a given cell is.

Until recently, epigenomic editing would have seemed a distant prospect. But the
speed with which new gene-editing techniques are being invented suggests it
would be risky to bet against it happening. For genetic engineering at the moment,
the possibilities seem limitless. 

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