2019-01-01_Discover

January/February 2019^ DISCOVER^37

FROM TOP: MONICA SCHROEDER/SCIENCE SOURCE; SALK INSTITUTE; HANNAH GRUNWALD

CRISPR’s New Target

The CRISPR field has mainly focused on

editing DNA, but many diseases could be

treated by altering RNA, the molecule

that carries out DNA’s instructions.

Unlike DNA edits, RNA changes

aren’t permanent, so targeting the

messenger molecule might mean

fewer safety risks.

In March in the journal Cell,

researchers at the Salk Institute unveiled

a new CRISPR enzyme that does just that.

Researchers conducted their initial tests in

cells from patients with a particular type

of dementia where proteins called tau

build up to unhealthy levels; the new

CRISPR system successfully rebalanced

tau levels.

Its name, CasRx, hints at its future

in medicine, according to lead

investigator Patrick Hsu. “It’s absolutely

inspired by our vision of its therapeutic

potential,” he says.

at the Karolinska Institute in

Sweden, and a senior author of

one of the studies.

And in July, U.K. geneticists

reported in Nature Biotechnology

that CRISPR sometimes

removed, ipped or swapped

surprisingly large chunks of

DNA at on-target sites. These

large-scale rearrangements could

be an issue if they involve one

of hundreds of potential cancer-

causing genes.

The new indings highlight

possible problems not just when

CRISPR misses its mark, but also

when it hits its target.

Gaétan Burgio, a geneticist at

Australian National University

who was not involved in the

aforementioned studies, is conident

that researchers can overcome the

problem, just as he’s conident there

will be more indings like these to

come. “There are a lot of things

we don’t know about the CRISPR

system,” he says. “So I would expect

more of this in the future.”

Mammalian Gene Drive Stuck in First Gear

So-called gene drives, which use

genetic engineering to preferentially

pass on specific genes to offspring,

can doom a species. Some

controversial proposals have called

for using them on mosquitoes to

eliminate malaria, or to rid islands of

invasive rodents. While CRISPR-based

gene drives have shown promise in

insects, no one had deployed one in

mammals — until now.

In July, researchers announced

the milestone in mice, although the

results scuttled optimism for a quick

pest-control solution. To prove how

this might work one day, a team at

the University of California, San Diego,

attempted to spread a mutation that

would turn the rodents white. But

only females copied over the change,

and sometimes with errors.

“It is much easier in mosquitoes

and flies,” says Australian National

University’s Gaétan Burgio, who

was not involved with the research.

Ultimately, he says, given technical

hurdles and biological differences

specific to mammals, he’s skeptical

a gene drive will work on them in

the wild anytime soon.

CRISPR-Cas9

Once the Cas9 enzyme and guide RNA enter

a cell, the RNA directs Cas9 to a specific

spot on the organism’s genome. There,

the enzyme can cut the targeted

sequence of genes.

Guide RNA

Cas9

Section of guide RNA

that matches genome

Targeted genome

to be cut

CRISPR failed to

turn all of these

pups white.

CasRx (pink) in

human cells (gray)