Science - USA (2021-11-12)

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SCIENCE science.org 12 NOVEMBER 2021 • VOL 374 ISSUE 6569 801

N

ations meeting here at a major cli-

mate summit announced new com-

mitments to cutting greenhouse

gases that would—if realized—put

the world on a path to meeting a key

goal of the 2015 Paris agreement. The

new pledges unveiled last week include re-

vised commitments from India, China, and

11 other nations, and could keep warming to

1.8°C to 1.9°C this century, two new analyses

find. That edges the world closer to the Paris

goal of keeping warming “well below” 2°C.

But the new commitments are “not cause

for unbounded optimism,” cautions Univer-

sity of Melbourne climate scientist Malte

Meinshausen, an author of one of the new

analyses, released on 4 November by analyt-

ics company Climate Resource. Meinshausen

worries countries won’t follow through. “The

world has set its course on roughly the right

horizon, but there’s still a lot of work to do.”

The new warming estimates don’t fall

far below other recent projections, notes

New pledges

could keep

global warming

below 2°C target

But can nations truly realize

ambitious goals and provide

developing countries with

needed financing?

CLIMATE CHANGE

Doudna and her team made the new tool By Cathleen O’Grady, in Glasgow, U.K.

by tweaking lab constructs called viruslike

particles (VLPs), which contain all the virus’

structural proteins but lack its genome. From

the outside, a SARS-CoV-2 VLP looks exactly

like the full-fledged virus. It can bind with

cells in a laboratory and invade them. But be-

cause it is stripped of the virus’ RNA genome,

it can’t hijack a cell’s machinery to replicate

and burst out of the host cell to infect more

cells. “It’s a one-way ticket. It doesn’t spread,”

says Charles Rice, a molecular virologist at

Rockefeller University.

Doudna and her colleagues, including co–

senior author Melanie Ott, a virologist and di-

rector of the Gladstone Institute of Virology,

added a new innovation to the VLP system.

They inserted a snippet of messenger RNA

(mRNA) that causes cells invaded by VLPs

to light up. The brighter cells glow, the more

mRNA the cells have received from the VLPs.

Next, the researchers tweaked the VLP

proteins with mutations. One was R203M,

a mutation found in Delta that alters the

nucleocapsid protein (N), a molecule tucked

inside the virus that plays a key role in viral

replication, including packaging and releas-

ing the virus’ genetic material. R203M con-

tains a mutational hot spot: a seven–amino

acid stretch mutated in most samples of

every SARS-CoV-2 variant of interest or con-

cern. R203M is one mutation in this hot spot.

That work “revealed a surprise,” Doudna

says. “A single amino acid change found in

Delta’s nucleocapsid protein supercharged

the [VLPs] with 10 times more mRNA com-

pared with the original virus!” For VLPs car-

rying N mutations found in the Alpha and

Gamma variants, the figures were 7.5 and

4.2, respectively.

The scientists next tested a real corona-

virus engineered to include the R203M muta-

tion, in appropriate lab biosafety conditions.

After invading lung cells in the lab, the mu-

tated virus produced 51 times more infectious

virus than an original SARS-CoV-2 strain.

In people infected with the coronavirus,

a very small proportion of viral particles

produced by a cell actually go on to infect

another cell, in part because many particles

lack a complete viral genome. So mutations

that make the viral genome more efficient at

putting RNA inside host cells can boost the

number of infectious particles produced.

“This mutation that’s found in Delta ...

makes the virus better at making infectious

particles and because of that, it spreads more

quickly,” says co-first author Abdullah Syed,

a biomedical engineer at the Gladstone Insti-

tute of Data Science and Biotechnology.

The finding has implications for treat-

ments, says Shan Lu, a cell biologist at UC

San Diego who studies the N protein. “The

field could think more about targeting the

nucleocapsid protein to really help control

infection and help treat patients.” For in-

stance, drugs could be targeted to any host

protein found to help Delta’s R203M muta-

tion boost the delivery of mRNA to cells.

Scientists are also excited by the new VLP

system, which will allow researchers with-

out high-level biosafety labs to study how

all four coronavirus structural proteins

work. Jasmine Cubuk, a biochemist and

biophysicist at Washington University in

St. Louis, calls it “a fascinating and a very

powerful tool.”

Rice cautions the new VLPs are a model

system that may not always mimic the real

thing. Researchers will still need to work

with the real virus in advanced biosafety

labs. But he praises the new tool. “It re-

ally provides a wonderful system to study

coronavirus assembly and also to look for

drugs, for inhibitors that interfere with

these processes.” j

A mutation in SARS-CoV-2’s nucleocapsid protein (large coil inside virus particle) may help Delta spread.

India, which relies heavily on coal, is among nations

that have made fresh pledges to cut emissions.