SCIENCE sciencemag.org 2 OCTOBER 2020 • VOL 370 ISSUE 6512 21ILLUSTRATION: KATTY HUERTAS
lenging research line, which needed to start
from scratch,” she says.
As a child growing up in Shanghai dur-
ing the Cultural Revolution, Wang would
listen to Mao Zedong’s speeches through a
loudspeaker in kindergarten. “I was think-
ing: ‘My God ... how does his voice trans-
fer from Beijing to Shanghai?’” Electrical
engineering became his passion. But after
getting into the prestigious East China Nor-
mal University, Wang was dismayed when
the faculty assigned him to study biology. “I
thought, ‘I don’t like plants, I don’t like ani-
mals,’” he says. Going to a renowned univer-
sity felt like going to heaven, he says, “but
the wrong door of heaven, basically, because
I went to a biology department.”
Secretly listening to Voice of America,
Wang eventually became so profi-
cient at English that he was chosen
for a scholarship to study abroad. He
did a Ph.D. in molecular biology at
the University of California, Davis,
and later moved to Australia, where
he studied infectious diseases in ani-
mals. His career took a turn when
a new virus emerged in the leafy
Brisbane suburb of Hendra in 1994,
killing 14 horses and a trainer. Wang
managed to sequence the virus, later
named Hendra virus, and helped de-
velop a vaccine for horses. The virus
turned out to be transmitted by bats.
A few years later Wang worked on
another novel virus, Nipah virus, also
from bats. Intrigued, Wang scoured
the literature and found numerous
other viruses linked to bats.
Then came severe acute respira-
tory syndrome (SARS). After the
World Health Organization (WHO)
declared the epidemic over in July
2003, it put together a mission of
eight scientists, including Wang, to
investigate the origins of the virus
in China. Wang had a hunch bats
could be the source, but the rest of
the team was skeptical. At a meet-
ing in Beijing, Wang met the head of
WIV, who suggested he collaborate
with a scientist at her institute: Shi Zhengli,
who was then studying viruses in fish and
shrimp. “She was the only virologist who be-
lieved me and was willing to collaborate with
me,” Wang says.
The two have since co-authored dozens
of papers, including one in Science in 2005
that pinpointed horseshoe bats as a reser-
voir of SARS-like coronaviruses. They also
like to team up in karaoke bars to sing clas-
sic Chinese ballads, says Peter Daszak, a re-
searcher at the EcoHealth Alliance, a New
York City nonprofit, and a longtime collabo-
rator with Wang and Shi. “Linfa is an excel-lent singer and to see him and Shi Zhengli
do a duet is very special.”
Now, Wang hopes to home in on the
origin of SARS-CoV-2—an effort that will
likely require screening thousands of ani-
mals and humans for signs of a prior infec-
tion. The gold standard for doing that is
called a virus neutralization assay, which
combines human cells and live virus with
a blood sample to see whether the sample
contains antibodies that keep the virus
from binding to the cells. But using live vi-
rus means working in a high-level biosafety
lab—expensive and very slow work. An al-
ternative called an enzyme-linked immuno-
sorbent assay (ELISA) is much easier to han-
dle, but a distinct version must be developed
for every animal species. “You need to have awhole panel of ELISAs that are optimized for
different bat species, and raccoon dogs, and
civet cats, and pangolins, and God knows
what,” says Malik Peiris of the University of
Hong Kong. “It’s a never-ending business.”
Wang’s new assay, published in July in
Nature Biotechnology and now produced by
Genscript Biotech, replaces the human cells
and live SARS-CoV-2 virus of the gold stan-
dard assay with human and viral proteins,
eliminating the need for a high-security
lab. The sample is tested on a plate impreg-
nated with angiotensin-converting enzyme
2 (ACE2), the human receptor protein thatSARS-CoV-2 attaches to when it invades cells.
Researchers then add a solution containing
the fragment of the viral spike protein that
can bind to ACE2. If the binding takes place,
an enzyme turns the solution blue and then
yellow. But when a sample contains anti-
bodies against SARS-CoV-2, they prevent
the binding, blocking the colorful reaction.
Wang’s assay works on a variety of species
almost as well as the gold standard, says
Peiris, who has been using it for several
weeks in infected cats, dogs, and hamsters.
“This is an extremely interesting ap-
proach,” says Isabella Eckerle, a virologist
at the Centre for Emerging Viral Diseases
at the University of Geneva. Eckerle and
colleagues validated the test for WHO and
published the result as a preprint in late
September. “Especially for screen-
ing potential plasma donors or
when looking for the animal reser-
voir it should be really useful.”
Wang hopes to use the test to
screen animals and people in South-
east Asia to identify “intermediate
hosts”—species that may have picked
up the virus from bats and transmit-
ted it to people—and learn whether
it crossed over into humans before
the fateful outbreak in Wuhan.
The bigger question that drives his
work is: why bats? Over the past de-
cade he has started to piece together
an evolutionary story as convoluted
as his own path to bats. As the only
flying mammals, bats expand huge
amounts of energy. This eventually
damages their DNA, and Wang con-
tends that they have adapted, in part,
by dampening immune responses to
DNA damage. RNA viruses like SARS-
CoV-2 can cause similar damage, so
the upshot is that bats tolerate low
levels of viruses in a kind of peace-
ful coexistence. “That’s why they are
such a good reservoir,” Wang says.
Koopmans is not yet convinced by
Wang’s immune system argument—
bat ecology may play a greater role,
she says. For instance, bats often
range over wide territories, potentially
picking up a greater variety of viruses than
other animals, and in many bat species mil-
lions of animals roost together, making it
easier for viruses to spread. But she says
that thanks to Wang’s work, there’s no doubt
that bats are key viral reservoirs.
It’s an ironic legacy for a student who
studied biology despite disliking animals. “I
am now fascinated with bats,” he concedes.
But, perhaps appropriately given what he has
learned about emerging infections, he says:
“I am still not an animal fan in the sense of
keeping animals near me.” j“I am now fascinated with bats
[but] I am still not an animal fan.”
Linfa Wang, Duke-NUS Medical School