20 2 OCTOBER 2020 • VOL 370 ISSUE 6512 sciencemag.org SCIENCE
cells,” says Kathy Niakan, a developmental
biologist at the Francis Crick Institute, whose
team reported key molecular signals for that
initial step in Nature last week. These cells
go on to form the trophoblast, a multilayered
ring that surrounds the embryo and helps it
implant into the wall of the uterus. Some of
these cells, TSCs, then give rise to cell types
that will make up the bulk of the placenta,
which enables mother and fetus to exchange
nutrients and gases and helps protect the fe-
tus from the mother’s immune system.
Scientists have derived TSC-like cells
from unused embryos created for in vitro
fertilization (IVF) or from the placentas of
terminated pregnancies, but both are lim-
ited resources. And in a dish, these cells
have tended to mature and stop dividing.
The same has been true of TSC-like cells
created from cultured embryonic stem (ES)
cells and from induced plurip-
otent stem (iPS) cells—mature
cells reprogrammed to an ES-
like state.
But in 2017, Tohoku Univer-
sity stem cell biologist Takahiro
Arima and colleagues described
a broth of nutrients and other
compounds that could make
TSCs from IVF embryos or
first trimester placentas thrive in a dish.
“An enormous amount of work that was
never possible before became possible,” says
William Pastor, a stem cell biologist at McGill
University. This year, Pastor’s group and two
others showed this culture medium could
also coax certain types of ES cells to become
self-renewing TSCs.
To make TSCs that genetically match a pa-
tient, however, researchers want to be able to
start from mature skin or blood cells. In the
two new studies, teams led by stem cell bio-
logists Jose Polo at Monash University and
Laurent David at the University of Nantes
found ways to convert adult skin cells into
“induced” TSCs. Both teams had been study-
ing how gene expression changes as mature
cells are reprogrammed into iPS cells. They
noticed that along the way, some expressed
genetic signatures of so-called trophecto-
derm cells, which give rise to the trophoblast.
“That was very weird,” Polo says, because a
cell’s decision to become trophectoderm hap-
pens so early in development—not anywhere
along the expected path backward from skin
cell to iPS cell. But by culturing the cells in
the newly available medium, the researchers
managed to push them to become TSCs.
In a 16 September Nature paper, Polo’s
team reported that these induced TSCs
could develop into two major types of tro-
phoblast cells and, like the cells surround-
ing an embryo, secrete human chorionic
gonadotropin, a hormone whose signals
are key to maintaining a pregnancy. David,
a co-author on that paper, separately used
gene expression data from human embryos
to estimate that his own group’s lab-derived
TSCs are equivalent to those seen 8 to
10 days after fertilization, the team reported
on 15 September in a preprint on bioRxiv.
It will be important to thoroughly compare
these induced TSCs to placenta-derived and
ES cell–derived TSCs, says Washington Uni-
versity in St. Louis stem cell biologist Thorold
Theunissen, whose team recently derived
TSCs from ES cells. That analysis should in-
clude comparing the chemical tags on DNA
that influence cell function and sizing up
how efficiently the cells differentiate into dif-
ferent types of specialized trophoblast cells.
Induced TSCs could now be used to study
genetic defects that can end a pregnancy, says
Soumen Paul, a stem cell biologist at the Uni-
versity of Kansas Medical Cen-
ter. By making TSCs from cells
from women with infertility
and watching them develop in
the lab, researchers could pin-
point how abnormal tropho-
blast cells prevent the embryo
from implanting in the uterus
or from developing normally
once implanted.
Or TSCs could help root out causes of
preeclampsia, in which a pregnant woman
suddenly develops high blood pressure that
sometimes can be relieved only by inducing
an early delivery. Preeclampsia is thought to
stem from a defect of the placenta, perhaps
in the way it invades the uterine wall and
interacts with the mother’s blood vessels,
Pastor says. Researchers should now be able
to make TSCs from umbilical cord blood or
from a baby’s blood or skin cells to observe
how placental precursor cells emerge and in-
teract with uterine cells.
The new TSCs could also add realism
to synthetic embryo models—stem cell–
derived structures that mimic early hu-
man development in a lab dish. So far, they
haven’t included trophoblast or other such
“extra-embryonic” cells, says Jianping Fu, a
bioengineer developing such models at the
University of Michigan, Ann Arbor. But sig-
nals from these cells are critical to normal
embryo growth, he says. Adding them would
take the models “to the next level.”
Better approximations of real embryos
will raise ethical concerns. The U.S. Na-
tional Institutes of Health has not released
formal guidelines, but Fu says the agency
discouraged him from including tropho-
blast tissue in a recent grant application.
But he thinks such experiments should pro-
ceed. “When you mix the cells together, al-
lowing them to self-organize ... they will do
amazing things.” j“It’s like
gaining a toehold
on Mars.”
Susan Fisher,
University of California,
San FranciscoB
y pure chance, Linfa Wang, one of the
world’s foremost experts on emerg-
ing viruses, was in the Chinese city
of Wuhan in January. The biologist
was visiting collaborators at the Wu-
han Institute of Virology (WIV) just
as SARS-CoV-2 was starting to spread from
the city to the rest of the world. Even among
those experts there was little fear then. “I was
mixing with all the lab people,” Wang says.
“We would go to a restaurant every night.”
Only when he left on 18 January did he
realize how serious the situation was. At the
airport, staff checked his temperature three
times before he could board his flight home
to Singapore. Five days later, Wuhan, a city
of 11 million people, was shut down. Wang
later learned that a woman on his plane had
carried the virus; luckily, he was not infected.
Wang, who heads the Emerging Infec-
tious Diseases Program at Duke-NUS Medi-
cal School in Singapore , immediately got to
work developing a new assay that can detect
antibodies against SARS-CoV-2 in blood
samples—an indication of prior infection.
The tool could help untangle how the pan-
demic began. So far, the evidence is that the
virus originated in bats, animals Wang has
long argued are uniquely suited to harboring
viruses that pose a danger to humans. Now,
he hopes his assay can help trace the path of
the virus to humans and pinpoint when and
where it first spilled over.
The work is a natural next chapter for
Wang, who has been tracking viruses from
bats to humans for more than 2 decades.
Marion Koopmans, a virologist at Erasmus
Medical Center, credits him for essentially
launching the field of bat immunology and
developing the tools to pursue it. “He has
made a heroic effort to establish a very chal-The ‘bat man’
tackles
COVID-
After a career investigating
why so many viruses
come from bats, Linfa Wang
eyes a new challenge
VOICES OF THE PANDEMICBy Kai KupferschmidtScience’s COVID-19 reporting is supported by the
Pulitzer Center and the Heising-Simons Foundation.NEWS | IN DEPTH