human host, male and female adult schisto-
somes—the focus of the studies by Wang et
al. and Wendt et al.—reside in pairs in the
mesenteric veins around the intestines (see
the micrograph, above) and can evade im-
mune destruction for up to 40 years. During
this time, they lay millions of eggs: Those
that do not escape the body through feces or
urine elicit strong host immune responses
and cause severe pathology when lodged in
host tissue ( 6 ). In the case of Schistosoma
mansoni infections, granulomas form in the
liver, leading to liver failure and death (see
the micrograph, right). Interventions that
eliminate adult worms or block egg produc-
tion are required to prevent transmission
and eliminate pathogenesis.Reducing infection, and pathology, of
schistosomiasis relies on regular targeted
or mass administration of the drug praziqu-
antel (PZ), which was developed 50 years
ago. However, PZ treatment typically leaves
30% of people positive for schistosome eggs,
and the drug is ineffective against juvenile
worms ( 7 ). Worryingly, resistance to PZ is
suspected in the field ( 8 ) and is easily se-
lected for in the laboratory ( 9 ). This makes
the reliance on PZ monotherapy risky, and
new interventions are needed, either to
replace or to use in combination with PZ.
Both Wang et al. and Wendt et al. provide a
plethora of targets and pathways to prime a
pipeline for therapeutic development.
Fortunately, the complete life cycle of
schistosome parasites—particularly S. man-
soni, the focus of both studies—is easily
maintained in the laboratory using rodent
and snail hosts, there is a growing molecu-
lar and cell biological toolkit ( 10 , 11 ), gene
manipulation is possible ( 12 ), and genetic
mapping studies can be conducted ( 13 ).
Genome sequences are available for all
three major species of schistosomes that in-
fect humans and a growing number (>100)
of other parasitic worm genomes, which
facilitates comparative genomic studies to
predict molecules and pathways of inter-
est ( 14 ). Wang et al. and Wendt et al. ex-
ploit genomic information to develop two
powerful approaches to functionally probe
schistosome biology: large-scale RNA inter-
ference (RNAi) screens and single-cell gene
expression atlases, respectively. Not only
do the authors demonstrate the feasibility
of applying these approaches to S. mansoni
but they also conduct extensive functional
analysis to reveal exciting features of para-
site biology.
Wang et al. targeted the expression of
~2320 schistosome genes, of which 195 were
critical for parasite attachment and 66 were
critical for stem cell maintenance. They
also identified a large number of genes that
were essential for adult viability and devel-
opment. Their analysis provides a treasure
trove of possible therapeutic targets for
further investigation and was enriched for
genes in the ubiquitin proteasome system
and muscle development. Many of the es-
sential genes that were identified have or-
thologs that are not essential in model or-
ganisms, suggesting a distinctive biology of
fluke parasites that cannot be inferred from
studies of invertebrate model organisms,
such as the nematode worm Caenorhabditis
elegans or fruit flies (Drosophila melano-
gaster), or even from the free-living flat-
worm Schmidtea mediterranea.
Although the functional RNAi screen
identified a long list of essential genes, Wang
et al. prioritized genes by examining the listfor druggability with existing compounds.
This allowed experimental validation of
proteins involved in the ubiquitin protea-
some system (p97) and muscle development
(TAO and STK25 kinases) as drug targets.
Small-molecule inhibitors with limited
host toxicity were identified from a library
of U.S. Food and Drug Administration–ap-
proved molecules, providing an impetus for
drug development. Encouragingly, treat-
ment with these small molecules resulted
in worm mortality in vivo.
Wendt et al. provide an elaborate picture
of schistosome body structure and develop-
ment through the creation of a single-cell
atlas of schistosome adult parasites. The
resolution is high, with 68 cell populations
mapping to almost all of the known tissues
of the worm, and spatial distributions of
different cell lineages are described using
in situ hybridization methods and electron
microscopy. This descriptive work gener-
ates many tantalizing observations that will
inspire future functional and cell biology
analyses. There are lineages of ciliated neu-ral cells with unknown functions, whereas
other neural markers show left-right asym-
metry in gene expression. In addition to
identifying cells that make up key organs
such as the nervous system and the sexual
organs, the authors follow their fundamen-
tal interest in stem cells and examine the
fate of a newly discovered stem cell lineage
involved in gut formation. Detailed func-
tional analysis reveals a central role for the
hepatocyte nuclear factor 4 (hnf4) gene not
only in gut development but also in feeding
and egg production. This study reveals gut
development as a key point of intervention
that results in a decrease in adult size and
fecundity, eliminating the egg-induced pa-
thology of schistosomiasis.SCIENCE sciencemag.orgPHOTO: J. WANG
ET AL., PLOS BIOLOGY
17
, E3000254 (2019)
Paired male (pink) and female
(green) adult schistosomes live
in the veins surrounding
the intestines. The micrograph
is colored to distinguish
the sexes. Adult worms are
about 1 cm long.10 μmSchistosoma mansoni egg with a characteristic spine
is captured with differential interference contrast
microscopy. Host immune reactions to eggs lodged in
the liver result in pathology in infected people.25 SEPTEMBER 2020 • VOL 369 ISSUE 6511 1563