1337-B 10 DECEMBER 2021 • VOL 374 ISSUE 6573 science.org SCIENCE
RESEARCH
CANCER
Progress with
oncolytic viruses
Oncolytic virotherapy was first
thought to work by viruses
selectively infecting and then
lysing tumor cells. These viruses
can be engineered to selectively
target tumor cells and also to
deliver various types of pay-
loads to improve their efficacy.
However, after much clinical
testing, it has become clear that
oncolytic viruses are a form of
immunotherapy whereby viral
infection drives an antiviral and
antitumor immune response.
In a Perspective, Melcher et al.
discuss the current challenges
of developing effective oncolytic
virotherapy that can induce an
antitumor response, often in
combination with other immu-
notherapeutics. Although some
encouraging phase 1 trials have
recently been reported, there
have been disappointments
in converting early promise to
long-term uptake and approval,
highlighting the need to incorpo-
rate tumor immunology analyses
in clinical trials and to consider
how combination trials can be
improved. —GKA
Science, abk3436, this issue p. 1325
IMMUNOLOGY
Atypical T cells take
a different path
Conventional T cells recognize
peptides that are presented by
polymorphic major histocom-
patibility complexes (MHCs). By
contrast, many tissue-resident
T cells, such as mucosal-associ-
ated invariant T cells, invariant
natural killer T cells, and gd
T cells, respond to modified
peptides and small molecules
presented by conserved MHC-
like molecules. Unconventional
T cells are important for host
defense and tissue repair and
seed tissues during critical
early-life windows of develop-
ment. Constantinides and
Belkaid review recent advances
describing how unconventional
T cell subsets compete for early-
life signals, including those from
the microbiota, which instruct
their development and have
enduring consequences for the
health of the host. —STS
Science, abf0095, this issue p. 1338CELL BIOLOGY
ESCRTing lenses away
from senescence
ESCRT proteins control
membrane fusion in various
key cellular processes, but
the mechanisms involved are
still incompletely understood.
Gulluni et al. report that ESCRT
recruitment at the cytokinetic
bridge is mediated by the bind-
ing of an ESCRT-II subunit to the
signaling lipid phosphatidylino-
sitol 3,4-bisphosphate (see the
Perspective by Brill and Wilde).
This pathway acts in parallel to
a known cascade driven by a
protein called ALIX, but its failure
is sufficient to lead to premature
senescence in the lens of fish,
mouse, and human eyes, where
ALIX is expressed at lower levels.
These results point to an evolu-
tionarily conserved pathway for
the cell-specific control of cyto-
kinesis that serves to protect
from senescence and the early
onset of cataracts. —SMH
Science, abk0410, this issue p. 1339;
see also abm7949, p. 1318STRUCTURE PREDICTION
Deep learning for
protein interactions
The use of deep learning has
revolutionized the field of protein
modeling. Humphreys et al.
combined this approach with
proteome-wide, coevolution-
guided protein interaction
identification to conduct a
large-scale screen of protein-
protein interactions in yeast
(see the Perspective by Pereira
and Schwede). The authors
generated predicted interac-
tions and accurate structures forcomplexes spanning key biologi-
cal processes in Saccharomyces
cerevisiae. The complexes
include larger protein assemblies
such as trimers, tetramers, and
pentamers and provide insights
into biological function. —VV
Science, abm4805, this issue p. 1340;
see also abm8295, p. 1319CELL BIOLOGY
Mechanosensitive
nuclear pores
The nucleus of eukaryotic cells
is enclosed by the nuclear
envelope, a double membrane
punctuated with nuclear pore
complexes (NPCs). These giant
channels in the nuclear envelope
mediate nucleocytoplasmic
exchange. Zimmerli et al. show
that the mechanical status of
the nuclear membranes controls
their nuclear pore diameter.
Pulling forces imposed through
nuclear membranes lead to
stretching of NPCs and dila-
tion of their diameter, whereas
relief of such forces causes NPC
constriction. Thus, the control
of nuclear size and shape is
functionally linked with NPC
conformation and nucleocy-
toplasmic transport activity.
—SMH
Science, abd9776, this issue p. 1341NEURODEVELOPMENT
Surveying brain
interneuron development
As transient structures in early
brain development, the gangli-
onic eminences generate dozens
of different types of interneu-
rons that go on to migrate
throughout and weave together
the developing brain. Shi et al.
analyzed human fetal ganglionic
eminences. Single-cell transcrip-
tomics revealed unexpected
diversity in the types of progeni-
tor cells involved. The human
ganglionic eminence depends
more heavily on intermediate
progenitor cells as workhorses
than does the developingneocortex, with its greater reli-
ance on radial glial cells. —PJH
Science, abj6641, this issue p. 1342CORONAVIRUS
Delta’s spike
Understanding the molecular
mechanisms of the increased
transmissibility and immune
evasion of severe acute respira-
tory syndrome coronavirus 2
(SARS-CoV-2) variants is critical
to guiding current and future
intervention strategies. Zhang
et al. determined cryo–elec-
tron microscopy structures of
the full-length spike protein
trimers of the Delta, Kappa, and
Gamma variants of SARS-CoV-2
and studied their function and
antigenic properties. The Delta
spike protein fused membranes
more efficiently at low levels of
the cellular receptor ACE2, and
its pseudotyped viruses infected
target cells substantially more
rapidly than all other variants
tested, possibly at least partly
accounting for its heightened
transmissibility. Mutations of
each variant rearranged the anti-
genic surface of the N-terminal
domain of the spike protein but
only caused local changes in
the receptor-binding domain,
consistent with greater resis-
tance to neutralizing antibodies.
These findings elucidate the
molecular events that have led
these viruses to adapt in human
communities and to evade host
immunity. —VV
Science, abl9463, this issue p. 1353CATA LYS I S
Rational design
of stable nanocatalysts
Sintering of nanoparticles is
one of the main causes of their
catalytic deactivation. Rational
design of nanocatalysts that
are stable against sintering is
a grand challenge in heteroge-
neous catalysis. Hu et al. present
kinetic theories for two com-
peting sintering mechanisms,
Ostwald ripening and particleEdited by Michael FunkALSO IN SCIENCE JOURNALS