997-B 28 FEBRUARY 2020 • VOL 367 ISSUE 6481 sciencemag.org SCIENCE
RESEARCH
CANCER
Improving the drug
development pipeline
Artificial intelligence (AI) appli-
cations are being developed to
improve cancer drug discovery
and administration. Moreover,
AI can improve clinical trial
design and therapeutic dos-
ing strategies such as adaptive
therapy, whereby patients are
treated according to tumor
response to avoid resistance.
In a Perspective, Ho discusses
how AI applications can improve
cancer drug development and
the challenges to be overcome.
—GKA
Science, this issue p. 982
CLINICAL TRIALS
CRISPR takes first
steps in humans
CRISPR-Cas9 is a revolution-
ary gene-editing technology
that offers the potential to treat
diseases such as cancer, but the
effects of CRISPR in patients are
currently unknown. Stadtmauer
et al. report a phase 1 clinical trial
to assess the safety and feasibil-
ity of CRISPR-Cas9 gene editing
in three patients with advanced
cancer (see the Perspective by
Hamilton and Doudna). They
removed immune cells called T
lymphocytes from patients and
used CRISPR-Cas9 to disrupt
three genes (TRAC, TRBC,
and PDCD1) with the goal of
improving antitumor immunity.
A cancer-targeting transgene,
NY-ESO-1, was also introduced
to recognize tumors. The engi-
neered cells were administered
to patients and were well toler-
ated, with durable engraftment
observed for the study duration.
These encouraging observations
pave the way for future trials to
study CRISPR-engineered can-
cer immunotherapies. —PNK
Science, this issue p. 1001;
see also p. 976
MICROBIOTA
Mouse mothers transfer
metabolic mode
Obesity and metabolic dis-
eases tend to go together, and
humans who become obese are
also prone to type 2 diabetes
and cardiovascular problems.
Starting with the observation
that offspring of germ-free
mice tended to become obese
on high-fat diets, Kimura et al.
investigated how the presence of
the microbiota might be protec-
tive in mice (see the Perspective
by Ferguson). Short-chain fatty
acids (SCFAs) from the micro-
biota are known to suppress
insulin signaling and reduce fat
deposition in adipocytes. Further
experiments showed that SCFAs
in the bloodstream were able
to pass from a non–germ-free
mother’s gut microbiota across
the placenta and into the devel-
oping embryos. The authors
found that in the embryos, the
SCFA propionate mediates
not only insulin levels through
GPR43 signaling but also
sympathetic nervous system
development through GPR41
signaling. A high-fiber diet
promoted propionate production
from the maternal microbiota,
and maternal antibiotic treat-
ment resulted in obese-prone
offspring. —CA
Science, this issue p. 1002;
see also p. 978IMMUNOLOGY
Hefty structures of IgA
and IgM complexes
Immunoglobulin M (IgM) and
IgA are antibody isotypes that
can form higher-order secre-
tory complexes (sIgM and sIgA),
which allows them to effectively
bind and neutralize antigens with
low-affinity repetitive epitopes,
such as those found on the
surface of many bacteria and
viruses. The assembly and trans-
port of these molecules is also
dependent on the joining chain
(J-chain) and the polymericimmunoglobulin receptor
(pIgR) secretory component
(SC). The architecture of these
complex, multimeric structures
has remained elusive. Li et al.
resolved cryo–electron micros-
copy structures of the sIgM-Fc
pentamer in complex with the
J-chain and SC. Using similar
techniques, Kumar et al. visual-
ized dimeric, tetrameric, and
pentameric structures of secre-
tory sIgA-Fc interacting with the
J-chain and SC. Both groups
report highly similar mecha-
nisms wherein the J-chain serves
as a template for antibody oligo-
merization. An unanticipated,
amyloid-like assembly of the
oligomerized structure is present
in both cases, with the J-chain
conferring asymmetry for pIgR
binding and transcytosis. These
studies may inform structure-
based engineering of these
molecules for future therapeutic
purposes. —STS
Science, this issue p. 1014, p. 1008BATTERIES
Metastable pathways
allow high rates
In batteries that allow for fast
charging and discharging,
lithium usually forms a solid
solution with the anode so that
the only limiting factor is the
ionic diffusion. However, for a
lithium titanate (Li 4 Ti 5 O 12 ) anode,
the lithium ions interact with
two phases and the diffusion is
slow in both, but it still shows
high-rate capabilities. Zhang et
al. used electron energy-loss
spectroscopy combined with
density functional theory calcu-
lations to probe the anomalous
behavior. They found that a dif-
fuse interface forms between the
starting and ending composi-
tions, Li 4 Ti 5 O 12 and Li 7 Ti 5 O 12 , and
this is what allows the lithium
ions to travel quickly. —MSL
Science, this issue p. 1030CELL BIOLOGY
Polymerization regulates
hexokinase activity
The yeast hexokinase Glk1 is
an actin-fold protein that forms
polymers in response to binding
its substrates and products.
Stoddard et al. now show that
Glk1 polymers are structurally
distinct from actin filaments
and suggest that polymerization
of Glk1 evolved independently
of the polymerization of other
actin-like polymers. Glk1 polym-
erization inhibits its hexokinase
activity, and the monomer-
polymer equilibrium appears
to set a maximum rate for the
entire enzyme pool rather than
a maximum rate per enzyme.
This inhibition was found to be
important for cell viability in the
context of nutrient shifts, allow-
ing yeast cells to modulate their
metabolism rapidly in response
to stochastic changes in the
environment. —SMH
Science, this issue p. 1039PRENATAL THERAPIES
When treating at birth
is too late
Mucopolysaccharidosis type
VII (MPS7) is a rare and severe
lysosomal storage disorder that
causes dysfunction of multiple
organs, including the brain. By
the time of birth, the organ dam-
age may already be severe and
the fetus may not survive. Thus,
the prenatal period provides
the most promising opportu-
nity for intervention. Nguyen
et al. assessed two prenatal
approaches—in utero enzyme
replacement therapy and in
utero hematopoietic stem cell
transplantation—and demon-
strated the potential of these
treatments to improve survival
and functional outcomes in a
mouse model of MPS7. —YN
Sci. Transl. Med. 12 , eaay8980 (2020).Edited by Michael FunkALSO IN SCIENCE JOURNALS
Published by AAAS