243-B 18 JANUARY 2019 • VOL 363 ISSUE 6424 sciencemag.org SCIENCE
RESEARCH
ORGANIC CHEMISTRY
Synthetic innovation in
drug development
Chemical synthesis plays a key
role in pharmaceu tical research
and development. Campos et al.
review some of the advantages
that have come from recent
innovations in synthetic meth-
ods. In particular, they highlight
small-molecule catalysts stimu-
lated by visible light, enzymes
engineered for versatility beyond
their intrinsic function, and
bio-orthogonal reactions to
selectively modify proteins for
conjugation. High-throughput
techniques are also poised to
accelerate methods optimiza-
tion from small-scale discovery
to large-scale production, and
complementary machine-learn-
ing approaches are just coming
into focus. —JSY
Science, this issue p. 244
IMAGING TECHNIQUES
Combining expansion and
the lattice light sheet
Optical and electron micros-
copy have made tremendous
inroads into understanding the
complexity of the brain. Gao
et al. introduce an approach
for high-resolution tracing of
neurons, their subassemblies,
and their molecular constituents
over large volumes. They applied
their method, which combines
expansion microscopy and
lattice light-sheet microscopy,
to the mouse cortical column
and the entire Drosophila brain.
The approach can be performed
at speeds that should enable
high-throughput comparative
studies of neural development,
circuit stereotypy, and structural
correlations to neural activity or
behavior. —SMH
Science, this issue p. 245
GENE THERAPY
CRISPRa corrects
haploinsufficient obesity
Loss-of-function mutation in one
gene copy, termed haploinsuf-
ficiency, can lead to insufficient
protein levels and result in
human disease. Matharu et al.
tested whether a CRISPR-based
activation system (CRISPRa)
could rescue a haploinsufficient
phenotype by increasing the
gene expression levels of the
existing normal copy (see the
Perspective by Montefiori and
Nobrega). By delivering this
system into the mouse hypothal-
amus using adeno-associated
virus, they rescued the obesity
phenotype caused by haploin-
sufficiency of either of two genes
known to promote obesity when
mutated in mice and humans.
These results highlight the trans-
lational potential of the CRISPR
activation system to treat haplo-
insufficient disease. —BAP
Science, this issue p. 246;
see also p. 231ASYMMETRIC CATALYSIS
Predicting catalyst
selectivity
Asymmetric catalysis is widely
used in chemical research and
manufacturing to access just one
of two possible mirror-image
products. Nonetheless, the
process of tuning catalyst
structure to optimize selectivity
is still largely empirical. Zahrt et
al. present a framework for more
efficient, predictive optimiza-
tion. As a proof of principle, they
focused on a known coupling
reaction of imines and thiols cata-
lyzed by chiral phosphoric acid
compounds. By modeling mul-
tiple conformations of more than
800 prospective catalysts, and
then training machine-learning
algorithms on a subset of experi-
mental results, they achieved
highly accurate predictions of
enantioselectivities. —JSY
Science, this issue p. 247NEUROSCIENCE
The cerebellum and
reward-driven behavior
Damage to the cerebellum mani-
fests itself in various forms of
cognitive impairment and abnor-
mal social behavior. However, the
exact role the cerebellum plays
in these conditions is far from
clear. Working in mice, Carta et
al. found direct projections from
the deep cerebellar nuclei to the
brain’s reward center, a region
called the ventral tegmental area
(see the Perspective by D’Angelo).
These direct projections allowed
the cerebellum to play a role
in showing a social preference.
Intriguingly, this pathway was not
prosocial on its own. Cerebellar
inputs into the ventral tegmental
area were more active during
social exploration. Depolarization
of ventral tegmental area neurons
thus represents a similar reward
stimulus as social interaction for
mice. —PRS
Science, this issue p. 248;
see also p. 229INORGANIC CHEMISTRY
Orange-glowing iron at
room temperature
Many photoactive coordination
compounds contain precious
metals. Replacing ruthenium
with more–earth-abundant iron
has been a long-sought goal, but
iron compounds generally relax
too rapidly after light absorption
to channel the energy produc-
tively. Kjær et al. prepared an
iron compound with an excited
state stable enough to emit light
for nanoseconds, or that could
engage in bimolecular electron
transfer (see the Perspective by
Young and Oldacre). Targeting
a ligand-to-metal rather than
metal-to-ligand charge-transfer
state was key to the achievement,
as was the octahedral coordina-
tion environment rigidly enforced
by two tridentate carbene
ligands. —JSY
Science, this issue p. 249;
see also p. 225ORGANIC CHEMISTRY
Journey to jorumycin
Jorumycin is a structurally
complex, pentacyclic organic
compound produced by a
marine mollusk. The success of
a similar compound, trabect-
edin, in treating certain types of
cancer has focused attention on
exploring jorumycin’s pharma-
ceutical properties. Welin et al.
developed a succinct route to
synthesizing jorumycin and the
closely related jorunnamycin A
that deliberately diverges from
the putative biosynthetic path-
way underlying prior chemical
syntheses. This route, which
hinges on a carefully optimized
asymmetric catalytic hydrogena-
tion, can be easily modified to
introduce unnatural structural
diversity for functional optimiza-
tion in further drug discovery
research. —JSY
Science, this issue p. 270CHEMICAL PHYSICS
Brief get-togethers
between NaK and K
Cooling molecules to nanokel-
vin temperatures places them
under the tightest quantum
mechanical constraints. Studies
in this intriguing regime have
been limited to diatomics:
Two cold atoms can be lured
together into weakly associated
Feshbach resonances, which
lasers can then shift into a more
stable molecular state. Yang
et al. now report the observa-
tion of triatomic Feshbach
resonances in ultracold colli-
sions between potassium (K)
atoms and sodium potassium
(NaK) diatomics. The findings
potentially set the stage for the
preparation and study of ultra-
cold triatomic molecules. —JSY
Science, this issue p. 261Edited by Stella Hurtley
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