INSIGHTS | PERSPECTIVES
sciencemag.org SCIENCEProsodic nuances in speech melody could
never be properly decoded without fine-
grained spectral processing, and musicians
could never play in sync without perceiv-
ing subtle rhythmic deviations. Hence, it
seems sensible to assume a weighted con-
tribution of left and right auditory regions
to different aspects in both domains, in
keeping with recent findings of right-later-
alized prosody perception ( 12 ). Moreover,
speech and music perception involves not
only the temporal lobe but also large-scale
fronto-temporo-parietal networks ( 13 , 14 ),
the concerted activity of which underpins
higher-order linguistic and musical pro-
cesses. The lateralization of these proc-
esses, and their dependency from and in-
teraction with auditory encoding, remain
pressing questions for future research.
Although previous studies have reported
opposite spectrotemporal preferences of
left and right auditory regions ( 9 , 10 ) and
have emphasized their optimized tuning
to human speech beyond other real-life
sounds ( 15 ), Albouy et al. have transferred
this approach to vocal musical melodies.
Their results emphasize the important role
of the right hemisphere for human com-
munication. Following ecological views
of brain functioning, these findings also
point toward the interesting idea that both
speech and music have shaped and opti-
mized—in complementary ways—the gen-
eral-purpose neural mechanisms through
which the human brain represents and
processes the sounds of the natural envi-
ronment today. Whether the observed au-
ditory asymmetries are specific to humans
or are shaped by individual experience
remains to be ascertained in experiments
with nonhuman species, infants, and
trained musicians. j
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Psychologie der Akustischen Wahrnehmung und
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10.1126/science.aba7913 ILLUSTRATION: V. ALTOUNIAN/
SCIENCEE
ngineered T cell therapies are revo-
lutionizing cancer treatment by
achieving long-lasting remission in
blood-related cancers, such as leukemia
and lymphoma. These therapies involve
removal of patient T cells, “reprogram-
ming” them to attack cancer cells, and then
transferring them back into the patient.
Targeted gene inactivation (knockout) us-
ing CRISPR-Cas9 can enhance T cell activ-
ity ( 1 , 2 ) and has the potential to expand cell
therapy applications. Until now, it has been
unknown whether CRISPR-Cas9–edited T
cells would be tolerated and thrive once re-
infused into a human. On page 1001 of this
issue, Stadtmauer et al. ( 3 ) present data from
a phase 1 clinical trial (designed to test safety
and feasibility) on the first cancer patients
treated with CRISPR-Cas9–modified T cells.
The findings represent an important advance
in the therapeutic application of gene editing
and highlight the potential to accelerate de-
velopment of cell-based therapies.
The production of engineered cell thera-
pies involves transduction of isolated patient
T cells with a disarmed virus to express a
receptor recognizing an antigen present on
the outside of cancer cells (through chimeric
antigen receptors, CARs) or on the inside of
cancer cells [through T cell receptors (TCRs)
specific for cancer-associated peptides]. Once
transduced, the engineered T cell population
is expanded and then reinfused back into the
patient. Although highly effective at treat-
ing some types of cancer, the specificity andlongevity of engineered T cell activity can
be improved. For example, T cell activity is
naturally down-regulated through the pro-
grammed cell death protein 1 (PD-1) recep-
tor. Systemic inhibition of PD-1 in patients
can enhance T cell activity but often triggers
adverse autoimmune reactions. Additionally,
endogenous TCR expression competes with
the transgenic receptor in engineered T cells,
interfering with signaling or cell trafficking.
Genetic knockout of the TCR and PDCD1
(the gene encoding PD-1) can enhance engi-
neered human T cell activity in preclinical
human tumor xenograft models in mice ( 4 ,
5 ). Stadtmauer et al. tested whether patient-
derived T cells containing these gene knock-
outs generated by CRISPR-Cas9 are safe and
persistent upon reinfusion into humans.
Six patients with either myeloma or sar-
coma were enrolled in the trial, and three
met the study’s criteria for T cell reinfusion.
A two-step process was used to achieve both
native TCR and PDCD1 gene knockout and
transgenic TCR expression in the engineered
cells (see the figure). In the first step, isolated
patient T cells were electroporated with pre-
formed ribonucleoproteins (RNPs) of Cas9
protein and guide RNA that targets the en-
dogenous TCR—TCRa (TRAC) and TCRb
(TRBC)—and PDCD1 for genetic disruption.
In the second step, cells were transduced
with a viral vector to express the transgenic
TCR, which recognizes cancer-testis antigen
1 (NY-ESO-1 ), and expanded in culture to cre-
ate NY-ESO-1 transduced CRISPR 3X edited(^1) Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. (^2) Howard Hughes Medical Institute,
University of California, Berkeley, CA 94720, USA.^3 Department of Chemistry, University of California, Berkeley, CA 94720, USA.
(^4) California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA 94720, USA. (^5) Innovative Genomics
Institute, University of California, Berkeley, CA 94720, USA.^6 MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA
94720, USA.^7 Gladstone Institutes, University of California, San Francisco, CA 94114, USA. Email: [email protected]
MEDICINE
Knocking out barriers
to engineered cell
activity
CRISPR-Cas9 gene-edited
T cells show safety and long-term
engraftment in humans
By Jennifer R. Hamilton1,2and Jennifer A. Doudna1,2,3,4,5,6,7
976 28 FEBRUARY 2020 • VOL 367 ISSUE 6481
Published by AAAS