Science - USA (2022-01-28)

SCIENCE science.org 28 JANUARY 2022 • VOL 375 ISSUE 6579 400-B

RESEARCH

BRAIN DEVELOPMENT

Physiopathology

in the human brain

Development of the human
brain involves processes
not seen in most animals.
Eichmüller et al. identified CLIP
cells, a human progenitor cell
type responsible for tuber-
ous sclerosis, a rare form of
epilepsy triggered by excessive
mechanistic target of rapamy-
cin (mTOR) signaling, and
recapitulated the disease in
human cerebral organoids (see
the Perspective by Ihrie and
Henske). Excessive CLIP cell
proliferation causes tumorigen-
esis and brain abnormalities.
The researchers found that
the sensitivity of these cells
for mTOR signaling, not loss of
healthy alleles, is responsible for
the disease. This work changes
our understanding of neurode-
velopmental disease and reveals
crucial aspects of human brain
development. —BAP
Science, abf5546, this issue p. 401;
see also abn6158, p. 382

NEURODEVELOPMENT

Nests of interneuron

proliferation

A transient structure in brain
development, the medial gangli-
onic eminence is the birthplace
of brain interneurons. These
cells will migrate tangentially
through the brain to contrib-
ute their inhibitory regulation
to neuronal circuits. Looking
closely at how the fetal human
medial ganglionic eminence
is structured, Paredes et al.
found clusters of proliferative
cells (see the Perspective by
Kessaris). When cells from
these clusters were trans-
planted into the neonatal mouse
brain, the human-derived cells
migrated and differentiated
throughout. The nests of prolif-
erative cells that characterize
the developing human brain
may support the greater need
for interneurons in the larger

human brain compared with the

smaller mouse brain. —PJH

Science, abk2346, this issue p. 402;

see also abn6333, p. 383

PALEOBOTANY

The origin of the

dipterocarps

The Dipterocarpaceae are a

prominent family of mainly tropi-

cal trees, reaching particularly

high diversity and dominance

in present-day Southeast Asian

rainforests, where several spe-

cies regularly reach heights of

50 meters or more. Bansal et

al. used fossil pollen, molecular

data, and paleobiogeographic

analysis to study the origin and

dispersal of the family (see the

Perspective by Hoorn and Lim).

The authors trace the origin of

the dipterocarps to the mid-Cre-

taceous of tropical Africa, and

postulate subsequent dispersal

eastward across an Indian Ocean

island arc to the then-isolated

Indian subcontinent. The colli-

sion of the subcontinent with the

Asian landmass then facili-

tated further dispersal toward

Southeast Asia. —AMS

Science, abk2177, this issue p. 455;

see also abn6191, p. 380

HIBERNATION

While they sleep

Hibernation has evolved to

remove animals from seasonal

periods that are especially

challenging for survival. Despite

this protective feature, hiberna-

tion poses its own challenges

because of the extensive fasting

period. One particularly chal-

lenging aspect is the lack of

dietary nitrogen, which can lead

to protein imbalance. Regan et

al. looked at gut microbiome

activity in hibernating thirteen-

lined ground squirrels and

found that symbionts recycled

nitrogen from urea into their own

metabolites, which were then

incorporated by the squirrels,

allowing them to maintain pro-

tein balance (see the Perspective

by Sommer and Bäckhed ).

These results reveal the impor-

tance of the gut microbiome to

hibernation and suggest that gut

microbes could play such a role

in other species. —SNV

Science, abh2950, this issue p. 460;

see also abn6187, p. 376

CORONAVIRUS

A site of vulnerability in

SARS-COV-2

Neutralizing antibodies are a key

defense against severe acute

respiratory syndrome corona-

virus 2 (SARS-CoV-2). Many

neutralizing antibodies target

the region of the viral spike

protein that is involved in binding

to the human ACE2 receptor,

known as the receptor binding

motif (RBM). This region of the

protein is divergent between

SARS-CoV-2 variants, leading

to failure of existing monoclo-

nal antibody treatments and

evasion of antibodies elicited by

previous infection or vaccination.

Park et al. describe a monoclo-

nal antibody that neutralizes a

broad range of sarbecoviruses,

including both the 2003 SARS-

CoV and SARS-CoV-2. This

antibody also binds in the RBM

but targets residues that are

more conserved because they

are involved in ACE2 binding. The

antibody protects against the

SARS-CoV-2 Beta variant, and

none of the individual mutations

in the Omicron variant affected

antibody binding. —VV

Science, abm8143, this issue p. 449

TUMOR IMMUNOLOGY

Hematopoietic tumors

SLAM macrophages

SLAM family receptors (SFRs)

are widely expressed on hema-

topoietic cells and have been

implicated in various innate

immune functions. Li et al. used

various cell lines and mice with

gene deletions to show that SFR

deficiency, specifically SLAMF3

and SLAMF4, increases the

ability of macrophages to phago-

cytose hematopoietic cells. Mice

with SFR deletion exhibited

hematopoietic tumor rejection,

and SFR deletion was able to

enhance the efficacy of chimeric

antigen receptor macrophage

therapy against hematopoietic

cancer. These data show that

SFR expression on hematopoi-

etic cells can inhibit the function

of macrophages, pointing to a

potential therapeutic target for

hematopoietic cancers. —DAE

Sci. Immunol. 6 , eabj5501 (2022).

HIV

PD-1 blockade for HIV

Strategies to target and reverse

the latent HIV reservoir are

required to cure HIV. Because

CD4+ T cells expressing pro-

grammed cell death protein

1 (PD-1) are preferentially

infected with HIV in individuals

on antiretroviral therapy, PD-1 is

an attractive target to manipu-

late the latent reservoir. To this

end, Uldrick et al. measured the

impact of anti–PD-1 treatment

with pembrolizumab on the HIV

reservoir in 32 individuals living

with HIV and diagnosed with can-

cer. They observed evidence of

increased unspliced HIV RNA and

an increased ratio of unspliced

RNA:DNA, consistent with

anti–PD-1 treatment having the

potential to reverse HIV latency.

Further studies are needed to

evaluate the dose and frequency

of anti–PD-1 treatment required

for latency reversal. —CSM

Sci. Transl. Med. 14 , eabl3836 (2022).

PLANT SCIENCE

Genomic handoff to

the next generation

Haploid plant pollen grains are

not simply passive carriers of

genomes but rather serve as a

developmentally and physiologi-

cally active bridge between the

diploid parental plant and the

diploid offspring plant. Nelms

and Walbot sequenced the

RNA content of single maize

Edited by Michael Funk

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