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GRAPHIC: V. ALTOUNIAN/SCIENCE
pramolecular network. This component com-
prises a ureidopyrimidinone (UPy) supramo-
lecular motif that forms long fiber bundles
(8). Although the UPy motif also interacts
with the surfactant, the assembled UPy fiber
bundles are not evidently disturbed by the
presence of surfactant. By this approach, the
system of BTA-EG4 and surfactant, at concen-
trations that previously formed a sol consist-
ing of spherical assemblies, can instead form
a gel by adding a high concentration of UPy
fibrillar structures. Dilution from this ini-
tial point surpasses the gelation capacity of
the UPy network while not yet reaching the
point of inducing BTA-EG4 filament forma-
tion, yielding a sol. Continued dilution acti-
vates BTA-EG4 filament formation, which in
combination with the remaining UPy fiber
bundles restores a gel state comprising two
orthogonal networks of supramolecular poly-
mers: the BTA-EG4 and UPy networks. Upon
further dilution, the system transitions back
to a sol once again.
The tunable nature of molecular-scale self-
assembly in these materials offers simple
synthetic analogues of more complex phe-
nomena observed in nature. For example,
membraneless organelles—distinct compart-
ments within a cell that are not enclosed by
a traditional lipid membrane—are thought
to arise from liquid-liquid phase separation
because of concentration gradients of as-
sociating multicomponent systems forming
these assemblies in a water environment (9).
The roles of membraneless organelles in bio-
logical signaling during both normal and dis-
eased states are increasingly appreciated (10).
The behavior of the simple systems described
by Su et al. is therefore reminiscent of more
complex self-assembly phenomena in biol-
ogy, illuminating the importance of subtle
thermodynamic driving forces that give rise
to concentration-dependent phase separa-
tion. This new paradigm in self-assembled
materials consisting of highly adaptive and
dilution-triggered hydrogels may further-
more lead to the design of stimuli-responsive
material platforms for in situ modulation of
function in therapeutic biomedicine. j
REFERENCES AND NOTES
1. M. A. Stuart et al ., Nat. Mater.9, 101 (2010).
2 . L. S u et al., Science 377, 213 (2022).
3. T. Aida, E. W. Meije r, S. I. Stup p, Science 335, 813 (2012).
4. M. J. Rose n, J. T. Kunjap pu, Surfactants and Interfacial
Phenomena (Wi ley, e d. 4, 2 012 ).
5. K. L. M orris et al ., Nat. Commun.4, 1480 (2013).
6. W. M. Jacobs , D. Frenkel , Biophys. J.112, 683 (2017).
7. C. M. Leende rs et a l., Chem. Commun. 49, 1963 (2013).
8. S. I. S. He ndriks e et a l., Chem. Commun.53, 2279 (2017).
9. J. A. Riba ck et al., Nature 581, 209 (2020).
10. Y. Shin, C. P. Brangwynne, Science 357, eaaf4382 (2017).
ACKNOWLEDGMENTS
M.J.W. acknowledges funding from the National Institutes of
Health (R35GM137987) and the National Science Foundation
(BMAT, 1944875).
10.1126/science.abo7656
By Tetsuto Miyashita
Scientists have long been searching
for fossils of distant vertebrate an-
cestors. In the 1990s, mysterious
fishlike forms—now known as yun-
nanozoans—were discovered at a
520-million-year-old Cambrian fossil
site in the Yunnan province of China (1–3).
More fishlike forms (e.g., Haikouichthys and
Myllokunmingia) were reported from the
same locality shortly thereafter (4, 5), while
the 508-million-year-old Burgess Shale in the
Canadian Rockies yielded Metaspriggina (6).
Having eyes and a b rain at the front end of an
otherwise wormlike soft body, these animals
appear to have branched off the phylogenetic
tree before the last common ancestor of all
living vertebrates. However, there is on going
controversy about precisely how close to
vertebrates these Cambrian forms were. On
page 218 of this issue, Tian et al. (7) present
compelling evidence in yunnanozoans for an
unmistakable vertebrate trait—a pharyngeal
skeleton made of cellular cartilage.
Interpreting organic stains on a shale slab
is both a science and an art. Wielding scan-
ning electron microscopy and computed mi-
crotomography scans to yield unprecedented
details, Tian et al. reveal cellular and subcel-
lular structures of the skeletal bars that best
compare to cartilaginous gill arches of mod-
ern vertebrates. These bars in yunnanozoans
are patterned in a s eries, ea ch associ ated with
gill filaments and connected by horizontal
rods. The morphology closely approximates
various predictions for vertebrate ancestors.
Of all the internal structures of the earli-
est vertebrates, pharyngeal skeletons perhaps
stand the best chance for fossilization given
their robustness. Nonetheless, the complex
evolutionary history of the pharynx has
EVOLUTION
“Arch”-etyping vertebrates
Cellular details of gill arches in Cambrian fossils reignite
a centuries-old debate
Metaspriggina
Haikouichthys
Yunnanozoan
Pharyngeal skeleton Gill laments Myomeres
C-shaped
element
Pharynx
INSIGHTS |
PERSPECTIVES
science.org SCIENCE
Of gills and jaws
Cambrian vertebrates each evolved distinct pharyngeal anatomy with a series of gill-supporting skeletons.
The yunnanozoan has a cartilaginous basket and the Haikouichthys has unjoined bars, whereas the
Metaspriggina has upper and lower rods. However, it remains an open question whether their gill anatomies
represent any evolutionary link to the jaws of modern vertebrates.
154 8 JULY 2022 • VOL 377 ISSUE 6602
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strained attempts to interpret fossil imprints.
Pharyngeal slits and skeletons long precede
the origins of vertebrates, and cellular car-
tilage has been found in the lips of a devel-
oping invertebrate chordate (8). Vertebrates
develop the entire pharyngeal skeleton from
cellular cartilage in the embryonic pharyn-
geal arches. This cartilage originates in the
vertebrate-specific cell lineage called the neu-
ral crest. To complicate matters further, the
pharynx is regionally and phylogenetically
differentiated among vertebrates. Depending
on whether similarities or differences are
emphasized, the pharyngeal arch I in which
jaws develop, that is, the mandibular arch,
may (9–11) or may not (12–14) share an evolu-
tionary origin with gill-supporting skeletons.
New information from yunnanozoans pre-
sents an opportunity to clarify these issues.
Tian et al. avoided jumping to conclusions,
as they did not explicitly identify which gill
bar in a yunnanozoan corresponds to which
arch in a modern vertebrate. But they did
signal their favored interpretation that yun-
nanozoans, with each gill bar identical to the
next, represent the ancestral vertebrate con-
dition. This view is in line with the belief that
all pharyngeal arches originally supported
gills and that one of them evolved into a jaw
(9–11). At face value, yunnanozoans could
serve as long-awaited evidence for the gill-
arch hypothesis of jaw origins.
However, this jaw-origin narrative relies
solely on how one chooses to identify the gill
bars of yunnanozoans—that is, whether the
first gill bar in yunnanozoans corresponds
to the mandibular arch in jawed vertebrates.
Historically, one or more additional arches
were postulated in front of the mandibu-
lar arch for vertebrate ancestors (11). Other
views posit no such extra arches and consider
the mandibular arch as distinct from the gill
arches (12–14). Yunnanozoan morphology
excludes none of these ideas. Their first gill
bar could be the elusive arch that was later
lost in vertebrates, or, conversely, the man-
dibular region might not have formed a full
skeletal arch. Consistent with the latter sce-
nario, the snout and lips either appear di-
minutive or are absent in yunnanozoans and
other Cambrian forms (5–7). Specifically, one
C-shaped oral structure, as identified by Tian
et al., may represent what might be a slim
mandibular arch of yunnanozoans. If this is
true, then a prominent snout and lips, which
arise from the neural crest, are a later innova-
tion of the living vertebrate group.
To discriminate between different hypoth-
eses, unequivocal correlates of arch identities
are needed. A mandibular arch is not defined
by being the most anterior pharyngeal arch.
Rather, its identity is predicated on the pres-
ence of a specific stream of neural crest cells,
a fifth cranial nerve, and specialized mouth
structures for pumping water and feeding.
Without these markers, and with variations
observed among different vertebrate lineages,
overall positions of the gills help little to de-
termine arch homology in yunnanozoans.
Tian et al. offer an emerging scope of
diversity in pharyngeal anatomy of early
vertebrates (see the figure). Among other
Cambrian fishlike forms, Haikouichthys
seems to have skeletal rods that support
the gills, whereas only the gill pouches
are described for Myllokunmingia (4).
Metaspriggina has skeletal bars segmented
into upper and lower halves (6). Hagfish and
lampreys evolved from the common ances-
tor with a cartilaginous basket around the
gill pouches and a specialized oral skeleton
(15). Similar pharyngeal skeletons also occur
in successive out-groups of jawed vertebrates
(12). And jawed vertebrates have a series of
jointed skeletal arches, the first of which dif-
ferentiate as jaws. These different patterns
are as anatomically disconnected from each
other as they are phylogenetically distant.
Given such a complex distribution of char-
acters, it seems premature to assume any sin-
gle form as the ancestral phenotype on a lin-
ear path toward modern vertebrates. In the
phylogenetic analysis by Tian et al., yunnano-
zoans are an out-group to all other vertebrate
branches. This suggests differential evolution
of pharyngeal patterning among early ver-
tebrate lineages. By the time yunnanozoans
were sloshing about in the Cambrian sea,
other primitive fishes had evolved to slurp
food differently with their uniquely derived
pharyngeal anatomy. Although evolutionary
biologists have been busy chasing the mythi-
cal ancestor that explains everything about
the vertebrate body plan, perhaps the oppo-
site is a sensible approach. In other words,
the meandering journey toward modern
vertebrates may be best understood by popu-
lating the family tree with divergent and dis-
continuous anatomical forms, guided by phy-
logenetic inference rather than by theory. j
REFERENCES AND NOTES
1. J.-Y. Chen et al ., Nature 377, 720 (1995).
2. J.-Y. Chen et a l., Nature 402, 518 (1999).
3. D. Shu et al ., Science 299, 1380 (2003).
4. D.-G. Shu et a l., Nature 402, 42 (1999).
5. D.-G. Shu et a l., Nature 421, 526 (2003).
6. S. Co nway Mor ris , J.-B . Ca ron, Nature 512, 419 (2014).
7. Q. Tian et a l., Science 377, 218 (2022).
8. D. Jandz ik et a l., Nature 518, 534 (2015).
9. J. A. Gillis et al. , Nat. C omm un. 4, 1436 (2013).
10. C. Hirschberger et a l., Mol. Biol. Evol. 38, 418 7 (2 021 ).
1 1. J. Mallatt, Zoolog. J. Lin n. Soc. 117, 329 (2008).
1 2. P. Janvie r, Early Vertebrates (Oxford Monographs on
Geology and Geophysics, Clarendon Press, 1996).
13. S. Kuratani, Evol . Dev. 14, 76 (2012).
14. T. Miyashita, Bio l. Rev. Cam b. Ph ilos . Soc . 91, 611 (2016).
15. T. Miyashita, Can. J. Zool. 98, 850 (2020).
10.1126/science.adc9198
By Rohini Kuner1 and Thomas Kuner2
The perception of physical pain is sub-
ject to variation depending on the
context and which other sensory in-
puts are being received, including
sound. The emerging field of music
therapy (1)—which is applied to con-
trol postoperative, pediatric, postpartum,
and cancer pain and is being increasingly
tested in chronic pain disorders—capital-
izes on the interactions between sound and
pain perception to attenuate pain. Given
that music and natural sounds can posi-
tively affect mood, relieve stress, and relax
the body, it is not unreasonable to think
that these factors underlie pain relief. On
page 198 of this issue, Zhou et al. (2) demon-
strate that pain relief by sound is not purely
attributable to stress reduction and distrac-
tion. They interrogate neural circuits to un-
ravel a specific pathway for sound-induced
analgesia in the brains of mice.
Using rodents to study how music and
sound are related to pain presents major
challenges, not least because it is unknown
how animals perceive music. Zhou et al. car-
ried out behavioral tests addressing pain
sensitivity and found that mice did not show
differential responses to melodic classical
music (consonant sounds), dissonant mu-
sic, or white noise. Notably, they found that
the decisive factor in eliciting pain relief is
a 5-dB increase in sound intensity in any of
these three types of sound relative to ambi-
ent sound levels, whereas 10-, 15-, or 20-dB
increases were ineffective. In mouse mod-
els, a 5-dB increase in sound intensity led
to inhibition of both sensory-discriminative
aspects of pain, such as evoked responses
aiding escape from noxious stimuli (nocicep-
tion), and affective behaviors that are linked
to suffering and negative emotions associated
with acute and chronic pain. Therapeutically
relevant findings were that repetitive ap-
plication of 5-dB sound over ambient levels
NEUROSCIENCE
Sounding
out pain
A circuit for sound-induced
analgesia has been found in
the mouse brain
1Institute of Pharmacology, Heidelberg University,
Heidelberg, Germany. 2Department of Functional
Neuroanatomy, Institute for Anatomy and Cell Biology,
Heidelberg University, Heidelberg, Germany.
Email: rohini.kuner@pharma.uni-heidelberg.de
Canadian Museum of Nature, Ottawa, Ontario K1P 6P4,
Canada. Email: tmiyashita@nature.ca
SCIENCE science.org 8 JULY 2022 • VOL 377 ISSUE 6602 155
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to original U.S. Government Works
“Arch”-etyping vertebrates
Tetsuto Miyashita
Science, 377 (6602), • DOI: 10.1126/science.adc9198
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