retinal image through an internal refractive index gradient,
which guides incident rays along
curved paths via the lens center
to the opposite side of the lens.
Eye lenses, including those of
fishes and squids, mostly consist
of crystallin proteins (3, 4). Squid
eyes mainly contain members of
the S-crystallin family. A radial
protein density gradient leads to
a low density (and hence low refractive index) at the edges and
a high density (high refractive
index) in the center of the lens
(5). S-crystallins contain a glutathione S-transferase (GST) domain and a flexible, disordered
protein loop region. The variable
length of the latter suggests a
role in determining the refractive index of the lens.
Cai et al. sequenced transcriptomes of mature lens tissue from
inshore squid (Doryteuthis pealeii) and identified more than 40
unique loop sequences that vary
in length from 3 to 110 amino
acids. It remains to be shown whether this
diversity, seen in the messenger RNA composition, is also present at the protein level. The
number of unique loops in squid is much
higher than in vertebrates, where a handful of a-, b-, and g-crystallin variants are the
main protein components of the eye lens (6).
Protein polydispersity has also been reported
for a-crystallins in a vertebrate lens, but this
polydispersity is encoded in a single protein,
involving formation of a range of differently
sized protein complexes (7).
Cai et al. show that the distribution of
protein variants varies between different
radial positions. Short sequences are more
abundant in the center of the lens, and
medium-sized linkers are more abundant
at its edge. S-crystallin variants with long
internal loops are found in all radial positions, although they may perform different
functions, given their diverse sequence and
The study offers a solution for the appar-
ent paradox that the refractive index gradi-
ent is highly stable throughout the lens and
does not fluctuate locally. If interactions be-
tween proteins are isotropic, as commonly
assumed, this would allow local fluctuations
of protein density and hence refractive in-
dex and would distort the transparency of
the lens. Cai et al. instead propose that the
proteins behave as anisotropic colloidal
molecules. They consider S-crystallins as
“patchy” colloids, which are characterized
by localized, short-range attractive surface
patches as well as hard-sphere repulsion,
The authors show that small-angle x-ray
scattering (SAXS) analysis of individual tis-
sue samples from all regions in the lens con-
firms the formation of pairwise linked chains
of S-crystallin proteins and the presence
of multiparticle nodes in the protein net-
work. SAXS analysis of tissue homogenates
(a slurry of broken tissue) shows that once
formed, the gel does not change its structure
upon dilution, which would be expected for
Hence, the proteins interact as patchy
colloids and form an ordered fluid. SAXS
and dilution experiments show that the
coordination number—that is, the number of connections per node in the protein
mesh—increases from around 2 at the edge
toward 6 at the center of the lens (see the
figure). Such variations in the coordination
number might enable the cell to prevent
gelation and cessation of protein synthesis
below the optimal protein density. According to the authors, gelation only occurs once
the optimal coordination number needed to
define a certain refractive index is reached
throughout the lens.
It remains to be shown how protein se-
quence, coordination number, and density
are related to each other. Future
studies should also determine
whether the S-crystallin di-
versity is encoded in the squid
genome or achieved by RNA
editing; the latter is a common
mechanism for recoding pro-
teins in the transcribed genes
of squid, octopuses, and cuttle-
fish (10). Deposited sequences
of S-crystallins from the simi-
lar squid species D. opalescens
show a loop diversity resem-
bling that of D. pealeii, though
lacking long linkers, and show
sequence variation in the GST
domain. Thus, it seems more
likely that the diversity is en-
coded in the squid genome.
In vitro work using purified
proteins is needed to confirm
that the disordered loops mediate different coordination
numbers and protein densities. Moreover, it is unclear
whether the high polydispersity
in loop sequence facilitates gel
formation and whether polydispersity in vertebrate lenses encoded in
single proteins (7) follows a similar concept. Posttranslational modifications have
been reported for human crystallins (11).
Researchers will need to clarify whether
posttranslational modification of the disordered loop constitutes another way through
which gel formation is regulated. This
knowledge may enable the design of artificial, aberration-free lenses based on simple
materials with properties similar to those of
S-crystallins, with potential applications in
optical instruments and clinics. j
REFERENCES AND NOTES
1. J. C. Maxwell, Camb. Dublin Math. J. 8, 188 (1854).
2. J. Cai et al ., Science 357, 564 (2017).
3. S.I. Tomarev,R.D.Zinovieva,J.Piatigorsky, J.Biol.Chem.
267, 8604 (1992).
4. H. Bloemendal, CRC Crit. Rev. Biochem.12, 1 (1982).
5. A. M. Sweeney, D. L. Des Marais, Y. E. Ban, S. Johnsen,
J. R. Soc. Interface4, 685 (2007).
6. H. Bloemendal et al. , Prog. Biophys. Mol. Biol. 86, 407
7. P. Schurtenberger, R. C. Augusteyn, Biopolymers 31, 1229
8. E. Bianchi, J. Largo, P. Tartaglia, E. Zaccarelli, F. Sciortino,
Phys. Rev. Lett. 97, 168301 (2006).
9. C. Gogelein etal. , J.Chem.Phys.129, 085102 (2008).
10. N. Liscovitch-Brauer et al. , Cell 169, 191 (2017).
11. L. R. Miesbauer et al. , J. Biol. Chem. 269, 12494 (1994).
The author thanks W. Graier for helpful discussions and
critical comments. The author is supported by the Integrative
Metabolism Research Center Graz, the Austrian infrastructure
program 2016/2017, BioTechMed-Graz, Omics Center Graz, the
President’s International Fellowship Initiative of the Chinese
Academy of Sciences (no. 2015VBB045), the National Natural
Science Foundation of China (no. 31450110423), and the
Austrian Science Fund (FWF: P28854 and W1226-B18).
11 AUGUST 2017 • VOL 357 ISSUE 6351 547 SCIENCE sciencemag.org
Graded refractive index
The image quality is much
lower for an image formed
by a spherical glass bead
with a single refractive
index (top) than through a
fsh lens with a graded
refractive index (bottom).
Single refractive index
Graded refractive index
Crystallin dimers assemble into larger structures, with
higher coordination numbers and hence higher protein
density in the center of the lens than near the edges.
Architecture of a perfect lens
In squid eye lenses, the refractive index decreases parabolically from the center
to the edge. Cai et al. show that this gradient is achieved through assemblies of
S-crystallin protein dimers that vary in size from the center to the edge of the lens.