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Issue 11 | April - June 2018

SUPERBUGS
MEET THEIR NEMESIS
Polymer could avert global
antibiotics crisis
page 8

ANALYSE TARGET CLOCKING UV
THIS PRACTISE EXPOSURE
Citizen science Cloned cancers provide A biomarker for
meets big data treatment testbed sun-damaged skin
page 28 page 49 page 18
www.research.a-star.edu.sg

A*STAR Research is a publication of The Agency for Science, Technology and Research
the Agency for Science, Technology (A*STAR) is Singapore’s lead government agency dedicated
and Research (A*STAR) — Singapore’s
to fostering world-class scientific research and talent for a
lead government agency for fostering
worldclass scientific research. vibrant knowledge-based economy.

A*STAR Research is published quarterly, A*STAR actively nurtures public-sector research and
presenting research highlights and feature development in biomedical sciences, physical sciences and
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A*STAR Research is published for A*STAR
by the Partnership and Custom Media unit Advanced Remanufacturing and Technology Centre (ARTC)
of Nature Research, part of Springer Nature. Bioinformatics Institute (BII)
Bioprocessing Technology Institute (BTI)
Editorial
Agency for Science, Technology Clinical Imaging Research Centre (CIRC)
and Research Data Storage Institute (DSI)
1 Fusionopolis Way, #20-10 Connexis North Experimental Power Grid Centre (EPGC)
Tower Singapore 138632, Singapore
Experimental Therapeutics Centre (ETC)

Editor-in-Chief David Lane Genome Institute of Singapore (GIS)
Editorial Board Huck Hui Ng Institute of Bioengineering and Nanotechnology (IBN)
Colin Stewart Institute of Chemical and Engineering Sciences (ICES)
Evan Newell
Institute of High Performance Computing (IHPC)
Keith Carpenter
Chandra Verma Institute for Infocomm Research (I2R)
David Wu Institute of Materials Research and Engineering (IMRE)
Boris Luk’yanchuk Institute of Medical Biology (IMB)
Patrick Cozzone
Institute of Microelectronics (IME)
Reginald Tan
Nicolas Plachta Institute of Molecular and Cell Biology (IMCB)
Arseniy Kuznetsov National Metrology Centre (NMC)
Florent Ginhoux Singapore Bioimaging Consortium (SBIC)
Managing Editor Adeline Sham
Singapore Institute for Clinical Sciences (SICS)
Administrative Assistant Lay Hoon Tan
Singapore Institute of Manufacturing Technology (SIMTech)
ISSN 2010-0531 Singapore Immunology Network (SIgN)
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

E D ITO R IA L
3 Notes from the editors

FE ATU R E S &
I N N OVATI O N S
4 Charging forward with the battery
revolution
COVER STORY
8 Beating bacteria
– looking beyond antibiotics

R E S E A RCH
H IG H LIG HT S
12 Spin memory: Dynamic solution
for accurate reading
14 Obesity: High-fat diet linked to
4 F E AT U R E S &
I N N O VAT I O N S skin conditions
15 Cancer: The stomach’s ‘chief’
source of stem cells
16 Immunology: Newly identified cells
in liver protection role
17 Materials: Nature inspires light,
robust lattice structures
COVER STORY
18 Cells: Glaring lessons on skin aging
19 Microbiome: Gut bacteria affect
the brain, even in the womb
20 Laser spectroscopy: Measurements
through entanglement

12 15 22 Mutations: Pinpointing cancer drivers
23 Chemistry: Building a better
ion channel
24 Cancer treatment: Photothermal
therapy blooms
25 Stem cells: Aiming for the heart
26 Cell biology: Putting muscle nuclei
in their place
27 Quantum matter: A surface that
makes light work
COVER STORY
28 Machine learning: Data analysis

20
tool empowers the people
30 Cancer treatments: Understanding
individual immune responses

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R E S E A RCH
H IG H LIG HT S
31 Printing: Tiny droplets for
big color impact
32 Therapeutics: Engineering a safer
antibody drug
33 Cancer: A sustainable source of
natural killers
34 Lithography: A bright idea for
on-demand nanopatterns
35 Immunology: Monocytes in the mix
36 Cancer: Relocated enzymes make
cancer more mobile
38 Drug delivery: Reach for the stars
39 Cancer research: A blood test for
cancer recurrence
40 Ultrafast lasers: New approach to
generating ultrashort pulses
41 Photonics: Light-bending
nano-patterns for LEDs
42 UV protection: Lignin’s strengths in
smaller packages
43 Laser: Pulses of light with a tilt and

32 a twist
44 Cancer therapeutics: Targeting
the root of the problem
46 Rehabilitation: An adaptive
approach to stroke recovery
47 Genetics: Mutation linked to rare
skin disease
48 Proteomics: Turning up the heat
on protein interactions

46 COVER STORY
49 Oncology: Cloned tumors used for
a cancer crystal ball
50 Cancer biology: The molecular
path to better oral cancer care
51 Catalysis: Porous silica protects
nickel catalyst

NEXT ISSUE
52 A sneak peek of Issue 12

36 48
2 A*STAR RESEARCH  Issue 11 | April – June 2018
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NOTES FROM THE EDITORS
The Editorial Team introduces the latest issue of A*STAR Research

A
ntibiotic resistance has We also have many more stories BIG DATA
emerged as one of the biggest from diverse areas of research, such as: • A fully automatic web-based system has
threats to global health, as been developed that empowers non-
bacteria acquire resistance STEM CELLS experts to analyze big data (page 28).
faster than new antibiotics can be • A subpopulation of chief cells that can • Another team have devised a novel
developed. Scientists have recently become stem cells in response to injury approach to predict cancer drivers with
developed a polymer that can kill has been identified, shedding light on improved accuracy, and made their
bacteria effectively without triggering how the stomach lining renews itself, tool freely available online (page 22).
the evolution of resistance, which could and how gastric cancer begins (page 15).
be the key to averting the antibiotic • Researchers have found a way to NANOSTRUCTURES
resistance crisis (page 8). generate large numbers of ‘universal’ • Scientists have found a way to assemble
Our second feature looks at solving natural killer cells from induced quantum dots into nanoscale grids
a very different problem that plagues pluripotent stem cells, for applications using focused electron beams, for
us on a daily basis – that of battery such as immunotherapies (page 33). applications ranging from biosensors
capacity. Lithium-ion batteries essentially to solar panels (page 41).
power our daily lives – from mobile CANCER TREATMENTS • A new printing technique based on sil-
phones to electric cars, and even entire • A single-base mutation has been icon nanostructures has been invented,
homes in some cases – but they are fast discovered that can strongly predict which could achieve resolutions of up
approaching their physical limits. Two whether an oral cancer patient will to 100,000 dpi (page 31).
award-winning A*STAR researchers are respond to specific treatments (page 50).
exploring an alternative – lithium-sulfur • Scientists have also devised a method For our latest stories, please visit
batteries, a 50-year old technology that to grow miniatures of patients’ tumors us at https://research.a-star.edu.sg/ or
can potentially provide energy densities in the lab, which could help doctors follow us on Twitter at: @astar_research.
up to five times that of lithium-ion choose the most effective treatments We hope you will enjoy reading the rest
batteries (page 4). for individual patients (page 49). of this magazine.

Issue 11 | April - June 2018
A*STAR RESEARCH

Lithium-sulfur
batteries could
outperform
lithium-ion batte-
ries. [page 4]
SUPERBUGS
MEET THEIR NEMESIS
Polymer could avert global
antibiotics crisis
page 8

ANALYSE TARGET CLOCKING UV
ISSUE 11 April - June 2018

THIS PRACTISE EXPOSURE
Citizen science Cloned cancers provide A biomarker for
meets big data treatment testbed sun-damaged skin
page 28 page 49 page 18

01_Cover.indd 3 2018/08/08 12:51

COVER IMAGE
Antimicrobial resistance is
© Andrey Suslov/Getty

a global issue [page 8]
© WLADIMIR BULGAR/
SCIENCE PHOTO LIBRARY;
Texture: © 4khz/iStock/Getty

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CHARGING
FORWARD
WITH THE BATTERY REVOLUTION
Imagine energy densities five times that of lithium-ion
batteries. An A*STAR team is leading the race to bring
lithium-sulfur batteries to the masses

T
he desire to super-charge
increasingly smart, portable
electronic devices using
more efficient, large-capacity
batteries is palpable. “We hear
very sensational reports. For example, that
(Bottom) © boonchai wedmakawand/Getty Images

Theoretically, you will soon be able to charge your mobile
cars powered by phone batteries in just a few seconds,” notes
lithium-sulfur batteries
will be able to travel
Guangyuan Wesley Zheng, a chemical
more than five times engineer at the Institute of Materials Research
farther than those and Engineering (IMRE) at A*STAR.
powered by lithium-ion
“However, while there is a lot of noise and
batteries.
Background © sumkinn

hype, it’s very important research”. Electric
car batteries, he points out, are going to play
a significant role in transportation. In fact,
Macquarie Research dubbed 2017 ‘the year
that electric cars came of age’, with global

4 A*STAR RESEARCH  Issue 11 | April – June 2018
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to electrical energy during such as cobalt, nickel and
discharge. The basic configuration manganese. Researchers have
of a lithium-ion battery involves been steadily improving battery
two electrodes made of different performance by incrementally
materials, both of which are able adjusting the composition
to store lithium. of electrode materials, along
When connected to a circuit with the battery cell design.
during discharge, the negative Nonetheless, because of the basic
In 2017, battery whiz
electrode (anode) undergoes limits of how lithium ions are
Zhi Wei Seh spoke to a
mixed crowd about his oxidation, while the positive stored in these materials, the
research into batteries electrode (cathode) undergoes energy density limit of lithium-
at the MIT Technology reduction. The change in the ion batteries is still theoretically
Review’s annual
chemical composition of the capped at roughly 420 watt-
EmTech conference.
electrodes stimulates an electric hours per kilogram (Wh/kg),
current to move from the anode just enough to power electric
to the cathode through the cars over distances expected of
circuitry of the device being conventional cars.
powered, and lithium-ions to But if we want to continue
move from one electrode to to charge forward lithium-
another within the battery. When sulfur batteries promise greater
the ions run out the battery performance using a different
becomes flat. When a battery storage mechanism, explains
demand up 51 per cent on FROM LITHIUM-ION TO is plugged in to recharge, this Seh. The basic function is
2016. Zheng adds that “Boeing LITHIUM-SULFUR BATTERIES process is reversed — the cathode similar to that of lithium-ion
and Airbus are also talking Many research groups are is oxidized, while the anode is batteries: during discharging,
about aircraft fully powered by looking into the potential of reduced — and both electrodes the lithium metal anode is
electricity” and more battery- lithium-sulfur batteries as are returned to their original state. oxidized to form lithium ions
powered electrical appliances an alternative to lithium-ion that travel through the liquid
are becoming possible — “like batteries, but Zheng and Seh electrolytes inside the battery to
vacuuming robots.” are among the most ambitious, ELECTRIC CARS could benefit hugely
reach the sulfur cathode, where
Lithium-ion batteries have both recently named among from improved battery technology and a reaction reduces sulfur to form
demand for them is growing.
been the dominant battery the MIT Technology Review’s lithium sulfide. As in lithium-
on the market since their top ‘Innovators under 35’ in ion batteries, the change in the
commercial debut in the early Asia Pacific. composition of the electrodes
1990s, used in everything Lithium-sulfur batteries are stimulates a flow of electrons
from mobile phones to cars.
Tesla, for example, a Silicon
attractive because sulfur is cheap
and abundant, and the batteries
51% from one electrode to another
through the circuitry of a device.
The rise in the global
Valley-based electric vehicle themselves theoretically have demand for electric Again, this process can be
cars between 2016
manufacturer, is now building energy densities five times larger and 2017 reversed during charging.
a ‘Gigafactory’ to dramatically than lithium-ion batteries. “That Unlike conventional lithium-
scale up the production of means, if we put batteries of the ion batteries, in which ions
lithium-ion batteries. same weight into a car, it could are inserted into the electrode
However, lithium-ion travel five times longer,” Zheng materials, lithium-sulfur
batteries are reaching the limit explains. That possibility could batteries use a metal plating and
of what they can achieve, says also pave the way for applications Energy density limits, stripping mechanism on the
Zheng’s colleague, Zhi Wei Seh, that lithium-ion batteries cannot which along with the lifetime lithium anode and a conversion
a materials scientist at IMRE. handle, such as high-energy of a battery determine the reaction, in which the electrode
“So, instead of making stationary grid storage systems commercial proposition of a material is transformed from
incremental improvements on for renewable energy sources like battery, hinge on the expense and sulfur into lithium sulfide, on the
what lithium-ion batteries can solar and wind power. ion-carrying limits of electrode sulfur cathode side1. Negating
© EmTech Asia 2017

theoretically do, we are exploring Like all batteries, lithium-ion materials. A lithium-ion battery’s the need for ions to be inserted
drastically different, revolutionary and lithium-sulfur batteries store anode is generally made from into electrode materials means
battery technologies.” energy in the form of chemical graphite, and the cathode from that the theoretical energy
energy, which is converted a mix of expensive metal oxides density of a sulfur-lithium

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CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

create a void inside the shell
Current
to accommodate the volume
Lithium-Ion
expansion of sulfur3. As a result,
121 km the capacity decay after 1,000
cycles was as small as 0.033 per
cent per cycle, which represented
the best performance of a
If the barriers to
lithium-sulfur battery at
commercialization can
be overcome, lithium- the time.
sulfur batteries could Inspired by this yolk-shell
carry electric vehicles structure, the performance
Theoretical roughly five times
of lithium-sulfur batteries
further than today’s
Lithium-Sulfur reported in literature improved
standard lithium-
644 km ion batteries. greatly, Seh says, and now some
groups have even demonstrated
10,000 cycles.
battery is much, much higher, at because of the build-up of framework made of porous Zheng, on the other
2,500 Wh/kg. lithium deposits, and because carbon, which is conductive2. hand, led a project on one of
The possibility of lithium- intermediate materials known However, as a sulfur particle’s the other issues that makes
sulfur batteries was discovered as lithium polysulfides, which volume expands by as much commercialization difficult,
as early as the 1960s, but are important to maintain as 80 per cent upon reacting the lithium anode. The anode
huge technical challenges still the cathode’s performance, with lithium, it often cracked tends to form dendritic and
obstruct commercialization. dissolve quickly into the the protective coating, and mossy metal deposits within the
On the cathode side, major battery’s electrolytes, leading to the problematic polysulfide battery, one of the major causes
problems include the low a continuous loss of important dissolution continued. Stable of the battery’s short lifetime.
electronic conductivity of sulfur active materials. performance could thus be His team initially considered
and lithium sulfide, as they Researchers have been achieved for only 20 charge- using a carbon thin film to
are naturally insulating. Also, trying to solve the first problem discharge cycles (by comparison, coat the lithium anode, but
faster lifetime decay occurs by coating sulfur particles the lifetime of a conventional the coating cracked after
during a battery’s energy cycling in a conductive material. lithium-ion AAA battery has a few cycles. After several
A breakthrough came in roughly 500–1,000 cycles). attempts, they resolved the
2009 when a Canadian team Nonetheless, since 2009, research issue using a hollow carbon
developed a technology to into lithium-sulfur batteries has nanosphere approach.
encapsulate sulfur particles been accelerating. Unlike conventional
within a highly-ordered approaches focused on
INSPIRATION FROM AN EGG modifying anode materials to
Both Seh and Zheng made prevent dendrite formation,
significant advancements in their approach focused on
the science several years ago accommodating shape changes
when they were PhD students of the anode. As the hollow
at the lab of Professor Yi Cui at carbon nanosphere coating is
© 2018 Top: Nature Research; Bottom: Guangyuan Wesley Zheng

Stanford University. It was Seh highly flexible and robust, it can
who looked into the volume withstand the large volumetric
expansion problem. “I came changes of the lithium anode
up with an idea similar to during energy cycling, thus
Guangyuan an egg structure,” allowing the battery to
Wesley Zheng is banking Seh says. “Imagine the sulfur is continue functioning4.
on a future in which an egg yolk and the white is “The result provided a new
drones can cover long
distances powered by
empty space.” perspective on how simple
batteries. He’s bidding to The team developed a nanotechnology can help
work on drone vaccine technology to coat sulfur address long-standing problems
deliveries on Vanuatu
nanoparticles with titanium in lithium batteries,” Zheng
for UNICEF.
oxide, and then allow some says. His team has since made
dissolution of the sulfur to more iterations, including

6 A*STAR RESEARCH  Issue 11 | April – June 2018
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using a self-healing polymer
and other coating methods,
and he says these results also
show good cycling at higher
current densities.
In 2018,
THE ROAD TO Guangyuan Wesley Zheng
was one of only 10 researchers
COMMERCIALIZATION
to be named in the MIT
Since moving back to Singapore Technology Review’s top
from Stanford in the USA ‘Innovators Under 35’ in the Asia
and joining A*STAR in 2016, Pacific. In 2017, Zhi Wei Seh also
received the honor. Both have
the two scientists have been spoken about their work at the
exploring new angles of the Review’s annual conference,
lithium-sulfur battery question. EmTech Asia.
Zheng is pushing hard for
commercialization. He runs a
San Francisco-based company
called Volans-i in collaboration
with a friend, Hannan Parvizian.
They build drones, and operate
a delivery service across long
distances. Volans-i still use aluminum ions are larger and
traditional lithium-ion batteries often reported in literature
because lithium-sulfur battery to be slow and sluggish, says
packs are still in development, Seh. His team is searching for
but they ultimately need a the best way to manipulate
battery platform robust enough these materials “to move ions
to “deploy drones around the very fast during charging
world,” Zheng says. scale up the production of and discharging.”
Their progress is impressive. sulfur nanoparticles as a first Both scientists believe next-
Volans-i has received funding step to practical application. In generation rechargeable sulfur-
from prominent investors such addition, his team is making lithium batteries are very close
as Y-Combinator, and hybrid pouch-cell prototypes (the type to commercialization. “With
battery and gasoline models have of battery used in newer laptops, our accumulated knowledge
achieved a long-range cruise mobile phones and electric cars) over the past few years, we
drone of up to 1,600 kilometers of lithium-sulfur batteries in a are now seeking companies to
at a maximum speed of 322 laboratory at IMRE, while trying work with, and we will have
kilometers per hour. UNICEF to produce a battery pack that more prototype cells by the end
has also recently approached the can power some devices such as of the year,” Zheng says. Seh
company and invited it to bid drones and small robots. adds: “As for magnesium and
in its drone project to distribute Seh’s team is investigating THIS COULD aluminum batteries, we still
vaccines to people on the small batteries that use alternatives PAVE THE WAY don’t fully understand these
Pacific island of Vanuatu. to lithium, such as magnesium emerging battery technologies,
Meanwhile, as many start- and aluminum, which are
FOR THINGS including what is the most
up companies and automakers not only plentiful and much LITHIUM-ION suitable electrode and electrolyte
© 2018 Courtesy of Guangyuan Wesley Zheng

are competing to develop cheaper, but have two to four BATTERIES materials. But we hope to start
prototypes of lithium-sulfur times greater charge capacity. CAN’T making coin cells over the next
batteries, Zheng last year set Using these materials could also HANDLE, 5–10 years and then build bigger
up a company called Coulomb help avoid the issue of dendritic SUCH AS GRID cells that can really impact
Innovation in Singapore with deposits, which are caused by our lives.”
a friend to commercialize the reactivity of lithium metal
STORAGE FOR
lithium-sulfur technology, with and eat away at the effectiveness SOLAR AND For references, visit the online

a focus on material production. and lifetime of the batteries. WIND ENERGY version of this article at:
www.research.a-star.edu.sg/
Zheng is now preparing to However, magnesium and STORAGE. feature-and-innovation/7886

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BEATING
BACTERIA
– LOOKING
BEYOND
ANTIBIOTICS
Genome specialists and bioengineers
have come up with a polymer to
fight superbugs, which could help solve
the world’s antibiotics crisis

8 A*STAR RESEARCH  Issue 11 | April – June 2018
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T
he standard SERENDIPITY: HOW introduced to the bloodstream,
treatment for a COMPUTER HARDWARE LED while leaving human cells alone.
serious bacterial TO INFECTION TREATMENTS Today, Hedrick, the lead scientist
infection is a Last year, the World Health for IBM Research’s advanced
dose of antibiotics, Organization (WHO) released organic materials group, is one of
which slow or halt the a list of 12 of the world’s most Yang’s main collaborators.
infection by hindering critical dangerous superbugs — a move Since then, Yang and a
cellular processes within intended to underline them as the handful of other researchers have
the bacteria. However, some highest priorities for antibiotic looked at various polymers, but
bacteria have evolved devious research. Marie-Paule Kieny, each new iteration encountered
mechanisms to protect the WHO’s assistant director- problems. Biodegradability is one
themselves against antibiotics, general for health systems, was — without a route for excretion,
for instance by producing pointed in a WHO communiqué: non-biodegradable polymers
enzymes that can destroy “If we leave it to market forces could build up in a patient’s body,
the antibiotic molecules, or alone, the new antibiotics we potentially causing problems.
by making themselves less most urgently need are not going Yang’s new polymer is broken
permeable to the antibiotic. to be developed in time […] down via a chemical reaction
The most resilient become The pipeline is practically dry.” with water, the products of which
better at this every time they’re However, a treatment that kills are excreted within days, meaning
exposed to the drugs. The class bacteria and doesn’t stimulate it’s a much more promising
of multi-drug resistant bacteria resistance could represent candidate for drug development.
that have become the most a new chapter in the fight In 2016, a University of
difficult, or, even impossible to against superbugs. Melbourne study published in
treat, are known as superbugs. Yang was aware of the Nature Microbiology attracted
Last year, a UK government problem when her team attention when it found a similar
report suggested that, by started their polymer work, but lack of drug resistance in their
2050, drug-resistant infections superbugs also just pique her polymer. Newspapers put a
could kill one person every curiosity. Bacteria, she says, are positive spin on the fact that it
three seconds. not unlike our own mammalian “ripped the bacteria apart”. But
In March 2018, a team cells in their ability to develop Yang says that, actually, this is
working under Yi Yan Yang, and learn. “They’re very smart.” not really a good thing. “With
a bioengineer from the If bacteria were in a classroom polymers that break down the
Institute of Bioengineering studying survival, superbugs bacteria cell membrane, you
and Nanotechnology (IBN), would be top students, she says. worry that a lot of endotoxins will
published a paper that could Yang, who is also interested be released from the bacteria cells,
signal a break in the spiraling in using nanotechnology for and those endotoxins may cause
battle between antibiotics drug delivery, seeks and attracts sepsis.” In other words, they could
and superbugs. It looks at the interesting collaborators. The be toxic. This was exactly what
properties of an infection- development of the most recent stopped Yang from proceeding
fighting synthetic polymer, the polymer began with multinational with drug trials for a polymer she
most eye-catching element of tech company IBM. While at a published about in 2011 in Nature
Harmful strains of
which is that the polymer doesn’t conference in Australia in 2007, Chemistry. In large quantities,
Escherichia coli bacteria appear to set off an adaptive Yang heard IBM’s James Hedrick endotoxins – toxins present in
can cause infections response in bacteria at all. talk about a unique, positively the membranes of many types
that lead to abdominal
cramps, bloody diarrhea
In their study, Yang and her charged synthetic polymer his of Gram-negative bacteria – can
and vomiting. E. coli team showed that the polymer team had accidentally made cause severe diarrhea, septic
is commonly found in is biodegradable, non-toxic while working on creating shock, and even death. Smaller
the large intestines of
and can kill the Acinetobacter silicon wafers for computer amounts may cause fever, chills,
© MedicalRF.com/Getty Images

mammals, and can be
ingested through food, baumannii superbug within an semiconductor technology. and can lower the number of
particularly undercooked hour. Genomic tests conducted The polymer was of particular white blood cells in the body,
meat or contaminated
water, among other things.
by the Genome Institute of interest to Yang: its positive leading to a compromised ability
Singapore (GIS) then confirmed charge means it has the potential to fight infection.
that the bacteria did not develop to become attached to negatively Yang’s new polymer, by
resistance to the polymer. charged bacteria surfaces when contrast, binds to bacteria

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Another way of treating
resistant bacteria is with
antimicrobial peptides. Here, Bacteria
one kills a bacterium by
penetrating its membrane: a
micelle forms in the bacterial
cell membrane, and the cell
is punctured. By contrast,
Yi Yan Yang’s new polymer
moves through the cell
membrane and condenses
the contents inside, killing the Endotoxins are present
cell. The latter strategy may in the membranes of
help prevent the release of many types of Gram-
dangerous endotoxins from negative bacteria, and,
the punctured bacteria cells. when released, can
cause severe diarrhea,
septic shock, fever,
chills and lower white
blood-cell counts.

cell surfaces, moving through In the first stage of testing With imipenem Yang next looked to

(Bottom) Reproduced from Ref 1. under CC BY 4.0 http://creativecommons.org/licenses/
the cells’ membranes into the the researchers compared the at sub-lethal concentrations, the genomes of the treated
cells. Once inside, the polymer polymer with imipenem, an the group began to see an bacteria for more detail on
condenses the proteins and DNA important injected antibiotic used increase in the effective the mechanisms behind their
inside, killing the cells. The dead in hospitals to treat pneumonia, concentration levels of imipenem findings. It was the team of Paola

(Top) © NICOLLE R. FULLER/Science Photo Library/Getty Images
bacterial cells are then digested sepsis, joint infection and several within eight to ten applications. Florez de Sessions at A*STAR’s
by macrophages, and preclinical other bacterial infections. They did By contrast, the same effective Genome Institute of Singapore
tests showed that the products this by repeatedly applying sub- concentration of their polymer who were tasked with analyzing
of the polymer are excreted lethal concentrations of the two stayed roughly the same even the antibiotic and polymer-
within days. agents on A. baumannii bacteria after 30 applications at sub- treated bacteria’s genes using
Getting all these and looking for changes in the lethal concentrations. RNA sequencing.
elements right took years of concentration at which the agents The group then proved In the imipenem-treated
communication between Yang were effective. “Any increase in that the polymer is not toxic to bacteria, the team observed an
and chemists at IBM, who the effective concentration of mice and is effective against five upregulation of genes associated
worked on the polymer design. antimicrobial agents against the globally important superbugs: with imipenem resistance, as
They eventually settled on a resilient bacteria means that the E. coli, methicillin-resistant well as those linked to resistance
guanidinium-functionalized bacteria have developed resistance Staphylococcus aureus (MRSA), against other classes of antibiotics
polycarbonate, which was then against the antimicrobial agents,” P. aeruginosa, K. pneumoniae and — a clear indication that the
synthesized in Yang’s laboratory. explains Yang. A. baumannii. imipenem-treated bacteria had

NOTE ON THE TERM ‘SUPERBUGS’
We’d like to note that, although commonly used, many microbiologists are trying not to proliferate the use and
misuse of the term ‘superbug’. The Mayo Clinic defines superbugs as “a term used to describe strains of bacteria
that are resistant to the majority of antibiotics commonly used today”. In this story, the term refers to bacteria
that are resistant to many drugs.

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developed cross-resistance, which
eventually leads to multi-drug
IBM’S what genome specialists already
know about bacterial resistance
high cost and unstable. That’s why
there are very few anti-microbial
resistance. By contrast, none of HEDRICK regulation. Those are already peptides in the clinic, and those
these genes were upregulated in DESCRIBES well-annotated responses, she peptides are only used in topical
the polymer-treated bacteria.
These results, together with the
IT AS THE says. GIS and IBM can then run
the treated bacteria’s genomic
applications.” Until now, polymers
had been a relatively untapped
other studies, strongly reinforce BEGINNING data through a machine-learning direction for drug research.
the polymer’s promise as an OF A NEW program and highlight any other “Compared to peptide people
effective, broad-spectrum and
long-lasting antibacterial agent.
CLASS OF patterns that might be relevant to
a person’s health outcome.
there are still very few polymer
people — although they’re now
TREATMENTS. As for Yang, she thinks increasing,” Yang explains.
THE BRAVE NEW WORLD synthetic polymers have the Yang and her team are
OF MACROMOLECULAR potential to provide a better and looking for partners to start
THERAPEUTICS cheaper response than one of the working on the comprehensive
GIS and gene sequencing will main alternatives to antibiotics preclinical studies they will need
also be key to the next stage of — peptides (there are others before they can start to look at
research on the polymer. Hedrick alternatives, including immune clinical trials.
has described the March paper modulation, antibody therapy
as the beginning of a whole new and phage therapy). Peptides are For references, visit the online
class of treatments, which he calls “not actually that stable in vivo” version of this article at:
‘macromolecular therapeutics’. and can easily be degraded by www.research.a-star.edu.sg/
While Hedrick may be correct enzymes, she notes. “So they’re feature-and-innovation/7849
in describing their findings as
seminal, the field’s newness
means that to move toward drug
development, Yang and GIS will GENOMICS FOR SUPERBUG OUTBREAKS Chen’s lab was called upon in 2015
have to continue to rigorously Genome technology’s dramatic drop in price when Singapore had an outbreak of Group B
test the polymer, which they are over the last few years has a lot to offer for the Streptococcus. Throughout that year, a severe
doing in collaboration with the study of infection, says Florez de Sessions. and invasive strain of this bacteria caused
U.S. National Institutes of Health. She adds that some of GIS’s current work serious infections including meningitis, septic
However, the hope is that supports economic arguments for using arthritis and spinal infection in over 300 people
— just as genome technology genomic analysis to isolate and halt superbug who were often young and otherwise healthy.
accelerates new discoveries — it outbreaks. A recent GIS study showed that However, many of these patients had recently
can help to speed up the vetting of whole-genome sequencing was very effective consumed raw freshwater fish. After fishmongers
drugs as well. Florez de Sessions at revealing the development of a Streptococcus and food handlers were screened and shown not
says GIS is keen to harness IBM’s outbreak in a male ward in a 200+ patient to be carriers of the superbug, Chen’s lab led the
machine-learning technology psychiatric hospital. GERMS genome sequencing effort to identify
to look in the treated bacteria “Even though the upfront sequencing the bacteria causing the infection.
sequence data for any other costs are more, if you have an outbreak in a By analyzing the genome sequences of
important patterns that might hospital and say you have to keep screening bacteria isolated from sick patients and fish
affect a person’s health. and swab all patients once a month for six dishes, Chen and his team provided genomic
“The premise of this months and they’re approximately $12 swabs, evidence that traced the infections to two
particular study is that the now, suddenly, by sheer numbers and sheer types of fishes, Song (Asian bighead carp) and
polymer is relatively inert amount, it ends up being cheaper to do whole- Toman (snakehead fish), which are used in yu
compared to the standard-of- genome sequencing.” sheng, a raw fish dish often served with congee.
care antibiotics, imipenem or While Florez de Sessions leads the GIS This corroborated traditional epidemiological
penicillin … or other antibiotics,” Efficient Rapid Microbial Sequencing (GERMS) studies suggesting that the infections
she says. “So, you don’t see a platform, GERMS consists of three labs: Swaine were emanating from those consuming
resistance, you don’t see some of Chen’s lab focuses on infectious diseases; contaminated raw fish. To prevent future
the things that you expect from Niranjan Nagarajan’s lab on computational and outbreaks, Singapore’s National Environment
antibiotics … but what about systems biology of microbes; and Florez de Agency has now banned food outlets from
the things that we don’t know?” Sessions’ lab on microbial sequencing. serving raw freshwater fish dishes.
What GIS can do, says Florez de
Sessions, is help to show IBM

www.research.a-star.edu.sg A*STAR RESEARCH 11
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The new voltage-sensing
scheme helps to address
one of the biggest
challenges for spin-based
memory— accurately
reading the difference
between binary on (1) and
off (0) states.

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to Trinh. The reference voltage
frequently unintentionally flips
SPIN the bitcell, or reads the wrong
MEMORY
memory state if the read margin
is small.
Trinh, Ruocco and Alioto
realized that they could avoid
read errors if they were to sense
DYNAMIC the bitline voltage and adjust the

SOLUTION reference voltage in response,
so that the read margin always
FOR ACCURATE remains high.

READING “Our new dynamic reference
scheme generates two reference
values, one for reading logic 0
A sensing scheme that
and another for reading logic
responds dynamically to 1,” explains Trinh. “In logic 0
voltage fluctuations could state, a small readout signal is
compared to a large reference
improve accuracy when
value, while in logic 1 state, a
reading data from spin-based large readout signal is compared
memory storage to a small reference value.”

‘‘STT-MRAM
is the leading
A voltage sensing scheme fast, high-density, low-power
candidate
developed by researchers alternative to existing charge-
from Singapore could based memories.
for future
improve the accuracy of “STT-MRAM is the non-volatile,
reading data from spin- leading candidate for future universal memory
based memory systems with non-volatile, universal technology.’’
only minimal modifications. memory technology,” says
The scheme responds Trinh. “It could serve in The team’s simulations
dynamically to voltage changes consumer devices, corporate suggest that their dynamic
in the system, so that it can data centers, and even high- reference scheme could be
better discern whether it is end critical applications such incorporated into existing STT-
reading a binary on (1) or as unmanned vehicles, aircraft, MRAM systems with minimal
off (0) state. and military.” modifications, and would
The cutting-edge data In STT-MRAM systems, reduce read errors by two orders
storage technology, called data bits are stored as either of magnitude.
spin-transfer torque magnetic 1s or 0s by flipping the “We look forward to
random-access memory orientation of magnetized exploiting the synergy between
(STT-MRAM), encodes data ‘bitcells’. To read a bitcell, our dynamic reference scheme
using the intrinsic angular the system compares its own and existing circuits,” says
© RICHARD KAIL/Science Photo Library/Getty

momentum of electrons reference voltage to the ‘bitline’ Trinh. “We are also working
— their spin, instead of voltage across the bitcell — the on solutions to reduce the
their charge. Quang-Kien 1 or 0 state is then identified energy consumption and
Trinh, Sergio Ruocco from based on the difference between design complexity.”
the A*STAR Data Storage the two voltages, called the
Institute and Massimo Alioto read margin. 1. Trinh, Q.-K., Ruocco, S. &
© xxxxxxxxxxxxxx

Alioto, M. Dynamic reference voltage
from the National University However, “the memory read
sensing scheme for read margin
of Singapore are at the forefront operation is recognized as one improvement in STT-MRAMs.
of global efforts to prove that of the major roadblocks of this IEEE Transactions on Circuits and
STT-MRAM can provide a emerging technology,” according Systems 65, 1269−1278 (2017).

www.research.a-star.edu.sg  A*STAR RESEARCH 13
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A high-fat diet could aggravate symptoms than the mice on the suggested that it was in fact
skin diseases such as psoriasis normal diet. the high-fat diet, and not the
OBESITY
by increasing the level of To understand this, the resulting obesity, that was
inflammatory cytokines in team took a closer look at contributing to higher levels of
the skin, an A*STAR-led what was happening to the skin inflammation.
study finds. immune cells in the skin of the While most people know
Previous research has obese mice. They discovered that a high-fat diet is associated
suggested that obesity is that the cells lining the blood with heart disease and diabetes,
HIGH-FAT a trigger for psoriasis, a vessels in the skin were putting not many would think about its
DIET LINKED disease characterized by
scaly, itches patches on the
out chemical signals that
caused an increase in a type
potential to cause skin disease,
says Satoshi Nakamizo, from
TO SKIN skin, thought to be associated of immune cell called a T cell. the Singapore Immunology
CONDITIONS with the immune system. So
researchers from A*STAR, and
This T cell produced another
chemical messenger called
Network and Institute of
Medical Biology at A*STAR.
A high-fat diet may colleagues in Japan, set out to IL-17, which is associated with “A high-fat diet acts on a
explore the cause underlying increased inflammation. large blood vessel such as the
worsen inflammatory the link between obesity But the researchers heart, causing arteriosclerosis,
skin conditions and psoriasis. still weren’t sure whether but it also acts on small
such as psoriasis Their study compared it was the obesity itself, or blood vessels of the skin and
obese mice which had been the high-fat diet that was causes skin inflammation,”
fed a high-fat diet and lean responsible for the immune Nakamizo says. “Diet and
mice on a normal diet. Both changes in the mice’s weight management are
groups of mice were treated skin. To answer this, they important not only for systemic
with a drug called imiquimod repeated the treatment on diseases but also for preventing
that can induce a psoriasis-like mice that were genetically skin diseases.”
skin condition. engineered to be obese even
After five days of without the input of a high- 1. Nakamizo, S. Honda, T. Adachi, A.
Nagatake, T. Kunisawa, J. et al.
imiquimod treatment, they fat diet. They found that
High fat diet exacerbates murine
noticed that the obese mice these mice responded to the
psoriatic dermatitis by increasing
that had been fed the high-fat imiquimod treatment in a the number of IL-17-producing
diet exhibited significantly manner similar to that of γδ T cells. Scientific Reports 7,
greater psoriasis-like lean, normal diet mice, which 14076 (2017).

A high-fat
diet makes
inflammatory
skin disease
© 2018 A*STAR Institute of Medical Biology

worse in mice.

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CANCER

THE STOMACH’S
‘CHIEF’ SOURCE OF
STEM CELLS The study
revealed that
Stem cell reserves found Lgr5-expressing
chief cells in the
in the stomach have corpus glands
implications for the genesis can become
gastric cancer
of gastric cancer precursors.

A team of researchers at where these stem cells reside In addition, the team helping to clarify the
A*STAR has found that — at the bottom of small has implicated these ongoing debate.”
certain cells in the stomach, pits in the stomach known cells in the genesis of In the future, the
called chief cells, become as corpus glands. They gastric cancer — the fourth team intends to explore
stem cells in response to discovered in a mouse model leading cause of cancer exactly what causes
injury, providing a source of that certain cells in this globally, according to the the cells to become stem
new cells1. As well as being World Health Organization. cells. “We are interested
significant for understanding They discovered that in better understanding
Reprinted by permission from Ref. 1 © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

how the stomach lining ‘‘The theory that when these cells undergo the mechanism
renews itself, the finding chief cells can a mutation, they become responsible for converting
sheds light on how gastric be activated a major source of tumors the normally quiescent,
cancer can begin. to serve as the at the base of the corpus differentiated chief
The stomach wall is a precursor to glands (see image above). cells into proliferative,
hostile place for cells, as they gastric cancer “The theory that multipotent stem cells,”
are constantly subjected under damage chief cells can be activated says Barker. He notes
to mechanical stress and conditions is to serve as the precursor that the same mechanism
high acidity and must be to gastric cancer under could be at play when the
controversial.’’
continually replaced. The damage conditions is cells become cancerous.
most likely source of such controversial,” says “We hope that these
reinforcements is adult stem location express the gene Barker. “Indeed, a recent findings will contribute
cells, but identifying these Lgr5, a marker of stem cells study concluded that to translatable clinical
cells has been challenging. in various organs, including other cells are the true outcomes,” he adds.
“The identity of the the intestine and skin. The precursors of cancer,
gastric stem cells has been researchers also found not chief cells. In this 1. Leushacke, M., Tan, S.
H., Wong, A., Swathi, Y.,
contentious,” says Nick that these cells are not study, we conclusively Hajamohideen, A. et al.
Barker of the A*STAR normally stem cells; rather, identified Lgr5+ cells as Lgr5-expressing chief cells
Institute of Medical Biology. they become stem cells in a source of spasmolytic drive epithelial regeneration
and cancer in the oxyntic
Now, Barker and response to damage to the polypeptide-expressing stomach. Nature Cell Biology
his co-workers have located stomach wall. metaplasia (SPEM), 19, 774−786 (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 15
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When liver capsular
macrophages, a
type of immune cell,
sense bacteria, they
recruit neutrophils,
which crawl up
their dendrites
to eliminate the
invading foreigner.

A distinct population of immune colleagues in Australia, used a
cells found under the fibrous fluorescent imaging technique,
capsule that surrounds the called two-photon microscopy to
IMMUNOLOGY
liver has been identified by an investigate this further.
international team. The cells, They found that their shape
called liver capsular macrophages, was different from Kupffer cells,
protect the liver from bacteria an immune cell residing in the
© KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty

in the peritoneal cavity that lies liver’s tissue that protects it from
NEWLY IDENTIFIED between the abdominal wall bacteria circulating in the blood.
CELLS IN LIVER and the membrane covering
abdominal organs.
The combination of molecules on
their surface distinguished them
PROTECTION ROLE Researchers had observed from other types of immune
immune cells in the liver’s cells, including Kupffer cells.
A subset of immune capsule almost 30 years ago, When the team analyzed the
cells in the liver shields it but had not agreed on what cells’ gene expression, they found
from bacteria in the gut type they were. Scientists from it similar to — and so classified
A*STAR’s Singapore Immunology them as — macrophages, a type
Network, in collaboration with of white blood cell that engulfs

16 A*STAR RESEARCH  Issue 11 | April – June 2018
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and destroys cellular debris, Advances in materials metamaterials with specific
microbes, and cancer cells. engineering have led to the mechanical and thermal
The team also found that these MATERIALS development of lightweight properties,” explains Daynes.
‘liver capsular macrophages’ structures that are both “Using a new biomimetic
were replenished by blood strong and stiff, which are method, we were able to create
monocytes, unlike Kupffer cells transforming aerospace, cellular and lattice structures
that self-renew. automotive and medical similar to those seen in bamboo

NATURE
These newly identified cells industries. Conventional and human bones.”
have branches, or dendrites, manufacturing techniques The researchers
that extend toward bacteria and INSPIRES like casting and machining, determined the principal lines

LIGHT,
other foreign substances. They however, limit the designs of stress, called isostatic lines,
are also involved in recruiting that can be fabricated as they in the lattice using a method
another type of immune ROBUST are prone to inaccuracies that combines topology

LATTICE
cell, neutrophils, to the liver. and struggle to achieve the and size optimization. This
Neutrophils crawl along the liver best results. approach allows the size,
capsular macrophages’ dendrites
to reach the liver capsule and
STRUCTURES Now, scientists at
A*STAR have invented a
shape and orientation of
each cell in the structure
provide additional immune New technique for method that uses additive to be tailored, significantly
protection against infection. creating lightweight manufacturing techniques reducing the stress between
“This study represents how to create lightweight neighboring lattice cells.
two-photon microscopy can
materials that are stiffer lattice structures with The researchers compared
contribute to the discovery and stronger than greatly improved stiffness the performance of their
of new immune cell subsets,” previously possible and strength1, paving the graded lattice structure with
says A*STAR immunologist way for new materials a uniform lattice core and
Lai Guan Ng, one of the for use in a wide range of found that their optimized
study’s co-authors. “Our study applications including impact design had increased stiffness
discovered that liver capsular absorbent materials and by 172 per cent and strength
macrophages serve as sensors sandwich structures. by 100 per cent.
for peritoneal bacteria and The design and “Our technique
recruit neutrophils to fight optimization of lightweight can create lightweight,
infection. This study shows cellular and lattice structures functionally graded lattices
that the liver has two separate is an emerging field made that greatly improve the
and non-overlapping niches possible by advances in stiffness and strength of
occupied by distinct resident metal and polymer additive additively manufactured
macrophage populations: manufacturing, such as the sandwich structures without
Kupffer cells in the liver for ability to accurately print increasing their mass,” says
mediating protection against highly complex geometries. Daynes. “These structures
systemic bacterial infection, By mimicking structures are particularly well suited
and liver capsular macrophages occurring in nature, Stephen to additive manufacturing
for protection against Daynes and colleagues processes since they are
Reproduced, with permission, from Ref. 1 © 2017 Elsevier

intraperitoneal infection.” from A*STAR’s Singapore largely unconstrained by
Ng says he is interested in Institute of Manufacturing manufacturing complexity.”
further investigating how liver Technology have developed “We plan to apply
capsular macrophages respond a method to create these the methodology to three
to liver diseases, and how they new robust materials in dimensional stress fields, where
are related to susceptibility collaboration with researchers employing spatially graded
to infection. from the National University lattices can lead to novel and
of Singapore. more weight efficient materials,”
1. Sierro, F., Evrard, M., Rizzetto, S., “Lattice structures exceed says Daynes.
Melino, M., Mitchell, A. J. et al.
A liver capsular network of the structural performance of
monocyte-derived macrophages conventional solid materials 1. Daynes, S., Feih, S., Lu, W. F., &
restricts hepatic dissemination Wei, J. Optimisation of functionally
for use in lightweight sandwich graded lattice structures using
of intraperitoneal bacteria by Lattice designs: (top) uniform
neutrophil recruitment. Immunity benchmark, (middle) diameter graded cores, medical implants and isostatic lines. Materials & Design
47, 374–388 (2017). and (bottom) spatially graded. a new class of lattice-type 127, 215-23 (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 17
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CELLS

GLARING LESSONS
ON SKIN AGING
A protein can be used to
measure the aging effect of
sun exposure on skin cells

Levels of a protein called lamin be experienced by someone
B1 could be used to measure spending around 18 minutes
how sun exposure accelerates in the Singaporean sun in the
skin aging. middle of the day.
Lamins are components of They found that in the
the nuclear lamina, a fibrous UVB-exposed cells, the levels of
layer on the nucleoplasmic side lamin B1 dropped, while in cells
of the inner nuclear membrane, that were protected with SPF50
which is thought to provide sunscreen, the levels remained
a framework for the nuclear the same, suggesting that the
envelope and may also interact UVB exposure was leading to
with chromatin. Researchers cell senescence.
from A*STAR and their
colleagues were studying the
cells of patients with progeria, ‘‘Lamin B1 could
a genetic disorder that causes be a useful new
them to age and die prematurely, marker to identify
when they realized that these aging cells.’’
patients’ senescent cells — those
that have stopped growing and
dividing — showed very low The researchers also wanted
levels of lamin B1. to know how UVB exposure
Lamin B1 stained green in human skin cells.
“Lamin B1 is expressed affected cells in different skin
in every cell type of the layers, so, in collaboration with
human body, so if this protein Carlos Clavel, also from the UVB exposure and the skin “The long-term goal is to
disappears when cells age, it Institute of Medical Biology, they regenerated, the levels of lamin set up a toolkit that allows us
could be a useful new marker to looked at lamin B1 levels in mice B1 returned to normal. to systematically look at how
identify aging cells,” says Oliver whose skin was treated with As well as providing a way senescent cells contribute to
© 2018 A*STAR Institute of Medical Biology

Dreesen, from the A*STAR UVB light daily for ten days. to measure sun damage of skin pathological and cosmetic
Institute of Medical Biology. “In our experiment, UVB light cells, lamin B1 levels could also changes that occur in aging
Researchers decided to use only affected the epidermis, the help in the study of age-related skin,” Dreesen says.
this knowledge to look at the top layer of the skin, and it didn’t skin problems such as actinic
effects of ultraviolet light on skin seem to affect the dermis, which is keratosis, which is caused by 1. Wang, A. S. Ong, P. F. Chojnowski,
A. Clavel, C. Dreesen, O. Loss
cell aging. To begin with, they the lower part,” Dreesen says. sun exposure. It could also help
of lamin B1 is a biomarker to
exposed human skin cells in a The researchers also explore the impact of other quantify cellular senescence in
petri dish to the same amount noticed that once the mice’s environmental conditions, such photoaged skin. Scientific Reports 7,
of ultraviolet B light that might skin recovered from the as pollution, on skin aging. 15678 (2017).

18 A*STAR RESEARCH  Issue 11 | April – June 2018
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in male fetuses than female But these differences are
ones. Conversely, in adult mice, highly suggestive since men are
females were more sensitive known to be more susceptible
MICROBIOME than males to the absence of than women to disorders such
the microbiome or its depletion as autism, and the early onset
through the use of antibiotics. of schizophrenia, both of which
are thought to originate from
‘‘This was really dysregulated development in
fetuses or early in life. On the
dramatic, we
GUT BACTERIA never thought
other hand, women are more

AFFECT THE BRAIN, that a fetus, which
likely to suffer from depression
and autoimmune diseases such
EVEN IN THE WOMB is inside a mother,
would be affected
as multiple sclerosis, which can
develop in teenagers or adults.
The effect of gut microbes on by her lack of a The team intends to
the mouse brain depends on both microbiome.’’ look at subtle changes to
the microbiome that more
sex and stage of development The scientists are as yet accurately reflect those likely
unsure what is causing this to occur in real life. They
difference. “At this stage, there also plan to investigate how
Immune cells in a mouse’s brain be affected by her lack of a is no really clear mechanism different treatments, such as
react differently to changes in microbiome. We had previously that explains why males are antibiotics or changes to diet,
gut-dwelling bacteria depending believed that the brain of a fetus so sensitive to this change,” can modulate microglia identity
on whether the mouse is male or is a closed system, not subject says Ginhoux. “We think there and function during pregnancy
female and whether it is a fetus to perturbations, and that it was may be a crucial window of and adulthood.
or an adult, A*STAR researchers only when the fetus goes out of development during which cells
have found1. This discovery has the womb, that the environment are very sensitive to changes in 1. Thion, M. S., Low, D., Silvin, A., Chen, J.,
Grisel, P. et al. Microbiome influences
potential implications for brain can influence it.” the environment, which is here prenatal and adult microglia in
development and disorders. This effect on microglia exemplified by the absence of a sex-specific manner. Cell 172,
Recently, scientists have was much more pronounced the microbiome.” 500−516 (2018).
found increasing evidence that
the microbes in our digestive
system, collectively known as
the microbiome, can affect the
brain via the metabolic products
they produce.
Now, Florent Ginhoux from
A*STAR’s Singapore Immunology
Network and an international
team of researchers have found
that this influence goes all the
way back to the womb. By
performing microscopy and
genomic analyses, they have
© KATERYNA KON/SCIENCE PHOTO LIBRARY

shown that, in mice, the absence
of a microbiome in a mother
affects the microglia, one of the
major immune cell populations of
the central nervous system, of her
developing fetuses.
“This was really dramatic,”
says Ginhoux. “We never
thought that a fetus, which
is inside a mother, would A*STAR researchers have shown that the bacteria in the gut can affect the microglia in a mouse’s brain.

www.research.a-star.edu.sg A*STAR RESEARCH 19
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A promising new type
of laser spectroscopy
developed at A*STAR
exploits the strange
phenomenon of quantum
entanglement to make
measurements of extremely
fast atomic processes, even
with low-cost lasers.

20 A*STAR RESEARCH  Issue 11 | April – June 2018
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MEASUREMENTS
LASER
SPECTROSCOPY THROUGH
ENTANGLEMENT
The extremely short relaxation times of
atoms can be measured by using quantum-
entangled photons

A new approach to laser different atoms or molecules After assembling and
spectroscopy based on quantum of the substance respond as aligning their HOM setup,
physics makes it cheaper and a coherent ensemble. For the team could measure
easier to observe ultrafast many substances this time lies the level of entanglement
processes inside materials, say within the femtosecond time in a beam by placing two
A*STAR researchers. scale (10-15 seconds) and is not photodetectors at the
In general, spectroscopy easy to measure.” beamsplitter outputs. If both
involves shining a laser on detectors clicked at the same
a sample and observing the ‘‘In the future time, then there was no
effect of the laser light to we will use this entanglement, but if only one
work out what is going on technology to detector clicked, the photons
inside the sample. However, were entangled.
study chemical
some processes in materials “When a sample is
and biological
happen so quickly that placed into the path of
very expensive lasers and
samples, with one of the photons, it
sophisticated detector systems even shorter causes the photon to become
are needed to observe them. dephasing times.’’ less identical to its twin,”
Powerful lasers can also explains Kalashnikov.
damage samples. Instead of investing in “Therefore, the distribution
Now, Dmitry costly femtosecond lasers, of clicks changes, and we
Kalashnikov and colleagues Kalashnikov’s team used a can estimate the dephasing
at the A*STAR Data Storage continuous-wave laser configured time.” Through this method,
Institute, Moscow State for Hong-Ou-Mandel (HOM) the researchers measured
University, and the Russian interference. This interference dephasing times as short
Academy of Sciences, effect describes what happens as 100 femtoseconds, in
have demonstrated a when quantum-entangled neodymium-doped crystals
method that exploits the photons, which are effectively and silicon nanodisks.
strange phenomenon of indistinguishable and “In the future we
quantum entanglement dependent on one another, will use this technology to
to measure extremely hit a semi-transparent mirror study chemical and biological
short-lived processes called a beamsplitter. samples, with even shorter
inside materials without “When HOM interference dephasing times,” says
expensive equipment. was discovered in the 1980s it Kalashnikov. “Our work
“By measuring the became the true manifestation could also be important
time over which a sample of quantum mechanics,” for developing quantum
responds to electromagnetic says Kalashnikov. “When computer memory.”
fields, we can learn about two entangled photons hit a
the connections between beamsplitter from different 1. Kalashnikov, D., Melik-Gaykazyan, E. V.,
© xxxxxxxxxxxxxx

© Stockbyte/Getty

Kalachev, A. A., Yu, Y. F., Kuznetsov, A. I.
components in the substance,” sides they always exit
& Krivitsky, L. A. Quantum interfer-
says Kalashnikov. “In particular, together from one or another ence in the presence of a resonant
the so-called dephasing beamsplitter outputs; they never medium. Scientific Reports 7,
time describes how long exit separately.” 11444 (2017).

www.research.a-star.edu.sg  A*STAR RESEARCH 21
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ConsensusDriver is
a new computational
method that integrates
the results from
multiple analyses to
improve prediction of
cancer drivers.

Combining different analyses has different ways of approaching
enabled A*STAR researchers to the problem. The performance of
MUTATIONS better identify gene mutations, the five approaches varied, with
which could lead to improved differing results based on the
personalized treatments. implicit tradeoffs in each. The
A major issue in cancer methods were generally robust to
genomics has been distinguishing messy data and weren’t misled by
between harmless mutations fake mutations introduced by the
PINPOINTING and ‘cancer driver’ mutations researchers. However, they also

CANCER that give rise to or exacerbate
cancer. Many computational
failed to predict any drivers in
10 per cent of the patients.
DRIVERS methods have been developed
to tackle this challenge, spurring ‘‘We’ve been
A consensus-based Niranjan Nagarajan of A*STAR’s excited about the
computational approach Genome Institute of Singapore concept that you
improves prediction to compare the performance of can pinpoint the
key alteration
© 2018 A*STAR Genome Institute of Singapore

different approaches. “We’ve been
of gene mutations excited about the concept that you among thousands.’’
linked to cancer can integrate diverse molecular
profiling data for tumors and Many of the methods
pinpoint the key alterations among predicted different drivers,
thousands,” says Nagarajan. which led the team to develop
Using data from 3,400 tumors a consensus approach that
spanning 15 cancer types, the integrated results from the
team assessed 18 prediction different methods, known
methods which represented five as ConsensusDriver, which

22 A*STAR RESEARCH  Issue 11 | April – June 2018
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consistently outperformed
the individual methods. In BUILDING A BETTER
addition, ConsensusDriver can
determine whether unfamiliar
CHEMISTRY ION CHANNEL
mutations are cancer drivers. A synthetic channel with a strong preference
“Most groups approach
for potassium ions offers rapid transport
the question from a basic
cancer biology perspective through an artificial membrane
of finding key cancer genes.
Our interest has always been
to go beyond this and see Artificial ion channels developed developed to mimic and based ‘tail’. These molecules
how far we can move towards by A*STAR researchers could eventually surpass the functions can self-assemble so that the
personalized medicine,” says pave the way for new kinds exhibited by naturally-occurring crown ether rings line up to
Nagarajan. “If methods like of antibacterial agents and protein channels.” However, it form a tube, which acts as an
ConsensusDriver were used for biomedical sensors1. has been difficult to develop ion channel.
precision oncology, it would Ion channels are biochemical artificial channels that have a The researchers created
double the number of patients superhighways that enable ions strong selectivity for potassium a library of molecules using
for whom we would be able of metals such as potassium and over sodium ions. various amino acids, different
to recommend treatments,” sodium to zoom in and out of Zeng and colleagues have lengths of alkyl chains, and
though he adds that precision cells. Crucially, the channels are now developed ion channels crown ethers that contained
oncology remains a distant typically very selective, allowing that offer rapid potassium ion five or six oxygen atoms. Then
goal requiring extensive only one type of ion through transport with a selectivity that they formed membranes from
clinical validation. and barring others. For example, is among the highest reported the stacked channels, and tested
The team has made the naturally-occurring KcsA for any artificial ion channel. their ion transport properties.
their research tools freely potassium ion channel can The channel is formed from a The most selective channel
available online, providing transport 100 million ions per series of identical molecules they studied contained a crown
the community with a second, and only lets one sodium that stack on one another. ether with five oxygen atoms,
convenient toolbox to run the ion through for every 10,000 Each molecule contains three a phenylalanine amino acid,
18 predictions methods as potassium ions. components. At one end is a and an alkyl chain containing
well as ConsensusDriver. With “But protein-based ion crown ether, a large ring of eight carbon atoms. This could
improved predictions from channels are costly and carbon and oxygen atoms; in the transport 30 million ions per
consensus-based methods, difficult to manipulate,” says middle is an amino acid, which second, and was about ten times
researchers may be able to find Huaqiang Zeng at the A*STAR contains chemical groups that more selective for potassium ion
new drug targets by identifying Institute of Bioengineering and allow the molecules to stack in than sodium ions. This offers a
genes which are frequently Nanotechnology. “Synthetic a specific pattern; and at the much better performance than
drivers across different versions are therefore being other end is a long, carbon- previous artificial potassium ion
Reprinted with permission from Ref. 1. Copyright (2017) American Chemical Society

cancer types. channels based on crown ethers
Meanwhile, Nagarajan’s or other molecular scaffolds.
team is developing sophisticated The molecules’ three
machine-learning techniques components can be readily
to predict drug response in altered to fine-tune the channels’
individual patients, as well as properties, so Zeng is optimistic
validating the predictions using that his team can improve their
cell cultures and exploring the performance further. They hope
value of single-cell approaches to test their optimized systems
in predicting cancer drivers in medical applications, such
and treatments. as antibacterial agents or hair
growth promoters.
1. Bertrand, D., Drissler, S., Chia,
B. K., Koh, J. Y., Li, C. et al. 1. Ren, C., Shen, J. & Zeng, H.
ConsensusDriver improves Combinatorial evolution of fast-
upon individual algorithms for conducting highly selective
predicting driver alterations K+-channels via modularly tunable
in different cancer types and directional assembly of crown ethers.
individual patients. Cancer This scanning electron microscope image shows that the artificial ion channels Journal of the American Chemical
Research 78, 290-301 (2018). self-assemble into fibers. Society 139, 12338–12341 (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 23
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CANCER
TREATMENT

PHOTOTHERMAL
THERAPY BLOOMS
Flower-shaped gold
nanocrystals are too hot
to handle for tumor cells

Gold nanocrystals
grown in star
fruit juice formed
flower-shaped
structures.
100nm

Gold nanoflowers grown in chemicals called capping agents all the time in tropical infrared laser light was shone on
starfruit juice are promising can be added to direct the areas, and because starfruit cells mixed with nanoflowers, 30
agents for photothermal crystals’ growth. is rich in vitamin C, which seconds of illumination killed
cancer therapy. When injected “Capping agents will serves as the reducing every cell within the laser spot. In
into a tumor and irradiated attach to different facets agent, and polyphenolic tests with mice, photothermally-
with near-infrared laser of the nanocrystal nuclei,” antioxidants,” says Ye. As treated animals’ tumors gradually
light, the nanoflowers heat says Ye. “They regulate the the team had predicted, the disappeared — whereas in
up and kill the cancer cells crystal’s growth and stabilize vitamin C initiated and animals given either laser
around them. the final nanocrystals.” directed nanocrystal growth, irradiation only, or nanoflower
Although photothermal However, conventional capping and the polyphenolic injection alone, the tumor
therapy is an established agents are not biocompatible, compounds acted as continued its rapid growth.
idea, the agents developed so they need to be eliminated capping agents, coating the The team now plans
so far have had drawbacks, before the nanocrystals are to take the research in two
explains Enyi Ye from the used for therapy. Removal, ‘‘We will directions, says Ye. “We
A*STAR Institute of Materials however, can be difficult and will continue to develop Reprinted from Ref. 1 with permission of The Royal Society of Chemistry
continue to
Research and Engineering, may damage the nanocrystal’s develop green green methods to prepare
who co-led the current work. shape, impairing its multifunctional nanocrystals.
methods
The challenge is to achieve light absorption. We would also like to
high efficacy, stability and Ye and his colleagues tried
to prepare further exploit the practical
biocompatibility in the same an alternative ‘green’ approach,
multifunctional applications of the gold
nanocrystal, which all relate using a natural material they nanocrystals.’’ nanoflowers in areas such as
to the way the nanocrystals hoped would contain the wound healing and bacterial
are grown. biological equivalent of capping flower-shaped nanocrystals infection control,” he says.
A nanomaterial’s shape agents. This would negate the with a stabilizing,
1. Yang, D.-P., Liu, X., Teng, C. P., Owh, C.,
dictates its light capturing need to remove the compounds biocompatible surface.
Win, K. Y. et al. Unexpected
ability. During the synthesis of before nanocrystal injection into The gold nanoflowers showed formation of gold nanoflowers
nanocrystals, when gold ions the patient. strong near-infrared light by a green synthesis method as
agents for a safe and effective
are mixed with a reducing agent “I selected starfruit absorption, and were non-toxic to photothermal therapy. Nanoscale 9,
to precipitate crystal formation, juice because it is available cells. When 808 nanometer near- 15753–15759 (2017).

24 A*STAR RESEARCH  Issue 11 | April – June 2018
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The discovery of a genetic differentiation,” Sampath
STEM CELLS ‘switch’ that triggers stem cells says. “With the down-
to turn into heart cells is a regulation of this gene, the
major step in finding treatment cells start differentiating into
for damaged hearts. cardiomyocytes.”
Researchers from A*STAR The NR2F2 protein has

AIMING FOR and their colleagues in India
have been investigating
not previously been linked
to cardiac differentiation, but
THE HEART the molecular and genetic
processes by which human
mutations in the NR2F2 gene
have been known to cause
Genetic switch activates embryonic stem cells the development of a type
transformation of stem cells differentiate into the body’s of congenital heart defect.
many types of cells — in “While it’s unlikely to be the
into heart muscle cells particular, cardiomyocytes, or only mechanism involved in
heart muscle cells. the differentiation of stem
“The effort is underway cells into cardiac cells, it’s an
globally to find ways to important step in the process”,
differentiate these stem cells says Mohsin Bin Bashir, also
into beating functional heart from the Institute of Medical
muscle cells so that they can be Biology. “If we can understand
used for cell-based therapies to how a stem cell becomes a
treat structural abnormalities,” cardiomyocyte, we have more
says Prabha Sampath, from chance of creating these cells in
the A*STAR Institute of a controlled fashion.”
Medical Biology. That process could also
In this study, researchers be used in reprogramming
used a method called adult stem cells, where normal
transcriptome profiling, which cells are taken from a patient,
examines the activity of a reprogrammed back into
wide range of genes in a cell, their stem cell state, then
to determine which are more differentiated into whatever cell
active when human embryonic type is needed for treatment.
stem cells differentiate into “You can convert them
heart cells. into cardiomyocytes and put
Two particular genes, them back into the patient,
NR2F2 and EZH2, show and one of the advantages with
increased expression during that [process is that] there
the differentiation process. would be no immune rejection
© Science Photo Library - MEHAU KULYK/Brand X Pictures/Getty

The proteins that these genes because these cells come
code for suppress the activity from the patient themselves,”
of another gene called OCT- Bashir says.
4, which is responsible for
1. Pursani, V., Pethe, P., Bashir,
keeping stem cells in their M., Sampath, P., Tanavde, V.,
A*STAR researchers undifferentiated state. et al. Genetic and epigenetic
profiling reveals EZH2-mediated
discover key genes “NR2F2 recruits EZH2 to down regulation of OCT-4
involved in the
gene OCT-4, and potentially involves NR2F2 during cardiac
transformation of differentiation of human
embryonic stem cells suppresses its expression, embryonic stem cells. Scientific
into heart muscle cells. propelling the cells towards Reports 7, 13051 (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 25
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Scientists at A*STAR have Yin Loon Lee, who
revealed how microtubules, part studied the centrosome during
CELL of a cell’s ‘skeleton’, position the his PhD before joining Burke’s
BIOLOGY multiple nuclei in muscle cells. lab, brought the topic to his
Malfunctions in this crucial attention. Burke’s recent
developmental process are linked research had revealed that
to muscular dystrophies, a group protein pairs in the nuclear
of debilitating diseases that cause envelope, known as LINC
PUTTING MUSCLE progressive weakness and loss of complexes, play a role in positioning
NUCLEI IN muscle mass.
Brian Burke of A*STAR’s
the nucleus in many cells. “It
seemed like a good bet that these
THEIR PLACE Institute of Medical Biology [complexes] might be involved in
was drawn to the topic anchoring centrosomal proteins
Microtubules anchored more by accident than by at the muscle cell nucleus,”
to proteins in the nuclear design. His research focuses explains Burke.
membrane position on the genes that encode
proteins that are active in the ‘‘It seemed like
muscle cell nuclei ‘nuclear envelope’, a membrane
a good bet that
around the cell nucleus. In
these [complexes]
muscle cells, the nuclear envelope
contains proteins usually
might be involved
associated with the centrosome, in anchoring
a cytoplasmic structure which centrosomal
organizes the microtubules, proteins at the
but for years this remained a muscle cell nucleus.’’
niche subject. “It was just an
odd phenomenon that no-one To test this idea, Lee and
working in the centrosome field Burke fished out proteins that
understood the significance of, interact with the LINC protein
and no-one outside the field was Nesprin-1 in early- and late-
aware of,” he says. stage muscle cells. Comparing

© 2018 A*STAR Institute of Medical Biology

3D structured illumination
microscopy image of microtu-
bule regrowth at the nuclear
envelope following microtubule
degradation in a differentiated
myoblast cell. Microtubules are in
green, a microtubule organizing
center protein is in red, and the
outer nuclear envelope protein
Nesprin-1 is in blue.

26 A*STAR RESEARCH  Issue 11 | April – June 2018
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the two lists revealed 446
proteins that interact with A SURFACE THAT
Nesprin-1 specifically in
late-stage muscle cells,
QUANTUM
MATTER
MAKES LIGHT WORK
including four centrosomal The quantum states on the surface
proteins. Meanwhile, of conducting materials can strongly
researchers in France had
performed an RNAi screen
interact with light

Reprinted with permission from Ref. 1 Copyright (2017) by the American Physical Society.
to identify genes involved
in microtubule nucleation
at the nuclear envelope. An exotic state of matter that
“The only candidate they is dazzling scientists with
came up with was Nesprin-1,” its electrical properties, can
says Burke. The teams also exhibit unusual optical
decided to collaborate to solve properties, as shown in a
the mystery. theoretical study by researchers
Lee engineered cells at A*STAR.
lacking either Nesprin-1 Atomically thin materials,
or its LINC partners. such as graphene, derive some
In these cells, three of the of their properties from the
four centrosomal proteins fact that electrons are confined
remained in the cytoplasm to traveling in just two-
rather than accumulating dimensions. Similar phenomena
at the nuclear envelope. are also seen in some three-
The same mislocalization dimensional materials, in which
The upper and lower electron bands in a semimetal touch at places known as
was apparent in cells from electrons confined to the surface Dirac points.
patients with a congenital behave very differently from
muscular dystrophy caused those within the bulk — for properties from those of and predicted the strength
by a Nesprin-1 mutation. example, topological insulators, the more conventional with which incident radiation
By depleting each of whose surface electrons conduct topological insulators. induces electron transitions from
the three centrosomal electricity even though their To prove this, Li-kun Shi and the lower band to the upper
proteins individually, the bulk electrons do not. Recently, Justin Song from the A*STAR one. They found that surface
team discovered which another exciting class of Institute of High Performance absorption depends heavily on
protein was required for materials has been identified: Computing used an ‘effective the polarization of light, being
microtubule formation at the the topological semimetal. Hamiltonian’ approximation to 100 to 1,000 times stronger when
nuclear envelope. The difference in insulator show that the two-dimensional light is polarized perpendicular
In muscle cells with a and conductor electrical surface states in semimetals, — rather than parallel — to the
missing or defective copy of properties is down to the known as Fermi arcs, possess a crystal’s rotational axis. This
Nesprin-1, the nuclei clumped bandgap: a gap between the light–matter interaction much strong anisotropy offers a way
together rather than spreading ranges, or bands, of energy that stronger than that found in of optically investigating and
out. Understanding how an electron traveling through other gapless two-dimensional probing the topological surfaces
Nesprin-1 and centrosomal the material can assume. In an systems, such as graphene. states of Dirac semimetals.
proteins position the nuclei insulator, the lower band is full “Typically, the bulk “Our goal is to identify more
of muscle cells may help of electrons and the bandgap is dominates material absorption,” unconventional optics that arise
clarify the development of too large to enable a current to explains Song. “But we show that due to Fermi arcs,” says Song.
muscular dystrophies. flow. In a semimetal, the lower Dirac semimetals are unusual in “Topological semimetals could
band is also full but the lower that they possess a very optically host unusual opto-electronic
1. Gimpel, P., Lee, Y. L., Sobota, and upper bands touch at some active surface due to these behavior that goes beyond
R. M., Calvi, A., Koullourou, V.,
et al. Nesprin-1a-dependent
points, enabling the flow of a peculiar Fermi arc states.” conventional materials.”
microtubule nucleation form small current. Shi and Song analyzed a
the nuclear envelope via This lack of a full bandgap proto-typical semimetal with a 1. Shi, L.-K. & Song, J. C. W. Large
Akap450 is necessary for optical conductivity of Dirac
means that topological symmetric band structure where
nuclear positioning in muscle semimetal Fermi arc surface
cells. Current Biology 27, semimetals should theoretically the electronic bands touch at two states. Physical Review B 96,
2999–3009 (2017). exhibit very different places, known as Dirac points, 081410 (2017).

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You don’t have to be an
expert to gain insights
from big data, thanks
to a new web-based,
machine-learning tool.

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The system is web-based
using cloud infrastructure,
MACHINE
LEARNING so there is no need to install
special software or use
dedicated computing power.
To evaluate whether
the LAS generated appropriate
DATA ANALYSIS workflows, Aye’s team
tested it on 114 data sets
TOOL EMPOWERS from the University of
THE PEOPLE California’s Irvine Machine
Learning Repository
Despairing of data sets? and benchmarked against
OpenML, an open-
Here’s an automatic, cloud-based source, online machine
system designed for data rookies learning platform.
For 87 data sets (about
76 per cent of the total),
Data production doubles selects the best-performing LAS-produced workflow
each year, but data scientists, workflows based on those accuracy was above the
who wrangle insights from similar repository data sets and 50th percentile of OpenML’s
reams of data, are in short passes them to the second part: performance. This figure could
supply. To bridge this gap, the workflow optimizer. improve over time too, Aye
a team at A*STAR has says. Users can plug their data
developed a fully automatic, ‘‘Non-experts sets and workflows back into
web-based system that usually take the repository, providing a
puts the power of big richer stock from which the
days to generate
data analysis in the hands workflow recommender can
of laypeople1.
a good workflow, later draw.
Uncovering patterns
in LAS, the Non-experts usually
and relationships hidden average time was take days to generate a good
in vast data sets requires a just over 3 hours.’’ workflow, however, in LAS,
machine learning pipeline the average time to produce
or ‘workflow’ — a string of Here, ‘genetic a workflow in 15 generations
algorithms and processes programming’ refines was just over 3 hours. In
called operators. But not the workflow. Operators the future, implementing a
every workflow is appropriate are randomly replaced, faster search technique, or
for every situation. So how analogous to random heuristic, could further cut
does the non-expert know genetic mutations in DNA. processing time. “Obviously,
which to use? To help, Theint Mutated workflows are we would want to run it
Theint Aye, from the A*STAR then crossed with each as efficiently as possible
Institute of High Performance other, which involves and also have good accuracy
Computing and her colleagues swapping pairs of operators values,” Aye says, adding
have produced an analytics between them. that a graphics processing
system (called the Layman The process then unit might also boost the
Analytics System, or ‘LAS’) for repeats — ‘fittest’ workflows LAS’s speed.
© Monty Rakusen/Cultura/Getty

the novice. are selected, mutated and
Say you have a data set to crossed — for a predefined 1. Aye, T. T., Lee, G. K. K., Su, Y.,
Zhang, T., Lee, C. et al. Layman
analyse. The first part of the LAS number of generations analytics system: a cloud-
— the workflow recommender (based on empirical enabled system for data analytics
— compares your data set’s experience). The result: an workflow recommendation.
IEEE Transactions on Automation
metadata to that of existing automatically generated Science and Engineering 14,
data sets in a repository. It then tailor-made workflow. 160−170 (2017).

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Checkpoint blockade immunotherapy

CANCER
TREATMENTS

t-SNE dimension-2
UNDERSTANDING
INDIVIDUAL
IMMUNE
RESPONSES
t-SNE dimension-1
A technique that identifies and
characterizes different immune A plot of all the different possible phenotypes of T cells without (left) vs. with (right) immune
checkpoint blockade immunotherapy. The colored dots represent T cells that are tumor
cell groups in individual neoantigen specific and colored by which tissue they were derived from: (red) tumor, (green)

patients could revolutionize dLN (draining lymphnode - the lymph-node closest to the tumor - peripheral immune tissue),
(blue) ndLN (non-draining lymphnode - peripheral immune tissue) and (orange) spleen (peripheral
cancer treatments immune tissue).

A pioneering technique at Washington University in St Newell’s team hypothesized 81 possible tumor antigens.
developed by A*STAR Louis, USA, have developed an that patients who were receptive They identified T cells
researchers can identify approach that can efficiently to effective immunotherapy specifically associated with
and profile specific groups identify and characterize would have tumor-specific T two neoantigens in spleens,
of immune cells that target neoantigen-specific CD8+ T cells with specific characteristics. tumors and lymph nodes.
cancer cells in individual cells in mice. Their technique The team’s technique combines Depending on the type of
patients. This approach could may help determine whether mass cytometry with heavy metal immunotherapy used, the
open the door to personalized a tumor will respond to staining to simultaneously screen neoantigen-specific T cells
cancer treatments. specific immunotherapies. and profile the multiplicity of such displayed different phenotypes
Cancer cells produce cells in blood and tumor samples. during treatment, whereas
many antigens that trigger ‘‘Our technique “Other approaches other T cell populations were
immune responses from could also identify require that you stimulate mostly unaffected.
the body. One group of the T cells with their specific “It’s possible we could
relevant antigens
immune cells called CD8+ antigens to identify them,” identify tumor-specific T cells
cytotoxic T cells recognize
to develop says Newell. “Instead, we used that could either be expanded
and bind to antigens attached
personalized isolated proteins from the and re-infused into patients to
to the surface of cancerous cancer vaccines.’’ antigens called peptide-MHCs boost their immune response,
cells. Often, mutations (major histocompatibility or used as biomarkers to
unique to individual patients “In theory, we might predict complex), which the T cell predict responses to any
create mutant antigens, or how someone will respond to receptors bind to. In addition given immunotherapy,” says
‘neoantigens’, which lead to certain immunotherapies by to formulating the proteins Newell. “Our technique could
© 2018 A*STAR Singapore Immunology Network

a tumor-specific immune looking at the characteristics carefully to promote stable also identify relevant tumor
response. Scientists hope to of the immune cells that are interactions, we labelled them antigens to develop personalized
harness these responses to create circulating in the patient’s with heavy metals so that cancer vaccines.”
personalized cancer treatments, blood,” explains Newell. they were detectable in high-
and possibly neoantigen-based “However, this is challenging, throughput mass cytometry.” 1. Fehlings, M., Simoni, Y., Penny,
H. L., Becht, E., Loh, C. Y. et al.
cancer vaccines. because there are huge In experiments on mice Checkpoint blockade therapy
Now, Evan Newell and numbers of circulating cells with sarcoma tumors that reshapes the high-dimensional
co-workers at A*STAR’s and only a tiny proportion of responded well to particular phenotypic heterogeneity of murine
intratumoural neoantigen-specific
Singapore Immunology them are neoantigen-specific immunotherapies, the team CD8 + T cells. Nature Communications
Network, along with scientists CD8+ T cells.” analyzed T cells targeting 8, 562 (2017).

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TINY DROPLETS FOR bound electrons. Consequently,
silicon is less affected by
PRINTING BIG COLOR IMPACT absorption losses than silver or
aluminum and so can produce
High-resolution full color images can be a sharper reflectance spectrum,
formed using silicon-nanostructure pixels meaning a better color purity.
The technology
for fabricating silicon
nanostructures is well developed
Color prints produced on metals, these optical resonances nanostructures made of silicon. due to its broad adoption in
contemporary printers have a are due to the excitation of They measure the optical the manufacture of electronics.
resolution of a few thousand dots plasmons — light strongly properties of an array of discs Thanks to this they were able
per inch (dpi), but an alternative couples to spatially-confined with diameters ranging from to reproduce masterpieces such
strategy that harnesses the power electrons on the surface, and 50 to 250 nanometers under as Edvard Munch’s The Scream
of nanotechnology can improve is either absorbed or reflected illumination conditions suited for in an area smaller than one
this resolution by an order depending on its wavelength. a practical implementation. square-millimeter.
of magnitude. The peak reflectivity wavelength, “We compared the quality “Our focus is on expanding
Depositing ink droplets on and thus the apparent color of colors generated by silicon the color gamut to go beyond the
a surface to create color pictures of the pixel, is tunable by particles with those from silver standard widely adopted in the
is a centuries-old technology. changing the dimensions of and aluminum plasmonic display industry,” says Paniagua-
A*STAR researchers are now the nanostructures. particles,” says Paniagua- Domínguez. “We will also explore
testing a new method, which uses Plasmonic materials are often Domínguez. “We showed that the mechanisms to actively control
an array of nanostructures that noble metals, such as gold and colors obtained are of far better the resonances, and therefore the
reflect light of the desired color. silver, or aluminum. But these quality in terms of hue, gamut color, of the particles, to bring this
As these structures, or pixels, are materials are constrained by price, and intensity.” technology closer to application in
much smaller than ink drops, a spectrum coverage, or the low The improvement is because ultra-high-definition displays.”
resolution of up to 100,000 dpi purity of the color they reflect. the colors from silicon do not
could, in principle, be achieved. Ramón Paniagua-Domínguez stem from plasmonic resonances 1. Flauraud, V., Reyes, M., Paniagua-
Domínguez, R., Kuznetsov, A. I. &
Nanostructures influence from the A*STAR Data Storage as they do in the noble metals, Brugger, J. Silicon nanostructures
light through so-called optical Institute and co-workers but rather from geometrical for bright field full color prints. ACS
resonances. In the case of investigate semiconductor resonances that originate from Photonics 4, 1913−1919 (2017).
© 2018 A*STAR Data Storage Institute

Cylindrical silicon
nanoparticles of
different sizes reflect
light across a wide
gamut of colors.

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THERAPEUTICS

ENGINEERING
A SAFER
ANTIBODY DRUG
By taking advantage of the
body’s natural diversity,
antibody drugs can be made
less toxic by having a more
localized effect

An innovative approach to be undertaken,” says Samuel isotypes that may have greater IgD versions of the antibody
protein engineering could Gan, head of the Antibody and tissue precision. drugs proved inferior, both
help make antibody-based Product Development group at Their finding lays the in terms of yield and HER2-
drug therapies less toxic and the Bioinformatics Institute and groundwork for future antibody targeting, but IgE and IgA
more effective. the p53 Laboratory at A*STAR. therapies that can be safer for versions both generally retained
Working with two antibody patients without compromising the effectiveness of the original
drugs taken by thousands of yield or potency. therapies — which raises
‘‘There is a
women with breast cancer The researchers worked with the possibility of developing
whole range of
each year, A*STAR researchers trastuzumab and pertuzumab, two safer versions of trastuzumab
have shown the possibility of
possibilities to using antibody drugs marketed under and pertuzumab based on
transforming these agents — more localized the brand names Herceptin® these alternate isotypes. Most
which normally circulate in antibodies as and Perjeta®, that selectively interestingly, the findings also
© ALFRED PASIEKA/SCIENCE PHOTO LIBRARY/Getty

the bloodstream, but can also prophylactics.’’ bind to different parts of human show that constant regions in
harm healthy heart tissue — into epidermal growth factor receptor antibodies can influence in
alternative forms that may have Antibodies are also known 2 (HER2), a protein that is the antibody’s ability to bind,
more localized tissue distribution. as immunoglobulins, and they implicated in approximately 20 a finding that is often not
This tweak should result in fewer come in five main ‘isotypes’: IgA, per cent of all breast cancer cases. noticed and often neglected in
side-effects, while potentially IgD, IgE, IgG and IgM. Most They transformed these IgG antibody research.
reducing the dosage needed, therapeutic antibody drugs are of antibodies into all five human As Gan points out, both IgE
which could help lower the cost the IgG isotype that circulate in isotypes and the four subtypes, and IgA antibodies are likely
of treatment. the bloodstream, but Gan’s team and examined what impact that to be more active in the ductal
“It’s proof-of-concept that showed they could remodel IgG change had on drug production tissues of the breast, where
such antibody modification can antibodies into some of the other and binding to the HER2 target. HER2-expressing tumor cells

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A SUSTAINABLE SOURCE
CANCER OF NATURAL KILLERS
Generating large numbers of universal immune
cells could transform cancer immunotherapy

A scalable method of generating cells. This can limit the use of body, including NK cells. This is
universal ‘off-the-shelf ’ natural therapies considerably,” says the first time peripheral blood
killer (NK) cells for cancer Shu Wang at the A*STAR cell-derived iPSCs have been
immunotherapies has been Institute of Bioengineering used to generate NK cells.
devised by A*STAR researchers. and Nanotechnology, who Wang’s team designed a
Their technique could ensure led the study. “We wanted new protocol to derive NK cells
that future NK cell-based cancer to devise a new method of from iPSCs, with a focus on
treatments can be used for generating large numbers of robustness and scalability. They
most patients. pure, universally-suitable NK co-cultured iPSCs with bone
NK cells are a group of cells that could widen the use of marrow connective tissue cells
small white blood cells from such immunotherapies.” — these activate the signaling
the innate immune system that processes needed for cell
help kill virus-infected cells differentiation and commitment
‘‘We may now
and malignant cancer cells. to a specific cell type, which
Scientists can harvest NK cells
have an invaluable resulted in large yields of
Changing the
isotype of and use them to directly target
cell source for NK cells.
Immunoglobulin cancer cells. However, existing a wider group “An unexpected bonus of
can make it easier
techniques generate limited of patients.’’ our protocol was that most
to target specific
parts of the body. numbers of NK cells from derived NK cells were free of a
selected donors that are suitable The team needed a readily particular group of inhibitory
for specific patients only. available, sustainable and non- receptor proteins that can
“Current donor-dependent controversial source of stem limit universal application in
are also found, and they could NK cell harvesting methods cells from which they could patients,” says Jieming Zeng, the
be combined with low doses of carry the risk of graft-versus- derive massive numbers of NK first author of the study. “This
blood-targeting IgG antibodies host disease, because traces cells. So they used peripheral means that we may now have
to guard against circulating of other cells and molecules blood cells to generate induced an invaluable cell source for a
metastatic cells while lowering from donors that are mixed human pluripotent stem cells, wider group of patients.”
the risk of other side-effects such in with the NK cells can iPSCs, which can differentiate Scaling up the manufacture
as cardiac toxicity. react to patients’ normal into every type of cell in the of NK cells will require
Additionally, Gan suggests considerable further investment,
that immunotherapies could particularly with its reliance
be developed with IgA and on the connective tissue cell
© 2018 A*STAR Institute of Bioengineering and Nanotechnology

IgE antibodies to better guard lines that may prove expensive
against mucosal infections such to provide in the form of cell
as influenza or AIDS. “There is banks. The team will continue
a whole range of possibilities to to streamline their technique,
using more localized antibodies and believe the breakthrough
as prophylactics,” he says. will inform the development
of universal ‘off-the-shelf ’
1. Lua, W. H., Ling, W. L., Yeo, J. Y., Poh, J. J., cancer treatments.
Lane, D .P. & Gan, S. K. The effects
of antibody engineering CH and CL
1. Zeng, J., Tang, S. Y., Toh, L. L. & Wang,
in trastuzumab and pertuzumab
S. Generation of ‘off-the-shelf’
recombinant models: Impact natural killer cells from peripheral
on antibody production and blood cell-derived induced
antigen-binding. Scientific Reports 8, A novel method to generate natural killer cells from peripheral blood cell-derived pluripotent stem cells. Stem Cell
718 (2018). stem cells (above) may transform immunotherapies for different cancers. Reports 9, 1796–1812 (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 33
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An A*STAR team has assembled patterned resist is transferred to
zinc sulfide (ZnS) quantum dots another substrate and a chemical
into nanoscale grids and arrays etching step generates the final
LITHOGRAPHY
of lens-like disks by performing nanoscale shapes. Saifullah and
electron-beam lithography on the team, however, had a different
a multipurpose thin film1. The strategy. “We developed a resist
photoluminescent properties of that can decompose and form
these patterns could make them a metal sulfide right under the
A BRIGHT IDEA useful components in applications electron beam,” he notes. “This was

FOR ON-DEMAND such as biosensors and solar cells.
While individual ZnS
a challenge because most resists
don’t have such functionalities.”
NANOPATTERNS nanoparticles have intriguing The team found a compound
optical properties, due to the called zinc butylxanthate that
Focused electron beams can effects of quantum coupling, their could meet their needs. In this
simultaneously synthesize light-emitting capabilities become molecule, zinc and sulfur atoms are
optically active nanocrystals more potent when positioned connected to long-chain organic
into ordered assemblies. Instead groups that potentially can be
and pattern them into intricate of conventional bottom-up detached using the energy from an
surface arrays approaches that use wet chemicals electron beam. Experiments with
to generate nanoparticle ensembles the new resist proved the efficiency
on silicon chips, many researchers of this conversion process: by
now approach this problem from gradually increasing the electron
the top down, using nanoscale beam exposure, the starting
lithography to strip away unwanted film was transformed into ZnS
material and write quantum dots nanocrystals with a conversion rate
directly on to surfaces. of almost 100 per cent
The A*STAR-led team
‘‘The nice exploited the properties of the zinc
butylxanthate resist to produce lines
thing about
of ZnS nanocrystals with diameters
photoluminescent
as thin as 6 nanometers. Then, after
ZnS nanocrystals characterizing the structures with
is that they can electron microscopy, they made
be arranged another serendipitous discovery
into practically — the nanopatterns emitted bright
any shape.’’ photoluminescent light when
exposed to ultraviolet radiation.

Reprinted with permission from Ref. 1. Copyright (2017) American Chemical Society
Carving shapes into Defect states on the nanocrystal
~6nm
semiconductor surfaces smaller surfaces were pinpointed as the
than 10 nanometers is a particular cause of the new optical behavior.
expertise of M. S. M. Saifullah “The nice thing about
6nm
from the A*STAR Institute photoluminescent ZnS
6nm of Materials Research and nanocrystals is they can be
Engineering, and colleagues. They arranged into practically any
direct high-powered electron shape,” says Saifullah. “In
beams on to special thin films the future, we would like to
called ‘resists’. Areas of the resist combine these nanostructures
exposed to the focused beams with plasmonics.”
7nm undergo chemical changes that
enable tiny features to stay in place 1. Lu, X., Denver, D., Chandar, J., Chen, Y. &
Lou, J. An overlapping domain decom-
50nm while the surrounding film is
position based near-far field coupling
washed away by solvents. method for wave structure interaction
Light-emitting ZnS nanostructures can be patterned into nearly any shape, In most electron-beam simulations. Coastal Engineering 126,
including grids as above, using a multipurpose photoresist. lithography techniques, the 37–50 (2017).

34 A*STAR RESEARCH  Issue 11 | April – June 2018
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into these vital antigen- a particularly
presenting cells, the team, significant surprise.
IMMUNOLOGY led by Joachim Schultze and “Through this work
Andreas Schlitzer of the we now understand the
University of Bonn, hope molecular make-up and
to learn how to stimulate clinical potential of the cells
their activities more much better,” says Ginhoux.
effectively to fight cancer and He explains that a logical
MONOCYTES other diseases. next step will be to examine

IN THE MIX ‘‘We now
similar cells that are being
used clinically, to see if they
Understanding how monocyte also display the mixed cell-
understand
type characteristics found
cells generate specialized the molecular in the lab studies. This may
immune system cells may help make-up and reveal ways to improve the
clinical potential
target immunity against cancer clinical use of the cells by
of the cells identifying and producing
much better.’’ the most effective specific
cells for the treatment of
An international research these white blood cells Their work, performed each disease and hopefully
team has helped unravel perform various roles in with cultured human individual patients.
important details of how immunity, and develop or cells, revealed details of “Drilling down to
blood cells called monocytes differentiate into a range the molecular signals that the single cell level will
develop into the crucial of more specialized cells. regulate the differentiation bring better treatments,”
‘helper’ cells of the immune Monocytes circulating in of monocytes into a Ginhoux emphasizes.
system1. “The work should the blood can ingest and complex mixture of cell
1. Sander, J., Schmidt, S. V.,
ultimately allow better destroy foreign invaders types. The team also
Cirovic, B., McGovern, N.,
and more personalized and promote inflammation identified time-dependent Papantonopoulou, O. et al.
treatment,” says team of diseased tissues. One of phenomena that control Cellular differentiation of human
monocytes is regulated by
member Florent Ginhoux their most crucial roles, the developmental fate of time-dependent Interleukin-4
of the A*STAR Singapore however, is to develop monocytes. The wide variety signaling and the transcriptional
regulator NCOR2. Immunity 47,
Immunology Network. further into specialized of cell types produced 1051-1066 (2017).
The immune system ‘antigen-presenting cells’. from the monocyte
is a complex network of These interact with parts population was
interacting cells circulating of foreign organisms or
throughout the body, diseased cells and display
© 2018 Benoit Malleret, Singapore Immunology Network (SIgN), A*STAR

protecting us from invading molecular tags called antigens
microorganisms and from on their surface, which can
diseases originating from interact with other cells of
within. Scientists and the immune system. This
clinicians are learning how antigen-presenting activity
to select and modify immune initiates an immune response
system cells to target them against the source of the A human
more effectively at specific antigens, whether invading monocyte cell
diseases, especially cancer. micro-organisms or diseased — these cells
may hold key
“Monocytes have cells such as cancer cells. information about
many faces,” says By understanding how supporting immunity
Ginhoux, explaining how monocytes differentiate against cancer.

www.research.a-star.edu.sg A*STAR RESEARCH 35
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Relocation of N-acetylga-
lactosaminyltransferases
from the Golgi apparatus to
the endoplasmic reticulum
makes cancer cells more
invasive. (above) Illustration
of cancer cells breaking
through tissue.

36 A*STAR RESEARCH  Issue 11 | April – June 2018
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genetic targeting of GALNT1
to the ER in mice with liver
cancer reduced survival from
CANCER 23 weeks to just 10 weeks.
Further experiments in the
mice and cultured cells revealed
that relocation of GALNT1
to the ER caused increased
RELOCATED glycosylation of the protein
matrix metalloproteinase 14
ENZYMES MAKE (MMP14). This in turn led to
CANCER MORE breakdown of the extracellular
matrix that keeps cells in place,
MOBILE making it easier for cancer cells
to break away from the primary
Relocation of enzymes involved tumor and invade other tissues.
in protein modification makes it “Glycosylation activates the
easier for cancer to spread mechanisms by which cancers
destroy normal tissue, making
space for their own growth,”
explains Bard.
Enzymes that are involved In liver cancers, some of the
in protein modification are enzymes involved in glycosyl-
‘‘Glycosylation is a
relocated in cancer cells, ation have been shifted from
altering protein processing the Golgi to the ER. Altered
poorly understood
and helping cancer to spread, glycosylation in cancer is process, yet it is
according to new work by associated with more invasive involved in virtually
A*STAR researchers. The — and therefore more deadly, every aspect of
mechanism, which was tumors — but the underlying human biology.’’
studied in liver cancer, reveals mechanisms are unclear. Bard
novel potential targets for and colleagues investigated The researchers say
cancer treatments. these mechanisms in liver their findings suggest that
During their production, cancer, focusing on the initial GALNTs, and the mechanisms
many cell surface proteins step of glycosylation in which that control their relocation
undergo glycosylation — a the glycan N-acetylgalac- to the ER, are potential
process which involves tosamine (GalNAc) is attached therapeutic targets for cancer
attachment of sugar molecules, to proteins by enzymes called treatments. Identification of
called glycans, to specific sites N-acetylgalactosaminyl- similar mechanisms could
on proteins. This normally transferases (GALNTs). The reveal further potential
takes place in the Golgi researchers had previously targets. “While we focused on
apparatus, after the protein proposed that relocation MMP14, we have preliminary
has been transferred from of GALNTs from the Golgi evidence that many cell
the endoplasmic reticulum apparatus to the ER affects surface proteins are regulated
(ER) where it was made. glycosylation in cancer, and by hyperglycosylation,” says
“Glycosylation is a poorly was investigating whether there Bard, “We are currently
understood process,” explains was further evidence to support exploring how these other
Frederic Bard from the A*STAR this case. proteins contribute to
Institute of Molecular and Cell The team first tumor development.
Biology, who led the new study, demonstrated that GALNTs are
© Callista Images/Getty

“yet it is involved in virtually active at the ER in liver tumor 1. Nguyen, A. T., Chia, J., Ros, M.,
Hui, K. M., Saltel, F. et al. Organelle
every aspect of human biology cells from mice and humans,
specific O-glycosylation drives
and it has long been known rather than being active at the MMP14 activation, tumor growth,
that glycosylation is altered Golgi apparatus as they are and metastasis. Cancer Cell 32,
in cancer.” in healthy cells. Furthermore, 639–653.e6 (2017).

www.research.a-star.edu.sg  A*STAR RESEARCH 37
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A*STAR researchers have synthetic methodologies
developed nanoscale drug into one macromolecular
DRUG delivery particles that can sense design,” says Li. At one of
DELIVERY their surroundings, and release the ends of each Y-shaped
their payload only after entering branch, the team attached
a cell, a discovery that could a temperature-sensitive
make many existing medicines polymer called PNIPAM.
more effective. At room temperature the
REACH FOR The new nanoparticles, PNIPAM polymer extends

THE STARS developed by Zibiao Li from the
A*STAR Institute of Materials
outward, but collapses once
body temperature, 37 degrees
Research and Engineering Celsius, is reached, allowing the
Star-shaped nanoparticles
and his collaborators, are nanoparticle’s drug molecule
that release their drug payload a significant upgrade from cargo to escape.
only after entering cells could previous generations of Mid-way along each
improve current treatments polymer-based drug delivery polymer arm, the team installed
nanoparticles. Early examples a sulfur-sulfur bond. When
typically consisted of simple the particles enter a cell, they
polymer chains with a polar, meet high levels of glutathione,
hydrophilic head and a non- a molecule that cleaves
polar, hydrophobic tail. In sulfur-sulfur bonds. Thus the
water, these chains naturally nanoparticle’s outer polymer
aggregate into spheres, with coat is snipped off, and the drug
their hydrophobic tails all is released even faster.
pointing inward to form a non- When the team tested
polar core. The core formed a this effect with an anti-cancer
good site for drug molecules drug called doxorubicin,
to nestle. In the bloodstream, the dual-action effect was
however, these aggregates tend clear. “The change from
to be torn apart. room temperature to body
Li and his colleagues temperature, and the effect of
used the latest polymer glutathione, showed synergistic
synthesis techniques to create and fast release of the drug,”
single-molecule nanoparticles. Li says. At lower temperatures,
Rather than a self-assembled or in the absence of glutathione,
aggregate of separate polymers, drug release was significantly
the team synthesized a slower, he says.
more robust structure in “The next plan is to
which the polymer chains integrate new functionality, for
were strongly covalently precision release of the drug for Reprinted from Ref. 1 with permission of The Royal Society of Chemistry

bonded to a central core. The targeted cancer therapy,” says
synthesis began with beta- Li. One end of each Y-shaped
cyclodextrin, a circular sugar branch could be functionalized
molecule with 21 hydroxyl with a molecule that sticks
groups on its surface. The selectively to cancer cells,
hydroxyl groups formed the delivering the drug precisely
chemical anchors from which where it is needed.
Temperature- and Redox-responsive the team constructed the
Drug release nanoparticle’s multiple long, 1. Fan, X., Wang, X., Cao, M., Wang, C.,
Hu, Z. et al. “Y”-shape armed
Y-shaped, multifunctional amphiphilic star-like copolymers:
Cytoplasm
polymer arms. design, synthesis and dual-
responsive unimolecular micelle
“The greatest challenge
formation for controlled drug
The change in temperature and chemical environment inside the cell triggers in making the [nanoparticle] delivery. Polymer Chemistry 8,
the nanoparticle to release its drug payload. was to integrate different 5611 (2017).

38 A*STAR RESEARCH  Issue 11 | April – June 2018
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CANCER
RESEARCH

A BLOOD TEST
FOR CANCER
RECURRENCE
A greater understanding
Assay for genetic quirk can provide of biomarkers will yield
a wealth of information on patient more accessible ways
to screen, monitor, and
disease status and prognosis treat conditions such as
breast cancer.

Despite great advances in and surgery, these cells can allows clinicians to inform in discussions to start a clinical
medicine, cancer remains survive, regrow, and cause patients of the increased risk trial with the drug pacritinib,
a death sentence for many. recurrence,” says Goh. The team, of breast cancer recurrence, as using our biomarker to guide
“Patients are still dying from led by A*STAR’s Qiang Yu, found well as monitor the progress of treatment,” explains Goh.
breast cancer relapse,” says Jian that TICs possess an abnormally treatment and the emergence “Pacritinib is not yet approved
Yuan Goh, of A*STAR’s Genome high number of copies of a of tumor resistance to therapy, for use in breast cancer, so we
Institute of Singapore. The specific section of DNA. This based on the changing levels of first need to see whether tumors
researcher and his colleagues, ‘copy number amplification’ the biomarker. The researchers respond to this treatment.”
a team from Singapore, China, results in an overproduction of also found the amplification to be “What we’re trying to
the United States, and Denmark, the proteins coded for by that correlated to cancer metastasis. do is provide a cost-effective
have recently identified section of genetic material. TIC presence might signal way for clinicians to track
a genetic aberration in a a bleak prognosis for patients breast cancer recurrence. The
particularly aggressive subtype if it didn’t also offer a unique alternative — genetic sequencing
‘‘What we’re trying
of breast cancer cells that, when avenue of treatment. With an — is comprehensive, but very
quantified, can provide insights
to do is provide a abnormally high number of expensive. You can’t imagine a
into a patient’s cancer status,
cost-effective way a specific set of genes, TICs patient coming in every month
chances of relapse, and treatment for clinicians to overproduce the S100A family to be sequenced for 3,000
progress. This discovery paves track breast cancer of proteins. As these proteins dollars, but, if we develop this
the way for an alternative recurrence.’’ provide TICs with their assay, testing will be a lot more
to invasive and expensive chemo-resistant properties, affordable,” says Goh.
biopsy testing. Goh and his colleagues have the researchers are now
© Image Source/Getty

One model of cancer’s produced a ‘liquid biopsy’ assay investigating pharmacological 1. Goh, J. Y., Feng, M., Wang, W., Oguz, G.,
Yatim, S. M. J. M. et al. Chromosome
proliferation involves the that detects this genetic quirk interventions that might block
1q21.3 amplification is a trackable
presence of chemotherapy- within circulating fragments of this pathway and provide a biomarker and actionable target for
resistant tumor-initiating cells tumor DNA found in blood. A lifeline in otherwise incurable breast cancer recurrence. Nature
(TICs). “Even after chemotherapy presence of TIC-linked DNA cases of breast cancer. “We’re Medicine 23, 1319–1330 (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 39
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A laser synthesizer developed by intense, ultrashort infrared pulses
an A*STAR researcher and his on to nonlinear crystals.
ULTRAFAST overseas collaborators produces Houkun Liang at A*STAR’s
LASERS infrared pulses shorter than the Singapore Institute of
wave period, which could enable Manufacturing Technology
scientists to probe how electrons and his colleagues in the United
move inside atoms and solids. States and Germany realized they
Importantly, these pulses are readily needed to rethink conventional
NEW APPROACH absorbed by many atoms and approaches for generating ultrashort

TO GENERATING molecules because their wavelengths
lie in the mid-infrared range.
mid-infrared pulses.
“To get a pulse that is shorter
ULTRASHORT PULSES Processes within atoms, such
as electrons moving from one
than the wave period, you need a
very broad spectral bandwidth,”
Extremely short mid- energy level to another, happen explains Liang. “Previously,
infrared laser pulses will extremely quickly, on time scales researchers had combined pulses
of femtoseconds (10 −15 second) or with different spectral coverages
help scientists explore even attoseconds (10 −18 second). to obtain such huge bandwidths,
ultrafast processes in atoms Consequently, researchers need but this is extremely difficult. The
very short, high-power laser pulses relative phase and amplitude of the
to observe these events. One way individual pulses have to be highly
to generate them is to shine highly precisely controlled, which makes

© Sophie Laidlaw/EyeEm/Getty

A new laser pulse
synthesizer developed
at SIMTech produces
extremely short
mid-infrared pulses that
enable observations
of ultrafast processes
within solids.

40 A*STAR RESEARCH  Issue 11 | April – June 2018
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the laser system very complex it is possible to create the
because it requires a lot of metasurfaces without the need
noise-control apparatus.” for an additional layer, while
PHOTONICS
To simplify things, Liang still maintaining a high level of
and his colleagues used an emission efficiency.”
optical parametric amplifier Metasurface modifications
— a device that produces two of LEDs have been attempted
pulses, which cover different in the past. These included
spectral ranges and whose LIGHT-BENDING patterning an additional
amplitudes and phases can be
fixed relative to one another.
NANO-PATTERNS layer with a very different
refractive index than the
The team constructed their FOR LEDS underlying GaN-on-sapphire
amplifier to have a very substrate to keep the light
short time delay between the Direct nanoscale patterning in the metasurface layer and
two pulses, meaning they of LED surfaces brings new enhance the light-matter
naturally combine into a interactions. The problem with
possibilities for the control of light
wide-bandwidth pulse with patterning GaN directly — a
no need for noise control. The major benefit for fabrication —
© 2018 A*STAR Data Storage Institute

resulting pulse could be made is a weakness of interactions
even shorter than the period of because of the lack of refractive
the wave because constructive index contrast.
interference occurs at its center, “To overcome this,
while destructive interference we worked with very deep
‘trims’ the pulse at its edges. structures with a large aspect
Perhaps the most useful 1µm 1µm ratio, effectively arrays of
characteristic of these nanopillars, to reduce the
mid-infrared pulses is that Nanopillar arrays fabricated directly on a GaN surface. influence of the substrate on the
when they are directed on to metasurface’s optical modes,”
certain solids, they can stimulate Nanoscale patterns designed light emitted by LEDs is explains Khaidarov (see image).
the emission of higher energy to bend, deflect and split light inefficiently dispersed in all The resulting design,
photons in the deep-ultraviolet can now be fabricated directly directions, including back into however, posed a major
or extreme-ultraviolet regions. on light-emitting diode (LED) the substrate on which the challenge for fabrication,
These higher energy photons can surfaces using an innovative light-emitting layer is fixed. requiring the team to develop
then be used to study the fastest etching method developed by So, while researchers have a precise nanofabrication
processes inside atoms, which A*STAR researchers1. The new made tremendous advances in procedure involving electron
occur on attosecond scales. fabrication scheme creates new light-emitting efficiency, there beam lithography and fast,
Liang’s team demonstrated this possibilities for the facile control remains room for improvement. high-temperature reactive
with their system by using the of light output. Egor Khaidarov and ion etching.
mid-infrared pulses to generate Recent advancements in colleagues from A*STAR’s Data “With our design concept
high-energy photons in thin LED lighting have transformed Storage Institute and Nanyang we have, in principle, full
silicon films. daily life and cutting-edge tech- Technological University have control of the output properties
“We are interested in nology — from efficient room now found a way to pattern GaN of light, which allows us to
using the pulse synthesizer to lighting, to TV and mobile with nanoscale features that can fabricate more complex optical
generate isolated attosecond device backlights, and the tiny control the behavior of light. components such as lenses,
electron pulses from different optical circuits that drive global “We have demonstrated vortex beam generators,
materials,” says Liang. These fiber-optic networks. that metasurfaces — surfaces polarimeters and holograms,”
would allow observations The light-emitting patterned with features says Khaidarov.
of even faster processes component of LEDs is a typically smaller than the
within materials. surprisingly simple structure, wavelength of emitted light — 1. Emani, N. K., Khaidarov, E.,
Paniagua-Domínguez, R., Fu,
typically a thin layer of a can be fabricated directly on Y. H., Valuckas, V. et al. High-
1. Liang, H., Krogen, P., Wang, Z.,
Park, H., Kroh, T. et al. High-energy
dielectric material such as a standard GaN-on-sapphire efficiency and low-loss gallium
mid-infrared sub-cycle pulse gallium nitride (GaN) on a platform,” says Khaidarov. nitride dielectric metasurfaces
synthesis from a parametric for nanophotonics at visible
amplifier. Nature Communications
crystalline sapphire substrate. “Most importantly, we have wavelengths. Applied Physics
8, 141 (2017). This structure means the shown that with good design, Letters 111, 221101 (2017).

www.research.a-star.edu.sg A*STAR RESEARCH 41
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Lignin, the natural polymer blocking ability, but can be
that gives tree trunks their more easily incorporated
UV strength, could be the into sunscreens and other
PROTECTION source of a new range of skin products1.
skincare products, new Although lignin itself is
research suggests. a readily-available renewable
The lignin polymer resource, the natural
contributes to plants’ physical polymer’s use in performance
LIGNIN’S STRENGTHS rigidity, and also absorbs materials and personal

IN SMALLER PACKAGES
UV rays, helping to protect care products is limited by
the plant’s more delicate two key factors, explains
cellulose structures from Balamurugan Ramalingam
Adapted polymer offers sun damage. Researchers at from the A*STAR
plant-based protection from A*STAR have found a way Institute of Chemical and
the Sun’s harmful rays to make short-chain lignin- Engineering Sciences,
like structures that retain who led the current work.
the parent molecule’s UV High molecular weight
natural lignin polymers
are inherently insoluble in
common solvents, and disperse
poorly into mixtures of other
materials, making it difficult to
work with.

‘‘We were
particularly
pleased by the
broader UV
blocking ability
and higher molar
absorptivity
exhibited by the
oligomers.’’

The lignin polymer can
be broken down into its

Reprinted from Ref 1. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
component small molecule
monomers to improve
workability, but this
removes natural lignin’s
UV-absorbing characteristics.
Ramalingam and his
coworkers suspected that the
sweet spot for making UV
blockers might be to form
lignin-like ‘oligomers’, short-
chain structures rather than
the long-chain polymers of
natural lignin.
The team showed they
could form lignin-like
A lignin-like short chain oligomer (right) absorbs UV light far more effectively than its component monomers (left). oligomers either by chemically

42 A*STAR RESEARCH  Issue 11 | April – June 2018
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breaking natural lignin into
smaller pieces, or by linking PULSES OF LIGHT WITH
lignin monomers into short
LASERS
A TILT AND A TWIST
chains. Tests confirmed the
lignin-like oligomers offered An exact mathematical solution reveals
the best of both worlds, how to tilt a laser pulse and move intensity
combining good solubility
and dispersion with useful
peaks at faster than the speed of light, or
sunscreen properties. “We even backwards
were particularly pleased
by the broader UV blocking
ability and higher molar A breakthrough in the tilt the wavefront of the pulse and the Technion, Israel,
absorptivity exhibited by mathematical solution for so that the energy delivery originally set out to develop
the oligomers in comparison manipulating pulses of light becomes slightly spread over exact mathematical solutions
with respective monomers,” clarifies the physics of ‘tilted’ time and in space, like the for a new type of laser pulse
Ramalingam says. The laser pulses, and shows how angle on the blade of a snow- called a needle pulse, but
oligomers’ UV blocking ability they can be used to produce plow. This effect can also be ended up with something
also appeared to be robust and exotic effects1. The solution, used to match pulses from much bigger.
long-lived in accelerated UV developed by researchers from different sources, which at such “This result was mostly
weathering tests. A*STAR and the Massachusetts ultrashort pulse-lengths can be serendipity,” says Wong.
The lignin-like oligomers Institute of Technology (MIT), extremely challenging. Until “We simply played around
have several potential could advance applications now, the mathematics used to with possible mathematical
advantages over existing such as terahertz lasers, X-ray calculate the parameters and expressions that could solve the
small molecule UV blockers generation and ultrafast behavior of tilted laser pulses equations exactly.”
that are used to stabilize electron imaging. have only been approximations, The new mathematical
plastics and in sunscreens, Pulsed lasers are with limited insight into the solution not only describes
Ramalingam says. “In commonly used in industrial physics involved. tilted pulses with exact
contrast to synthetic small and research applications “It is interesting to study physical precision (see image),
molecule UV stabilizers, to deliver precision doses very short tilted-pulse-front allowing for rigorous study
the present lignin-like of high-intensity laser pulses not only because of for optimization of existing
oligomers are bio-derived and energy, which for example the new physics they contain, applications, but also reveals
presumably non-toxic,” he says. can prevent the target from but also because such pulses that a beam of tilted-pulse-
As oligomers are physically being damaged while still can allow us to achieve front pulses can be tailored for
larger structures than small heating or exciting it to a target intensities with much some exotic physics.
molecule UV blockers, they are certain energy state. Some lower energies, which could “We can create wave
also less likely to leach out of of the latest techniques use translate to cost savings,” packets with intensity peaks
plastics into the environment, ultrashort pulses which last says Liang Jie Wong from that can propagate at faster
Reprinted with permission from Ref. 1. Copyright (2017) American Chemical Society.

or penetrate the skin when just a few femtoseconds — one A*STAR’s Singapore Institute or slower than the speed of
used in sunscreens. quadrillionth of a second — to of Manufacturing Technology light, and even backwards,”
“We are currently excite atoms and molecules and (SIMTech). “However, it says Wong.
evaluating the possibility observe how they respond. is notoriously challenging
of incorporating lignin- One of the methods used to obtain exact analytical 1. Wong, L. J. & Kaminer, I.
Ultrashort tilted-pulse-
like oligomers into commercial to enhance the interaction solutions for realistic pulses.”
front pulses and nonparaxial
sunscreens, towards between a laser pulse and the Wong and collaborator, tilted‑phase‑front beams. ACS
developing nature-inspired target atom or molecule is to Ido Kaminer, from MIT Photonics 4, 2257−2264 (2017).
personal care products,”
Ramalingam says. 1
10
1. Lim, J., Sana, B., Krishnan, R.,
Seayad, J., Ghadessy, F. J. et al.
Laccase-catalyzed synthesis 0 0 A progression
of low-molecular-weight lignin-
of femtosecond
like oligomers and their application
-10 tilted-pulse-
as UV-blocking materials.
front pulses.
Chemistry — An Asian Journal 13, -1
284 (2018). -20 -10 0 -10 -20

www.research.a-star.edu.sg A*STAR RESEARCH 43
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

A*STAR researchers
have developed an
RNA-based anticancer
therapy that targets a
metabolic pathway in
tumor-initiating cells.

44 A*STAR RESEARCH  Issue 11 | April – June 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

GLDC protein in human lung
cancer cells, hindering their
CANCER proliferation and preventing
THERAPEUTICS
tumor formation.
Working with colleagues
at A*STAR’s Genome Institute
of Singapore, the team showed

TARGETING that when the GLDC-targeting
shAON sequences were
THE ROOT OF injected into mice bearing

THE PROBLEM NSCLC enriched with TIC,
tumor growth was reduced
by 60 per cent compared with
Tumor growth in a mouse model mice injected with scrambled
of lung cancer is reduced using control sequences.
an RNA-based therapeutic that The shAONs disrupt
a key step in the process
inhibits a metabolic pathway in through which the gene that
tumor-initiating cells encodes GLDC is translated into
protein. “We have designed three
shAONs that efficiently interfere
RNA-based therapeutics to thwart the progression of with the process that normally
that prevent a key metabolic various cancers. removes non-protein coding
enzyme from being expressed Previous studies have sequences from the GLDC
in tumor-initiating cells (TIC) shown that TIC of non- pre-mRNA transcribed from
hold promise for the treatment small cell lung carcinoma the gene’s DNA template,”
of lung cancer, an A*STAR team (NSCLC) tumors contain Surana explains. “The resultant
has shown. high levels of glycine aberrant transcripts are
As implied by their name, decarboxylase (GLDC), an primed for degradation and
TIC — also known as cancer enzyme that breaks down GLDC protein production is
stem cells — are a subset of the amino-acid glycine. dramatically reduced”.
tumor cells with the capacity Overexpression of GLDC Future work will determine
to self-renew and start new stimulates the generation of whether these shAONs can
tumors. Abnormal metabolism tumors and the proliferation of be delivered through the nose
is a key feature of TIC as the TIC, and high GLDC levels are to target tumors grafted in
high proliferation rate and associated with poor survival the lungs of mice, and test
tumorigenic potential of these rates in NSCLC patients. their efficacy against other
cells require changes to the types of cancer in which
metabolic pathways that are ‘‘They offer important an upregulation of GLDC
normally used by healthy advantages over contributes to TIC metabolism,
cells to produce energy and such as breast and thyroid
small molecule drugs,
biosynthetic precursors. cancers. Because of shAONs’
The discovery of elevated
which have a higher high target specificity, they
expression of normal or mutant
risk of resistance offer important advantages over
forms of metabolic enzymes and toxicity.’’ small molecule drugs, which
in a variety of cancers has have a higher risk of resistance
created great interest in cancer No therapeutic agents and toxicity.
© SMC Images/Photodisc/Getty

metabolism, explains Uttam have been developed against
Surana from the Institute of GLDC until now. Surana 1. Lin, J., Lee, J. H. J., Paramasivam,
K., Pathak, E., Wang, Z., et al.
Molecular and Cell Biology, and and Wee identified short Induced-decay of glycine
© xxxxxxxxxxxxxx

Dave Wee from the Institute of synthetic RNA sequences decarboxylase transcripts as an
High Performance Computing. (steric hindrance antisense anticancer therapeutic strategy
for non-small-cell lung carcinoma.
Targeting TIC metabolism is oligonucleotides, or shAONs) Molecular Therapy Nucleic Acids 9,
emerging as a promising strategy that supressed the production of 263-273 (2017).

www.research.a-star.edu.sg  A*STAR RESEARCH 45
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

A*STAR scientists have found a visualization takes place
new way to give stroke patients entirely in the mind’s eye, it
REHABILITATION
instructive feedback during has been difficult for clinicians
rehabilitation exercises aimed at and patients to know if the
restoring mobility. correct brain connections are
For stroke patients, the being made.
long road to recovery starts
with rehabilitation exercises, ‘‘This feedback will
AN ADAPTIVE including visualizations help stroke patients
APPROACH TO in which people imagine
enacting motions they are
in rehabilitation
STROKE RECOVERY physically unable to perform.
restore brain
functions
This ‘rewires’ their brains,
A new method for reading brain and leads to real-life bodily
and improve
waves improves the usefulness improvements. The exercises motor recovery.’’
of motor imagery exercises only work if you’re performing
them correctly, and since To get a glimpse inside
the brain, patients typically
wear caps fitted with electrodes
that track neural activity
via electroencephalography
(EEG) readings. Now scientists
from the A*STAR Institute
for Infocomm Research have
validated a more accurate way of
turning those EEG signals into
clinically meaningful feedback
for stroke sufferers.
“This feedback will help
stroke patients in rehabilitation
restore brain functions and
improve motor recovery,” says
study author, Kai Keng Ang, an
A*STAR senior scientist who
heads the Neural and Biomedical
Technology Department.
Ang and his colleagues
— including Cuntai Guan,
formerly with A*STAR and
now a professor at Nanyang
Technological University
in Singapore — previously
ran a clinical trial in which
© MEHAU KULYK/SCIENCE PHOTO LIBRARY/Getty

stroke patients relearned hand
grasping and knob manipulation
through combined mental
and physical training.
A*STAR researchers Traditionally, patients have
demonstrate that a more had to teach themselves
personalized method of
analyzing brain waves
over the course of several
boosts the efficacy of sessions to produce predefined
motor imagery exercises EEG rhythms in their
for stroke patients. brains while performing a
motor imagery exercise, but

46 A*STAR RESEARCH  Issue 11 | April – June 2018
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Ang’s team used a newer
machine-learning strategy
that automatically calibrates GENETICS
the EEG patterns associated
with a particular mental
exercise to an individual’s unique
brain waves while engaged in

MUTATION
that task.
This strategy helps correct
for brain differences between LINKED TO RARE
SKIN DISEASE
individuals, and avoids the
hassle of multiple preparative
sessions. However, it doesn’t
account for the fact that Impaired melanin production
individuals themselves can differ underlies an inherited A patient with hypo- and hyper-pigmented macules (white and black
in their brain activity associated pigmentation disorder arrowheads, respectively) and atopic eczema (open arrowhead).
with a motor imagery exercise
from one rehab appointment to
the next.
It is this gap that is filled by A genetic mutation that affects that their form of the disease colleagues identified a mutation
the newest adaptive strategy. the production of the skin requires two copies of the in a different region of the
It works much the same as pigment melanin is associated altered gene and thus, ENPP1 protein. As Reversade
the machine-learning model, with a previously unknown follows a recessive pattern explains: “We found a mutation
but it doesn’t stop at just one form of Cole disease — a rare of inheritance. that affects the SMB1 domain
calibration session. It keeps condition characterized by The team found that of ENPP1 and interferes with
updating its model of how the unusually light-colored and the eight patients had a the protein’s ability to pair
patient’s EEG patterns match dark-colored skin areas as well common mutation in the with itself ”.
motor imagery exercises as as spots of thickened skin on gene encoding ectonucleotide Further examination
new information comes in after the palms of the hands and the pyrophosphatase/ of the skin from a patient
each and every session, thereby soles of the feet. phosphodiesterase 1 (ENPP1), and their unaffected sibling
correcting for day-to-day A team led by Bruno a protein that regulates the revealed that in the patient’s
changes in neural connectivity. Reversade at the A*STAR production of extracellular skin there was an upregulation
Ang and Guan have Institute of Medical Biology inorganic pyrophosphate (PPi). of melanin production in the
retrospectively applied the analyzed the DNA of eight PPi prevents the accumulation darker skin regions and a
adaptive model to the clinical patients from three unrelated of calcium in the body and has downregulation in the lighter
data from their earlier trial. families in Sousse, Tunisia, a key role in bone development colored areas compared with
As they report in their new presenting the clinical features and the formation of abnormal normal skin, indicating that
paper, this would have of Cole disease. All patients calcium deposits in soft tissues, the SMB1 mutation impairs
significantly improved motor developed the symptoms including skin. melanin production.
imagery detection in the within the first three months Interestingly, the identified “The association of
Reprinted from Ref. 1, Copyright 2017, with permission from Elsevier

patients. The researchers of life and went on to mutation differs from others different ENPP1 mutations
have also tested the adaptive develop eczema. in the same gene that have with Cole disease suggests that
strategy on 11 additional Until now Cole disease been associated with the there is a spectrum of skin
stroke patients in another has been reported to follow dominant form of Cole pigmentation anomalies that
clinical trial last year. “We are a dominant pattern of disease. Previous studies share some clinical features,
now analyzing the results and inheritance, which means have shown that mutations but have different patterns
will be reporting the findings one copy of an altered affecting the SMB2 domain of inheritance and severity”
soon,” Ang says. gene in each cell is enough of ENPP1 protein disrupt the Reversade concludes.
to cause pigmentation transport of melanin from the
1. Chourabi, M., Liew, M. S., Lim, S.,
1. Ang, K. K. & Guan, C. EEG-based abnormalities. However, cells in which it is produced
strategies to detect motor imagery H’mida-Ben Brahim, D. &
parents and siblings of (melanocytes) to epidermal Boussofara, L. et al. ENPP1
for control and rehabilitation. IEEE
Transactions on Neural Systems
these eight patients carrying cells in response to insulin. mutation causes recessive Cole
disease by altering melanogen-
and Rehabilitation Engineering 25, one copy of an altered gene With the help of L’Oréal esis. The Journal of Investigative
392–401 (2017). were unaffected, indicating Research, Reversade and Dermatology 138, 291–300 (2018).

www.research.a-star.edu.sg A*STAR RESEARCH 47
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

Interacting proteins
have similar protein
solubility across
different denaturing
temperatures.

Protein-protein interactions have been described before, but
are at the heart of all cellular as Tan explains, “until now there
PROTEOMICS functions and biological has been no way of monitoring
processes. These interactions the dynamics of these protein
are carefully regulated in space complexes in a high-throughput
and time to meet the cell’s and untargeted manner”.
requirements and are often Exposing proteins to

TURNING UP THE
disrupted in disease states. increasing temperature causes
An international study led them to precipitate out of solution.
HEAT ON PROTEIN by Chris Soon Heng Tan at the Thermal proximity coaggregation

INTERACTIONS
A*STAR Institute of Molecular (TPCA) is based on the idea that
and Cell Biology describes a new proteins that are part of a stable
technique that uses powerful protein complex will coprecipitate,
Deep data analytics drive the data analytics to infer protein- by virtue of close proximity, and
© Brandy Arivett/EyeEm/Getty

development of a technique that protein interaction dynamics have a similar precipitation profile
sheds light on drug action by from the melting behavior of across different temperatures (or
protein complexes inside cells1. melting curve).
monitoring the dynamics of thousands
Methods to capture In isolation, different
of protein complexes simultaneously snapshots of protein-protein proteins are likely to have
within intact cells interaction networks in cells different melting curves, but

48 A*STAR RESEARCH  Issue 11 | April – June 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

the team showed that in more CLONED TUMORS
USED FOR A CANCER
than 350 well-characterized
human protein complexes, the ONCOLOGY
melting curves of interacting
proteins are statistically similar.
CRYSTAL BALL
Thus, by quantifying similarity Growing models of patients’ tumors in dishes will
between melting curves, the allow doctors to optimize individual treatments
TPCA method can be used to
determine which proteins are
likely to interact with each other A powerful new approach and takes many years before it tumor will respond to standard
and form stable complexes across to individualized cancer benefits patients. chemotherapy; how the
different samples. treatments has been Ramanuj DasGupta at the tumors might progress under
“We were quite surprised demonstrated by A*STAR A*STAR Genome Institute treatment; whether the cancer
that the TPCA signatures were researchers. It involves growing of Singapore and co-workers will recur, and, if so, whether
so strong and detectable,” micro-models of tumors outside have now demonstrated a alternative treatments can be
admits Tan. TPCA signatures a patient’s body, testing their complementary approach that administered to the patient,”
were found to correlate with the response to various treatments, provides information with explains DasGupta.
amount of interaction between then applying the most the potential that can benefit The researchers are excited
two proteins. Accordingly, they effective ones1. patients immediately. about the potential of their
show that some complexes Traditionally, medical The researchers took tumor approach. “Our work highlights
change their melting curves treatment has been based on cells from 24 patients with the tremendous promise of
depending on the cell type or a ‘one size fits all’ mentality, head and neck cancers and precision medicine for treating
cell cycle stage, suggesting that but clinicians are increasingly grew models of the tumors in cancer,” says DasGupta. “Our
TPCA could be used to identify realizing that patients often dishes. They then tested these dream is to make cancer into
changes in protein interactions respond differently to the micro-tumor models to see a chronically managed disease
under different conditions. same therapy. This has led how susceptible they were to a so that patients can enjoy a
When explaining the them to pursue the concept of range of treatments, including good quality of life while being
advantages of TPCA, Tan says personalized medicine, which chemotherapy, radiotherapy treated with the most effective
that when compared with seeks to give the right drug to and targeted anti-cancer drugs. drugs. We strongly believe that
current methods, TPCA does the right patient at the right Of the 24 patients, two went on our approach will go a long way
not rely on the availability of dose and at the right time. to receive tailored treatments toward realizing this dream.
appropriate affinity reagents, To date, personalized in clinical trials. Both patients This is just the beginning.”
such as antibodies, nor does medicine has largely been responded very well to their The team wants to extend
it require genetic engineering. driven by genomics. This means respective treatments. the study to include many more
This allows it to be applied to that researchers sequence the These results demonstrate patients, as well as finding
tissues and clinical samples to DNA of the tumors from many that patient tumors can be used multiple indicators of cancers.
identify protein complexes that patients, identify key mutations to generate critical information
are driving disease progression and then develop therapies that can help clinicians 1. Chia, S., Low, J.-L. Zhang, X., Kwang,
X.-L., Chong, F.-T. et al. Phenotype-
and that could serve as and drugs that target these prescribe the best treatment
driven precision oncology as
potential prognosis markers or genes. While this approach options. “It is akin to making a guide for clinical decisions
therapeutic targets. is very important for making a cancer ‘crystal ball’ that one patient at a time. Nature
The team is already using new discoveries, it is expensive can help to predict whether a Communications 8, 435 (2017).
the technique to study the
molecular effects of drugs and
synthetic chemicals, and plans
© 2018 A*STAR Genome Institute of Singapore

to extend the technique to study
the progression of selected The expression of
different proteins stained
human diseases. in red and green indicates
the variation in the make-
1. Tan, C. S. H., Go, K. D., Bisteau, X., up of a patient-derived
Dai, L., Yong, C. H. et al. Thermal model of a tumor. Such
proximity coaggregation for models can be used to
system-wide profiling of protein determine the most
complex dynamics in cells. Science effective treatment for
359, 1170–1177 (2018). individual patients.

www.research.a-star.edu.sg A*STAR RESEARCH 49
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

CANCER
BIOLOGY

THE MOLECULAR
PATH TO
BETTER ORAL
CANCER CARE
A better understanding of
how genetics influences
responses to mouth
cancer drugs could lead to
improved treatment

A single letter DNA advanced OSCC that recurs patient-derived cells
mutation is a big following treatment is just with the above A/A
determinant of whether six to nine months. genotype were sensitive
patients with advanced Epidermal growth factor to gefitinib and erlotinib, of a long non-coding RNA
oral cancer respond to receptors (EGFRs) play another EGFR blocker. (lncRNA) known as EGFR-
treatments. Researchers important roles in driving Those with the G/G or G/A AS1. Gene expression tests
from the National the progression of some variants exhibited resistance showed that levels of this
Cancer Centre Singapore OSCCs. Drugs that target lncRNA were significantly
(NCCS) and A*STAR who them, however, only work in higher in G/G genotype cells
uncovered the mechanisms a small number of patients.
‘‘We were than in A/A cells.
behind this effect hope A 2012 clinical trial pretty surprised When cells with the G/G
their findings will help led by Daniel Tan at NCCS it had such a genotype were exposed to
doctors target treatment and A*STAR’s Genome dramatic effect.’’ small interfering RNAs that
more effectively. Institute of Singapore had reduced their production of
Oral squamous cell found that the EGFR- to the drugs. EGFR-AS1, their sensitivity
carcinoma (OSCC) is blocking drug gefitinib Editing the DNA of to EGFR-blocking drugs
© LAGUNA DESIGN/Science Photo Library/Getty

characterized by the worked well in two the G/G genotype cells to increased significantly.
uncontrolled growth of patients with two copies of become G/A at the same They also found
thin, scale-like squamous the EGFR coding gene with location increased their that the tumors of seven
cells in the outer layer of an adenine (A) nucleobase sensitivity to the drugs patients with the A/A
the mouth. Only around in place of the more 70-fold. “We were pretty genotype shrank following
50 per cent of patients who common guanine (G) at a surprised it had such a treatment with EGFR-
are treated through surgery particular location. dramatic effect,” says Iyer. inhibiting drugs.
or radiotherapy are cured, More recently, tests by The genetic mutation While the mechanism
and the average duration Gopal Iyer, also at NCCS, occurs in a section of DNA underlying this effect is not
of survival of those with and Tan showed that OSCC that modulates the stability fully understood, the group

50 A*STAR RESEARCH  Issue 11 | April – June 2018
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

processing, they activated
the nickel by reacting it with
hydrogen at 600 degrees Celsius,
CATALYSIS forming particles that contained
about 40 per cent nickel by
weight. The researchers tested
their catalyst with syngas
derived from a gasification
POROUS SILICA PROTECTS process, and with a simulated

NICKEL CATALYST syngas, both of which contained
sulfur. Using techniques such
as transmission electron
Nanoparticles avoid deactivation and microscopy, X-ray diffraction
convert biomass-derived gas into methane and thermal gravimetric
analysis, they found that the
catalyst experienced very little
By wrapping nickel nanoparticles become deactivated during this sintering or coking during the
in a protective shield of porous high temperature methanation reaction, unlike a commercial
silica, A*STAR researchers have reaction, either through a build- catalyst that was tested using the
developed a highly active and up of carbon called coking, or same syngas samples. “Porous
An illustration robust catalyst that could help to by a process called sintering silica protects by isolating each
of the gefitinib produce methane from biomass1. in which catalyst particles particle, to prevent sintering,”
drug molecule.
Biomass is a potentially clump together. Moreover, any says Chen.
carbon neutral feedstock to traces of sulfur compounds The nickel-silica catalyst
make fuels or other useful in the syngas can very quickly also withstood sulfur impurities
has demonstrated that chemicals. Through a process switch off nickel’s catalytic for three times as long as
cells of the G/A and A/A called gasification, biomass is activity, so syngas must go its commercial rival before
genotypes produced higher converted to a mixture, known through an expensive cleaning deactivating. Improving the
ratios of one of four variants as syngas, comprising carbon process to remove sulfur sulfur resistance of the catalyst in
of EGFR relative to another, monoxide, carbon dioxide and before methanation. this way could lead to significant
and that EFGR-AS1 helps hydrogen. Syngas can be turned Luwei Chen of the A*STAR cost savings in the syngas
mediate this difference. into a range of other chemicals, Institute of Chemical and cleaning process. The researchers
Iyer said that new including methane, which may Engineering Sciences and are now collaborating with
RNA-interference therapies be used as a transportation colleagues have now embedded IHI, a Japanese engineering
could be developed to fuel or town gas, or burned to nickel nanoparticles in porous company, to scale up their
target cancers dependent generate electricity. silica, which allows gases synthesis of the catalyst, and the
on EGFR signaling. The Various catalysts convert to access the catalyst, but methanation process.
group is conducting a syngas to methane. Nickel is one prevents the problems that
1. Kamata, H., Tian, Z. Q., Izumi, Y.,
larger human trial to better of the most common, due to its cause deactivation.
Choong, C. K. S., Chang, J. et al.
understand the biomarkers high activity and moderate cost, They prepared the catalyst Dispersed and high loading Ni
Reprinted from Ref. 1, Copyright 2018, with permission from Elsevier.

that could provide for and it is typically supported on by mixing particles of nickel catalyst stabilized in porous SiO 2
matrix for substituted natural gas
improved targeting of another material such as alumina hydroxide with tetraethyl production. Catalysis Today 299,
existing treatments. or silica. But the catalyst can orthosilicate. After further 193–200 (2018).

1. Tan, D. S. W., Chong, F. T.,
Leong, H. S., Toh, S. Y., Lau,
D. P. et al. Long noncoding
RNA EGFR-AS1 mediates
epidermal growth factor
receptor addiction and
modulates treatment
response in squamous cell
carcinoma. Nature Medicine
23, 1167–1175 (2017).

50nm 20nm 5nm

Transmission electron microscopy images of (left, center) nickel-silica catalyst and (right) a commercial catalyst.

www.research.a-star.edu.sg A*STAR RESEARCH 51
CONTENTS | F E AT U R E S | RESEARCH HIGHLIGHTS | NEXT ISSUE

NEXT ISSUE Here’s a sneak peek of the material covered
in the next issue of A*STAR Research

POWER SOURCES INFECTIOUS DISEASES CONCRETE GLAUCOMA
SHEDDING LIGHT ON DOUBLING A HARD LOOK AT A BIRD’S EYE VIEW
TOMORROW’S DOWN POLYMERS FOR IMPROVED
SOLAR ENERGY ON INFECTION IN CEMENT MIX DIAGNOSIS
Improved forecasting of A new understanding of the way Computer simulations have zoomed An algorithm paves the way
sunlight could help increase chikungunya virus protects mice in on the role of superplasticizers in for accurate, rapid diagnosis of
solar energy generation against malaria could lead to concrete performance closed-angle glaucoma
improved patient care

© aaaaimages/Moment/Getty; ©KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty; Reproduced from Scientific Reports 7, 16599 (2017) and
licensed under CC-BY-4.0 (https://creativecommons.org/licenses/by/4.0) © T. Hirata et al.; © 2018 A*STAR Institute for Infocomm Research
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52 A*STAR RESEARCH  Issue 11 | April – June 2018
Push the frontier with
an A*STAR scholarship
X-ray sources used in medicine and other industries have remained virtually unchanged for
over a century. Leveraging the unique properties of novel 2D materials, Dr. Wong Liang Jie
and a team of collaborators have conceived a method to generate intense, continuously
tunable X-rays on a microchip scale. The laser beam-like quality of the X-ray output also
allows for more precise pinpointing of medical and dental X-rays, enabling lower dosages
and leading to safer, more efficient and less costly X-ray sources in the future.

CHIP-SCALE SOURCES OF POWERFUL
X-RAYS MAY SOON BECOME A REALITY

Infrared or optical light creates
nanoscale electromagnetic
structures on the surface of
2D materials such as graphene.

INDUSTRIAL QUALITY
CONTROL

BIOMEDICAL IMAGING

KEY APPLICATIONS

Rapid wiggling in modestly
relativistic electrons produces
high quality, hard X-rays.
Nanoscale electromagnetic
structures induce wiggling in
electrons sent through them.

MEDICAL TREATMENT

Dr. Wong Liang Jie
Scientist, Singapore Institute of Manufacturing Technology
PhD and Postdoctoral Fellow, Massachusetts Institute of Technology

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